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. Fri, 19 Mar 2010 17:19:14 +0100 http://www.medworm.com/index.php?rid=3379593&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%3D20234001%26dopt%3DAbstract Authors: Bennett V, Vanhook AM This is a conversation with Vann Bennett about a Research Article published in the 16 March 2010 issue of Science Signaling. PMID: 20234001 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=3379593 Fri, 19 Mar 2010 05:24:03 +0100 3379593 http://www.medworm.com/index.php?rid=3379592&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%3D20234002%26dopt%3DAbstract Authors: Healy JA, Nilsson KR, Hohmeier HE, Berglund J, Davis J, Hoffman J, Kohler M, Li LS, Berggren PO, Newgard CB, Bennett V Parasympathetic stimulation of pancreatic islets augments glucose-stimulated insulin secretion by inducing inositol trisphosphate receptor (IP(3)R)-mediated calcium ion (Ca(2+)) release. Ankyrin-B binds to the IP(3)R and is enriched in pancreatic beta cells. We found that ankyrin-B-deficient islets displayed impaired potentiation of insulin secretion by the muscarinic agonist carbachol, blunted carbachol-mediated intracellular Ca(2+) release, and reduced the abundance of IP(3)R. Ankyrin-B-haploinsufficient mice exhibited hyperglycemia after oral ingestion but not after intraperitoneal injection of glucose, consistent with impaired parasympathetic potentiation ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3379592 Fri, 19 Mar 2010 05:24:03 +0100 3379592 http://www.medworm.com/index.php?rid=3379591&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%3D20234003%26dopt%3DAbstract Authors: Xu TR, Vyshemirsky V, Gormand A, von Kriegsheim A, Girolami M, Baillie GS, Ketley D, Dunlop AJ, Milligan G, Houslay MD, Kolch W The specification of biological decisions by signaling pathways is encoded by the interplay between activation dynamics and network topologies. Although we can describe complex networks, we cannot easily determine which topology the cell actually uses to transduce a specific signal. Experimental testing of all plausible topologies is infeasible because of the combinatorially large number of experiments required to explore the complete hypothesis space. Here, we demonstrate that Bayesian inference-based modeling provides an approach to explore and constrain this hypothesis space, permitting the rational ranking of pathway models. Our approach can use m... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3379591 Fri, 19 Mar 2010 05:24:03 +0100 3379591 http://www.medworm.com/index.php?rid=3379590&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%3D20234004%26dopt%3DAbstract Authors: Gurumurthy RK, Mäurer AP, Machuy N, Hess S, Pleissner KP, Schuchhardt J, Rudel T, Meyer TF Chlamydiae are obligate intracellular bacterial pathogens that have a major effect on human health. Because of their intimate association with their host, chlamydiae depend on various host cell functions for their survival. Here, we present an RNA-interference-based screen in human epithelial cells that identified 59 host factors that either positively or negatively influenced the replication of Chlamydia trachomatis (Ctr). Two factors, K-Ras and Raf-1, which are members of the canonical Ras-Raf-MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase)-ERK (extracellular signal-regulated kinase) pathway, were identified as central components of signaling networ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3379590 Fri, 19 Mar 2010 05:24:03 +0100 3379590 http://www.medworm.com/index.php?rid=3353789&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%3D20215644%26dopt%3DAbstract Authors: Sacktor TC Long-term memories are thought to be maintained by persistent changes in the strength of synaptic connections among neurons, but how such changes can persist for days to years has been one of the fundamental enigmas of neuroscience. Recently, however, one mechanism that is dependent on the persistent increased activity of an enzyme has been shown to be necessary for the persistence of long-term memory. The transient inhibition of the brain-specific, constitutively active protein kinase C isoform PKMzeta erases memories that are even months old. This finding raises a number of issues; chief among them is the question, how can PKMzeta maintain memories for months when its half-life is probably much shorter? New data suggest how the high abundance of PKMzeta can be mai... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3353789 Thu, 11 Mar 2010 17:46:02 +0100 3353789 http://www.medworm.com/index.php?rid=3353788&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%3D20215645%26dopt%3DAbstract Authors: Westmark PR, Westmark CJ, Wang S, Levenson J, O'Riordan KJ, Burger C, Malter JS Some forms of learning and memory and their electrophysiologic correlate, long-term potentiation (LTP), require dendritic translation. We demonstrate that Pin1 (protein interacting with NIMA 1), a peptidyl-prolyl isomerase, is present in dendritic spines and shafts and inhibits protein synthesis induced by glutamatergic signaling. Pin1 suppression increased dendritic translation, possibly through eukaryotic translation initiation factor 4E (eIF4E) and eIF4E binding proteins 1 and 2 (4E-BP1/2). Consistent with increased protein synthesis, hippocampal slices from Pin(-/-) mice had normal early LTP (E-LTP) but significantly enhanced late LTP (L-LTP) compared to wild-type controls. Protein kinase C zet... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3353788 Thu, 11 Mar 2010 17:46:02 +0100 3353788 http://www.medworm.com/index.php?rid=3353787&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%3D20215646%26dopt%3DAbstract Authors: Sykiotis GP, Bohmann D Cap'n'collar (Cnc) transcription factors are conserved in metazoans and have important developmental and homeostatic functions. The vertebrate Nrf1, Nrf2, and Nrf3; the Caenorhabditis elegans SKN-1; and the Drosophila CncC comprise a subgroup of Cnc factors that mediate adaptive responses to cellular stress. The most studied stress-activated Cnc factor is Nrf2, which orchestrates the transcriptional response of cells to oxidative stressors and electrophilic xenobiotics. In rodent models, signaling by Nrf2 defends against oxidative stress and aging-associated disorders, such as neurodegeneration, respiratory diseases, and cancer. In humans, polymorphisms that decrease Nrf2 abundance have been associated with various pathologies of the skin, respiratory sy... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3353787 Thu, 11 Mar 2010 17:46:02 +0100 3353787 http://www.medworm.com/index.php?rid=3315353&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%3D20179268%26dopt%3DAbstract Authors: Li CY, Vanhook AM This is a conversation with Chuan-Yuan Li about a Research Article published in the 23 February 2010 issue of Science Signaling. PMID: 20179268 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=3315353 Sun, 28 Feb 2010 12:16:03 +0100 3315353 http://www.medworm.com/index.php?rid=3315352&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%3D20179269%26dopt%3DAbstract Authors: Duan Y, Giger RJ It has been known for more than two decades that chondroitin sulfate proteoglycans (CSPGs) inhibit axonal growth and regeneration. In the adult nervous system, CSPGs are enriched in perineuronal nets, and their abundance is increased in reactive astrocytes following injury to brain or spinal cord. Degradation of chondroitin sulfate (CS) sugar moieties by the local infusion of the bacterial enzyme chondroitinase ABC (ChaseABC) enhances experience-dependent neuronal plasticity in the adult visual cortex and results in substantially improved behavioral outcomes after spinal cord injury (SCI). Although the positive effects of ChaseABC treatment on neuronal plasticity have been known for some time, the underlying mechanisms remained enigmatic. The receptor protein ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3315352 Sun, 28 Feb 2010 12:16:03 +0100 3315352 http://www.medworm.com/index.php?rid=3315351&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%3D20179270%26dopt%3DAbstract Authors: Eizirik DL, Cnop M Secretory cells, such as pancreatic beta cells, face the challenge of increasing protein synthesis severalfold during acute or chronic stimulation. This poses a burden on the endoplasmic reticulum (ER), the organelle where proinsulin synthesis and folding takes place. Thus, beta cells use various adaptive mechanisms to adjust the functional capacity of the ER to the prevailing demand. These check-and-balance mechanisms are collectively known as the unfolded protein response (UPR). It remains unclear how UPR signaling is ultimately regulated and what delineates the boundaries between a physiological and a pathological response. New discoveries point to the divergent effects of acute and chronic metabolic fluxes and chemical ER stressors on the formation of co... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3315351 Sun, 28 Feb 2010 12:16:03 +0100 3315351 http://www.medworm.com/index.php?rid=3315350&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%3D20179271%26dopt%3DAbstract We report a role for apoptotic cell death in promoting wound healing and tissue regeneration in mice. Apoptotic cells released growth signals that stimulated the proliferation of progenitor or stem cells. Key players in this process were caspases 3 and 7, proteases activated during the execution phase of apoptosis that contribute to cell death. Mice lacking either of these caspases were deficient in skin wound healing and in liver regeneration. Prostaglandin E(2), a promoter of stem or progenitor cell proliferation and tissue regeneration, acted downstream of the caspases. We propose to call the pathway by which executioner caspases in apoptotic cells promote wound healing and tissue regeneration in multicellular organisms the "phoenix rising" pathway. PMID: 20179271 [PubMed - in proce... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3315350 Sun, 28 Feb 2010 12:16:03 +0100 3315350 http://www.medworm.com/index.php?rid=3315349&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%3D20179272%26dopt%3DAbstract Authors: Rajagopalan S, Moyle MW, Joosten I, Long EO Endosomes are emerging as specialized signaling compartments that endow receptors with distinct signaling properties. The diversity of endosomal signaling pathways and their contribution to various biological responses is still unclear. CD158d, which is also known as the killer cell immunoglobulin-like receptor (KIR) 2DL4 (KIR2DL4), is an endosome-resident receptor in natural killer (NK) cells that stimulates the release of a unique set of proinflammatory and proangiogenic mediators in response to soluble human leukocyte antigen G (HLA-G). Here, we identified the CD158d signaling cascade. In response to soluble agonist antibody or soluble HLA-G, signaling by CD158d was dependent on the activation of nuclear factor kappaB (NF-kappaB) ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3315349 Sun, 28 Feb 2010 12:16:03 +0100 3315349 http://www.medworm.com/index.php?rid=3291257&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%3D20159849%26dopt%3DAbstract Authors: Gfeller A, Dubugnon L, Liechti R, Farmer EE Plants possess a family of potent fatty acid-derived wound-response and developmental regulators: the jasmonates. These compounds are derived from the tri-unsaturated fatty acids alpha-linolenic acid (18:3) and, in plants such as Arabidopsis thaliana and tomato, 7(Z)-, 10(Z)-, and 13(Z)-hexadecatrienoic acid (16:3). The lipoxygenase-catalyzed addition of molecular oxygen to alpha-linolenic acid initiates jasmonate synthesis by providing a 13-hydroperoxide substrate for formation of an unstable allene oxide by allene oxide synthase (AOS). This allene oxide then undergoes enzyme-guided cyclization to produce 12-oxophytodienoic acid (OPDA). These first steps take place in plastids, but further OPDA metabolism occurs in peroxisomes. OPDA... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3291257 Sun, 21 Feb 2010 00:36:02 +0100 3291257 http://www.medworm.com/index.php?rid=3291256&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%3D20159850%26dopt%3DAbstract Authors: Gfeller A, Liechti R, Farmer EE Jasmonates control defense gene expression, growth, and fertility throughout the plant kingdom and have been studied extensively in Arabidopsis thaliana. The prohormone jasmonic acid (JA) is conjugated to amino acids such as isoleucine to form the active hormone jasmonoyl-isoleucine (JA-Ile). A series of breakthroughs has identified the SCF [SCF consists of four subunits: a cullin, SKP1 (S-phase kinase-associated protein 1), a RING finger protein (RBX1/HRT1/ROC1), and an F-box protein] CORONATINE INSENSITIVE1 (COI1) E3 ubiquitin ligase complex and the JASMONATE ZIM-DOMAIN (JAZ) proteins as central components in the perception of and transcriptional response to JA-Ile. JAZ proteins (most probably as dimers) bind transcription factors such as MYC2... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3291256 Sun, 21 Feb 2010 00:36:02 +0100 3291256 http://www.medworm.com/index.php?rid=3291255&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%3D20159851%26dopt%3DAbstract Authors: Hajishengallis G, Vanhook AM This is a conversation with George Hajishengallis about a Research Article published in the 16 February 2010 issue of Science Signaling. PMID: 20159851 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=3291255 Sun, 21 Feb 2010 00:36:02 +0100 3291255 http://www.medworm.com/index.php?rid=3291254&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%3D20159852%26dopt%3DAbstract We report a previously unknown immune subversion mechanism involving microbial exploitation of communication between complement and TLRs. Porphyromonas gingivalis, a major oral and systemic pathogen with complement C5 convertase-like activity, synergizes with C5a (fragment of complement protein C5) to increase cyclic adenosine monophosphate (cAMP) concentrations, resulting in suppression of macrophage immune function and enhanced pathogen survival in vitro and in vivo. This synergy required TLR2 signaling, a pertussis toxin- and thapsigargin-sensitive C5a receptor pathway, with protein kinase A and glycogen synthase kinase-3beta as downstream effectors. Antagonistic blockade of the C5a receptor abrogated this evasive strategy and may thus have important therapeutic implications for periodo... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3291254 Sun, 21 Feb 2010 00:36:02 +0100 3291254 http://www.medworm.com/index.php?rid=3291253&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%3D20159853%26dopt%3DAbstract Authors: Mok J, Kim PM, Lam HY, Piccirillo S, Zhou X, Jeschke GR, Sheridan DL, Parker SA, Desai V, Jwa M, Cameroni E, Niu H, Good M, Remenyi A, Ma JL, Sheu YJ, Sassi HE, Sopko R, Chan CS, De Virgilio C, Hollingsworth NM, Lim WA, Stern DF, Stillman B, Andrews BJ, Gerstein MB, Snyder M, Turk BE Phosphorylation is a universal mechanism for regulating cell behavior in eukaryotes. Although protein kinases target short linear sequence motifs on their substrates, the rules for kinase substrate recognition are not completely understood. We used a rapid peptide screening approach to determine consensus phosphorylation site motifs targeted by 61 of the 122 kinases in Saccharomyces cerevisiae. By correlating these motifs with kinase primary sequence, we uncovered previously unappreciated rules fo... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3291253 Sun, 21 Feb 2010 00:36:02 +0100 3291253 http://www.medworm.com/index.php?rid=3261803&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%3D20145207%26dopt%3DAbstract Authors: Garabedian MJ, Logan SK The glucocorticoid receptor (GR) is a paradigmatic DNA binding transcription factor and was described over 20 years ago as one of the first proteins identified to bind the enhancer region of genes called "response elements." Since that time, an immense amount of work has revealed that GR transcriptional regulation is controlled at virtually every step of its activity: ligand binding, nuclear translocation, transcriptional cofactor binding, and DNA binding. Just when the major modes of GR regulation appear known, a new study provides yet another mechanism whereby GR transcriptional activity is controlled under conditions of cell growth arrest. In this case, GR activity is repressed by a small noncoding RNA (ncRNA) from the growth arrest-specific transcri... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3261803 Thu, 11 Feb 2010 15:56:03 +0100 3261803 http://www.medworm.com/index.php?rid=3261802&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%3D20145208%26dopt%3DAbstract Authors: Sehat B, Tofigh A, Lin Y, Trocmé E, Liljedahl U, Lagergren J, Larsson O The insulin-like growth factor 1 receptor (IGF-1R) plays crucial roles in developmental and cancer biology. Most of its biological effects have been ascribed to its tyrosine kinase activity, which propagates signaling through the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways. Here, we report that IGF-1 promotes the modification of IGF-1R by small ubiquitin-like modifier protein-1 (SUMO-1) and its translocation to the nucleus. Nuclear IGF-1R associated with enhancer-like elements and increased transcription in reporter assays. The SUMOylation sites of IGF-1R were identified as three evolutionarily conserved lysine residues-Lys(1025), Lys(1100), and Lys(1120)-in the beta su... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3261802 Thu, 11 Feb 2010 15:56:03 +0100 3261802 http://www.medworm.com/index.php?rid=3261801&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%3D20145209%26dopt%3DAbstract Authors: Kuo HP, Lee DF, Chen CT, Liu M, Chou CK, Lee HJ, Du Y, Xie X, Wei Y, Xia W, Weihua Z, Yang JY, Yen CJ, Huang TH, Tan M, Xing G, Zhao Y, Lin CH, Tsai SF, Fidler IJ, Hung MC Mammalian target of rapamycin (mTOR) regulates various cellular functions, including tumorigenesis, and is inhibited by the tuberous sclerosis 1 (TSC1)-TSC2 complex. Here, we demonstrate that arrest-defective protein 1 (ARD1) physically interacts with, acetylates, and stabilizes TSC2, thereby repressing mTOR activity. The inhibition of mTOR by ARD1 inhibits cell proliferation and increases autophagy, thereby inhibiting tumorigenicity. Correlation between ARD1 and TSC2 abundance was apparent in multiple tumor types. Moreover, evaluation of loss of heterozygosity at Xq28 revealed allelic loss in 31% of tested ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3261801 Thu, 11 Feb 2010 15:56:03 +0100 3261801 http://www.medworm.com/index.php?rid=3244537&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%3D20124549%26dopt%3DAbstract Authors: Obradovic Wagner D, Sieber C, Bhushan R, Börgermann JH, Graf D, Knaus P The family of bone morphogenetic proteins (BMPs) comprises approximately 30 secreted cytokines that signal through transmembrane serine/threonine kinase receptors. The BMP signaling pathways are fine-tuned on multiple levels: Extracellular antagonists modify ligand activity; several co-receptors enhance or inhibit downstream signaling events through multiple mechanisms; and intracellular molecules further regulate the signaling outcome and mediate crosstalk with other pathways. BMPs affect structures and processes throughout the entire body, ranging from embryonic patterning and development through stem cells and their niches, to tissue homeostasis and regeneration. This comprehensive involvement in v... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3244537 Sat, 06 Feb 2010 01:14:06 +0100 3244537 http://www.medworm.com/index.php?rid=3244536&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%3D20124550%26dopt%3DAbstract Authors: Kino T, Vanhook AM This is a conversation with Tomoshige Kino about a Research Article published in the 2 February 2010 issue of Science Signaling. PMID: 20124550 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=3244536 Sat, 06 Feb 2010 01:14:06 +0100 3244536 http://www.medworm.com/index.php?rid=3244535&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%3D20124551%26dopt%3DAbstract Authors: Kino T, Hurt DE, Ichijo T, Nader N, Chrousos GP The availability of nutrients influences cellular growth and survival by affecting gene transcription. Glucocorticoids also influence gene transcription and have diverse activities on cell growth, energy expenditure, and survival. We found that the growth arrest-specific 5 (Gas5) noncoding RNA, which is abundant in cells whose growth has been arrested because of lack of nutrients or growth factors, sensitized cells to apoptosis by suppressing glucocorticoid-mediated induction of several responsive genes, including the one encoding cellular inhibitor of apoptosis 2. Gas5 bound to the DNA-binding domain of the glucocorticoid receptor (GR) by acting as a decoy glucocorticoid response element (GRE), thus competing with DNA GREs for b... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3244535 Sat, 06 Feb 2010 01:14:06 +0100 3244535 http://www.medworm.com/index.php?rid=3217684&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%3D20103771%26dopt%3DAbstract Authors: Hall MC Walther Flemming and his contemporaries first described the process of mitotic cell division on the basis of microscopic observations over a century ago. In the ensuing 100-plus years, the disciplines of cell biology, genetics, biochemistry, and molecular biology have provided a detailed, yet incomplete, molecular view of the mechanics and regulation of eukaryotic cell division and its relationship to diseases such as cancer. Now, genomic and proteomic technologies offer new and powerful tools to enhance our understanding of this amazingly intricate and fundamental life process. Proteomic studies shed new light on cell division through the large-scale mapping of cell cycle-dependent protein modifications. These studies alter our perception of the complexity of the cell... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3217684 Fri, 29 Jan 2010 13:42:03 +0100 3217684 http://www.medworm.com/index.php?rid=3217669&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%3D20103772%26dopt%3DAbstract Authors: de Diego I, Kuper J, Bakalova N, Kursula P, Wilmanns M Death-associated protein kinase (DAPK) provides a model for calcium-bound calmodulin (CaM)-dependent protein kinases (CaMKs). Here, we report the crystal structure of the binary DAPK-CaM complex, using a construct that includes the DAPK catalytic domain and adjacent autoregulatory domain. When DAPK was in a complex with CaM, the DAPK autoregulatory domain formed a long seven-turn helix. This DAPK-CaM module interacted with the DAPK catalytic domain through two separate domain-domain interfaces, which involved the upper and the lower lobe of the catalytic domain. When bound to DAPK, CaM adopted an extended conformation, which was different from that in CaM-CaMK peptide complexes. Complementary biochemical analysis showed th... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3217669 Fri, 29 Jan 2010 13:42:03 +0100 3217669 http://www.medworm.com/index.php?rid=3217668&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%3D20103773%26dopt%3DAbstract Authors: Qiu Y, Mao T, Zhang Y, Shao M, You J, Ding Q, Chen Y, Wu D, Xie D, Lin X, Gao X, Kaufman RJ, Li W, Liu Y Autophosphorylation of inositol-requiring enzyme 1alpha (IRE1alpha) is required for its activation, which elicits the cellular unfolded protein response (UPR) and is functionally connected with insulin biosynthesis in pancreatic beta cells. We found that the scaffold protein receptor for activated C-kinase 1 (RACK1) interacted with IRE1alpha in a glucose-stimulated or endoplasmic reticulum (ER) stress-responsive manner in pancreatic beta cells and primary islets. RACK1 mediated the glucose-inducible assembly of a complex containing IRE1alpha, RACK1, and protein phosphatase 2A (PP2A) to promote dephosphorylation of IRE1alpha by PP2A, thereby inhibiting glucose-stimulated IRE... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3217668 Fri, 29 Jan 2010 13:42:03 +0100 3217668 http://www.medworm.com/index.php?rid=3194480&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%3D20086235%26dopt%3DAbstract Authors: Weber A, Wasiliew P, Kracht M The interleukin-1 (IL-1) family of cytokines comprises 11 proteins (IL-1F1 to IL-1F11) encoded by 11 distinct genes in humans and mice. IL-1-type cytokines are major mediators of innate immune reactions, and blockade of the founding members IL-1alpha or IL-1beta by the interleukin-1 receptor antagonist (IL-1RA) has demonstrated a central role of IL-1 in a number of human autoinflammatory diseases. IL-1alpha or IL-1beta rapidly increase messenger RNA expression of hundreds of genes in multiple different cell types. The potent proinflammatory activities of IL-1alpha and IL-1beta are restricted at three major levels: (i) synthesis and release, (ii) membrane receptors, and (iii) intracellular signal transduction. This pathway summarizes extracellular ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3194480 Fri, 22 Jan 2010 02:46:07 +0100 3194480 http://www.medworm.com/index.php?rid=3194479&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%3D20086236%26dopt%3DAbstract Authors: Weber A, Wasiliew P, Kracht M The innate immune system senses molecular patterns from invading microorganisms. Once activated, it orchestrates the inflammatory response by secreting proinflammatory cytokines, such as interleukin-1 (IL-1)-type cytokines, in particular IL-1beta. IL-1 mediates the expression of a vast array of genes involved in secondary inflammation. IL-1-responsive genes coordinate all aspects of local inflammation and also attract and activate cells of the adaptive immune system at sites of infection. Moreover, the innate immune system can also sense a wide range of nonmicrobial molecular patterns that represent danger or damage signals. These signals activate the NALP3-inflammasome pathway, which plays a central role in acute and chronic sterile inflammation.... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3194479 Fri, 22 Jan 2010 02:46:07 +0100 3194479 http://www.medworm.com/index.php?rid=3194478&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%3D20086237%26dopt%3DAbstract Authors: Foley JF, Gough NR This Focus Issue of Science Signaling, which complements the Science Special Issue on Innate Immunity (http://www.sciencemag.org/special/immunity), highlights the effects of viral and bacterial components on host cells, signaling pathways involved in regulating innate immune responses, and factors that modulate the functions of dendritic cells, which are required for effective adaptive immunity. PMID: 20086237 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=3194478 Fri, 22 Jan 2010 02:46:07 +0100 3194478 http://www.medworm.com/index.php?rid=3194477&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%3D20086238%26dopt%3DAbstract This study introduces a paradigm shift in the still-evolving mechanism of regulation of NF-kappaB. PMID: 20086238 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=3194477 Fri, 22 Jan 2010 02:46:07 +0100 3194477 http://www.medworm.com/index.php?rid=3194476&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%3D20086239%26dopt%3DAbstract Authors: Arima K, Watanabe N, Hanabuchi S, Chang M, Sun SC, Liu YJ Our adaptive immune system induces distinct responses to different pathogens because of the functional plasticity of dendritic cells (DCs); however, how DCs program unique responses remains unclear. Here, we found that the cytokine thymic stromal lymphopoietin (TSLP) potently transduced a unique T helper type 2 (T(H)2)-inducing compound signal in DCs. Whereas activation of nuclear factor kappaB (predominantly p50) drove DCs to produce OX40L to induce T(H)2 differentiation, the activation of signal transducer and activator of transcription 6 (STAT6) triggered DCs to secrete chemokines necessary for the recruitment of T(H)2 cells. In addition, TSLP signaling limited the activation of STAT4 and interferon regulatory factor... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3194476 Fri, 22 Jan 2010 02:46:07 +0100 3194476 http://www.medworm.com/index.php?rid=3170739&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%3D20068229%26dopt%3DAbstract Authors: Amieux PS, McKnight GS Brown adipose tissue (BAT) is rich in mitochondria and can uncouple oxidative phosphorylation to produce heat as a by-product of fatty acid metabolism. This thermogenic effect helps to maintain body temperature and also plays a critical role in energy homeostasis and the regulation of body weight. Both cyclic adenosine monophosphate and cyclic guanosine monophosphate (cGMP) contribute to the intracellular regulation of mitochondrial biogenesis and the differentiation of BAT. New evidence has defined the essential role of the cGMP-dependent protein kinase I in a pathway that modulates the RhoA-ROCK pathway and insulin receptor signaling to elicit BAT differentiation and stimulate thermogenesis. PMID: 20068229 [PubMed - in process] (Source: Science Sig... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3170739 Thu, 14 Jan 2010 16:10:04 +0100 3170739 http://www.medworm.com/index.php?rid=3170730&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%3D20068230%26dopt%3DAbstract Authors: Wang Z, Udeshi ND, Slawson C, Compton PD, Sakabe K, Cheung WD, Shabanowitz J, Hunt DF, Hart GW Like phosphorylation, the addition of O-linked beta-N-acetylglucosamine (O-GlcNAcylation) is a ubiquitous, reversible process that modifies serine and threonine residues on nuclear and cytoplasmic proteins. Overexpression of the enzyme that adds O-GlcNAc to target proteins, O-GlcNAc transferase (OGT), perturbs cytokinesis and promotes polyploidy, but the molecular targets of OGT that are important for its cell cycle functions are unknown. Here, we identify 141 previously unknown O-GlcNAc sites on proteins that function in spindle assembly and cytokinesis. Many of these O-GlcNAcylation sites are either identical to known phosphorylation sites or in close proximity to them. Furthermore... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3170730 Thu, 14 Jan 2010 16:10:04 +0100 3170730 http://www.medworm.com/index.php?rid=3170713&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%3D20068231%26dopt%3DAbstract Authors: Olsen JV, Vermeulen M, Santamaria A, Kumar C, Miller ML, Jensen LJ, Gnad F, Cox J, Jensen TS, Nigg EA, Brunak S, Mann M Eukaryotic cells replicate by a complex series of evolutionarily conserved events that are tightly regulated at defined stages of the cell division cycle. Progression through this cycle involves a large number of dedicated protein complexes and signaling pathways, and deregulation of this process is implicated in tumorigenesis. We applied high-resolution mass spectrometry-based proteomics to investigate the proteome and phosphoproteome of the human cell cycle on a global scale and quantified 6027 proteins and 20,443 unique phosphorylation sites and their dynamics. Co-regulated proteins and phosphorylation sites were grouped according to their cell cycle kinet... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3170713 Thu, 14 Jan 2010 16:10:04 +0100 3170713 http://www.medworm.com/index.php?rid=3170712&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%3D20068232%26dopt%3DAbstract Authors: Corriden R, Insel PA Cells release adenosine triphosphate (ATP), which activates plasma membrane-localized P2X and P2Y receptors and thereby modulates cellular function in an autocrine or paracrine manner. Release of ATP and the subsequent activation of P2 receptors help establish the basal level of activation (sometimes termed "the set point") for signal transduction pathways and regulate a wide array of responses that include tissue blood flow, ion transport, cell volume regulation, neuronal signaling, and host-pathogen interactions. Basal release and autocrine or paracrine responses to ATP are multifunctional, evolutionarily conserved, and provide an economical means for the modulation of cell, tissue, and organismal biology. PMID: 20068232 [PubMed - in process] (Source... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3170712 Thu, 14 Jan 2010 16:10:04 +0100 3170712 http://www.medworm.com/index.php?rid=3119381&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%3D20029028%26dopt%3DAbstract Authors: Vogel SS Cell surface area is maintained in most cells by coupling exocytotic activity to compensatory endocytosis, a process that specifically retrieves membrane inserted by exocytosis. Although such coupling mechanisms seem to be ubiquitous, the mechanisms through which these membrane trafficking events are linked have remained elusive. A mechanism for coupling exocytosis to endocytosis in fruit fly nerve terminals that depends on the exocytotic insertion of vesicular calcium channels into the plasma membrane has recently been identified. This coupling mechanism resembles one previously described in sea urchin eggs. Here, I compare the similarities and differences of the processes involved in linking exocytosis to endocytosis in these two invertebrate systems and speculate o... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3119381 Fri, 25 Dec 2009 06:12:03 +0100 3119381 http://www.medworm.com/index.php?rid=3119380&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%3D20029029%26dopt%3DAbstract This study illustrates the complexity of the EGFR-associated interactome and identifies protein acetylation as a previously unknown regulator of receptor endocytosis and degradation. PMID: 20029029 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=3119380 Fri, 25 Dec 2009 06:12:03 +0100 3119380 http://www.medworm.com/index.php?rid=3119379&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%3D20029030%26dopt%3DAbstract Authors: Mounir Z, Krishnamoorthy JL, Robertson GP, Scheuner D, Kaufman RJ, Georgescu MM, Koromilas AE Inhibition of protein synthesis by phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2) at Ser(51) occurs as a result of the activation of a family of kinases in response to various forms of stress. Although some consequences of eIF2alpha phosphorylation are cytoprotective, phosphorylation of eIF2alpha by RNA-dependent protein kinase (PKR) is largely proapoptotic and tumor suppressing. Phosphatase and tensin homolog deleted from chromosome 10 (PTEN) is a tumor suppressor protein that is mutated or deleted in various human cancers, with functions that are mediated through phosphatase-dependent and -independent pathways. Here, we demonstrate that the... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3119379 Fri, 25 Dec 2009 06:12:03 +0100 3119379 http://www.medworm.com/index.php?rid=3119378&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%3D20029031%26dopt%3DAbstract This study provides the first evidence that Cbl regulates receptor fate by controlling the fusion of sorting endosomes. We postulate that it does so by modulating the abundance of tyrosine-phosphorylated Hrs. PMID: 20029031 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=3119378 Fri, 25 Dec 2009 06:12:03 +0100 3119378 http://www.medworm.com/index.php?rid=3105247&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%3D20009101%26dopt%3DAbstract Authors: Mischel PS, Vanhook AM This is a conversation with Paul Mischel about a Research Article published in the 15 December 2009 issue of Science Signaling. PMID: 20009101 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=3105247 Sat, 19 Dec 2009 16:46:02 +0100 3105247 http://www.medworm.com/index.php?rid=3105246&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%3D20009102%26dopt%3DAbstract Authors: Fernandez-Gonzalez R, Zallen JA Actomyosin contractility is the major force-generating machinery that shapes cells and tissues during morphogenesis. New evidence from Drosophila demonstrates that these forces are spatially organized by a combination of biochemical and mechanical signals that provide dynamic feedback in a complex cellular environment. PMID: 20009102 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=3105246 Sat, 19 Dec 2009 16:46:02 +0100 3105246 http://www.medworm.com/index.php?rid=3105244&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%3D20009103%26dopt%3DAbstract Authors: Miller WT Biochemistry of Signal Transduction and Regulation by Gerhard Krauss is a one-volume introduction to the field of cell signaling best suited for undergraduates or beginning graduate students. The coverage of topics is broad and particularly strong regarding the regulation of gene expression in response to signaling. PMID: 20009103 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=3105244 Sat, 19 Dec 2009 16:46:02 +0100 3105244 http://www.medworm.com/index.php?rid=3105242&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%3D20009104%26dopt%3DAbstract Authors: Guo D, Prins RM, Dang J, Kuga D, Iwanami A, Soto H, Lin KY, Huang TT, Akhavan D, Hock MB, Zhu S, Kofman AA, Bensinger SJ, Yong WH, Vinters HV, Horvath S, Watson AD, Kuhn JG, Robins HI, Mehta MP, Wen PY, Deangelis LM, Prados MD, Mellinghoff IK, Cloughesy TF, Mischel PS Glioblastoma, the most common malignant brain tumor, is among the most lethal and difficult cancers to treat. Although epidermal growth factor receptor (EGFR) mutations are frequent in glioblastoma, their clinical relevance is poorly understood. Studies of tumors from patients treated with the EGFR inhibitor lapatinib revealed that EGFR induces the cleavage and nuclear translocation of the master transcriptional regulator of fatty acid synthesis, sterol regulatory element-binding protein 1 (SREBP-1). This respons... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3105242 Sat, 19 Dec 2009 16:46:02 +0100 3105242 http://www.medworm.com/index.php?rid=3105241&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%3D20009105%26dopt%3DAbstract Authors: Saveliev A, Vanes L, Ksionda O, Rapley J, Smerdon SJ, Rittinger K, Tybulewicz VL The guanine nucleotide exchange factor (GEF) Vav1 is essential for transducing T cell antigen receptor (TCR) signals and therefore plays a critical role in the development and activation of T cells. It has been presumed that the GEF activity of Vav1 is important for its function; however, there has been no direct demonstration of this. Here, we generated mice expressing enzymatically inactive, but normally folded, Vav1 protein. Analysis of these mice showed that the GEF activity of Vav1 was necessary for the selection of thymocytes and for the optimal activation of T cells, including signal transduction to Rac1, Akt, and integrins. In contrast, the GEF activity of Vav1 was not required for TCR-ind... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3105241 Sat, 19 Dec 2009 16:46:02 +0100 3105241 http://www.medworm.com/index.php?rid=3080101&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%3D19996455%26dopt%3DAbstract Authors: Archbold JK Maturation of T cells in the thymus involves input from a number of signaling pathways; their combined input determines whether thymic precursor cells will differentiate into mature alphabeta or gammadelta T cells. This Journal Club article highlights recent research showing that the role of Notch signaling in human T cell maturation differs from that in mice. In mice, reducing Notch gene dosage in vivo promotes gammadelta T cell differentiation. In humans, an increase in Notch activity early in development will trigger gammadelta T cell development. This research emphasizes how the molecular events controlling T cell development are fundamentally different in humans and mice. PMID: 19996455 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=3080101 Sat, 12 Dec 2009 06:52:03 +0100 3080101 http://www.medworm.com/index.php?rid=3080100&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%3D19996456%26dopt%3DAbstract Authors: Bertotti A, Burbridge MF, Gastaldi S, Galimi F, Torti D, Medico E, Giordano S, Corso S, Rolland-Valognes G, Lockhart BP, Hickman JA, Comoglio PM, Trusolino L Tumor onset and progression require the accumulation of many genetic and epigenetic lesions. In some cases, however, cancer cells rely on only one of these lesions to maintain their malignant properties, and this dependence results in tumor regression upon oncogene inactivation ("oncogene addiction"). Determining which nodes of the many networks operative in the transformed phenotype specifically mediate this response to oncogene neutralization is crucial to identifying the vulnerabilities of cancer. Using the Met receptor as the major model system, we combined multiplex phosphoproteomics, genome-wide expression profiling... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3080100 Sat, 12 Dec 2009 06:52:03 +0100 3080100 http://www.medworm.com/index.php?rid=3080099&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%3D19996457%26dopt%3DAbstract This study highlights functions of microRNAs in health and disease that may extend to the recruitment of progenitor cells during other forms of tissue repair or homeostasis. PMID: 19996457 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=3080099 Sat, 12 Dec 2009 06:52:03 +0100 3080099 http://www.medworm.com/index.php?rid=3080098&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%3D19996458%26dopt%3DAbstract Authors: Roy J, Cyert MS Phosphoserine- and phosphothreonine-directed phosphatases display remarkable substrate specificity, yet the sites that they dephosphorylate show little similarity in amino acid sequence. Studies reveal that docking interactions are key for the recognition of substrates and regulators by two conserved phosphatases, protein phosphatase 1 (PP1) and the Ca(2+)-calmodulin-dependent phosphatase calcineurin. In each case, a small degenerate sequence motif in the interacting protein directs low-affinity binding to a docking surface on the phosphatase that is distinct from the active site; several such interactions combine to confer overall binding specificity. Some docking surfaces are conserved, such as a hydrophobic groove on a face opposite the active site that serv... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3080098 Sat, 12 Dec 2009 06:52:03 +0100 3080098 http://www.medworm.com/index.php?rid=3057132&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%3D19952368%26dopt%3DAbstract Authors: Yaffe MB Quantitation of an article's worth by the impact of the journal in which it appears is a path to undermining scientific enterprise. Through a process analogous to rating medical care, rating journals can lead to loss of research effort in the most challenging questions. A paper should be evaluated on its own impact, not by some arbitrary score for the journal as a whole. PMID: 19952368 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=3057132 Fri, 04 Dec 2009 20:44:03 +0100 3057132 http://www.medworm.com/index.php?rid=3057131&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%3D19952369%26dopt%3DAbstract Authors: Pfeifer A, Vanhook AM This is a conversation with Alexander Pfeifer about a Research Article published in the 1 December 2009 issue of Science Signaling. PMID: 19952369 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=3057131 Fri, 04 Dec 2009 20:44:03 +0100 3057131 http://www.medworm.com/index.php?rid=3057130&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%3D19952370%26dopt%3DAbstract Authors: Kraft CA, Garrido JL, Leiva-Vega L, Romero G The fluorescent properties of the amino acid tryptophan make it a useful tool for fluorometric assays. Because tryptophan fluorescence is remarkably sensitive to the polarity of the environment, it can be used to determine the affinity of tryptophan-containing peptides for phospholipid vesicles of varying compositions. Here, we describe a method for using tryptophan fluorescence to determine the binding affinities of peptides derived from the proteins Raf-1 and KSR-1 to small unilamellar vesicles containing phosphatidic acid. The method can be extrapolated to measure the binding of other tryptophan-containing peptides or proteins to lipid vesicles. PMID: 19952370 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=3057130 Fri, 04 Dec 2009 20:44:03 +0100 3057130 http://www.medworm.com/index.php?rid=3057129&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%3D19952371%26dopt%3DAbstract Authors: Haas B, Mayer P, Jennissen K, Scholz D, Diaz MB, Bloch W, Herzig S, Fässler R, Pfeifer A Brown adipose tissue (BAT) is a primary site of energy expenditure through thermogenesis, which is mediated by the uncoupling protein-1 (UCP-1) in mitochondria. Here, we show that protein kinase G (PKG) is essential for brown fat cell differentiation. Induction of adipogenic markers and fat storage was impaired in the absence of PKGI. Furthermore, PKGI mediated the ability of nitric oxide (NO) and guanosine 3',5'-monophosphate (cGMP) to induce mitochondrial biogenesis and increase the abundance of UCP-1. Mechanistically, we found that PKGI controlled insulin signaling in BAT by inhibiting the activity of RhoA and Rho-associated kinase (ROCK), thereby relieving the inhibitory effects o... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3057129 Fri, 04 Dec 2009 20:44:03 +0100 3057129 http://www.medworm.com/index.php?rid=3057128&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%3D19952372%26dopt%3DAbstract Authors: Patsoukis N, Lafuente EM, Meraner P, Kim JS, Dombkowski D, Li L, Boussiotis VA Rap1-guanosine triphosphate (GTP)-interacting adaptor molecule (RIAM) plays a critical role in actin reorganization and inside-out activation of integrins in lymphocytes and platelets. We investigated the role of RIAM in T cell receptor (TCR)-mediated signaling. Although phosphorylation of the kinase ZAP-70 and formation of a signalosome recruited to the adaptor protein LAT were unaffected, elimination of endogenous RIAM by short hairpin RNA impaired generation of inositol 1,4,5-trisphosphate, mobilization of intracellular calcium ions (Ca(2+)), and translocation of the transcription factor NFAT to the nucleus. The activation of Ras guanine nucleotide-releasing protein 1 was also impaired, which led... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3057128 Fri, 04 Dec 2009 20:44:03 +0100 3057128 http://www.medworm.com/index.php?rid=3031274&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%3D19934431%26dopt%3DAbstract Authors: Pawson T, Vanhook AM This is a conversation with Tony Pawson about a Research Article published in the 24 November 2009 issue of Science Signaling. PMID: 19934431 [PubMed - as supplied by publisher] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=3031274 Fri, 27 Nov 2009 11:06:03 +0100 3031274 http://www.medworm.com/index.php?rid=3031273&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%3D19934432%26dopt%3DAbstract Authors: Hill DA, Artis D The first reports of diplomatic relations between human communities date back to the 14th century B.C.E. and the age of the Egyptian pharaohs. However, the evolution of analogous relations between mammals and mutualistic microbial communities is as old as multicellular organisms themselves. A fundamental issue surrounding the biology of these mutualistic relationships is how the immune system recognizes beneficial microbes and tolerates their colonization of barrier surfaces while simultaneously preventing their outgrowth and potentially lethal dissemination throughout the host. New evidence provides insight into the molecular mechanisms that orchestrate diplomacy between the mammalian immune system and bacterial communities in the gut. PMID: 19934432 [Pub... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3031273 Fri, 27 Nov 2009 11:06:03 +0100 3031273 http://www.medworm.com/index.php?rid=3031272&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%3D19934433%26dopt%3DAbstract Authors: Chen C, Liu Y, Liu Y, Zheng P Age-related declines in hematopoietic stem cell (HSC) function may contribute to anemia, poor response to vaccination, and tumorigenesis. Here, we show that mammalian target of rapamycin (mTOR) activity is increased in HSCs from old mice compared to those from young mice. mTOR activation through conditional deletion of Tsc1 in the HSCs of young mice mimicked the phenotype of HSCs from aged mice in various ways. These included increased abundance of the messenger RNA encoding the CDK inhibitors p16(Ink4a), p19(Arf), and p21(Cip1); a relative decrease in lymphopoiesis; and impaired capacity to reconstitute the hematopoietic system. In old mice, rapamycin increased life span, restored the self-renewal and hematopoiesis of HSCs, and enabled effective ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3031272 Fri, 27 Nov 2009 11:06:03 +0100 3031272 http://www.medworm.com/index.php?rid=3031271&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%3D19934434%26dopt%3DAbstract Authors: Jin J, Xie X, Chen C, Park JG, Stark C, James DA, Olhovsky M, Linding R, Mao Y, Pawson T Modular protein domains are functional units that can be modified through the acquisition of new intrinsic activities or by the formation of novel domain combinations, thereby contributing to the evolution of proteins with new biological properties. Here, we assign proteins to groups with related domain compositions and functional properties, termed "domain clubs," which we use to compare multiple eukaryotic proteomes. This analysis shows that different domain types can take distinct evolutionary trajectories, which correlate with the conservation, gain, expansion, or decay of particular biological processes. Evolutionary jumps are associated with a domain that coordinately acquires a new ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3031271 Fri, 27 Nov 2009 11:06:03 +0100 3031271 http://www.medworm.com/index.php?rid=3031270&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%3D19934435%26dopt%3DAbstract Authors: Smith IF, Wiltgen SM, Shuai J, Parker I Intracellular calcium ion (Ca(2+)) signaling crucially depends on the clustered organization of inositol trisphosphate receptors (IP(3)Rs) in the endoplasmic reticulum (ER) membrane. These ligand-gated ion channels liberate Ca(2+) to generate local signals known as Ca(2+) puffs. We tested the hypothesis that IP(3) itself elicits rapid clustering of IP(3)Rs by using flash photolysis of caged IP(3) in conjunction with high-resolution Ca(2+) imaging to monitor the activity and localization of individual IP(3)Rs within intact mammalian cells. Our results indicate that Ca(2+) puffs arising with latencies as short as 100 to 200 ms after photorelease of IP(3) already involve at least four IP(3)R channels, and that this number does not subsequen... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3031270 Fri, 27 Nov 2009 11:06:03 +0100 3031270 http://www.medworm.com/index.php?rid=3008954&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%3D19920249%26dopt%3DAbstract Authors: Dang CV New evidence suggests that the receptor tyrosine kinase FGFR1 (fibroblast growth factor receptor 1) directly phosphorylates pyruvate kinase M2 (PKM2), resulting in reduced conversion of phosphoenolpyruvate to pyruvate, which is further catabolized to lactate by lactate dehydrogenase A. Mutation of the critical tyrosine Tyr(105) to Phe rendered PKM2 more active but was associated with decreased cellular lactate production, increased oxygen consumption, and decreased hypoxic cell proliferation relative to wild-type PKM2. The apparent paradoxical effect of growth signaling through tyrosine phosphorylation, which decreases rather than increases PKM2 activity, stimulates a revised perspective of the Warburg effect. This effect, which describes the propensity for cancer cell... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3008954 Fri, 20 Nov 2009 01:16:03 +0100 3008954 http://www.medworm.com/index.php?rid=3008953&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%3D19920250%26dopt%3DAbstract Authors: Norris KL, Lee JY, Yao TP For the first 30 years since its discovery, reversible protein acetylation has been studied and understood almost exclusively in the context of histone modification and gene transcription. With the discovery of non-histone acetylated proteins and acetylation-modifying enzymes in cellular compartments outside the nucleus, the regulatory potential of reversible acetylation has slowly been recognized in the last decade. However, the scope of protein acetylation involvement in complex biological processes remains uncertain. The recent development of new technology has enabled, for the first time, the identification and quantification of the acetylome, acetylation events at the whole-proteome level. These efforts have uncovered a stunning complexity of the... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3008953 Fri, 20 Nov 2009 01:16:03 +0100 3008953 http://www.medworm.com/index.php?rid=3008952&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%3D19920251%26dopt%3DAbstract Authors: Hitosugi T, Kang S, Vander Heiden MG, Chung TW, Elf S, Lythgoe K, Dong S, Lonial S, Wang X, Chen GZ, Xie J, Gu TL, Polakiewicz RD, Roesel JL, Boggon TJ, Khuri FR, Gilliland DG, Cantley LC, Kaufman J, Chen J The Warburg effect describes a pro-oncogenic metabolism switch such that cancer cells take up more glucose than normal tissue and favor incomplete oxidation of glucose even in the presence of oxygen. To better understand how tyrosine kinase signaling, which is commonly increased in tumors, regulates the Warburg effect, we performed phosphoproteomic studies. We found that oncogenic forms of fibroblast growth factor receptor type 1 inhibit the pyruvate kinase M2 (PKM2) isoform by direct phosphorylation of PKM2 tyrosine residue 105 (Y(105)). This inhibits the formation of acti... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3008952 Fri, 20 Nov 2009 01:16:03 +0100 3008952 http://www.medworm.com/index.php?rid=3008951&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%3D19920252%26dopt%3DAbstract Authors: Chuenkova MV, Pereiraperrin M The parasite Trypanosoma cruzi, which causes Chagas' disease, differentiates in the cytosol of its host cell and then replicates and spreads infection, processes that require the long-term survival of the infected cells. Here, we show that in the cytosol, parasite-derived neurotrophic factor (PDNF), a trans-sialidase that is located on the surface of T. cruzi, is both a substrate and an activator of the serine-threonine kinase Akt, an antiapoptotic molecule. PDNF increases the expression of the gene that encodes Akt while suppressing the transcription of genes that encode proapoptotic factors. Consequently, PDNF elicits a sustained functional response that protects host cells from apoptosis induced by oxidative stress and the proinflammatory cytok... Science Signaling journals http://www.medworm.com/rss/comments.php?id=3008951 Fri, 20 Nov 2009 01:16:03 +0100 3008951 http://www.medworm.com/index.php?rid=2983820&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%3D19903934%26dopt%3DAbstract Authors: Wong W Organisms constantly face potential damage from internal and external sources, thus necessitating signaling cascades that couple specific cellular stresses to the appropriate responses. This Focus Issue of Science Signaling highlights the signaling pathways that are activated by and that mediate responses to diverse types of stresses. PMID: 19903934 [PubMed - as supplied by publisher] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2983820 Thu, 12 Nov 2009 15:38:03 +0100 2983820 http://www.medworm.com/index.php?rid=2983819&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%3D19903935%26dopt%3DAbstract Authors: Snyder SH, Vanhook AM This is a conversation with Solomon Snyder about a Research Article published in the 10 November 2009 issue of Science Signaling. PMID: 19903935 [PubMed - as supplied by publisher] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2983819 Thu, 12 Nov 2009 15:38:03 +0100 2983819 http://www.medworm.com/index.php?rid=2983818&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%3D19903936%26dopt%3DAbstract Authors: Garcia JA The cellular response to a reduced oxygen state (or hypoxia) includes de novo alterations in gene expression patterns, many of which are controlled by hypoxia-inducible factor (HIF) transcription factors. HIF signaling is predominantly regulated by the dioxygenase family of prolyl hydroxylases (PHDs), also known as EGL nine homologs (EGLNs). The PHD family in higher eukaryotes, like the HIF alpha family, is composed of multiple members that have some shared biochemical properties yet have unique biological roles. Although HIF members are the major substrates identified to date for the PHD members, a reasonable expectation is that other proteins whose activities are altered by hypoxia may also serve as PHD substrates. Indeed, the beta(2)-adrenergic receptor, a major a... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2983818 Thu, 12 Nov 2009 15:38:03 +0100 2983818 http://www.medworm.com/index.php?rid=2983817&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%3D19903937%26dopt%3DAbstract Authors: Jung K, Jung H Histidine protein kinases and serine, threonine, or tyrosine protein kinases play essential roles in signal transduction in prokaryotes and eukaryotes. A third type of protein kinase, an arginine protein kinase, has been identified. McsB of Bacillus subtilis phosphorylates the heat shock transcriptional regulator CtsR and can be regarded as the founding member of arginine protein kinases. PMID: 19903937 [PubMed - as supplied by publisher] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2983817 Thu, 12 Nov 2009 15:38:03 +0100 2983817 http://www.medworm.com/index.php?rid=2983816&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%3D19903938%26dopt%3DAbstract Authors: Rutkowski DT The transcriptional output of a cell reflects the sum of cooperative and competing interactions among hundreds of transcriptional regulators that are themselves regulated according to cellular conditions. In this way, disparate signaling cascades intersect at the level of gene expression; perturbation in one area of the cell will necessarily and fundamentally affect other areas as the cell strives to integrate information from multiple pathways. The consequences of such transcriptional cross-talk are highlighted by a newly discovered connection, through a common co-regulator, between stress in the endoplasmic reticulum and control of gluconeogenesis. These findings hint at the possible functions of stress pathways as regulators of basal cellular homeostasis. P... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2983816 Thu, 12 Nov 2009 15:38:03 +0100 2983816 http://www.medworm.com/index.php?rid=2983815&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%3D19903939%26dopt%3DAbstract Authors: Shiloh Y The DNA damage response (DDR)-a central axis in the maintenance of genomic stability-has emerged as a complex signaling network that affects many aspects of cellular metabolism. A major arm of the DDR activates special checkpoints that temporarily arrest cell cycle progression while damage is being assessed and processed. Many DDR arms are driven by several parallel pathways acting in concert. Such is the case with the damage-induced G(1)/S checkpoint. A new pathway driving this checkpoint draws attention to the complexity of the DDR, which allows tight but fine-tuned control of the cellular response to threats to genomic integrity. PMID: 19903939 [PubMed - as supplied by publisher] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2983815 Thu, 12 Nov 2009 15:38:03 +0100 2983815 http://www.medworm.com/index.php?rid=2983814&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%3D19903940%26dopt%3DAbstract Authors: Shiozaki K For decades, the fission yeast Schizosaccharomyces pombe has been used as an excellent model with which to explore how cellular growth is coordinated with the division cycle, a yet-unanswered question in biology. New studies in this organism show that TOR (target of rapamycin) kinase and stress-responsive MAPK (mitogen-activated protein kinase) form a signaling pathway that readjusts the timing of mitotic onset in response to poor nutrient conditions. Nutritional environment appears to be translated into graded activity of the protein kinases that influence the activation of Cdc2, a cyclin-dependent kinase driving cell-cycle progression. PMID: 19903940 [PubMed - as supplied by publisher] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2983814 Thu, 12 Nov 2009 15:38:03 +0100 2983814 http://www.medworm.com/index.php?rid=2983813&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%3D19903941%26dopt%3DAbstract Authors: Mustafa AK, Gadalla MM, Sen N, Kim S, Mu W, Gazi SK, Barrow RK, Yang G, Wang R, Snyder SH Hydrogen sulfide (H(2)S), a messenger molecule generated by cystathionine gamma-lyase, acts as a physiologic vasorelaxant. Mechanisms whereby H(2)S signals have been elusive. We now show that H(2)S physiologically modifies cysteines in a large number of proteins by S-sulfhydration. About 10 to 25% of many liver proteins, including actin, tubulin, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), are sulfhydrated under physiological conditions. Sulfhydration augments GAPDH activity and enhances actin polymerization. Sulfhydration thus appears to be a physiologic posttranslational modification for proteins. PMID: 19903941 [PubMed - as supplied by publisher] (Source: Science Signalin... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2983813 Thu, 12 Nov 2009 15:38:03 +0100 2983813 http://www.medworm.com/index.php?rid=2968001&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%3D19887678%26dopt%3DAbstract Authors: Blandino G, Shaul Y, Strano S, Sudol M, Yaffe M Researchers from around the world met for two days in April this year in Rome, Italy, to discuss progress in the rapidly developing field of Hippo signaling, which is relevant to cancer and the control of organ size. Most of the participants presented data related to previously uncharacterized proteins that physically and functionally interact with known components of the Hippo pathway and regulate its biological output. PMID: 19887678 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2968001 Sat, 07 Nov 2009 02:10:03 +0100 2968001 http://www.medworm.com/index.php?rid=2968000&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%3D19887679%26dopt%3DAbstract Authors: Patel S, Docampo R Transient receptor potential (TRP) channels are a large family of cation channels, many of which are predominantly localized to the plasma membrane, where they transduce the effects of diverse and often sensory stimuli. Two members of the TRP melastatin subfamily, TRPM1 and TRPM2, are localized in intracellular compartments and are involved in melanin synthesis and oxidative stress-induced cell death, respectively. These findings provide new insight into the location and function of TRP channels. PMID: 19887679 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2968000 Sat, 07 Nov 2009 02:10:03 +0100 2968000 http://www.medworm.com/index.php?rid=2967999&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%3D19887680%26dopt%3DAbstract Authors: Ashique AM, Choe Y, Karlen M, May SR, Phamluong K, Solloway MJ, Ericson J, Peterson AS Regulatory factor X (Rfx) homologs regulate the transcription of genes necessary for ciliogenesis in invertebrates and vertebrates. Primary cilia are necessary for Hedgehog signaling and regulation of the activity of the transcriptional regulators known as Gli proteins, which are targets of Hedgehog signaling. Here, we describe an Rfx4(L298P) mouse mutant with distinct dorsoventral patterning defects in the ventral spinal cord and telencephalon due to aberrant Sonic hedgehog (Shh) signaling and Gli3 activity. We find that Ift172, which encodes an intraflagellar transport protein necessary for ciliogenesis, is a direct transcriptional target of Rfx4, and the decrease in its expression in the ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2967999 Sat, 07 Nov 2009 02:10:03 +0100 2967999 http://www.medworm.com/index.php?rid=2967998&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%3D19887681%26dopt%3DAbstract Authors: Christen M, Coye LH, Hontz JS, LaRock DL, Pfuetzner RA, Megha , Miller SI The Rho family of guanosine triphosphatases (GTPases) are essential eukaryotic signaling molecules that regulate cellular physiology. Virulence factors from various pathogens alter the signaling of GTPases by acting as GTPase activating factors, guanine nucleotide exchange factors, or direct covalent modifiers; however, bacterial virulence factors that sense rather than alter the signaling states of Rho GTPases have not been previously described. Here, we report that the translocated Salmonellae virulence factor SseJ binds to the guanosine triphosphate-bound form of RhoA. This interaction stimulates the lipase activity of SseJ, which results in the esterification of cholesterol in the host cell membrane.... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2967998 Sat, 07 Nov 2009 02:10:03 +0100 2967998 http://www.medworm.com/index.php?rid=2943834&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%3D19861687%26dopt%3DAbstract Authors: Hamaratoglu F, Basler K, Affolter M Morphogens are crucial for regulating the patterning and the growth of organs. In the developing fly wing, graded distributions of the morphogens Decapentaplegic and Wingless are essential for tissue patterning, but when it comes to growth, evidence suggests that it may not be so. PMID: 19861687 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2943834 Fri, 30 Oct 2009 16:34:19 +0100 2943834 http://www.medworm.com/index.php?rid=2943832&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%3D19861688%26dopt%3DAbstract Authors: Leslie NR The phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10) antagonizes phosphoinositide 3-kinase (PI3K) signaling and is one of the most frequently mutated tumor suppressors in human cancers. Its regulation appears complex and is of great potential clinical importance. The protein P-REX2a (phosphatidylinositol 3,4,5-trisphosphate Rac exchanger 2a), better known as a regulator of the small guanosine triphosphatase Rac, has been identified as a direct regulator of PTEN activity and as a potential oncoprotein. P-REX2a can stimulate cell proliferation by inhibiting PTEN and stimulating downstream PI3K-dependent signaling. This suggests that aberrant control of PTEN by P-REX2a may represent a key tumorigenic mechanism, in agreement with recent studies ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2943832 Fri, 30 Oct 2009 16:34:19 +0100 2943832 http://www.medworm.com/index.php?rid=2943831&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%3D19861689%26dopt%3DAbstract Authors: Bönigk W, Loogen A, Seifert R, Kashikar N, Klemm C, Krause E, Hagen V, Kremmer E, Strünker T, Kaupp UB Sperm of the sea urchin Arbacia punctulata can respond to a single molecule of chemoattractant released by an egg. The mechanism underlying this extreme sensitivity is unknown. Crucial signaling events in the response of A. punctulata sperm to chemoattractant include the rapid synthesis of the intracellular messenger guanosine 3',5'-monophosphate (cGMP) and the ensuing membrane hyperpolarization that results from the opening of potassium-selective cyclic nucleotide-gated (CNGK) channels. Here, we use calibrated photolysis of caged cGMP to show that approximately 45 cGMP molecules are generated during the response to a single molecule of chemoattractant. The CNGK cha... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2943831 Fri, 30 Oct 2009 16:34:19 +0100 2943831 http://www.medworm.com/index.php?rid=2943829&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%3D19861690%26dopt%3DAbstract Authors: Marasa BS, Srikantan S, Masuda K, Abdelmohsen K, Kuwano Y, Yang X, Martindale JL, Rinker-Schaeffer CW, Gorospe M MKK4 (mitogen-activated protein kinase kinase 4) is a pivotal upstream activator of c-Jun N-terminal kinase and p38. Here, we report that the abundance of MKK4 increases in senescent human diploid fibroblasts through enhanced translation. We identified four microRNAs (miR-15b, miR-24, miR-25, and miR-141) that target the MKK4 messenger RNA (mRNA); the abundance of these microRNAs decreased during replicative senescence. Individually modulating the amount of each microRNA did not modify MKK4 abundance, but their concomitant overexpression decreased and their joint reduction increased MKK4 abundance. Reporter analyses indicated that these microRNAs acted through the M... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2943829 Fri, 30 Oct 2009 16:34:19 +0100 2943829 http://www.medworm.com/index.php?rid=2943824&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%3D19861691%26dopt%3DAbstract Authors: Burks RL, Chumchal MM This Teaching Resource emphasizes the value of publishing with undergraduates and may be particularly helpful to incoming faculty who are new to the process of working with students. Beyond simply extolling the virtues of undergraduate research, we examine how such deep learning experiences for students can translate into unique opportunities for the faculty to demonstrate devotion to both teaching and scholarship. Along with highlighting the reasons faculty should consider publishing with undergraduates, we identify the particular challenges that accompany this suggestion and discuss strategies for overcoming them. Our resource includes two decision trees for helping faculty determine whether publishing with undergraduates represents a reasonable and att... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2943824 Fri, 30 Oct 2009 16:34:19 +0100 2943824 http://www.medworm.com/index.php?rid=2917006&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%3D19843954%26dopt%3DAbstract Authors: Gough NR This week Science and Science Signaling turn the spotlight on neuroscience, with Science highlighting how advances in methodology are providing insight into the organization and regulation of neural circuits and the behavior of neurons. Science Signaling features unexpected connections between signaling processes and diseases affecting the brain. PMID: 19843954 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2917006 Fri, 23 Oct 2009 07:10:02 +0100 2917006 http://www.medworm.com/index.php?rid=2917005&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%3D19843955%26dopt%3DAbstract Authors: Gujral TS, Macbeath G Recording the state and dynamics of intracellular signaling networks in clinical specimens can help identify and validate biomarkers, but may also prove useful in developing and monitoring targeted therapies. Studying cell signaling on a system-wide level in solid tissue, however, is often not feasible using mass spectrometry, because this technique generally requires relatively large sample quantities. A number of promising miniaturized proteomic technologies have emerged, which circumvent these limitations and offer the ability to monitor protein abundances and posttranslational modification states in a multiplexed and quantitative fashion. These technologies have the potential to accelerate molecular diagnostics and therapeutics, and may ultimately fac... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2917005 Fri, 23 Oct 2009 07:10:02 +0100 2917005 http://www.medworm.com/index.php?rid=2917004&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%3D19843956%26dopt%3DAbstract Authors: Ryder PV, Faundez V Genome-wide association studies have identified multiple genetic polymorphisms associated with schizophrenia. These polymorphisms conform to a polygenic disease model in which multiple alleles cumulatively increase the risk of developing disease. Two genes linked to schizophrenia, DTNBP1 and MUTED, encode proteins that belong to the endosome-localized Biogenesis of Lysosome-related Organelles Complex-1 (BLOC-1). BLOC-1 plays a key role in endosomal trafficking and as such has been found to regulate cell-surface abundance of the D2 dopamine receptor, the biogenesis and fusion of synaptic vesicles, and neurite outgrowth. These functions are pertinent to both neurodevelopment and synaptic transmission, processes tightly regulated by selective cell-surface deli... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2917004 Fri, 23 Oct 2009 07:10:02 +0100 2917004 http://www.medworm.com/index.php?rid=2917003&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%3D19843957%26dopt%3DAbstract Authors: Lee TK, Denny EM, Sanghvi JC, Gaston JE, Maynard ND, Hughey JJ, Covert MW Nearly identical cells can exhibit substantially different responses to the same stimulus. We monitored the nuclear localization dynamics of nuclear factor kappaB (NF-kappaB) in single cells stimulated with tumor necrosis factor-alpha (TNF-alpha) and lipopolysaccharide (LPS). Cells stimulated with TNF-alpha have quantitative differences in NF-kappaB nuclear localization, whereas LPS-stimulated cells can be clustered into transient or persistent responders, representing two qualitatively different groups based on the NF-kappaB response. These distinct behaviors can be linked to a secondary paracrine signal secreted at low concentrations, such that not all cells undergo a second round of NF-kappaB activati... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2917003 Fri, 23 Oct 2009 07:10:02 +0100 2917003 http://www.medworm.com/index.php?rid=2917002&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%3D19843958%26dopt%3DAbstract Authors: Yamazaki K, Gohda J, Kanayama A, Miyamoto Y, Sakurai H, Yamamoto M, Akira S, Hayashi H, Su B, Inoue J The cytokine interleukin-1 (IL-1) mediates immune and inflammatory responses by activating the transcription factor nuclear factor kappaB (NF-kappaB). Although transforming growth factor-beta-activated kinase 1 (TAK1) and mitogen-activated protein kinase (MAPK) kinase kinase 3 (MEKK3) are both crucial for IL-1-dependent activation of NF-kappaB, their potential functional and physical interactions remain unclear. Here, we showed that TAK1-mediated activation of NF-kappaB required the transient formation of a signaling complex that included tumor necrosis factor receptor-associated factor 6 (TRAF6), MEKK3, and TAK1. Site-specific, lysine 63-linked polyubiquitination of TAK1 at l... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2917002 Fri, 23 Oct 2009 07:10:02 +0100 2917002 http://www.medworm.com/index.php?rid=2917001&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%3D19843959%26dopt%3DAbstract Authors: Berna-Erro A, Braun A, Kraft R, Kleinschnitz C, Schuhmann MK, Stegner D, Wultsch T, Eilers J, Meuth SG, Stoll G, Nieswandt B Excessive cytosolic calcium ion (Ca(2+)) accumulation during cerebral ischemia triggers neuronal cell death, but the underlying mechanisms are poorly understood. Capacitive Ca(2+) entry (CCE) is a process whereby depletion of intracellular Ca(2+) stores causes the activation of plasma membrane Ca(2+) channels. In nonexcitable cells, CCE is controlled by the endoplasmic reticulum (ER)-resident Ca(2+) sensor STIM1, whereas the closely related protein STIM2 has been proposed to regulate basal cytosolic and ER Ca(2+) concentrations and make only a minor contribution to CCE. Here, we show that STIM2, but not STIM1, is essential for CCE and ischemia-induced cy... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2917001 Fri, 23 Oct 2009 07:10:02 +0100 2917001 http://www.medworm.com/index.php?rid=2917000&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%3D19843960%26dopt%3DAbstract Authors: Thathiah A, De Strooper B The beta-amyloid (Abeta) peptide is associated with the pathogenesis of Alzheimer's disease (AD). Evidence gathered over the last two decades suggests that the gradual accumulation of soluble and insoluble Abeta peptide species triggers a cascade of events that leads to the clinical manifestation of AD. Abeta accumulation has also been associated with the cholinergic dysfunction observed in AD, which is characterized by diminished acetylcholine release and impaired coupling of the muscarinic acetylcholine receptors (mAChRs) to heterotrimeric GTP-binding proteins (G proteins). Although the mechanism of Abeta-mediated toxicity is not clearly understood, evidence shows that Abeta accumulation has an effect on the oligomerization of the angiotensin II (An... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2917000 Fri, 23 Oct 2009 07:10:02 +0100 2917000 http://www.medworm.com/index.php?rid=2895162&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%3D19825825%26dopt%3DAbstract Authors: Meyn MA, Vanhook AM This is a conversation with Malcolm Meyn about a Research Article published in the 13 October 2009 issue of Science Signaling. PMID: 19825825 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2895162 Thu, 15 Oct 2009 21:34:04 +0100 2895162 http://www.medworm.com/index.php?rid=2895161&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%3D19825826%26dopt%3DAbstract Authors: Levin SD Engagement of the interleukin-17 (IL-17) receptor complex triggers activation of the transcription factor nuclear factor kappaB (NF-kappaB). A wide array of signaling molecules can contribute to the activation of NF-kappaB, but a number of common themes link the receptors engaged to activate it with the translocation of the active complex to the nucleus; among these is a clear role for ubiquitination. Ubiquitination is essential to the degradation of the inhibitor of NF-kappaB (IkappaB) subunits, which otherwise retain the inactive NF-kappaB complex in the cytosol. However, additional roles for ubiquitination in the assembly of signaling complexes and in enzyme activation are underappreciated aspects of NF-kappaB induction pathways. These roles require a form of ubiqu... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2895161 Thu, 15 Oct 2009 21:34:04 +0100 2895161 http://www.medworm.com/index.php?rid=2895160&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%3D19825827%26dopt%3DAbstract Authors: Iliopoulos D, Polytarchou C, Hatziapostolou M, Kottakis F, Maroulakou IG, Struhl K, Tsichlis PN Although Akt is known to play a role in human cancer, the relative contribution of its three isoforms to oncogenesis remains to be determined. We expressed each isoform individually in an Akt1(-/-)/Akt2(-/-)/Akt3(-/-) cell line. MicroRNA profiling of growth factor-stimulated cells revealed unique microRNA signatures for cells with each isoform. Among the differentially regulated microRNAs, the abundance of the miR-200 family was decreased in cells bearing Akt2. Knockdown of Akt1 in transforming growth factor-beta (TGFbeta)-treated MCF10A cells also decreased the abundance of miR-200; however, knockdown of Akt2, or of both Akt1 and Akt2, did not. Furthermore, Akt1 knockdown in MCF10A... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2895160 Thu, 15 Oct 2009 21:34:04 +0100 2895160 http://www.medworm.com/index.php?rid=2895159&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%3D19825828%26dopt%3DAbstract Authors: Liu C, Qian W, Qian Y, Giltiay NV, Lu Y, Swaidani S, Misra S, Deng L, Chen ZJ, Li X Interleukin-17 (IL-17), a proinflammatory cytokine mainly produced by cells of the T helper 17 (T(H)17) lineage, is required for host defense against bacterial and fungal infections and plays a critical role in the pathogenesis of inflammatory and autoimmune diseases. Act1 is an essential adaptor molecule in IL-17-mediated signaling and is recruited to the IL-17 receptor (IL-17R) upon IL-17 stimulation through an interaction between its SEFIR domain and that of the IL-17R. Here, we report that Act1 is a U-box E3 ubiquitin ligase and that its activity is essential for IL-17-mediated signaling pathways. Through the use of the Ubc13-Uev1A E2 complex, Act1 mediated the lysine-63-linked ubiquitinati... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2895159 Thu, 15 Oct 2009 21:34:04 +0100 2895159 http://www.medworm.com/index.php?rid=2895158&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%3D19825829%26dopt%3DAbstract Authors: Meyn MA, Smithgall TE Multiple Src family kinases (SFKs) are present in murine embryonic stem (mES) cells. Whereas complete inhibition of SFK activity blocks mES cell differentiation, sole inhibition of the SFK member c-Yes induces differentiation. Thus, individual SFKs may have opposing roles in the regulation of mES cell fate. To test this possibility, we generated SFK mutants with engineered resistance to a nonselective SFK inhibitor. The presence of an inhibitor-resistant c-Src mutant, but not analogous mutants of Hck, Lck, c-Yes, or Fyn, reversed the differentiation block associated with inhibitor treatment, resulting in the formation of cells with properties of primitive ectoderm. These results show that distinct SFK signaling pathways regulate mES cell fate and demonstr... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2895158 Thu, 15 Oct 2009 21:34:04 +0100 2895158 http://www.medworm.com/index.php?rid=2877135&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%3D19809088%26dopt%3DAbstract Authors: Adrain C, Martin SJ Apoptosis is a controlled form of cellular demolition, catalyzed by a family of cysteine proteases called caspases. In response to diverse proapoptotic stimuli, caspase-9 is recruited and activated within an oligomeric complex called the apoptosome. The apoptosome drives autocatalytic processing of caspase-9, triggering a proteolytic caspase cascade that results in the biochemical and morphological changes characteristic of cell death. It is unclear why caspase-9 undergoes autocatalytic processing following apoptosome recruitment, because interdomain processing is dispensable for caspase-9 activity. A study has shed light on this issue by demonstrating that caspase-9 processing within the apoptosome promotes its displacement from the complex, leading to ina... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2877135 Sat, 10 Oct 2009 09:04:02 +0100 2877135 http://www.medworm.com/index.php?rid=2877134&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%3D19809089%26dopt%3DAbstract Authors: Rittinger K Small guanosine triphosphatases (GTPases) regulate a vast array of cellular functions. Their highly controlled activation, which is catalyzed by guanine nucleotide exchange factors (GEFs), links input signals emanating from various events such as stimulation of cell surface receptors to a similarly diverse range of downstream responses. Due to the central role of GEFs in the regulation of GTPase-mediated signaling processes, their mode of action has been intensively investigated. A new structural study on the DOCK family of Rho family-specific GEFs now uncovers an unusual variation in the way in which GEFs can regulate the nucleotide status of GTPases and provides the most complete picture of a GDP-GTP exchange cycle to date. PMID: 19809089 [PubMed - in process... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2877134 Sat, 10 Oct 2009 09:04:02 +0100 2877134 http://www.medworm.com/index.php?rid=2877133&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%3D19809090%26dopt%3DAbstract Authors: Baena-Lopez LA, Franch-Marro X, Vincent JP Morphogens form concentration gradients that organize patterns of cells and control growth. It has been suggested that, rather than the intensity of morphogen signaling, it is its gradation that is the relevant modulator of cell proliferation. According to this view, the ability of morphogens to regulate growth during development depends on their graded distributions. Here, we describe an experimental test of this model for Wingless, one of the key organizers of wing development in Drosophila. Maximal Wingless signaling suppresses cellular proliferation. In contrast, we found that moderate and uniform amounts of exogenous Wingless, even in the absence of endogenous Wingless, stimulated proliferative growth. Beyond a few cell diameters... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2877133 Sat, 10 Oct 2009 09:04:02 +0100 2877133 http://www.medworm.com/index.php?rid=2877132&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%3D19809091%26dopt%3DAbstract Authors: Lee KW, Chen PW, Lu CA, Chen S, Ho TH, Yu SM Flooding is a widespread natural disaster that leads to oxygen (O(2)) and energy deficiency in terrestrial plants, thereby reducing their productivity. Rice is unusually tolerant to flooding, but the underlying mechanism for this tolerance has remained elusive. Here, we show that protein kinase CIPK15 [calcineurin B-like (CBL)-interacting protein kinase] plays a key role in O(2)-deficiency tolerance in rice. CIPK15 regulates the plant global energy and stress sensor SnRK1A (Snf1-related protein kinase 1) and links O(2)-deficiency signals to the SnRK1-dependent sugar-sensing cascade to regulate sugar and energy production and to enable rice growth under floodwater. Our studies contribute to understanding how rice grows under the cond... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2877132 Sat, 10 Oct 2009 09:04:02 +0100 2877132 http://www.medworm.com/index.php?rid=2858106&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%3D19797265%26dopt%3DAbstract Authors: Gough NR Reduction-oxidation reactions produce reactive species that regulate cellular behavior, predominantly by posttranslationally modifying cysteine residues on target proteins. Research Articles, as well as a Perspective and Review in this issue, provide insight into the pathological potential of reactive oxygen species (ROS), as well as the important physiological signals that the reactive molecules transmit and the biological processes that they regulate. PMID: 19797265 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2858106 Sun, 04 Oct 2009 15:52:02 +0100 2858106 http://www.medworm.com/index.php?rid=2858105&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%3D19797266%26dopt%3DAbstract Authors: Wong HL, Shimamoto K Plants have to contend with biotic stress, such as disease, mechanical wounding, and herbivory, as well as abiotic stress, such as heat, cold, and salinity. An early warning system for these threats would prevent or reduce the damage suffered by plants. Such a warning system should allow the signal to be rapidly generated and sent over long distances. The study of systemic signaling in plants has been a major scientific challenge. Reactive oxygen species (ROS) are among the systemic signals that have been proposed. Now, the exciting discovery that systemic ROS signaling is mediated by an NADPH (nicotinamide adenine dinucleotide phosphate, reduced form) oxidase opens the door to understanding the molecular mechanisms that initiate and propagate a rapid syst... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2858105 Sun, 04 Oct 2009 15:52:02 +0100 2858105 http://www.medworm.com/index.php?rid=2858104&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%3D19797267%26dopt%3DAbstract Authors: Reich NC Tyrosine phosphorylation of signal transducers and activators of transcription (STATs) promotes their dimerization and ability to bind target genes in the nucleus. However, evidence shows that one member of the STAT family, STAT3, has an additional property independent of its classical role in the nucleus. STAT3 modifed by serine phosphorylation augmented oxidative phosphorylation in mitochondria and supported cellular transformation by oncogenic Ras. PMID: 19797267 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2858104 Sun, 04 Oct 2009 15:52:02 +0100 2858104 http://www.medworm.com/index.php?rid=2858103&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%3D19797268%26dopt%3DAbstract We report that, in addition to SHP-1