MedWorm.com provides a medical RSS filtering service. Over 6000 RSS medical sources are combined and output via different filters. This feed contains the latest items from the 'Science Signaling' source. Mon, 06 Feb 2012 14:01:07 +0100 http://www.medworm.com/index.php?rid=5654615&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22275218%26dopt%3DAbstract Authors: Warner DF, Mizrahi V Abstract Mycobacterium tuberculosis, the causative agent of tuberculosis, has a complex cellular envelope that comprises both the cytoplasmic membrane and the outer cell wall. Despite advances in elucidating the structural and biochemical composition of these features, the processes that ensure cell wall homeostasis remain poorly understood. New findings implicate the essential mycobacterial serine-threonine protein kinase (STPK), PknB, in regulating the formation of a regulatory complex that includes the integral membrane protein MviN, which is required for peptidoglycan biosynthesis, and a forkhead-associated (FHA) domain protein, FhaA. A model has emerged in which a peptidoglycan-derived muropeptide signal triggers the PknB-mediated phosphorylation ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5654615 Fri, 03 Feb 2012 14:18:02 +0100 5654615 http://www.medworm.com/index.php?rid=5654614&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22275219%26dopt%3DAbstract Authors: Rusakov DA Abstract Over the past decade, rapid signal exchange between astroglia and neurons across the interstitial space emerged as an essential element of synaptic circuit functioning in the brain. How and where exactly this exchange occurs in various physiological scenarios and the underlying cellular cascades remain a subject of intense study. The excitatory neurotransmitter glutamate and the inhibitory neurotransmitter γ-aminobutyric acid are thought to be the primary signal carriers that are regularly dispatched by active synapses to engage target receptors and transporters on the surface of astrocytes. New evidence identifies another ubiquitous messenger, extracellular calcium ions (Ca(2+)), which can report neural network activity to astroglia. Astrocytes in the... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5654614 Fri, 03 Feb 2012 14:18:02 +0100 5654614 http://www.medworm.com/index.php?rid=5654613&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22275220%26dopt%3DAbstract Authors: Gee CL, Papavinasasundaram KG, Blair SR, Baer CE, Falick AM, King DS, Griffin JE, Venghatakrishnan H, Zukauskas A, Wei JR, Dhiman RK, Crick DC, Rubin EJ, Sassetti CM, Alber T Abstract Prokaryotic cell wall biosynthesis is coordinated with cell growth and division, but the mechanisms regulating this dynamic process remain obscure. Here, we describe a phosphorylation-dependent regulatory complex that controls peptidoglycan (PG) biosynthesis in Mycobacterium tuberculosis. We found that PknB, a PG-responsive Ser-Thr protein kinase (STPK), initiates complex assembly by phosphorylating a kinase-like domain in the essential PG biosynthetic protein, MviN. This domain was structurally diverged from active kinases and did not mediate phosphotransfer. Threonine phosphorylation of the... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5654613 Fri, 03 Feb 2012 14:18:02 +0100 5654613 http://www.medworm.com/index.php?rid=5654612&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22275221%26dopt%3DAbstract Authors: Torres A, Wang F, Xu Q, Fujita T, Dobrowolski R, Willecke K, Takano T, Nedergaard M Abstract Defining the pathways through which neurons and astrocytes communicate may contribute to the elucidation of higher central nervous system functions. We investigated the possibility that decreases in extracellular calcium ion concentration ([Ca(2+)](e)) that occur during synaptic transmission might mediate signaling from neurons to glia. Using noninvasive photolysis of the photolabile Ca(2+) buffer diazo-2 {N-[2-[2-[2-[bis(carboxymethyl)amino]-5-(diazoacetyl)phenoxy]ethoxy]-4-methylphenyl]-N-(carboxymethyl)-, tetrapotassium salt} to reduce [Ca(2+)](e) or caged glutamate to simulate glutamatergic transmission, we found that a local decline in extracellular Ca(2+) triggered astrocytic... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5654612 Fri, 03 Feb 2012 14:18:02 +0100 5654612 http://www.medworm.com/index.php?rid=5654611&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22296834%26dopt%3DAbstract Authors: Chen CL, Wang Y, Sesaki H, Iijima M Abstract Class I myosins participate in various interactions between the cell membrane and the cytoskeleton. Several class I myosins preferentially bind to acidic phospholipids, such as phosphatidylserine and phosphatidylinositol 4,5-bisphosphate [PI(4,5)P(2)], through a tail homology 1 (TH1) domain. Here, we show that the second messenger lipid phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) binds to the TH1 domain of a subset of Dictyostelium class I myosins (ID, IE, and IF) and recruits them to the plasma membrane. The PIP(3)-regulated membrane recruitment of myosin I promoted chemotaxis and induced chemoattractant-stimulated actin polymerization. Similarly, PIP(3) recruited human myosin IF to the plasma membrane upon chemotactic st... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5654611 Fri, 03 Feb 2012 14:18:02 +0100 5654611 http://www.medworm.com/index.php?rid=5654610&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22296835%26dopt%3DAbstract Authors: Cardon CM, Beck T, Hall MN, Rutter J Abstract In Saccharomyces cerevisiae, phosphorylation of Ugp1 by either of the yeast PASK family protein kinases (yPASK), Psk1 or Psk2, directs this metabolic enzyme to deliver glucose to the periphery for synthesis of the cell wall. However, we isolated PSK1 and PSK2 in a high-copy suppressor screen of a temperature-sensitive mutant of target of rapamycin 2 (TOR2). Posttranslational activation of yPASK, either by cell integrity stress or by growth on nonfermentative carbon sources, also suppressed the growth defect resulting from tor2 mutation. Although suppression of the tor2 mutant growth phenotype by activation of the kinase activity of yPASK required phosphorylation of the metabolic enzyme Ugp1 on serine 11, this resulted in the fo... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5654610 Fri, 03 Feb 2012 14:18:02 +0100 5654610 http://www.medworm.com/index.php?rid=5618493&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22234609%26dopt%3DAbstract Authors: Gough NR Abstract The Wnt pathways represent key signaling networks involved in development, both in tissue specification and in cellular migration. Wnt signaling also plays key roles in tissue homeostasis in adult animals, and aberrant Wnt signaling is associated with several forms of cancer. This issue includes descriptions of a proapoptotic function for Wnt signaling in melanoma, an interplay between Wnt and bone morphogenetic proteins in tooth organogenesis, and a noncanonical role for Wnt in neuronal guidance. PMID: 22234609 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=5618493 Sun, 22 Jan 2012 17:18:02 +0100 5618493 http://www.medworm.com/index.php?rid=5618492&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22234610%26dopt%3DAbstract We describe a bead-based array and its use in characterizing the different forms and functions of β-catenin, as well as lysate microarrays (reverse-phase protein arrays) and their use in detecting and quantifying proteins involved in the canonical and noncanonical Wnt signaling pathways. As an application of this dual approach, we characterized the state of β-catenin signaling in cell lysates and linked these molecule-specific data with pathway-wide changes in signaling. The Protocols described here provide detailed instructions for cell culture methods, bead arrays, and lysate microarrays and outline how to use these complementary approaches to obtain insight into a complex network at a systems level. PMID: 22234610 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=5618492 Sun, 22 Jan 2012 17:18:02 +0100 5618492 http://www.medworm.com/index.php?rid=5618491&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22234611%26dopt%3DAbstract Authors: Hutchins BI, Li L, Kalil K Abstract Wnt5a gradients guide callosal axons by repulsion through Ryk receptors in vivo. We recently found that Wnt5a repels cortical axons and promotes axon outgrowth through calcium signaling in vitro. Here, using cortical slices, we show that Wnt5a signals through Ryk to guide and promote outgrowth of callosal axons after they cross the midline. Calcium transient frequencies in callosal growth cones positively correlate with axon outgrowth rates in vitro. In cortical slices, calcium release through inositol 1,4,5-trisphosphate (IP(3)) receptors and calcium entry through transientreceptor potential channels modulate axon growth and guidance. Knocking down Ryk inhibits calcium signaling in cortical axons, reduces rates of axon outgrowth subsequ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5618491 Sun, 22 Jan 2012 17:18:02 +0100 5618491 http://www.medworm.com/index.php?rid=5618490&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22234612%26dopt%3DAbstract Authors: Biechele TL, Kulikauskas RM, Toroni RA, Lucero OM, Swift RD, James RG, Robin NC, Dawson DW, Moon RT, Chien AJ Abstract Because the Wnt/β-catenin signaling pathway is linked to melanoma pathogenesis and to patient survival, we conducted a kinome small interfering RNA (siRNA) screen in melanoma cells to expand our understanding of the kinases that regulate this pathway. We found that BRAF signaling, which is constitutively activated in many melanomas by the BRAF(V600E) mutation, inhibits Wnt/β-catenin signaling in human melanoma cells. Because inhibitors of BRAF(V600E) show promise in ongoing clinical trials, we investigated whether altering Wnt/β-catenin signaling might enhance the efficacy of the BRAF(V600E) inhibitor PLX4720. We found that endogenous β-catenin was req... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5618490 Sun, 22 Jan 2012 17:18:02 +0100 5618490 http://www.medworm.com/index.php?rid=5618489&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22234613%26dopt%3DAbstract Authors: O'Connell DJ, Ho JW, Mammoto T, Turbe-Doan A, O'Connell JT, Haseley PS, Koo S, Kamiya N, Ingber DE, Park PJ, Maas RL Abstract Many vertebrate organs form through the sequential and reciprocal exchange of signaling molecules between juxtaposed epithelial and mesenchymal tissues. We undertook a systems biology approach that combined the generation and analysis of large-scale spatiotemporal gene expression data with mouse genetic experiments to gain insight into the mechanisms that control epithelial-mesenchymal signaling interactions in the developing mouse molar tooth. We showed that the shift in instructive signaling potential from dental epithelium to dental mesenchyme was accompanied by temporally coordinated genome-wide changes in gene expression in both compartments. T... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5618489 Sun, 22 Jan 2012 17:18:02 +0100 5618489 http://www.medworm.com/index.php?rid=5618488&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22253260%26dopt%3DAbstract Authors: Ghabrial AS Abstract The hexosamine biosynthetic pathway, whose end product is UDP-N acetylglucosamine (UDP-GlcNAc), lies at the base of cellular glycosylation pathways, including glycosylation of lipids, formation of heparin sulfated proteoglycans, and N- and O-linked glycosylation of proteins. Forward genetic studies in Drosophila have revealed that mutations in genes encoding different enzymes of the hexosamine biosynthetic pathway result in reduction of UDP-GlcNAc to different extents, with a consequent disruption of distinct glycosylation pathways and developmental processes. A maternal and zygotic loss-of-function screen has identified mutations in nesthocker (nst), which encodes an enzyme in the hexosamine biosynthetic pathway. Embryos lacking maternal and zygotic n... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5618488 Sun, 22 Jan 2012 17:18:02 +0100 5618488 http://www.medworm.com/index.php?rid=5618487&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22253261%26dopt%3DAbstract Authors: Lewis PA, Manzoni C Abstract Leucine-rich repeat kinase 2 (LRRK2) is linked to various diseases, including Parkinson's disease, cancer, and leprosy. Data from LRRK2 knockout mice has highlighted a possible role for LRRK2 in regulating signaling pathways that are linked to the pathogenesis of Crohn's disease. Here, we examine how LRRK2's role as a signaling hub in the cell could lead to diverse pathologies. PMID: 22253261 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=5618487 Sun, 22 Jan 2012 17:18:02 +0100 5618487 http://www.medworm.com/index.php?rid=5618486&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22253262%26dopt%3DAbstract Authors: Nishina T, Komazawa-Sakon S, Yanaka S, Piao X, Zheng DM, Piao JH, Kojima Y, Yamashina S, Sano E, Putoczki T, Doi T, Ueno T, Ezaki J, Ushio H, Ernst M, Tsumoto K, Okumura K, Nakano H Abstract Apoptotic cells can stimulate the compensatory proliferation of surrounding cells to maintain tissue homeostasis. Although oxidative stress is associated with apoptosis and necrosis, whether it contributes to compensatory proliferation is unknown. Here, we showed that interleukin-11 (IL-11), a member of the IL-6 family of proinflammatory cytokines, was produced by cells in an oxidative stress-dependent manner. IL-11 production depended on the activation in dying cells of extracellular signal-regulated kinase 2, which in turn caused the phosphorylation and accumulation of the transcript... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5618486 Sun, 22 Jan 2012 17:18:02 +0100 5618486 http://www.medworm.com/index.php?rid=5618485&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22253263%26dopt%3DAbstract Authors: Wang Y, He H, Srivastava N, Vikarunnessa S, Chen YB, Jiang J, Cowan CW, Zhang X Abstract Plexins are cell surface receptors that bind to semaphorins and transduce signals that regulate neuronal development, immune responses, and other processes. Signaling through plexins has been proposed to rely on specific guanosine triphosphatase (GTPase)-activating protein (GAP) activity for R-Ras and M-Ras. Activation of this GAP activity of plexins appears to require simultaneous binding of semaphorin to the plexin extracellular domain and of the Rho GTPases Rac1 or Rnd1 to the cytoplasmic region. However, GAP activity of plexins has eluded detection in several recent studies. We show that the purified cytoplasmic region of plexin uses a noncanonical catalytic mechanism to act as a G... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5618485 Sun, 22 Jan 2012 17:18:02 +0100 5618485 http://www.medworm.com/index.php?rid=5576133&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22215729%26dopt%3DAbstract Authors: Adler EM Abstract The editors of Science Signaling are pleased to start 2012 with our 10th compilation of the most exciting cell signaling research to emerge in the previous year. The Signaling Breakthroughs list is selected from articles nominated by members of the Science Signaling Editorial Board as providing major advances in cell signaling, particularly those that were unexpected or likely to open up new avenues of research. This edition includes breakthroughs in the structural analysis of signaling proteins, technological advances in imaging, and insights into the mechanisms controlling gene expression, immune function, and the cellular response to stress. PMID: 22215729 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=5576133 Mon, 09 Jan 2012 21:18:02 +0100 5576133 http://www.medworm.com/index.php?rid=5576132&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22215730%26dopt%3DAbstract Comment on "load-induced modulation of signal transduction networks": reconciling ultrasensitivity with bifunctionality? Sci Signal. 2012;5(205):lc1 Authors: Straube R Abstract Jiang et al. (Research Article, 11 October 2011, DOI: 10.1126/scisignal.2002152) used a combined experimental and computational modeling approach to study the dynamic response behavior of covalent modification cycles in the presence of downstream targets ("loads"). Despite remarkable agreement between experiments and model predictions, there exists an apparent discrepancy in their approach because the utilized theoretical model does not reflect the bifunctional nature of the enzyme system used in experiments. Furthermore, a simple extension of the model to the case of bifunctional enzymes yields pred... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5576132 Mon, 09 Jan 2012 21:18:02 +0100 5576132 http://www.medworm.com/index.php?rid=5576131&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22215731%26dopt%3DAbstract Response to comment on "'load-induced modulation of signal transduction networks': reconciling ultrasensitivity with bifunctionality?". Sci Signal. 2012;5(205):lc2 Authors: Jiang P, Ventura AC, Sontag ED, Merajver SD, Ninfa AJ, Del Vecchio D Abstract Straube suggests that a model that reflects the bifunctional nature of the cycle enzyme uridylyltransferase/uridylyl-removing enzyme (UTase/UR) should be used, in which the UT and UR activities are distinct and reciprocally regulated activity states of the enzyme, and notes that if such a model is used, the effects of retroactivity at intermediate stimulation will be different. However, such a model does not accurately match the observed enzyme regulatory properties and fails to predict the ultrasensitive response obtained in t... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5576131 Mon, 09 Jan 2012 21:18:02 +0100 5576131 http://www.medworm.com/index.php?rid=5576130&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22215732%26dopt%3DAbstract Authors: Cougot D, Allemand E, Rivière L, Benhenda S, Duroure K, Levillayer F, Muchardt C, Buendia MA, Neuveut C Abstract The regulatory protein HBx is essential for hepatitis B virus (HBV) replication in vivo and for transcription of the episomal HBV genome. We previously reported that in infected cells HBx activates genes targeted by the transcription factor CREB [cyclic adenosine monophosphate (cAMP) response element-binding protein]. cAMP induces phosphorylation and activation of CREB, and CREB inactivation is promoted by protein phosphatase 1 (PP1), which binds to CREB through histone deacetylase 1 (HDAC1). We showed that CREB was recruited to HBV DNA. Phosphorylation induced by cAMP had a longer half-life when CREB was bound to the episomal HBV genome compared to when it was... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5576130 Mon, 09 Jan 2012 21:18:02 +0100 5576130 http://www.medworm.com/index.php?rid=5576129&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22215733%26dopt%3DAbstract Authors: Takeda K, Shao D, Adler M, Charest PG, Loomis WF, Levine H, Groisman A, Rappel WJ, Firtel RA Abstract Adaptation in signaling systems, during which the output returns to a fixed baseline after a change in the input, often involves negative feedback loops and plays a crucial role in eukaryotic chemotaxis. We determined the dynamical response to a uniform change in chemoattractant concentration of a eukaryotic chemotaxis pathway immediately downstream from G protein-coupled receptors. The response of an activated Ras showed near-perfect adaptation, leading us to attempt to fit the results using mathematical models for the two possible simple network topologies that can provide perfect adaptation. Only the incoherent feedforward network accurately described the experimental r... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5576129 Mon, 09 Jan 2012 21:18:02 +0100 5576129 http://www.medworm.com/index.php?rid=5525010&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22126962%26dopt%3DAbstract Authors: Guttridge DC Abstract Activation of G protein-coupled receptors is involved in regulating many cellular responses, but less is known regarding the role of these receptors in the differentiation and maintenance of skeletal muscle. New findings implicate the inhibitor subunit Gα(i2) as a vital mediator of myofiber maturation and growth, operating through multiple signaling pathways to selectively stimulate protein synthesis or inhibit cytokine-dependent protein turnover. PMID: 22126962 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=5525010 Thu, 22 Dec 2011 06:54:02 +0100 5525010 http://www.medworm.com/index.php?rid=5525009&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22126963%26dopt%3DAbstract Authors: Minetti GC, Feige JN, Rosenstiel A, Bombard F, Meier V, Werner A, Bassilana F, Sailer AW, Kahle P, Lambert C, Glass DJ, Fornaro M Abstract Skeletal muscle atrophy results in loss of strength and an increased risk of mortality. We found that lysophosphatidic acid, which activates a G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor, stimulated skeletal muscle hypertrophy through activation of Gα(i2). Expression of a constitutively active mutant of Gα(i2) stimulated myotube growth and differentiation, effects that required the transcription factor NFAT (nuclear factor of activated T cells) and protein kinase C. In addition, expression of the constitutively active Gα(i2) mutant inhibited atrophy caused by the cachectic cytokine TNFα (tumor necr... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5525009 Thu, 22 Dec 2011 06:54:02 +0100 5525009 http://www.medworm.com/index.php?rid=5525008&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22126964%26dopt%3DAbstract Authors: Carlin LM, Evans R, Milewicz H, Fernandes L, Matthews DR, Perani M, Levitt J, Keppler MD, Monypenny J, Coolen T, Barber PR, Vojnovic B, Suhling K, Fraternali F, Ameer-Beg S, Parker PJ, Thomas NS, Ng T Abstract Natural killer (NK) cells kill tumor cells and virally infected cells, and an effective NK cell response requires processes, such as motility, recognition, and directional secretion, that rely on cytoskeletal rearrangement. The Rho guanosine triphosphatase (GTPase) Cdc42 coordinates cytoskeletal reorganization downstream of many receptors. The Rho-related GTPase from plants 1 (ROP1) exhibits oscillatory activation behavior at the apical plasma membrane of growing pollen tubes; however, a similar oscillation in Rho GTPase activity has so far not been demonstrated in m... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5525008 Thu, 22 Dec 2011 06:54:02 +0100 5525008 http://www.medworm.com/index.php?rid=5525007&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22126965%26dopt%3DAbstract Authors: Joshi-Saha A, Valon C, Leung J Abstract The soluble receptors of abscisic acid (ABA) have been identified in Arabidopsis thaliana. The 14 proteins in this family, bearing the double name of PYRABACTIN RESISTANCE/PYRABACTIN-LIKE (PYR/PYL) or REGULATORY COMPONENTS OF ABA RECEPTOR (RCAR) (collectively referred to as PYR/PYL/RCAR), contain between 150 and 200 amino acids with homology to the steroidogenic acute regulatory-related lipid transfer (START) protein. Structural studies of these receptors have provided rich insights into the early mechanisms of ABA signaling. The binding of ABA to PYR/PYL/RCAR triggers the pathway by inducing structural changes in the receptors that allows them to sequester members of the clade A negative regulating protein phosphatase 2Cs (PP2Cs). T... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5525007 Thu, 22 Dec 2011 06:54:02 +0100 5525007 http://www.medworm.com/index.php?rid=5525006&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22126966%26dopt%3DAbstract Authors: Okada H, Uezu A, Mason FM, Soderblom EJ, Moseley MA, Soderling SH Abstract Rho family GAPs [guanosine triphosphatase (GTPase) activating proteins] negatively regulate Rho family GTPase activity and therefore modulate signaling events that control cytoskeletal dynamics. The spatial distribution of these GAPs and their specificity toward individual GTPases are controlled by their interactions with various proteins within signaling complexes. These interactions are likely mediated through the Src homology 3 (SH3) domain, which is abundant in the Rho family GAP proteome and exhibits a micromolar binding affinity, enabling the Rho family GAPs to participate in transient interactions with multiple binding partners. To capture these elusive GAP signaling complexes in situ, we dev... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5525006 Thu, 22 Dec 2011 06:54:02 +0100 5525006 http://www.medworm.com/index.php?rid=5525005&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22155785%26dopt%3DAbstract Authors: Yaffe MB Abstract If the results of collaborations between experimentalists and computational biologists are hard to understand for those in the collaboration, then reviewers and readers of the paper will also struggle. Thus, authors are encouraged to present the results of these studies as clearly as possible and to avoid obscure, convoluted, jargonistic, or impenetrable descriptions. PMID: 22155785 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=5525005 Thu, 22 Dec 2011 06:54:02 +0100 5525005 http://www.medworm.com/index.php?rid=5525004&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22155786%26dopt%3DAbstract Authors: Deinhardt K, Kim T, Spellman DS, Mains RE, Eipper BA, Neubert TA, Chao MV, Hempstead BL Abstract Growth of axons and dendrites is a dynamic process that involves guidance molecules, adhesion proteins, and neurotrophic factors. Although neurite extension is stimulated by the neurotrophin nerve growth factor (NGF), we found that the precursor of NGF, proNGF, induced acute collapse of growth cones of cultured hippocampal neurons. This retraction was initiated by an interaction between the p75 neurotrophin receptor (p75(NTR)) and the sortilin family member SorCS2 (sortilin-related VPS10 domain-containing receptor 2). Binding of proNGF to the p75(NTR)-SorCS2 complex induced growth cone retraction by initiating the dissociation of the guanine nucleotide exchange factor Trio from... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5525004 Thu, 22 Dec 2011 06:54:02 +0100 5525004 http://www.medworm.com/index.php?rid=5525003&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22155787%26dopt%3DAbstract Authors: Liu BA, Shah E, Jablonowski K, Stergachis A, Engelmann B, Nash PD Abstract The Src homology 2 (SH2) domains are participants in metazoan signal transduction, acting as primary mediators for regulated protein-protein interactions with tyrosine-phosphorylated substrates. Here, we describe the origin and evolution of SH2 domain proteins by means of sequence analysis from 21 eukaryotic organisms from the basal unicellular eukaryotes, where SH2 domains first appeared, through the multicellular animals and increasingly complex metazoans. On the basis of our results, SH2 domains and phosphotyrosine signaling emerged in the early Unikonta, and the numbers of SH2 domains expanded in the choanoflagellate and metazoan lineages with the development of tyrosine kinases, leading to rapi... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5525003 Thu, 22 Dec 2011 06:54:02 +0100 5525003 http://www.medworm.com/index.php?rid=5525002&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22155788%26dopt%3DAbstract Authors: Fu G, Hu J, Niederberger-Magnenat N, Rybakin V, Casas J, Yachi PP, Feldstein S, Ma B, Hoerter JA, Ampudia J, Rigaud S, Lambolez F, Gavin AL, Sauer K, Cheroutre H, Gascoigne NR Abstract Protein kinase C η (PKCη) is abundant in T cells and is recruited to the immunological synapse that is formed between a T cell and an antigen-presenting cell; however, its function in T cells is unknown. We showed that PKCη was required for the activation of mature CD8(+) T cells through the T cell receptor. Compared with wild-type T cells, PKCη(-/-) T cells showed poor proliferation in response to antigen stimulation, a trait shared with T cells deficient in PKCθ, which is the most abundant PKC isoform in T cells and was thought to be the only PKC isoform with a specific role in T cell... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5525002 Thu, 22 Dec 2011 06:54:02 +0100 5525002 http://www.medworm.com/index.php?rid=5525001&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22155789%26dopt%3DAbstract This study delineates an essential role for PDLIM2 in inhibiting T(H)17 cell-mediated inflammatory responses by suppressing STAT3 signaling and provides a potential therapeutic target for the treatment of autoimmune diseases. PMID: 22155789 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=5525001 Thu, 22 Dec 2011 06:54:02 +0100 5525001 http://www.medworm.com/index.php?rid=5525000&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22169475%26dopt%3DAbstract Authors: Douglas AE Abstract The sustained health of an individual animal depends on the composition and activities of its resident microbiota. A major challenge is to identify the processes by which the microbiota and animal interact, recognizing that this research should lead ultimately to novel strategies to promote human health. Drosophila is emerging as a tractable model system to investigate these interactions. New evidence reveals that the gut microbiota promotes insulin signaling in Drosophila, leading to increased growth and development rates. Different gut bacteria and bacterial effectors were implicated: acetic acid produced by Acetobacter pomorum and branched-chain amino acids produced by Lactobacillus plantarum, respectively. These findings raise the possibility that m... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5525000 Thu, 22 Dec 2011 06:54:02 +0100 5525000 http://www.medworm.com/index.php?rid=5524999&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22169476%26dopt%3DAbstract We present a simple method, based on partial membrane permeabilization with detergent followed by density gradient centrifugation, that provides rapid separation of cytosolic, nucleosolic, nuclear insoluble, and membrane components in various mammalian cell lines. PMID: 22169476 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=5524999 Thu, 22 Dec 2011 06:54:02 +0100 5524999 http://www.medworm.com/index.php?rid=5524998&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22169477%26dopt%3DAbstract Authors: Krishnan N, Fu C, Pappin DJ, Tonks NK Abstract Although originally considered toxic, hydrogen sulfide (H(2)S) has been implicated in mediating various biological processes. Nevertheless, its cellular targets and mode of action are not well understood. Protein tyrosine phosphatases (PTPs), which regulate numerous signal transduction pathways, use an essential cysteine residue at the active site, which is characterized by a low pK(a) and is susceptible to reversible oxidation. Here, we report that PTP1B was reversibly inactivated by H(2)S, in vitro and in cells, through sulfhydration of the active-site cysteine residue. Unlike oxidized PTP1B, the sulfhydrated enzyme was preferentially reduced in vitro by thioredoxin, compared to glutathione or dithiothreitol. Sulfhydration o... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5524998 Thu, 22 Dec 2011 06:54:02 +0100 5524998 http://www.medworm.com/index.php?rid=5524997&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22169478%26dopt%3DAbstract Authors: Ueno T, Falkenburger BH, Pohlmeyer C, Inoue T Abstract A limited set of phosphoinositide membrane lipids regulate diverse cellular functions including proliferation, differentiation, and migration. We developed two techniques based on rapamycin-induced protein dimerization to rapidly change the concentration of plasma membrane phosphatidylinositol 4,5-bisphosphate [PI(4,5)P(2)]. First, using a membrane-recruitable form of PI(4)P 5-kinase, we increased PI(4,5)P(2) synthesis from phosphatidylinositol 4-phosphate [PI(4)P] and found that COS-7, HeLa, and human embryonic kidney 293 cells formed bundles of motile actin filaments known as actin comets. In contrast, a second technique that increased the concentration of PI(4,5)P(2) without consuming PI(4)P induced membrane ruffles... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5524997 Thu, 22 Dec 2011 06:54:02 +0100 5524997 http://www.medworm.com/index.php?rid=5452722&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22114140%26dopt%3DAbstract Authors: Vanhook AM Abstract Hedgehog (Hh) signaling plays varied and critical roles in animal development, homeostasis, and disease. The core components of the canonical pathway and many key modulators of signaling have been identified, as have mechanisms by which the quantity and quality of signaling through the pathway are modulated. New research reveals details about generation and interpretation of Hh gradients, noncanonical Hh signaling, and fine-tuning the biological response to Hh signaling, particularly in the context of human diseases such as cancer. PMID: 22114140 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=5452722 Tue, 29 Nov 2011 00:24:02 +0100 5452722 http://www.medworm.com/index.php?rid=5452721&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22114141%26dopt%3DAbstract Authors: Kornberg TB Abstract Hedgehog, an essential protein for the development of many vertebrate and invertebrate organs, signals at both short and long distances to control growth and patterning. The mechanism by which it moves between source and target cells is not known, but characterization of the covalent modification of its N terminus with palmitate and of its C terminus with cholesterol has led to the suggestion that the lipophilic properties of the modified protein serve to regulate movement after its secretion into the extracellular space. Another interpretation and model is that the C-terminal cholesterol acts to target Hedgehog to an intracellular trafficking pathway that prepares Hedgehog for release in an encapsulated form. PMID: 22114141 [PubMed - in process] (... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5452721 Tue, 29 Nov 2011 00:24:02 +0100 5452721 http://www.medworm.com/index.php?rid=5452720&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22114142%26dopt%3DAbstract Authors: Polizio AH, Chinchilla P, Chen X, Manning DR, Riobo NA Abstract The vertebrate Hedgehog (Hh) pathway has essential functions during development and tissue homeostasis in normal physiology, and its dysregulation is a common theme in cancer. The Hh ligands (Sonic Hh, Indian Hh, and Desert Hh) bind to the receptors Patched1 and Patched2, resulting in inhibition of their repressive effect on Smoothened (Smo). Smo is a seven-transmembrane protein, which was only recently shown to function as a G protein-coupled receptor (GPCR) with specificity toward the heterotrimeric guanine nucleotide-binding protein G(i). In addition to activating G(i), Smo signals through its C-terminal tail to inhibit Suppressor of Fused, resulting in stabilization and activation of the Gli family of tran... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5452720 Tue, 29 Nov 2011 00:24:02 +0100 5452720 http://www.medworm.com/index.php?rid=5452719&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22114143%26dopt%3DAbstract Authors: Roy S, Kornberg TB Abstract This Presentation focuses on how morphogen signaling proteins disperse across developmental fields. Although the steady-state distributions of morphogen signaling proteins have been described well in a number of contexts, the mechanisms that generate these distributions have remained uncertain. Results presented here show that these proteins transfer from producing to target cells at points of direct contact, even when the producing and target cells are not immediate neighbors. PMID: 22114143 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=5452719 Tue, 29 Nov 2011 00:24:02 +0100 5452719 http://www.medworm.com/index.php?rid=5452718&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22114144%26dopt%3DAbstract Authors: Ruiz I Altaba A Abstract The Hedgehog (Hh)-Gli signaling pathway is an essential pathway involved in development and cancer. It controls the Gli code-the sum of all activator and repressor functions of the Gli transcription factors. Through the Gli code, and Gli1 in particular, it modulates the fate and behavior of stem and cancer stem cells, as well as tumor growth and survival in many human cancer types. It also affects recurrence and metastasis and is enhanced in advanced tumors, where it promotes an embryonic stem (ES) cell-like gene expression signature. A central component of this signature, Nanog, is critical for glioblastoma and cancer stem cell survival and expansion. Gli1 activity is also enhanced by several oncogenic proteins, including Ras, Myc, and Akt, and by... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5452718 Tue, 29 Nov 2011 00:24:02 +0100 5452718 http://www.medworm.com/index.php?rid=5452717&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22114145%26dopt%3DAbstract Authors: Grant MP, Stepanchick A, Cavanaugh A, Breitwieser GE Abstract Calcium-sensing receptors (CaSRs) regulate systemic calcium homeostasis in the parathyroid gland, kidney, intestine, and bone and translate fluctuations in serum calcium into peptide hormone secretion, cell signaling, and regulation of gene expression. The CaSR is a G protein (heterotrimeric guanosine triphosphate-binding protein)-coupled receptor that operates in the constant presence of agonist, sensing small changes with high cooperativity and minimal functional desensitization. Here, we used multiwavelength total internal reflection fluorescence microscopy to demonstrate that the signaling properties of the CaSR result from agonist-driven maturation and insertion of CaSRs into the plasma membrane. Plasma mem... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5452717 Tue, 29 Nov 2011 00:24:02 +0100 5452717 http://www.medworm.com/index.php?rid=5452716&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22114146%26dopt%3DAbstract Authors: Gabay M, Pinter ME, Wright FA, Chan P, Murphy AJ, Valenzuela DM, Yancopoulos GD, Tall GG Abstract Ric-8A (resistance to inhibitors of cholinesterase 8A) and Ric-8B are guanine nucleotide exchange factors that enhance different heterotrimeric guanine nucleotide-binding protein (G protein) signaling pathways by unknown mechanisms. Because transgenic disruption of Ric-8A or Ric-8B in mice caused early embryonic lethality, we derived viable Ric-8A- or Ric-8B-deleted embryonic stem (ES) cell lines from blastocysts of these mice. We observed pleiotropic G protein signaling defects in Ric-8A(-/-) ES cells, which resulted from reduced steady-state amounts of Gα(i), Gα(q), and Gα(13) proteins to <5% of those of wild-type cells. The amounts of Gα(s) and total Gβ protein were... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5452716 Tue, 29 Nov 2011 00:24:02 +0100 5452716 http://www.medworm.com/index.php?rid=5436332&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22087031%26dopt%3DAbstract Authors: Merline R, Moreth K, Beckmann J, Nastase MV, Zeng-Brouwers J, Tralhão JG, Lemarchand P, Pfeilschifter J, Schaefer RM, Iozzo RV, Schaefer L Abstract The mechanisms linking immune responses and inflammation with tumor development are not well understood. Here, we show that the soluble form of the extracellular matrix proteoglycan decorin controls inflammation and tumor growth through PDCD4 (programmed cell death 4) and miR-21 (microRNA-21) by two mechanisms. First, decorin acted as an endogenous ligand of Toll-like receptors 2 and 4 and stimulated production of proinflammatory molecules, including PDCD4, in macrophages. Second, decorin prevented translational repression of PDCD4 by decreasing the activity of transforming growth factor-β1 and the abundance of oncogenic miR-... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5436332 Wed, 23 Nov 2011 04:18:02 +0100 5436332 http://www.medworm.com/index.php?rid=5436331&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22087032%26dopt%3DAbstract Authors: Nakamuta S, Funahashi Y, Namba T, Arimura N, Picciotto MR, Tokumitsu H, Soderling TR, Sakakibara A, Miyata T, Kamiguchi H, Kaibuchi K Abstract Neurons are highly polarized cells that have structurally distinct processes-the axons and dendrites-that differentiate from common immature neurites. In cultured hippocampal neurons, one of these immature neurites stochastically initiates rapid extension and becomes an axon, whereas the others become dendrites. Various extracellular and intracellular signals contribute to axon specification; however, the specific intracellular pathways whereby particular extracellular stimuli lead to axon specification remain to be delineated. Here, we found that the neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) w... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5436331 Wed, 23 Nov 2011 04:18:02 +0100 5436331 http://www.medworm.com/index.php?rid=5436330&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22087033%26dopt%3DAbstract Authors: Sinclair C, Saini M, van der Loeff IS, Sakaguchi S, Seddon B Abstract The homeostatic maintenance of normal numbers of mature T lymphocytes in the immune system depends on signaling from the T cell antigen receptor (TCR) and the interleukin-7 receptor (IL-7R); however, it is unclear whether there is crosstalk between these two receptors. Here, we have identified a central role for TCR signaling during the development of T lymphocytes in the thymus in the determination of IL-7 function in mature T lymphocytes. We showed that Il7r expression in mature T cells was modulated by developmental TCR-dependent signals elicited during the process of positive selection in the thymus and that this mechanism was common to both CD4(+) and CD8(+) T cells. Control of Il7r expression by th... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5436330 Wed, 23 Nov 2011 04:18:02 +0100 5436330 http://www.medworm.com/index.php?rid=5411324&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22067458%26dopt%3DAbstract Authors: Eichner A, Sixt M Abstract In their search for antigens, lymphocytes continuously shuttle among blood vessels, lymph vessels, and lymphatic tissues. Chemokines mediate entry of lymphocytes into lymphatic tissues, and sphingosine 1-phosphate (S1P) promotes localization of lymphocytes to the vasculature. Both signals are sensed through G protein-coupled receptors (GPCRs). Most GPCRs undergo ligand-dependent homologous receptor desensitization, a process that decreases their signaling output after previous exposure to high ligand concentration. Such desensitization can explain why lymphocytes do not take an intermediate position between two signals but rather oscillate between them. The desensitization of S1P receptor 1 (S1PR1) is mediated by GPCR kinase 2 (GRK2). Deletion of... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5411324 Thu, 17 Nov 2011 07:36:01 +0100 5411324 http://www.medworm.com/index.php?rid=5411323&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22067459%26dopt%3DAbstract Authors: Ishibashi O, Ali MM, Luo SS, Ohba T, Katabuchi H, Takeshita T, Takizawa T Abstract Short double-stranded RNAs (dsRNAs) induce type I interferon (IFN)-mediated innate immune responses. In functional studies with short interfering RNAs or synthetic mimics of microRNA precursors in vitro, we found that short dsRNAs readily induced apoptosis in cells derived from human granulosa cell tumors, but not in other cell types. Apoptosis was independent of the sequence of the dsRNA, but depended on its length, and was induced by 23- and 24-nucleotide (nt) dsRNAs, but not by shorter dsRNAs (<22 nt) or by the long dsRNA polyinosinic-polycytidylic acid. Microarray analysis revealed that apoptosis was accompanied by the increased expression of IFN-stimulated genes; however, several lin... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5411323 Thu, 17 Nov 2011 07:36:01 +0100 5411323 http://www.medworm.com/index.php?rid=5411322&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22067460%26dopt%3DAbstract Authors: Hegemann B, Hutchins JR, Hudecz O, Novatchkova M, Rameseder J, Sykora MM, Liu S, Mazanek M, Lénárt P, Hériché JK, Poser I, Kraut N, Hyman AA, Yaffe MB, Mechtler K, Peters JM Abstract Progression through mitosis depends on a large number of protein complexes that regulate the major structural and physiological changes necessary for faithful chromosome segregation. Most, if not all, of the mitotic processes are regulated by a set of mitotic protein kinases that control protein activity by phosphorylation. Although many mitotic phosphorylation events have been identified in proteome-scale mass spectrometry studies, information on how these phosphorylation sites are distributed within mitotic protein complexes and which kinases generate these phosphorylation sites is large... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5411322 Thu, 17 Nov 2011 07:36:01 +0100 5411322 http://www.medworm.com/index.php?rid=5376480&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21990428%26dopt%3DAbstract Authors: Ham H, Orth K Abstract AMPylation, a posttranslational modification in which adenosine monophosphate (AMP) is added to hydroxyl side chains of protein substrates, is employed by many bacterial pathogens to subvert host signaling pathways during infection. The Legionella pneumophila effector protein SidM is a multifunctional enzyme that targets the guanosine triphosphatase (GTPase) Rab1 to manipulate intracellular vesicular trafficking in the host cell. SidM recruits Rab1 to the membranes of Legionella-containing vacuoles and activates Rab1 through its guanine nucleotide exchange factor activity. SidM then AMPylates Rab1, converting it into a constitutively active form that cannot be accessed by LepB, a GTPase-activating protein that is secreted by L. pneumophila. However, ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5376480 Sat, 05 Nov 2011 01:35:15 +0100 5376480 http://www.medworm.com/index.php?rid=5376479&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21990429%26dopt%3DAbstract Authors: Jiang P, Ventura AC, Sontag ED, Merajver SD, Ninfa AJ, Del Vecchio D Abstract Biological signal transduction networks are commonly viewed as circuits that pass along information-in the process amplifying signals, enhancing sensitivity, or performing other signal-processing tasks-to transcriptional and other components. Here, we report on a "reverse-causality" phenomenon, which we call load-induced modulation. Through a combination of analytical and experimental tools, we discovered that signaling was modulated, in a surprising way, by downstream targets that receive the signal and, in doing so, apply what in physics is called a load. Specifically, we found that non-intuitive changes in response dynamics occurred for a covalent modification cycle when load was present. Load... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5376479 Sat, 05 Nov 2011 01:35:15 +0100 5376479 http://www.medworm.com/index.php?rid=5376478&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21990430%26dopt%3DAbstract Authors: Eivers E, Demagny H, Choi RH, De Robertis EM Abstract Bone morphogenetic proteins (BMPs) and Wnts are growth factors that provide essential patterning signals for cell proliferation and differentiation. Here, we describe a molecular mechanism by which the phosphorylation state of the Drosophila transcription factor Mad determines its ability to transduce either BMP or Wingless (Wg) signals. Previously, Mad was thought to function in gene transcription only when phosphorylated by BMP receptors. We found that the unphosphorylated form of Mad was required for canonical Wg signaling by interacting with the Pangolin-Armadillo transcriptional complex. Phosphorylation of the carboxyl terminus of Mad by BMP receptor directed Mad toward BMP signaling, thereby preventing Mad from fu... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5376478 Sat, 05 Nov 2011 01:35:15 +0100 5376478 http://www.medworm.com/index.php?rid=5376477&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22009150%26dopt%3DAbstract Authors: Vadas O, Burke JE, Zhang X, Berndt A, Williams RL Abstract Phosphoinositide 3-kinases (PI3Ks) are implicated in a broad spectrum of cellular activities, such as growth, proliferation, differentiation, migration, and metabolism. Activation of class I PI3Ks by mutation or overexpression correlates with the development and maintenance of various human cancers. These PI3Ks are heterodimers, and the activity of the catalytic subunits is tightly controlled by the associated regulatory subunits. Although the same p85 regulatory subunits associate with all class IA PI3Ks, the functional outcome depends on the isotype of the catalytic subunit. New PI3K partners that affect the signaling by the PI3K heterodimers have been uncovered, including phosphate and tensin homolog (PTEN), cyc... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5376477 Sat, 05 Nov 2011 01:35:15 +0100 5376477 http://www.medworm.com/index.php?rid=5376476&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22009151%26dopt%3DAbstract Authors: Aoki R, Li YR Abstract Parkinson's disease (PD) is a neurodegenerative disorder that results in a progressively debilitating loss of motor function and hypokinesia and is characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Recent evidence suggests that caspase-3-dependent proteolytic cleavage and nuclear translocation of the δ isoform of protein kinase C (PKCδ) may be required for oxidative stress-induced dopaminergic cell death. Whereas several proteins have been postulated to contribute to dopaminergic neuron loss, the signaling cascades that mediate this selective neuron loss in PD are not well understood. The presynaptic protein α-synuclein (α-syn), mutations in which cause familial PD, has been implicated in pathways ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5376476 Sat, 05 Nov 2011 01:35:15 +0100 5376476 http://www.medworm.com/index.php?rid=5376475&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22009152%26dopt%3DAbstract Authors: Magori S, Citovsky V Abstract The SCF (Skp1-Cul1-F-box protein) ubiquitin ligase complex plays a pivotal role in various biological processes, including host-pathogen interactions. Many pathogens exploit the host SCF machinery to promote efficient infection by translocating pathogen-encoded F-box proteins into the host cell. How pathogens ensure sufficient amounts of the F-box effectors in the host cell despite the intrinsically unstable nature of F-box proteins, however, remains unclear. We found that the Agrobacterium F-box protein VirF, an important virulence factor, undergoes rapid degradation through the host proteasome pathway. This destabilization of VirF was counteracted by VirD5, another bacterial effector that physically associated with VirF. These observations r... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5376475 Sat, 05 Nov 2011 01:35:15 +0100 5376475 http://www.medworm.com/index.php?rid=5376474&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22028465%26dopt%3DAbstract Authors: Gough NR Abstract The extracellular signal-regulated kinase (ERK) pathway is one of the superfamily of mitogen-activated protein kinase pathways. Signals transmitted by this kinase cascade activate a pair of related proteins, ERK1 and ERK2. Research published in Science Signaling shows that, despite the wealth of knowledge about this pathway, previously unknown functions continue to be discovered and additional components in this pathway continue to be identified. Thus, we are continuing to learn the plays and recruit the players in the game that is ERK signaling. PMID: 22028465 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=5376474 Sat, 05 Nov 2011 01:35:15 +0100 5376474 http://www.medworm.com/index.php?rid=5376473&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22028466%26dopt%3DAbstract Authors: Yosef N, Zalckvar E, Rubinstein AD, Homilius M, Atias N, Vardi L, Berman I, Zur H, Kimchi A, Ruppin E, Sharan R Abstract Genome-scale screening studies are gradually accumulating a wealth of data on the putative involvement of hundreds of genes in various cellular responses or functions. A fundamental challenge is to chart the molecular pathways that underlie these systems. ANAT is an interactive software tool, implemented as a Cytoscape plug-in, for elucidating functional networks of proteins. It encompasses a number of network inference algorithms and provides access to networks of physical associations in several organisms. In contrast to existing software tools, ANAT can be used to infer subnetworks that connect hundreds of proteins to each other or to a given set of "... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5376473 Sat, 05 Nov 2011 01:35:15 +0100 5376473 http://www.medworm.com/index.php?rid=5376472&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22028467%26dopt%3DAbstract Authors: Xin M, Kim Y, Sutherland LB, Qi X, McAnally J, Schwartz RJ, Richardson JA, Bassel-Duby R, Olson EN Abstract The Hippo signaling pathway regulates growth of the heart and other tissues. Hippo pathway kinases influence the activity of various targets, including the transcriptional coactivator Yap, but the specific role of Yap in heart growth has not been investigated. We show that Yap is necessary and sufficient for embryonic cardiac growth in mice. Deletion of Yap in the embryonic mouse heart impeded cardiomyocyte proliferation, causing myocardial hypoplasia and lethality at embryonic stage 10.5. Conversely, forced expression of a constitutively active form of Yap in the embryonic heart increased cardiomyocyte number and heart size. Yap activated the insulin-like growth fac... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5376472 Sat, 05 Nov 2011 01:35:15 +0100 5376472 http://www.medworm.com/index.php?rid=5376471&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22028468%26dopt%3DAbstract Authors: Rodríguez J, Crespo P Abstract The mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase 1 (ERK1) and ERK2 play well-characterized roles in the regulation of key cellular processes, such as proliferation, differentiation, and survival, by acting as serine and threonine kinases in the phosphorylation of ~200 substrates that are distributed in different subcellular localizations. However, over the past few years, evidence has mounted that indicates that the mechanism of action of ERK1 and ERK2 may extend beyond their role as canonical kinases. For example, proteins such as poly(ADP-ribose) polymerase 1, topoisomerase II, and MAPK phosphatase 3 (MKP-3) are activated by a direct interaction with ERK2 that does not involve any phosphotransfer activity... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5376471 Sat, 05 Nov 2011 01:35:15 +0100 5376471 http://www.medworm.com/index.php?rid=5376470&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22028469%26dopt%3DAbstract We report in vivo roles for several of the previously unknown regulators, including CG10289 and PpV, the Drosophila orthologs of two components of the serine/threonine-protein phosphatase 6 complex; the Drosophila ortholog of TepIV, a glycophosphatidylinositol-linked protein mutated in human cancers; CG6453, a noncatalytic subunit of glucosidase II; and Rtf1, a histone methyltransferase. PMID: 22028469 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=5376470 Sat, 05 Nov 2011 01:35:15 +0100 5376470 http://www.medworm.com/index.php?rid=5376469&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22028470%26dopt%3DAbstract Authors: Carlson SM, Chouinard CR, Labadorf A, Lam CJ, Schmelzle K, Fraenkel E, White FM Abstract The mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase 2 (ERK2) is ubiquitously expressed in mammalian tissues and is involved in a wide range of biological processes. Although MAPKs have been intensely studied, identification of their substrates remains challenging. We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. The 80 substrates are associated with diverse cellular processes, including regulation of transcriptio... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5376469 Sat, 05 Nov 2011 01:35:15 +0100 5376469 http://www.medworm.com/index.php?rid=5376468&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22045851%26dopt%3DAbstract We report that p53 transactivated microRNA-34 (miR-34), which consequently suppressed the transcriptional activity of β-catenin-T cell factor and lymphoid enhancer factor (TCF/LEF) complexes by targeting the untranslated regions (UTRs) of a set of conserved targets in a network of genes encoding elements of the Wnt pathway. Loss of p53 function increased canonical Wnt signaling by alleviating miR-34-specific interactions with target UTRs, and miR-34 depletion relieved p53-mediated Wnt repression. Gene expression signatures reflecting the status of β-catenin-TCF/LEF transcriptional activity in breast cancer and pediatric neuroblastoma patients were correlated with p53 and miR-34 functional status. Loss of p53 or miR-34 contributed to neoplastic progression by triggering the Wnt-dependent,... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5376468 Sat, 05 Nov 2011 01:35:15 +0100 5376468 http://www.medworm.com/index.php?rid=5376467&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22045852%26dopt%3DAbstract Authors: Liu C, Swaidani S, Qian W, Kang Z, Sun P, Han Y, Wang C, Gulen MF, Yin W, Zhang C, Fox PL, Aronica M, Hamilton TA, Misra S, Deng J, Li X Abstract Interleukin-17 (IL-17) and IL-25 signaling induce the expression of genes encoding inflammatory factors and are implicated in the pathology of various inflammatory diseases. Nuclear factor κB (NF-κB) activator 1 (Act1) is an adaptor protein and E3 ubiquitin ligase that is critical for signaling by either IL-17 or IL-25, and it is recruited to their receptors (IL-17R and IL-25R) through heterotypic interactions between the SEFIR [SEF (similar expression to fibroblast growth factor genes) and IL-17R] domain of Act1 and that of the receptor. SEFIR domains have structural similarity with the Toll-IL-1 receptor (TIR) domains of Toll... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5376467 Sat, 05 Nov 2011 01:35:15 +0100 5376467 http://www.medworm.com/index.php?rid=5376466&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22045853%26dopt%3DAbstract Authors: Shi P, Zhu S, Lin Y, Liu Y, Liu Y, Chen Z, Shi Y, Qian Y Abstract The proinflammatory cytokine interleukin-17 (IL-17) is important for the immune response to pathogens and also contributes to the pathogenesis of various inflammatory diseases. To avoid persistent inflammation, signaling by the IL-17 receptor (IL-17R), which involves the adaptor protein Act1, must be tightly controlled. Here, we report that persistent stimulation of HeLa cells with IL-17 resulted in degradation of Act1 and desensitization of IL-17R signaling. IL-17 stimulated the Lys(48)-linked polyubiquitination and degradation of Act1, which was phosphorylation-dependent, similar to the IL-17-dependent degradation of inhibitor of nuclear factor κB α. Act1 was recruited to SCF (Skp1-cullin-1-F-box)-type E... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5376466 Sat, 05 Nov 2011 01:35:15 +0100 5376466 http://www.medworm.com/index.php?rid=5293606&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21971038%26dopt%3DAbstract Authors: Watanabe K, Dai X Abstract New evidence has revealed interesting aspects of how the Wnt-β-catenin pathway controls self-renewal and lineage differentiation of pluripotent embryonic stem cells. Although Wnt-β-catenin signaling is dispensable for the self-renewal of naive mouse embryonic stem cells, it facilitates their expansion and resistance to differentiation through an unconventional dual mechanism involving the transcriptional repressor T cell factor (TCF) 3 and the transcriptional activator TCF1. PMID: 21971038 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=5293606 Tue, 04 Oct 2011 04:00:00 +0100 5293606 http://www.medworm.com/index.php?rid=5293605&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21971039%26dopt%3DAbstract Authors: Wexler EM, Rosen E, Lu D, Osborn GE, Martin E, Raybould H, Geschwind DH Abstract Wnt proteins are critical to mammalian brain development and function. The canonical Wnt signaling pathway involves the stabilization and nuclear translocation of β-catenin; however, Wnt also signals through alternative, noncanonical pathways. To gain a systems-level, genome-wide view of Wnt signaling, we analyzed Wnt1-stimulated changes in gene expression by transcriptional microarray analysis in cultured human neural progenitor (hNP) cells at multiple time points over a 72-hour time course. We observed a widespread oscillatory-like pattern of changes in gene expression, involving components of both the canonical and the noncanonical Wnt signaling pathways. A higher-order, systems-level anal... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5293605 Tue, 04 Oct 2011 04:00:00 +0100 5293605 http://www.medworm.com/index.php?rid=5293604&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21971040%26dopt%3DAbstract Authors: Singleton KL, Gosh M, Dandekar RD, Au-Yeung BB, Ksionda O, Tybulewicz VL, Altman A, Fowell DJ, Wülfing C Abstract During T cell activation by antigen-presenting cells (APCs), the diverse spatiotemporal organization of components of T cell signaling pathways modulates the efficiency of activation. Here, we found that loss of the tyrosine kinase interleukin-2 (IL-2)-inducible T cell kinase (Itk) in mice altered the spatiotemporal distributions of 14 of 16 sensors of T cell signaling molecules in the region of the interface between the T cell and the APC, which reduced the segregation of signaling intermediates into distinct spatiotemporal patterns. Activation of the Rho family guanosine triphosphatase Cdc42 at the center of the cell-cell interface was impaired, although the... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5293604 Tue, 04 Oct 2011 04:00:00 +0100 5293604 http://www.medworm.com/index.php?rid=5272662&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21954288%26dopt%3DAbstract Authors: Mounir Z, Krishnamoorthy JL, Wang S, Papadopoulou B, Campbell S, Muller WJ, Hatzoglou M, Koromilas AE Abstract Metazoans respond to various forms of environmental stress by inducing the phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) at serine-51, a modification that leads to global inhibition of mRNA translation. We demonstrate induction of the phosphorylation of eIF2α in mammalian cells after either pharmacological inhibition of the phosphoinositide 3-kinase (PI3K)-Akt pathway or genetic or small interfering RNA-mediated ablation of Akt. This increase in the extent of eIF2α phosphorylation also occurred in Drosophila cells and depended on the endoplasmic reticulum (ER)-resident protein kinase PERK, which was inhibited by Akt-dep... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5272662 Tue, 27 Sep 2011 04:00:00 +0100 5272662 http://www.medworm.com/index.php?rid=5272661&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21954289%26dopt%3DAbstract Authors: Adrover MÀ, Zi Z, Duch A, Schaber J, González-Novo A, Jimenez J, Nadal-Ribelles M, Clotet J, Klipp E, Posas F Abstract Control of cell cycle progression by stress-activated protein kinases (SAPKs) is essential for cell adaptation to extracellular stimuli. Exposure of yeast to hyperosmotic stress activates the SAPK Hog1, which delays cell cycle progression through G(1) by direct phosphorylation of the cyclin-dependent kinase (CDK) inhibitor Sic1 and by inhibition of the transcription of the genes encoding the G(1) cyclins Cln1 and 2. Additional targets of Hog1 may also play a role in this response. We used mathematical modeling and quantitative in vivo experiments to define the contributions of individual components of the G(1)-S network downstream of Hog1 to this stress-... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5272661 Tue, 27 Sep 2011 04:00:00 +0100 5272661 http://www.medworm.com/index.php?rid=5272660&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21954290%26dopt%3DAbstract Authors: Lin C, Ear J, Pavlova Y, Mittal Y, Kufareva I, Ghassemian M, Abagyan R, Garcia-Marcos M, Ghosh P Abstract GIV (Gα-interacting vesicle-associated protein; also known as Girdin) enhances Akt activation downstream of multiple growth factor- and G protein (heterotrimeric guanosine 5'-triphosphate-binding protein)-coupled receptors to trigger cell migration and cancer invasion. We demonstrate that GIV is a tyrosine phosphoprotein that directly binds to and activates phosphoinositide 3-kinase (PI3K). Upon ligand stimulation of various receptors, GIV was phosphorylated at tyrosine-1764 and tyrosine-1798 by both receptor and non-receptor tyrosine kinases. These phosphorylation events enabled direct binding of GIV to the amino- and carboxyl-terminal Src homology 2 domains of p85α... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5272660 Tue, 27 Sep 2011 04:00:00 +0100 5272660 http://www.medworm.com/index.php?rid=5272659&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21954291%26dopt%3DAbstract Authors: Sobie EA Abstract This Teaching Resource provides lecture notes, slides, and a student assignment for a two-part lecture on the principles underlying bistability in biochemical signaling networks, which are illustrated with examples from the literature. The lectures cover analog, or graded, versus digital, all-or-none, responses in cells, with examples from different types of biological processes requiring each. Rate-balance plots are introduced as a method for determining whether generic one-variable systems exhibit one or several stable steady states. Bifurcation diagrams are presented as a more general method for detecting the presence of bistability in biochemical signaling networks. The examples include an artificial toggle switch, the lac operon in bacteria, and the ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5272659 Tue, 27 Sep 2011 04:00:00 +0100 5272659 http://www.medworm.com/index.php?rid=5272658&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21954292%26dopt%3DAbstract Authors: Sobie EA Abstract This Teaching Resource provides lecture notes, slides, and a problem set for introducing graduate-level students to computational biology through a simple mathematical model of the cell cycle. The model simulates interactions between cyclin B and cyclin-dependent kinase 1, proteins that together form the mitosis-promoting factor (MPF), which initiates the processes leading to mitosis. The lecture begins with a biological background describing the importance of MPF for mitosis, the components of MPF, and the changes in cellular MPF observed during different phases of the cell cycle. The model is compared with newer, more mechanistically detailed models of the same process, which allows for a discussion of the insights that can be gained even from simplifie... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5272658 Tue, 27 Sep 2011 04:00:00 +0100 5272658 http://www.medworm.com/index.php?rid=5272657&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21954293%26dopt%3DAbstract Authors: Neves SR Abstract This Teaching Resource provides lecture notes, slides, and a student assignment for a two-part lecture on mathematical modeling using the Virtual Cell environment. The lectures discuss the steps involved in developing and running simulations using Virtual Cell, with particular focus on spatial partial differential equation models. We discuss how to construct both ordinary differential equation models, in which the cytoplasm is considered a well-mixed cellular compartment, and partial differential equation models, which calculate how chemical species change as a function of both time and location. The Virtual Cell environment is especially well suited for models that explore spatial specificity of cellular reactions. Partial differential equation models in... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5272657 Tue, 27 Sep 2011 04:00:00 +0100 5272657 http://www.medworm.com/index.php?rid=5272656&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21954294%26dopt%3DAbstract Authors: Hayot F Abstract This Teaching Resource provides lecture notes, slides, and a student assignment for a two-part lecture that introduces stochastic modeling of biological systems. The first lecture uses biological examples to present the concept of cell-to-cell variability and makes the connection between the variability of single-cell measurements and concepts from statistical mechanics and probability theory. This section makes the point that for low copy number of a species, the usual differential equation formalism is no longer applicable and needs to be replaced by a probabilistic approach based on the so-called Master Equation. As an example, a simple model of gene transcription is discussed in detail, the different contributions to the relevant Master Equation are hi... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5272656 Tue, 27 Sep 2011 04:00:00 +0100 5272656 http://www.medworm.com/index.php?rid=5272655&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21954295%26dopt%3DAbstract Authors: Sirovich L Abstract This Teaching Resource provides lecture notes, slides, and a student assignment for a lecture on probabilistic reasoning in the analysis of biological data. General probabilistic frameworks are introduced, and a number of standard probability distributions are described using simple intuitive ideas. Particular attention is focused on random arrivals that are independent of prior history (Markovian events), with an emphasis on waiting times, Poisson processes, and Poisson probability distributions. The use of these various probability distributions is applied to biomedical problems, including several classic experimental studies. PMID: 21954295 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=5272655 Tue, 27 Sep 2011 04:00:00 +0100 5272655 http://www.medworm.com/index.php?rid=5272654&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21954296%26dopt%3DAbstract Authors: Costa KD, Kleinstein SH, Hershberg U Abstract This Teaching Resource introduces students to curve fitting and error analysis; it is the second of two lectures on developing mathematical models of biomedical systems. The first focused on identifying, extracting, and converting required constants-such as kinetic rate constants-from experimental literature. To understand how such constants are determined from experimental data, this lecture introduces the principles and practice of fitting a mathematical model to a series of measurements. We emphasize using nonlinear models for fitting nonlinear data, avoiding problems associated with linearization schemes that can distort and misrepresent the data. To help ensure proper interpretation of model parameters estimated by inverse... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5272654 Tue, 27 Sep 2011 04:00:00 +0100 5272654 http://www.medworm.com/index.php?rid=5240217&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21934106%26dopt%3DAbstract Authors: Yagi H, Tan W, Dillenburg-Pilla P, Armando S, Amornphimoltham P, Simaan M, Weigert R, Molinolo AA, Bouvier M, Gutkind JS Abstract Tumor cells can co-opt the promigratory activity of chemokines and their cognate G protein-coupled receptors (GPCRs) to metastasize to regional lymph nodes or distant organs. Indeed, the migration toward SDF-1 (stromal cell-derived factor 1) of tumor cells bearing CXCR4 [chemokine (C-X-C motif) receptor 4] has been implicated in the lymphatic and organ-specific metastasis of various human malignancies. Here, we used chimeric G proteins and GPCRs activated solely by artificial ligands to selectively activate the signaling pathways downstream of specific G proteins and showed that CXCR4-mediated chemotaxis and transendothelial migration of metasta... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5240217 Tue, 20 Sep 2011 04:00:00 +0100 5240217 http://www.medworm.com/index.php?rid=5240216&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21934107%26dopt%3DAbstract Authors: Ramel D, Lagarrigue F, Pons V, Mounier J, Dupuis-Coronas S, Chicanne G, Sansonetti PJ, Gaits-Iacovoni F, Tronchère H, Payrastre B Abstract The phosphoinositide metabolic pathway, which regulates cellular processes implicated in survival, motility, and trafficking, is often subverted by bacterial pathogens. Shigella flexneri, a bacterium that causes dysentery, injects IpgD, a phosphoinositide phosphatase that generates the lipid phosphatidylinositol 5-phosphate (PI5P), into host cells, thereby activating the phosphoinositide 3-kinase-Akt survival pathway. We show that epidermal growth factor receptor (EGFR) is required for PI5P-dependent activation of Akt in infected HeLa cells or cells ectopically expressing IpgD. Cells treated with PI5P had increased numbers of early end... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5240216 Tue, 20 Sep 2011 04:00:00 +0100 5240216 http://www.medworm.com/index.php?rid=5240215&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21934108%26dopt%3DAbstract Authors: Rogers LD, Brown NF, Fang Y, Pelech S, Foster LJ Abstract Salmonella enterica is a bacterial pathogen that causes gastroenteritis and typhoid fever. Virulence is achieved by two type III secretion systems that translocate effector proteins into host cells, where they mimic or block host protein function. Effectors translocated into host cells by the first type III secretion system facilitate invasion and stimulate intracellular signaling cascades leading to inflammation. Here, we performed global temporal analysis of host signaling events induced during the initial stages of Salmonella infection and identified the dynamics of host protein phosphorylation as well as differences between growth factor-stimulated and bacteria-induced signaling. Informatics analysis predicted t... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5240215 Tue, 20 Sep 2011 04:00:00 +0100 5240215 http://www.medworm.com/index.php?rid=5240214&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21934109%26dopt%3DAbstract Authors: Sobie EA Abstract This Teaching Resource provides lecture notes, slides, and a problem set that can assist in teaching concepts related to dynamical systems tools for the analysis of ordinary differential equation (ODE)-based models. The concepts are applied to familiar biological problems, and the material is appropriate for graduate students or advanced undergraduates. The lecture explains how equations describing biochemical signaling networks can be derived from diagrams that illustrate the reactions in graphical form. Because such reactions are most frequently described using systems of ODEs, the lecture discusses and illustrates the principles underlying the numerical solution of ODEs. Methods for determining the stability of steady-state solutions of one or two-dime... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5240214 Tue, 20 Sep 2011 04:00:00 +0100 5240214 http://www.medworm.com/index.php?rid=5240213&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21934110%26dopt%3DAbstract Authors: Sobie EA Abstract This two-part lecture introduces students to the scientific computing language MATLAB. Prior computer programming experience is not required. The lectures present basic concepts of computer programming logic that tend to cause difficulties for beginners in addition to concepts that relate specifically to the MATLAB language syntax. The lectures begin with a discussion of vectors, matrices, and arrays. Because many types of biological data, such as fluorescence images and DNA microarrays, are stored as two-dimensional objects, processing these data is a form of array manipulation, and MATLAB is especially adept at handling such array objects. The students are introduced to basic commands in MATLAB, as well as built-in functions that provide useful shortcut... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5240213 Tue, 20 Sep 2011 04:00:00 +0100 5240213 http://www.medworm.com/index.php?rid=5240212&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21934111%26dopt%3DAbstract Authors: Neves SR Abstract This Teaching Resource provides lecture notes, slides, and a student assignment for a lecture on strategies for the development of mathematical models. Many biological processes can be represented mathematically as systems of ordinary differential equations (ODEs). Simulations with these mathematical models can provide mechanistic insight into the underlying biology of the system. A prerequisite for running simulations, however, is the identification of kinetic parameters that correspond closely with the biological reality. This lecture presents an overview of the steps required for the development of kinetic ODE models and describes experimental methods that can yield kinetic parameters and concentrations of reactants, which are essential for the develop... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5240212 Tue, 20 Sep 2011 04:00:00 +0100 5240212 http://www.medworm.com/index.php?rid=5225491&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21917713%26dopt%3DAbstract Authors: Clague MJ Abstract The activated hepatocyte growth factor (HGF) receptor (Met) undergoes rapid endocytosis and ubiquitin-dependent sorting to the lysosomal degradative pathway. New data suggest that this mode of down-regulation can be circumvented by mutant receptors bearing kinase-activating mutations that instead recycle to the plasma membrane. These mutant receptors can elicit enhanced signaling from endosomes, which is critical for cell motility and tumorigenesis. A proportion of HGF-activated wild-type receptors will also take the endosomal recycling route. This requires the recruitment of the adaptor protein GGA3, mediated through the interaction of GGA3 with the activated form of the small guanosine triphosphatase Arf6 and indirect binding to phosphorylated Met rece... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5225491 Tue, 13 Sep 2011 04:00:00 +0100 5225491 http://www.medworm.com/index.php?rid=5225490&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21917714%26dopt%3DAbstract Authors: Andreu-Pérez P, Esteve-Puig R, de Torre-Minguela C, López-Fauqued M, Bech-Serra JJ, Tenbaum S, García-Trevijano ER, Canals F, Merlino G, Avila MA, Recio JA Abstract The RAS to extracellular signal-regulated kinase (ERK) signal transduction cascade is crucial to cell proliferation, differentiation, and survival. Although numerous growth factors activate the RAS-ERK pathway, they can have different effects on the amplitude and duration of the ERK signal and, therefore, on the biological consequences. For instance, nerve growth factor, which elicits a larger and more sustained increase in ERK phosphorylation in PC12 cells than does epidermal growth factor (EGF), stimulates PC12 cell differentiation, whereas EGF stimulates PC12 cell proliferation. Here, we show that protein... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5225490 Tue, 13 Sep 2011 04:00:00 +0100 5225490 http://www.medworm.com/index.php?rid=5225489&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21917715%26dopt%3DAbstract Authors: Schoenborn JR, Tan YX, Zhang C, Shokat KM, Weiss A Abstract The Src family kinase Lck is crucial for the initiation of TCR signaling. The activity of Lck is tightly controlled to prevent erroneous immune activation, yet it enables rapid cellular responses over a range of sensitivities to antigens. Here, in experiments with an analog-sensitive variant of the tyrosine kinase Csk, we report that Lck in T cells is dynamically controlled by an equilibrium between Csk and the tyrosine phosphatase CD45. By rapidly inhibiting Csk, we showed that changes in this equilibrium were sufficient to activate canonical TCR signaling pathways independently of ligand binding to the TCR. The activated signaling pathways showed sustained and enhanced phosphorylation compared to that in TCR-sti... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5225489 Tue, 13 Sep 2011 04:00:00 +0100 5225489 http://www.medworm.com/index.php?rid=5225488&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21917716%26dopt%3DAbstract Authors: Sobie EA, Lee YS, Jenkins SL, Iyengar R Abstract Because of the complexity inherent in biological systems, many researchers frequently rely on a combination of global analysis and computational approaches to gain insight into both (i) how interacting components can produce complex system behaviors, and (ii) how changes in conditions may alter these behaviors. Because the biological details of a particular system are generally not taught along with the quantitative approaches that enable hypothesis generation and analysis of the system, we developed a course at Mount Sinai School of Medicine that introduces first-year graduate students to these computational principles and approaches. We anticipate that such approaches will apply throughout the biomedical sciences and that ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5225488 Tue, 13 Sep 2011 04:00:00 +0100 5225488 http://www.medworm.com/index.php?rid=5225487&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21917717%26dopt%3DAbstract Authors: Clark NR, Ma'ayan A Abstract This Teaching Resource provides lecture notes, slides, and a problem set for a series of lectures from a course entitled "Systems Biology: Biomedical Modeling." The materials are a lecture introducing the mathematical concepts behind principal components analysis (PCA). The lecture describes how to handle large data sets with correlation methods and unsupervised clustering with this popular method of analysis, PCA. PMID: 21917717 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=5225487 Tue, 13 Sep 2011 04:00:00 +0100 5225487 http://www.medworm.com/index.php?rid=5225486&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21917718%26dopt%3DAbstract Authors: Clark NR, Ma'ayan A Abstract This Teaching Resource provides lecture notes, slides, and a problem set for a series of lectures introducing the mathematical concepts behind gene-set enrichment analysis (GSEA) and were part of a course entitled "Systems Biology: Biomedical Modeling." GSEA is a statistical functional enrichment analysis commonly applied to identify enrichment of biological functional categories in sets of ranked differentially expressed genes from genome-wide mRNA expression data sets. PMID: 21917718 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=5225486 Tue, 13 Sep 2011 04:00:00 +0100 5225486 http://www.medworm.com/index.php?rid=5225485&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21917719%26dopt%3DAbstract Authors: Abstract This Teaching Resource provides lecture notes, slides, and a problem set for a set of three lectures from a course entitled "Systems Biology: Biomedical Modeling." The materials are from three separate lectures introducing applications of graph theory and network analysis in systems biology. The first lecture describes different types of intracellular networks, methods for constructing biological networks, and different types of graphs used to represent regulatory intracellular networks. The second lecture surveys milestones and key concepts in network analysis by introducing topological measures, random networks, growing network models, and topological observations from molecular biological systems abstracted to networks. The third lecture discusses methods for... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5225485 Tue, 13 Sep 2011 04:00:00 +0100 5225485 http://www.medworm.com/index.php?rid=5215424&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21900203%26dopt%3DAbstract Authors: Gough NR Abstract The application of computational biology and systems biology is yielding quantitative insight into cellular regulatory phenomena. For the month of September, Science Signaling highlights research featuring computational approaches to understanding cell signaling and investigation of signaling networks, a series of Teaching Resources from a course in systems biology, and various other articles and resources relevant to the application of computational biology and systems biology to the study of signal transduction. PMID: 21900203 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=5215424 Tue, 06 Sep 2011 04:00:00 +0100 5215424 http://www.medworm.com/index.php?rid=5215420&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21900204%26dopt%3DAbstract Authors: Prill RJ, Saez-Rodriguez J, Alexopoulos LG, Sorger PK, Stolovitzky G Abstract Computational analyses of systematic measurements on the states and activities of signaling proteins (as captured by phosphoproteomic data, for example) have the potential to uncover uncharacterized protein-protein interactions and to identify the subset that are important for cellular response to specific biological stimuli. However, inferring mechanistically plausible protein signaling networks (PSNs) from phosphoproteomics data is a difficult task, owing in part to the lack of sufficiently comprehensive experimental measurements, the inherent limitations of network inference algorithms, and a lack of standards for assessing the accuracy of inferred PSNs. A case study in which 12 research group... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5215420 Tue, 06 Sep 2011 04:00:00 +0100 5215420 http://www.medworm.com/index.php?rid=5215416&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21900205%26dopt%3DAbstract Authors: Maiguel D, Faridi MH, Wei C, Kuwano Y, Balla KM, Hernandez D, Barth CJ, Lugo G, Donnelly M, Nayer A, Moita LF, Schürer S, Traver D, Ruiz P, Vazquez-Padron RI, Ley K, Reiser J, Gupta V Abstract The integrin CD11b/CD18 (also known as Mac-1), which is a heterodimer of the α(M) (CD11b) and β(2) (CD18) subunits, is critical for leukocyte adhesion and migration and for immune functions. Blocking integrin-mediated leukocyte adhesion, although beneficial in experimental models, has had limited success in treating inflammatory diseases in humans. Here, we used an alternative strategy of inhibiting leukocyte recruitment by activating CD11b/CD18 with small-molecule agonists, which we term leukadherins. These compounds increased the extent of CD11b/CD18-dependent cell adhesion of t... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5215416 Tue, 06 Sep 2011 04:00:00 +0100 5215416 http://www.medworm.com/index.php?rid=5215409&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21900206%26dopt%3DAbstract Authors: Vinayagam A, Stelzl U, Foulle R, Plassmann S, Zenkner M, Timm J, Assmus HE, Andrade-Navarro MA, W.er EE Abstract Cellular signal transduction is a complex process involving protein-protein interactions (PPIs) that transmit information. For example, signals from the plasma membrane may be transduced to transcription factors to regulate gene expression. To obtain a global view of cellular signaling and to predict potential signal modulators, we searched for protein interaction partners of more than 450 signaling-related proteins by means of automated yeast two-hybrid interaction mating. The resulting PPI network connected 1126 proteins through 2626 PPIs. After expansion of this interaction map with publicly available PPI data, we generated a directed network resembling the s... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5215409 Tue, 06 Sep 2011 04:00:00 +0100 5215409 http://www.medworm.com/index.php?rid=5186794&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21878678%26dopt%3DAbstract Authors: Cooper J, Li W, You L, Schiavon G, Pepe-Caprio A, Zhou L, Ishii R, Giovannini M, Hanemann CO, Long SB, Erdjument-Bromage H, Zhou P, Tempst P, Giancotti FG Abstract Integrin-mediated activation of PAK (p21-activated kinase) causes phosphorylation and inactivation of the FERM (4.1, ezrin, radixin, moesin) domain-containing protein Merlin, which is encoded by the NF2 (neurofibromatosis type 2) tumor suppressor gene. Conversely, cadherin engagement inactivates PAK, thus leading to accumulation of unphosphorylated Merlin. Current models imply that Merlin inhibits cell proliferation by inhibiting mitogenic signaling at or near the plasma membrane. We have recently shown that the unphosphorylated, growth-inhibiting form of Merlin accumulates in the nucleus and binds to the E3 ubi... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5186794 Mon, 29 Aug 2011 23:00:00 +0100 5186794 http://www.medworm.com/index.php?rid=5186793&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21878679%26dopt%3DAbstract Authors: Chan JC, Hannan KM, Riddell K, Ng PY, Peck A, Lee RS, Hung S, Astle MV, Bywater M, Wall M, Poortinga G, Jastrzebski K, Sheppard KE, Hemmings BA, Hall MN, Johnstone RW, McArthur GA, Hannan RD, Pearson RB Abstract Precise regulation of ribosome biogenesis is fundamental to maintain normal cell growth and proliferation, and accelerated ribosome biogenesis is associated with malignant transformation. Here, we show that the kinase AKT regulates ribosome biogenesis at multiple levels to promote ribosomal RNA (rRNA) synthesis. Transcription elongation by RNA polymerase I, which synthesizes rRNA, required continuous AKT-dependent signaling, an effect independent of AKT's role in activating the translation-promoting complex mTORC1 (mammalian target of rapamycin complex 1). Sustaine... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5186793 Mon, 29 Aug 2011 23:00:00 +0100 5186793 http://www.medworm.com/index.php?rid=5186792&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21878680%26dopt%3DAbstract Authors: Chakraborty A, Kim S, Snyder SH Abstract Inositol pyrophosphates are highly energetic inositol polyphosphate molecules present in organisms from slime molds and yeast to mammals. Distinct classes of enzymes generate different forms of inositol pyrophosphates. The biosynthesis of these substances principally involves phosphorylation of inositol hexakisphosphate (IP(6)) to generate the pyrophosphate IP(7). Initial insights into functions of these substances derived primarily from yeast, which contain a single isoform of IP(6) kinase (yIP(6)K), as well as from the slime mold Dictyostelium. Mammalian functions for inositol pyrophosphates have been investigated by using cell lines to establish roles in various processes, including insulin secretion and apoptosis. More recently,... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5186792 Mon, 29 Aug 2011 23:00:00 +0100 5186792 http://www.medworm.com/index.php?rid=5170913&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21868362%26dopt%3DAbstract This study provides an example by which the innate immune response directly regulates cargo recruitment into autophagosomes. PMID: 21868362 [PubMed - as supplied by publisher] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=5170913 Mon, 22 Aug 2011 23:00:00 +0100 5170913 http://www.medworm.com/index.php?rid=5170912&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21868363%26dopt%3DAbstract Authors: Hatziapostolou M, Koukos G, Polytarchou C, Kottakis F, Serebrennikova O, Kuliopulos A, Tsichlis PN Abstract The mitogen-activated protein kinase kinase kinase (MAPKKK or MAP3K) tumor progression locus 2 (Tpl2) is required for the transduction of signals initiated by the thrombin-activated G protein-coupled receptor (GPCR) protease-activated receptor-1 (PAR1), which promote reorganization of the actin cytoskeleton and cell migration. Here, we show that Tpl2 is activated through Gα(i2)-transduced GPCR signals. Activated Tpl2 promoted the phosphorylation and activation of phospholipase C-β3 (PLCβ(3)); consequently, Tpl2 was required for thrombin-dependent production of inositol 1,4,5-trisphosphate (IP(3)), IP(3)-mediated cytoplasmic calcium ion (Ca(2+)) signals, and the ac... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5170912 Mon, 22 Aug 2011 23:00:00 +0100 5170912 http://www.medworm.com/index.php?rid=5170915&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21868360%26dopt%3DAbstract Authors: Stinson S, Lackner MR, Adai AT, Yu N, Kim HJ, O'Brien C, Spoerke J, Jhunjhunwala S, Boyd Z, Januario T, Newman RJ, Yue P, Bourgon R, Modrusan Z, Stern HM, Warming S, de Sauvage FJ, Amler L, Yeh RF, Dornan D Abstract Compared with the luminal subtype, the basal-like subtype of breast cancer has an aggressive clinical behavior, but the reasons for this difference between the two subtypes are poorly understood. We identified microRNAs (miRNAs) miR-221 and miR-222 (miR-221/222) as basal-like subtype-specific miRNAs that decrease expression of epithelial-specific genes and increase expression of mesenchymal-specific genes. In addition, expression of these miRNAs increased cell migration and invasion, which collectively are characteristics of the epithelial-to-mesenchymal transi... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5170915 Mon, 15 Aug 2011 23:00:00 +0100 5170915 http://www.medworm.com/index.php?rid=5170914&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21868361%26dopt%3DAbstract Authors: Jin M, Errede B, Behar M, Mather W, Nayak S, Hasty J, Dohlman HG, Elston TC Abstract The maintenance and detection of signaling gradients are critical for proper development and cell migration. In single-cell organisms, gradient detection allows cells to orient toward a distant mating partner or nutrient source. Budding yeast expand their growth toward mating pheromone gradients through a process known as chemotropic growth. MATα cells secrete α-factor pheromone that stimulates chemotropism and mating differentiation in MATa cells and vice versa. Paradoxically, MATa cells secrete Bar1, a protease that degrades α-factor and that attenuates the mating response, yet is also required for efficient mating. We observed that MATa cells avoid each other during chemotropic growt... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5170914 Mon, 15 Aug 2011 23:00:00 +0100 5170914 http://www.medworm.com/index.php?rid=5170922&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21868353%26dopt%3DAbstract Authors: Gough NR Abstract As one of the largest and most extensively therapeutically targeted class of receptors, G protein-coupled receptors (also known as seven-transmembrane receptors) are clinically important regulators of physiology. Research highlighted in this issue of Science Signaling provides insight into how receptor phosphoryl-ation enables agonists to trigger distinct cellular responses and how mutations associated with disease affect receptor responsiveness to ligands. This research helps reveal how signaling by these receptors is encoded and decoded to produce ligand-specific, cell-specific, and genome-specific responses. PMID: 21868353 [PubMed - as supplied by publisher] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=5170922 Mon, 08 Aug 2011 23:00:00 +0100 5170922 http://www.medworm.com/index.php?rid=5170921&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21868354%26dopt%3DAbstract Authors: Liggett SB Abstract A unifying mechanism by which G protein-coupled receptors (GPCRs) signal in cell type-dependent and G protein-independent ways has developed over the past decade. GPCR kinases (GRKs) are mediators of homologous desensitization: GRK phosphorylation of the receptors leads to the subsequent binding of β-arrestins, which partially quenches receptor coupling to G proteins. For some receptors, this GRK-mediated phosphorylation stimulates additional signaling through the scaffolding action of β-arrestin. These downstream signals are configured by β-arrestin conformation, which is dictated by the GRK phosphoacceptors on the receptors in a barcode-like fashion. Furthermore, each of the GRKs can potentially phosphorylate different serine and threonine residues... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5170921 Mon, 08 Aug 2011 23:00:00 +0100 5170921 http://www.medworm.com/index.php?rid=5170920&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21868355%26dopt%3DAbstract {beta}2-Adrenergic Receptor Polymorphisms and Signaling: Do Variants Influence the "Memory" of Receptor Activation? Sci Signal. 2011 Aug 9;4(185):pe37 Authors: Insel PA Abstract Nonsynonymous, coding sequence single-nucleotide polymorphisms in β(2)-adrenergic receptors were first recognized almost 20 years ago, but a full understanding of their impact on signal transduction-especially on receptor abundance in native cells and their clinical importance-remains unclear. New evidence has revealed a feature of the Arg(16)Gly variant of β(2)-adrenergic receptors that has not been previously noted: a difference in the rate of response upon repeated stimulation of the receptors, such that the Arg(16) variant shows slower activation and the Gly(16) variant faster activation of cy... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5170920 Mon, 08 Aug 2011 23:00:00 +0100 5170920 http://www.medworm.com/index.php?rid=5170919&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21868356%26dopt%3DAbstract Authors: Han SK, Simon MI Abstract The skin is the largest sensory organ of the body. It is innervated by a diverse array of primary sensory neurons, including a heterogeneous subset of unmyelinated afferents called C fibers. C fibers, sometimes classified as nociceptors, can detect various painful stimuli, including temperature extremes. However, it is increasingly evident that these afferents respond to various pruritic stimuli and transmit information to the brain that is perceived as itch; this can subsequently drive scratching behavior. Although itch and pain are distinct sensations, they are closely related and can, under certain circumstances, antagonize each other. However, it is not clear precisely when, where, and how the processes generating these two sensations originat... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5170919 Mon, 08 Aug 2011 23:00:00 +0100 5170919 http://www.medworm.com/index.php?rid=5170918&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21868357%26dopt%3DAbstract Authors: Nobles KN, Xiao K, Ahn S, Shukla AK, Lam CM, Rajagopal S, Strachan RT, Huang TY, Bressler EA, Hara MR, Shenoy SK, Gygi SP, Lefkowitz RJ Abstract Phosphorylation of G protein-coupled receptors (GPCRs, which are also known as seven-transmembrane spanning receptors) by GPCR kinases (GRKs) plays essential roles in the regulation of receptor function by promoting interactions of the receptors with β-arrestins. These multifunctional adaptor proteins desensitize GPCRs, by reducing receptor coupling to G proteins and facilitating receptor internalization, and mediate GPCR signaling through β-arrestin-specific pathways. Detailed mapping of the phosphorylation sites on GPCRs targeted by individual GRKs and an understanding of how these sites regulate the specific functional conseq... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5170918 Mon, 08 Aug 2011 23:00:00 +0100 5170918 http://www.medworm.com/index.php?rid=5170917&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21868358%26dopt%3DAbstract Authors: Lau EK, Trester-Zedlitz M, Trinidad JC, Kotowski SJ, Krutchinsky AN, Burlingame AL, von Zastrow M Abstract In comparison to endogenous ligands of seven-transmembrane receptors, which typically act as full agonists, many drugs act as partial agonists. Partial agonism is best described as a "macroscopic" property that is manifest at the level of physiological systems or cell populations; however, whether partial agonists also encode discrete regulatory information at the "microscopic" level of individual receptors is not known. Here, we addressed this question by focusing on morphine, a partial agonist drug for μ-type opioid peptide receptors (MORs), and by combining quantitative mass spectrometry with cell biological analysis to investigate the reduced efficacy of morphine... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5170917 Mon, 08 Aug 2011 23:00:00 +0100 5170917 http://www.medworm.com/index.php?rid=5170916&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21868359%26dopt%3DAbstract A Polymorphism-Specific "Memory" Mechanism in the {beta}2-Adrenergic Receptor. Sci Signal. 2011 Aug 9;4(185):ra53 Authors: Ahles A, Rochais F, Frambach T, Bünemann M, Engelhardt S Abstract Signaling through G protein (heterotrimeric guanosine triphosphate-binding protein)-coupled receptors is affected by polymorphisms in receptor-encoding genes. Using fluorescence resonance energy transfer, we found that the β(2)-adrenergic receptor (β(2)AR) responded to repeated activation with altered activation kinetics. Polymorphic variants of the β(2)AR displayed divergent changes of β(2)AR activation kinetics that closely mimicked their different efficacies to generate cyclic adenosine 3',5'-monophosphate. More efficacious variants became faster in their activation kinetics, wher... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5170916 Mon, 08 Aug 2011 23:00:00 +0100 5170916 http://www.medworm.com/index.php?rid=5088668&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21775280%26dopt%3DAbstract Authors: Johnson EA Notch signaling is used to choose cell fates in many developmental contexts. New evidence shows that circulating blood cells in Drosophila, in the absence of Notch ligand provided by neighboring cells, activate Notch signaling through stabilization with the hypoxia-inducible factor-α (HIF-α) transcription factor. Although HIF-α is a key regulator of the low-oxygen stress response, here it acts without its HIF-β partner by interacting with and stabilizing the Notch receptor. These roles for HIF-α and Notch are atypical in multiple ways, from the activity of HIF-α under normal oxygen tensions and without its partner HIF-β to the ligand-independent activity of Notch, and serve as a challenge to identify other noncanonical uses of well-studied signaling pathways.... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5088668 Wed, 03 Aug 2011 17:15:07 +0100 5088668 http://www.medworm.com/index.php?rid=5088667&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21775281%26dopt%3DAbstract Authors: Liu Q, Weng HJ, Patel KN, Tang Z, Bai H, Steinhoff M, Dong X Itch has been defined as an unpleasant skin sensation that triggers the urge to scratch. Primary sensory dorsal root ganglia neurons detect itch stimuli through peripheral axons in the skin, playing an important role in generating itch. Itch is broadly categorized as histaminergic (sensitive to antihistamines) or nonhistaminergic. The peptide Ser-Leu-Ile-Gly-Arg-Leu (SLIGRL) is an itch-inducing agent widely used to study histamine-independent itch. Here, we show that Mrgprs (Mas-related G protein-coupled receptors), particularly MrgprC11, rather than PAR2 (protease-activated receptor 2) as previously thought, mediate this type of itch. A shorter peptide, SLIGR, which specifically activates PAR2 but not MrgprC11, indu... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5088667 Wed, 03 Aug 2011 17:15:07 +0100 5088667 http://www.medworm.com/index.php?rid=5088666&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21775282%26dopt%3DAbstract Authors: Ilagan MX, Lim S, Fulbright M, Piwnica-Worms D, Kopan R Notch signaling regulates many cellular processes during development and adult tissue renewal. Upon ligand binding, Notch receptors undergo ectodomain shedding followed by γ-secretase-mediated release of the Notch intracellular domain (NICD), which translocates to the nucleus and associates with the DNA binding protein CSL [CBF1/RBPjκ/Su(H)/Lag1] to activate gene expression. Mammalian cells contain four Notch receptors that can have both redundant and specific activities. To monitor activation of specific Notch paralogs in live cells and in real time, we developed luciferase complementation imaging (LCI) reporters for NICD-CSL association and validated them as a specific, robust, and sensitive assay system that enables ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5088666 Wed, 03 Aug 2011 17:15:07 +0100 5088666 http://www.medworm.com/index.php?rid=5088664&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21775283%26dopt%3DAbstract Authors: Mistry H, Toppin P Cells have specific proteins that serve as gatekeepers of information, much as the media serve as gatekeepers of information for society. With examples of DNA damage detection and rapid reporting of tainted meat, the importance of gatekeepers in science and society is illustrated. PMID: 21775283 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=5088664 Wed, 03 Aug 2011 17:15:07 +0100 5088664 http://www.medworm.com/index.php?rid=5088662&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21775284%26dopt%3DAbstract Authors: Tan CS With the increasing amount of information about the phosphoproteomes of diverse organisms, it is now possible to begin to evaluate this information in the context of evolution. Work described at the inaugural Keystone Symposium on "The Evolution of Protein Phosphorylation" covered a wide range of eukaryotic and prokaryotic organisms, revealing insights into the evolution of protein phosphorylation at the sequence, network, and structural levels. PMID: 21775284 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=5088662 Wed, 03 Aug 2011 17:15:07 +0100 5088662 http://www.medworm.com/index.php?rid=5088661&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21775285%26dopt%3DAbstract Authors: Sundaresan NR, Pillai VB, Wolfgeher D, Samant S, Vasudevan P, Parekh V, Raghuraman H, Cunningham JM, Gupta M, Gupta MP Signaling through the kinase Akt regulates many biological functions. Akt is activated during growth factor stimulation through a process that requires binding of Akt to phosphatidylinositol 3,4,5-trisphosphate (PIP(3)), which promotes membrane localization and phosphorylation of Akt by the upstream kinase PDK1 (phosphoinositide-dependent protein kinase 1). We show that Akt and PDK1 are acetylated at lysine residues in their pleckstrin homology domains, which mediate PIP(3) binding. Acetylation blocked binding of Akt and PDK1 to PIP(3), thereby preventing membrane localization and phosphorylation of Akt. Deacetylation by SIRT1 enhanced binding of Akt and PDK1 ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5088661 Wed, 03 Aug 2011 17:15:07 +0100 5088661 http://www.medworm.com/index.php?rid=5088660&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21775286%26dopt%3DAbstract Authors: Mahtani-Patching J, Neves JF, Pang DJ, Stoenchev KV, Aguirre-Blanco AM, Silva-Santos B, Pennington DJ Whether thymocytes adopt an αβ or a γδ T cell fate in the thymus is determined at the β selection checkpoint by the relatively weak or strong signals that are delivered by either the pre-T cell receptor (preTCR) or the γδ TCR, respectively. Signal initiation at the β selection checkpoint is thought to be independent of ligand engagement of these receptors. Some reports have suggested that receptor oligomerization, which is thought to be mediated by either the immunoglobulin (Ig)-like domain of the preTCRα (pTα) chain or the variable domain of TCRδ, is a unifying mechanism that initiates signaling in early CD4(-)CD8(-) double-negative (DN) thymocyte progenitors. Here... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5088660 Wed, 03 Aug 2011 17:15:07 +0100 5088660 http://www.medworm.com/index.php?rid=5088659&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21791701%26dopt%3DAbstract Authors: Flores ER, Halder G Epithelial tissues in the human body undergo constant renewal. For example, the skin is regenerated continuously through the periodic proliferation of normally quiescent stem cells in the basal compartment of the skin. Proper balance between stem cell quiescence and proliferation is maintained over the lifetime of the organism to preserve pools of stem cells required to maintain and repair tissues. However, mechanisms controlling the rate of stem cell renewal are poorly understood. Additionally, whether deregulation of these mechanisms within epidermal stem cells leads to skin cancer is not known. The adherens junction component α-catenin has been identified as a regulator of epidermal stem cell proliferation and as a suppressor of skin cancer through its ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5088659 Wed, 03 Aug 2011 17:15:07 +0100 5088659 http://www.medworm.com/index.php?rid=5088658&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21791702%26dopt%3DAbstract Authors: Weinert BT, Wagner SA, Horn H, Henriksen P, Liu WR, Olsen JV, Jensen LJ, Choudhary C Posttranslational modification of proteins by acetylation and phosphorylation regulates most cellular processes in living organisms. Surprisingly, the evolutionary conservation of phosphorylated serine and threonine residues is only marginally higher than that of unmodified serines and threonines. With high-resolution mass spectrometry, we identified 1981 lysine acetylation sites in the proteome of Drosophila melanogaster. We used data sets of experimentally identified acetylation and phosphorylation sites in Drosophila and humans to analyze the evolutionary conservation of these modification sites between flies and humans. Site-level conservation analysis revealed that acetylation sites are h... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5088658 Wed, 03 Aug 2011 17:15:07 +0100 5088658 http://www.medworm.com/index.php?rid=5088657&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21791703%26dopt%3DAbstract Authors: Quintavalle M, Elia L, Price JH, Heynen-Genel S, Courtneidge SA Acquisition of invasive cell behavior underlies tumor progression and metastasis. To further define the molecular mechanisms underlying invasive behavior, we developed a high-throughput screening strategy to quantitate invadopodia, which are actin-rich membrane protrusions of cancer cells that contribute to tissue invasion and matrix remodeling. We tested the LOPAC 1280 collection of pharmacologically active agents in a high-content, image-based assay and identified compounds that inhibited invadopodium formation without overt toxicity, as well as compounds that increased invadopodia number. The chemotherapeutic agent paclitaxel increased both the number of invadopodia and the invasive behavior of various human ca... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5088657 Wed, 03 Aug 2011 17:15:07 +0100 5088657 http://www.medworm.com/index.php?rid=5038835&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21730324%26dopt%3DAbstract Authors: Lesser CF, Leong JM Many microbial pathogens use specialized secretion systems to inject proteins referred to as effectors directly into eukaryotic host cells. These effectors directly target various eukaryotic signaling pathways and cellular processes, often by mimicking the activity of host cell proteins. Effectors of pathogenic Escherichia coli and Salmonella typhimurium can also act as molecular scaffolds that not only recruit but also directly regulate the activity and localization of multiple eukaryotic proteins. By assembling and localizing disparate signaling pathways, the bacteria can reengineer host cell processes to generate novel processes not previously observed in eukaryotic cells. PMID: 21730324 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=5038835 Wed, 20 Jul 2011 06:15:03 +0100 5038835 http://www.medworm.com/index.php?rid=5038834&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21730325%26dopt%3DAbstract Authors: Su Y, Ospina JK, Zhang J, Michelson AP, Schoen AM, Zhu AJ The correct interpretation of a gradient of the morphogen Hedgehog (Hh) during development requires phosphorylation of the Hh signaling activator Smoothened (Smo); however, the molecular mechanism by which Smo transduces graded Hh signaling is not well understood. We show that regulation of the phosphorylation status of Smo by distinct phosphatases at specific phosphorylated residues creates differential thresholds of Hh signaling. Phosphorylation of Smo was initiated by adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase (PKA) and further enhanced by casein kinase I (CKI). We found that protein phosphatase 1 (PP1) directly dephosphorylated PKA-phosphorylated Smo to reduce signaling mediated by intermediate co... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5038834 Wed, 20 Jul 2011 06:15:03 +0100 5038834 http://www.medworm.com/index.php?rid=5038833&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21730326%26dopt%3DAbstract We report that chloroquine promoted the transrepression of proinflammatory cytokines by the glucocorticoid receptor (GR). In a mouse collagen-induced arthritis model, chloroquine enhanced the therapeutic effects of glucocorticoid treatment. By inhibiting lysosome function, chloroquine synergistically activated glucocorticoid signaling. Lysosomal inhibition by either bafilomycin A1 (an inhibitor of the vacuolar adenosine triphosphatase) or knockdown of transcription factor EB (TFEB, a master activator of lysosomal biogenesis) mimicked the effects of chloroquine. The abundance of the GR, as well as that of the androgen receptor and estrogen receptor, correlated with changes in lysosomal biogenesis. Thus, we showed that glucocorticoid signaling is regulated by lysosomes, which provides a mech... Science Signaling journals http://www.medworm.com/rss/comments.php?id=5038833 Wed, 20 Jul 2011 06:15:03 +0100 5038833 http://www.medworm.com/index.php?rid=4994802&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21693762%26dopt%3DAbstract This article highlights recent reports describing Ub-mediated selective autophagy regulated by the Toll-like receptor 4-induced immune response. PMID: 21693762 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=4994802 Mon, 04 Jul 2011 16:30:03 +0100 4994802 http://www.medworm.com/index.php?rid=4994801&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21693763%26dopt%3DAbstract Authors: Yoo YG, Christensen J, Gu J, Huang LE Although tumor progression involves genetic and epigenetic alterations to normal cellular biology, the underlying mechanisms of these changes remain obscure. Numerous studies have shown that hypoxia-inducible factor 1α (HIF-1α) is overexpressed in many human cancers and up-regulates a host of hypoxia-responsive genes for cancer growth and survival. We recently identified an alternative mechanism of HIF-1α function that induces genetic alterations by suppressing DNA repair. Here, we show that long-term hypoxia, which mimics the tumor microenvironment, drives a perpetual epithelial-mesenchymal transition (EMT) through up-regulation of the zinc finger E-box binding homeobox protein ZEB2, whereas short-term hypoxia induces a reversible EMT ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4994801 Mon, 04 Jul 2011 16:30:03 +0100 4994801 http://www.medworm.com/index.php?rid=4994800&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21693764%26dopt%3DAbstract Authors: Tatham MH, Matic I, Mann M, Hay RT The small ubiquitin-like modifiers (SUMOs) alter the functions of diverse cellular proteins by covalent posttranslational modification and thus influence many cellular functions, including gene transcription, cell cycle, and DNA repair. Although conjugation by ubiquitin and SUMO-2/3 are largely functionally and mechanistically independent from one another, both appear to increase under conditions of proteasome inhibition. To better understand the relationship between SUMO and protein degradation by the proteasome, we performed a quantitative proteomic analysis of SUMO-2 substrates after short- and long-term inhibition of the proteasome with MG132. Comparisons with changes to the SUMO-2 conjugate subproteome in response to heat stress revealed... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4994800 Mon, 04 Jul 2011 16:30:03 +0100 4994800 http://www.medworm.com/index.php?rid=4994799&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21712543%26dopt%3DAbstract Authors: Gough NR Phosphoproteomic analysis of mammalian or yeast cells arrested in mitosis provides a comprehensive view of how phosphorylation contributes to this process, and the research highlighted in this issue implicates previously unrecognized players in this complex process of cell division. Analysis of substrate selectivity and the motifs targeted by specific kinases suggests that cells combine negative and positive site selection, along with spatial segregation, to ensure that the multiple kinases that participate in mitosis find their proper targets. Because alterations in the activities of these kinases can lead to uncontrolled cell proliferation and because of their essential roles in regulating cell division, these kinases are the targets of anticancer therapeutic agents... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4994799 Mon, 04 Jul 2011 16:30:03 +0100 4994799 http://www.medworm.com/index.php?rid=4994798&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21712544%26dopt%3DAbstract Authors: Johnson LN Most signaling pathways in cells involve numerous phosphorylation reactions. Some of the rules for kinase-substrate specificity are known, but a complete description of all substrates is missing. Research published in Science Signaling addresses the process of mitosis and asks how the relevant kinases recognize substrate sequence motifs and, in the cellular context, what substrates are phosphorylated and where. The results increase our molecular understanding of how individual events are coordinated during the process of cell division and show the importance of both sequence epitopes for kinase specificity and the notion of a sense of place through localization in subcellular compartments. PMID: 21712544 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=4994798 Mon, 04 Jul 2011 16:30:03 +0100 4994798 http://www.medworm.com/index.php?rid=4994797&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21712545%26dopt%3DAbstract Authors: Alexander J, Lim D, Joughin BA, Hegemann B, Hutchins JR, Ehrenberger T, Ivins F, Sessa F, Hudecz O, Nigg EA, Fry AM, Musacchio A, Stukenberg PT, Mechtler K, Peters JM, Smerdon SJ, Yaffe MB The timing and localization of events during mitosis are controlled by the regulated phosphorylation of proteins by the mitotic kinases, which include Aurora A, Aurora B, Nek2 (never in mitosis kinase 2), Plk1 (Polo-like kinase 1), and the cyclin-dependent kinase complex Cdk1/cyclin B. Although mitotic kinases can have overlapping subcellular localizations, each kinase appears to phosphorylate its substrates on distinct sites. To gain insight into the relative importance of local sequence context in kinase selectivity, identify previously unknown substrates of these five mitotic kinases, and... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4994797 Mon, 04 Jul 2011 16:30:03 +0100 4994797 http://www.medworm.com/index.php?rid=4994796&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21712546%26dopt%3DAbstract Authors: Kettenbach AN, Schweppe DK, Faherty BK, Pechenick D, Pletnev AA, Gerber SA Mitosis is a process involving a complex series of events that require careful coordination. Protein phosphorylation by a small number of kinases, in particular Aurora A, Aurora B, the cyclin-dependent kinase-cyclin complex Cdk1/cyclinB, and Polo-like kinase 1 (Plk1), orchestrates almost every step of cell division, from entry into mitosis to cytokinesis. To discover more about the functions of Aurora A, Aurora B, and kinases of the Plk family, we mapped mitotic phosphorylation sites to these kinases through the combined use of quantitative phosphoproteomics and selective targeting of kinase activities by small-molecule inhibitors. Using this integrated approach, we connected 778 phosphorylation sites o... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4994796 Mon, 04 Jul 2011 16:30:03 +0100 4994796 http://www.medworm.com/index.php?rid=4994795&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21712547%26dopt%3DAbstract Authors: Koch A, Krug K, Pengelley S, Macek B, Hauf S Kinases of the Aurora family are essential for the proper execution of mitosis in eukaryotes, and Aurora inhibitors are in clinical trials as anticancer drugs. We applied site-specific quantitative phosphoproteomics in conjunction with chemical inhibition of Aurora to identify mitotic Aurora substrates in fission yeast on a proteome-wide scale. We detected 8000 phosphorylation events, of which we assigned almost 6000 to a specific residue; 220 were reduced in cells exposed to the Aurora inhibitor. After controlling for unspecific effects of the inhibitor, we classified 70 sites (on 42 proteins) as probable targets of Aurora, which enabled refinement of the consensus sequence for phosphorylation by Aurora. Several of the substrate ca... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4994795 Mon, 04 Jul 2011 16:30:03 +0100 4994795 http://www.medworm.com/index.php?rid=4945907&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21653226%26dopt%3DAbstract Authors: Whitington T, Jolma A, Taipale J Cell differentiation during development is controlled by extracellular morphogens, which induce responding cells to differentiate into distinct cell fates based on the dose of morphogen they receive. Genes that specify the distinct cell fates are differentially responsive to morphogens, and the extracellular morphogen gradient is converted in responding cells to graded activity of transcription factors. In the case of Hedgehog, the gradient is converted to opposing gradients of transcriptional activator and repressor forms of the transcription factor Cubitus interruptus (Ci). It has been generally assumed that the balance between activator and repressor determines target gene responses within this gradient. However, new evidence shows that enha... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4945907 Mon, 20 Jun 2011 11:45:09 +0100 4945907 http://www.medworm.com/index.php?rid=4945906&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21653227%26dopt%3DAbstract Authors: Ma L, Zhang X, Chen H Background potassium (K(+)) channels, which are normally selectively permeable to K(+), maintain the cardiac resting membrane potential at around -80 mV. In subphysiological extracellular K(+) concentrations ([K(+)](o)), which occur in pathological hypokalemia, the resting membrane potential of human cardiomyocytes can depolarize to around -50 mV, whereas rat and mouse cardiomyocytes become hyperpolarized, consistent with the Nernst equation for K(+). This paradoxical depolarization of cardiomyocytes in subphysiological [K(+)](o), which may contribute to cardiac arrhythmias, is thought to involve an inward leak sodium (Na(+)) current. Here, we show that human cardiac TWIK-1 (also known as K2P1) two-pore domain K(+) channels change ion selectivity, becomin... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4945906 Mon, 20 Jun 2011 11:45:09 +0100 4945906 http://www.medworm.com/index.php?rid=4945905&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21653228%26dopt%3DAbstract Authors: Parker DS, White MA, Ramos AI, Cohen BA, Barolo S Gradients of diffusible signaling proteins control precise spatial patterns of gene expression in the developing embryo. Here, we use quantitative expression measurements and thermodynamic modeling to uncover the cis-regulatory logic underlying spatially restricted gene expression in a Hedgehog (Hh) gradient in Drosophila. When Hh signaling is low, the Hh effector Gli, known as Cubitus interruptus (Ci) in Drosophila, acts as a transcriptional repressor; when Hh signaling is high, Gli acts as a transcriptional activator. Counterintuitively and in contrast to previous models of Gli-regulated gene expression, we found that low-affinity binding sites for Ci were required for proper spatial expression of the Hh target gene decapenta... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4945905 Mon, 20 Jun 2011 11:45:09 +0100 4945905 http://www.medworm.com/index.php?rid=4945904&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21653229%26dopt%3DAbstract Authors: Dushek O, Aleksic M, Wheeler RJ, Zhang H, Cordoba SP, Peng YC, Chen JL, Cerundolo V, Dong T, Coombs D, van der Merwe PA T cell activation, a critical event in adaptive immune responses, depends on productive interactions between T cell receptors (TCRs) and antigens presented as peptide-bound major histocompatibility complexes (pMHCs). Activated T cells lyse infected cells, secrete cytokines, and perform other effector functions with various efficiencies, which depend on the binding parameters of the TCR-pMHC complex. The mechanism through which binding parameters are translated to the efficiency of T cell activation, however, remains controversial. The "affinity model" suggests that the dissociation constant (K(D)) of the TCR-pMHC complex determines the response, whereas the "... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4945904 Mon, 20 Jun 2011 11:45:09 +0100 4945904 http://www.medworm.com/index.php?rid=4945903&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21673314%26dopt%3DAbstract Authors: Gould GW The ability to coordinate membrane trafficking events in space and time is of fundamental importance in biology. Polarized trafficking is essential for processes as diverse as cytokinesis, regulated endocytosis, cell motility, and morphogenesis, yet the interface between cellular signaling systems and the trafficking machinery remains ill defined. Using Drosophila mechanosensory bristle growth as a paradigm for polarized trafficking, a study has uncovered a role for localized activation of the inhibitor of nuclear factor κB kinase, subtype ε (IKKε) at the tip of these bristles, where it regulates the trafficking of recycling endosomal vesicles into and out of the bristle tip. IKKε phosphorylates the Rab11 effector Nuf (which is encoded by nuclear fallout), and in ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4945903 Mon, 20 Jun 2011 11:45:09 +0100 4945903 http://www.medworm.com/index.php?rid=4945902&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21673315%26dopt%3DAbstract We describe the structures of pentavalent and trivalent G-actin•RPEL domain complexes. In the pentavalent complex, each RPEL motif and the two intervening spacer sequences bound an actin monomer, forming a compact assembly. In contrast, the trivalent complex lacked the C-terminal spacer- and RPEL-actins, both of which bound only weakly in the pentavalent complex. Cytoplasmic localization of MRTF-A in unstimulated fibroblasts also required binding of G-actin to the spacer sequences. The bipartite MRTF-A nuclear localization sequence was buried in the pentameric assembly, explaining how increases in G-actin concentration prevent nuclear import of MRTF-A. Analyses of the pentavalent and trivalent complexes show how actin loads onto the RPEL domain and reveal a molecular mechanism by which a... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4945902 Mon, 20 Jun 2011 11:45:09 +0100 4945902 http://www.medworm.com/index.php?rid=4945901&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21673316%26dopt%3DAbstract Authors: Stinson S, Lackner MR, Adai AT, Yu N, Kim HJ, O'Brien C, Spoerke J, Jhunjhunwala S, Boyd Z, Januario T, Newman RJ, Yue P, Bourgon R, Modrusan Z, Stern HM, Warming S, de Sauvage FJ, Amler L, Yeh RF, Dornan D The basal-like subtype of breast cancer has an aggressive clinical behavior compared to that of the luminal subtype. We identified the microRNAs (miRNAs) miR-221 and miR-222 (miR-221/222) as basal-like subtype-specific miRNAs and showed that expression of miR-221/222 decreased expression of epithelial-specific genes and increased expression of mesenchymal-specific genes, and increased cell migration and invasion in a manner characteristic of the epithelial-to-mesenchymal transition (EMT). The transcription factor FOSL1 (also known as Fra-1), which is found in basal-like bre... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4945901 Mon, 20 Jun 2011 11:45:09 +0100 4945901 http://www.medworm.com/index.php?rid=4945900&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21674991%26dopt%3DAbstract A correction to the research article titled: "Amplification of the driving oncogene, KRAS or BRAF, underpins acquired resistance to MEK1/2 inhibitors in colorectal cancer cells" by A. S. Little, K. Balmanno, M. J. Sale, S. Newman, J. R. Dry, M. Hampson, P. A. W. Edwards, P. D. Smith, S. J. Cook. Sci Signal. 2011;4(170):er2 Authors: Little AS, Balmanno K, Sale MJ, Newman S, Dry JR, Hampson M, Edwards PA, Smith PD, Cook SJ The acquisition of resistance to protein kinase inhibitors is a growing problem in cancer treatment. We modeled acquired resistance to the MEK1/2 (mitogen-activated or extracellular signal–regulated protein kinase kinases 1 and 2) inhibitor selumetinib (AZD6244) in colorectal cancer cell lines harboring mutations in BRAF (COLO205 and HT29 lines) or KRAS (HCT1... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4945900 Mon, 20 Jun 2011 11:45:09 +0100 4945900 http://www.medworm.com/index.php?rid=4897440&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21598745%26dopt%3DAbstract Authors: Ugolini S, Vivier E, VanHook AM This Podcast features a conversation with the senior authors of a Research Article published in the April 5 issue of Science Signaling. Sophie Ugolini and Eric Vivier discuss their team's finding that signaling through inhibitory NK cell receptors determines the distribution of activating receptors, which, in turn, determines the responsiveness of the cells to activating stimuli. This finding suggests that inhibitory receptors can affect membrane receptor organization and hence the responsiveness of NK cells. PMID: 21598745 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=4897440 Mon, 06 Jun 2011 04:45:03 +0100 4897440 http://www.medworm.com/index.php?rid=4897439&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21610250%26dopt%3DAbstract Authors: Hottiger MO, Boothby M, Koch-Nolte F, Lüscher B, Martin NM, Plummer R, Wang ZQ, Ziegler M Adenosine 5'-diphosphate (ADP)-ribosylation is a protein posttranslational modification that is catalyzed by ADP-ribosyltransferases (ARTs), using nicotinamide adenine dinucleotide (NAD(+)) as a substrate. Mono-ribosylation can be extended into polymers of ADP-ribose (PAR). Poly(ADP-ribosyl)polymerase (PARP) 1, the best-characterized cellular enzyme catalyzing this process, is the prototypical member of a family of mono- and poly(ADP-ribosyl)transferases. The physiological consequences of ADP-ribosylation are inadequately understood. PARP2010, the 18th International Conference on ADP-Ribosylation, attracted scientists from all over the world to Zurich, Switzerland. Highlights from this m... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4897439 Mon, 06 Jun 2011 04:45:03 +0100 4897439 http://www.medworm.com/index.php?rid=4897438&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21610251%26dopt%3DAbstract Authors: Silvis MR, Kreger BT, Lien WH, Klezovitch O, Rudakova GM, Camargo FD, Lantz DM, Seykora JT, Vasioukhin V The Hippo pathway regulates contact inhibition of cell proliferation and, ultimately, organ size in diverse multicellular organisms. Inactivation of the Hippo pathway promotes nuclear localization of the transcriptional coactivator Yap1, a Hippo pathway effector, and can cause cancer. Here, we show that deletion of αE (α epithelial) catenin in the hair follicle stem cell compartment resulted in the development of skin squamous cell carcinoma in mice. Tumor formation was accelerated by simultaneous deletion of αE-catenin and the tumor suppressor-encoding gene p53. A small interfering RNA screen revealed a functional connection between αE-catenin and Yap1. By interacting ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4897438 Mon, 06 Jun 2011 04:45:03 +0100 4897438 http://www.medworm.com/index.php?rid=4897437&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21610252%26dopt%3DAbstract Authors: Wen HC, Avivar-Valderas A, Sosa MS, Girnius N, Farias EF, Davis RJ, Aguirre-Ghiso JA The stress-activated protein kinase (SAPK) p38 can induce apoptosis, and its inhibition facilitates mammary tumorigenesis. We found that during mammary acinar morphogenesis in MCF-10A cells grown in three-dimensional culture, detachment of luminal cells from the basement membrane stimulated mitogen-activated protein kinase (MAPK) kinases 3 and 6 (MKK3/6) and p38α signaling to promote anoikis. p38α signaling increased transcription of the death-promoting protein BimEL by phosphorylating the activating transcription factor 2 (ATF-2) and increasing c-Jun protein abundance, leading to cell death by anoikis and acinar lumen formation. Inhibition of p38α or ATF-2 caused luminal filling reminiscen... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4897437 Mon, 06 Jun 2011 04:45:03 +0100 4897437 http://www.medworm.com/index.php?rid=4897436&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21632467%26dopt%3DAbstract Authors: Wang B The Eph subfamily of receptor tyrosine kinases and their membrane-anchored ephrin ligands mediate cell-cell contact signaling and are versatile regulators of cell migration and tissue patterning, which are often exploited by cancer cells during tumor progression. New evidence shows that prostate cancer cells use EphA2 and EphA4 receptors and ephrin-As to mediate homotypic contact inhibition of locomotion while co-opting ephrin-B2 on stromal cells through EphB3 and EphB4 receptors to propel migration. These processes could enhance cancer cell scattering from the primary tumor mass and promote unimpeded migration and invasion through the stromal space. The results provide another example in which Eph receptors are converted into pro-oncogenic proteins, contrary to their o... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4897436 Mon, 06 Jun 2011 04:45:03 +0100 4897436 http://www.medworm.com/index.php?rid=4897435&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21632468%26dopt%3DAbstract Authors: Kim JR, Kim J, Kwon YK, Lee HY, Heslop-Harrison P, Cho KH The network of biomolecular interactions that occurs within cells is large and complex. When such a network is analyzed, it can be helpful to reduce the complexity of the network to a "kernel" that maintains the essential regulatory functions for the output under consideration. We developed an algorithm to identify such a kernel and showed that the resultant kernel preserves the network dynamics. Using an integrated network of all of the human signaling pathways retrieved from the KEGG (Kyoto Encyclopedia of Genes and Genomes) database, we identified this network's kernel and compared the properties of the kernel to those of the original network. We found that the percentage of essential genes to the genes encoding node... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4897435 Mon, 06 Jun 2011 04:45:03 +0100 4897435 http://www.medworm.com/index.php?rid=4897434&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21632469%26dopt%3DAbstract Authors: Mesecke S, Urlaub D, Busch H, Eils R, Watzl C Natural killer (NK) cells are effector cells of the immune system whose activation is carefully regulated by the interplay of signals from activating and inhibitory receptors. Signals from activating receptors induce phosphorylation of the guanine nucleotide exchange factor Vav1, whereas those from inhibitory receptors lead to the dephosphorylation of Vav1 by the Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1). Here, we used mathematical modeling and experiments with NK cells to gain insight into this integration of positive and negative signals at a molecular level. Our data showed a switch-like regulation of Vav1 phosphorylation, the extent of which correlated with the cytotoxic activity of NK cells. Compa... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4897434 Mon, 06 Jun 2011 04:45:03 +0100 4897434 http://www.medworm.com/index.php?rid=4851101&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21558552%26dopt%3DAbstract PP2A Phosphatases: The "On-Off" Regulatory Switches of Brassinosteroid Signaling. Sci Signal. 2011;4(172):pe25 Authors: Di Rubbo S, Irani NG, Russinova E Inactivation of ligand-bound plasma membrane receptors is crucial for the regulation of their signaling outputs. The internalization of activated receptors and their subsequent targeting for recycling or degradation is controlled by posttranslational modifications, of which phosphorylation and dephosphorylation play an important role. Recent work suggests that a similar mechanism acts on the brassinosteroid (BR) receptor BR INSENSITIVE 1 (BRI1) in Arabidopsis thaliana to switch off BR signaling. The degradation of BRI1 requires a protein phosphatase 2A (PP2A)-mediated dephosphorylation that is specified by methylation of the p... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4851101 Mon, 23 May 2011 03:45:02 +0100 4851101 http://www.medworm.com/index.php?rid=4851100&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21558553%26dopt%3DAbstract Authors: Filhol O, Cochet C Networks of aspartic acid-directed caspases play a major role in the execution of programmed cell death. Studies have provided evidence that caspases or their substrates are subjected to phosphorylation, which suggests a potential convergence of protein kinase and caspase signaling pathways. Various caspase substrates, but also several procaspases, are protected from cleavage when they are phosphorylated at sites adjacent to caspase cleavage sites. Whereas many distinct protein kinases could potentially protect substrates from caspase-mediated cleavage, a study has identified protein kinase CK2 as the most prominent kinase that exerts a global inhibition of caspase signaling pathways. CK2 is a component of protein kinase networks that are involved in tumors ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4851100 Mon, 23 May 2011 03:45:02 +0100 4851100 http://www.medworm.com/index.php?rid=4851099&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21558554%26dopt%3DAbstract We report the identification, in A. thaliana, of a suppressor of bri1, sbi1, which caused selective accumulation of BR-activated BRI1, but not the BR co-receptor BAK1 (BRI1-ASSOCIATED KINASE 1), in the membranous compartment. SBI1 mRNA was induced by BRs, and SBI1 encodes a leucine carboxylmethyltransferase (LCMT) that methylated PP2A and controlled its membrane-associated subcellular localization. We propose that BRs increase production of SBI1, which methylates PP2A, thus facilitating its association with activated BRI1. This leads to receptor dephosphorylation and degradation, and thus to the termination of BR signaling. PMID: 21558554 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=4851099 Mon, 23 May 2011 03:45:02 +0100 4851099 http://www.medworm.com/index.php?rid=4851098&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21558555%26dopt%3DAbstract Authors: Duncan JS, Turowec JP, Duncan KE, Vilk G, Wu C, Lüscher B, Li SS, Gloor GB, Litchfield DW The convergence of caspase and protein kinase signaling pathways has become increasingly evident, as illustrated by the protection of caspase substrates from cleavage upon undergoing phosphorylation at or near to their caspase recognition motifs. To investigate the global role of phosphorylation in the regulation of caspase signaling, we designed a peptide match program to identify sequences from the human proteome that contained overlapping recognition motifs for caspases and kinases. We identified the protein kinase CK2 as the most prominent kinase with a consensus site for phosphorylation that overlapped with caspase recognition motifs. We then evaluated potential targets of CK2 and c... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4851098 Mon, 23 May 2011 03:45:02 +0100 4851098 http://www.medworm.com/index.php?rid=4851097&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21586726%26dopt%3DAbstract Authors: Ren D Mammalian sperm cells are equipped with sophisticated Ca(2+) signaling mechanisms that are fundamental to sperm's success in fertilization. Unlike most other cells, however, mature sperm generally do not have the luxury of synthesizing new proteins. New evidence indicates that human sperm have a very clever way to solve the conflict between the critical demand for Ca(2+) signaling tools and the silence of protein translation. Just before encountering the female reproductive tract, sperm acquire some of the key molecules for Ca(2+) signaling from the male reproductive tract itself: prostasomes secreted by the prostate gland. PMID: 21586726 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=4851097 Mon, 23 May 2011 03:45:02 +0100 4851097 http://www.medworm.com/index.php?rid=4851096&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21586727%26dopt%3DAbstract Authors: Farkas IJ, Korcsmáros T, Kovács IA, Mihalik A, Palotai R, Simkó GI, Szalay KZ, Szalay-Beko M, Vellai T, Wang S, Csermely P In the past few years, network-based tools have become increasingly important in the identification of novel molecular targets for drug development. Systems-based approaches to predict signal transduction-related drug targets have developed into an especially promising field. Here, we summarize our studies, which indicate that modular bridges and overlaps of protein-protein interaction and signaling networks may be of key importance in future drug design. Intermodular nodes are very efficient in mediating the transmission of perturbations between signaling modules and are important in network cooperation. The analysis of stress-induced rearrangements of... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4851096 Mon, 23 May 2011 03:45:02 +0100 4851096 http://www.medworm.com/index.php?rid=4851095&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21586728%26dopt%3DAbstract Authors: Park KH, Kim BJ, Kang J, Nam TS, Lim JM, Kim HT, Park JK, Kim YG, Chae SW, Kim UH Progesterone-induced calcium ion (Ca(2+)) signals in the neck region of sperm play a pivotal role in promoting sperm motility. Here, we show that a long-lasting Ca(2+) signal required for sperm motility in response to progesterone depends on their pH-dependent fusion with prostasomes, which are small vesicles secreted by the prostate. We found that prostasome fusion led to the transfer of progesterone receptors, cyclic adenosine diphosphoribose (cADPR)-synthesizing enzymes, ryanodine receptors (RyRs), and other Ca(2+) signaling tools from prostasomes to the sperm neck. Progesterone-induced sperm motility relied on cADPR-mediated Ca(2+) mobilization through RyR located on acidic Ca(2+) stores, fol... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4851095 Mon, 23 May 2011 03:45:02 +0100 4851095 http://www.medworm.com/index.php?rid=4851094&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21586729%26dopt%3DAbstract Authors: Geiger D, Maierhofer T, Al-Rasheid KA, Scherzer S, Mumm P, Liese A, Ache P, Wellmann C, Marten I, Grill E, Romeis T, Hedrich R S-type anion channels are direct targets of abscisic acid (ABA) signaling and contribute to chloride and nitrate release from guard cells, which in turn initiates stomatal closure. SLAC1 was the first component of the guard cell S-type anion channel identified. However, we found that guard cells of Arabidopsis SLAC1 mutants exhibited nitrate conductance. SLAH3 (SLAC1 homolog 3) was also present in guard cells, and coexpression of SLAH3 with the calcium ion (Ca(2+))-dependent kinase CPK21 in Xenopus oocytes mediated nitrate-induced anion currents. Nitrate, calcium, and phosphorylation regulated SLAH3 activity. CPK21-dependent SLAH3 phosphorylation and a... Science Signaling journals http://www.medworm.com/rss/comments.php?id=4851094 Mon, 23 May 2011 03:45:02 +0100 4851094 http://www.medworm.com/index.php?rid=4797941&cid=s_37170_61_f&fid=37170&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21447795%26dopt%3DAbstract Authors: Adler EM, Gough NR In conjunction with the Science special issue on cancer (http://www.sciencemag.org/special/cancer2011/), this issue of Science Signaling focuses on mechanisms whereby cancer cells become resistant to antineoplastic therapy. This issue explores mechanisms whereby cancer cells can become resistant to classical chemotherapy drugs aimed at rapidly proliferating cells or to newer agents that depend on specific inhibition of oncogenic kinases or downstream components of aberrantly activated signaling pathways. PMID: 21447795 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=4797941 Sun, 08 May 2011 13:30:03 +0100 4797941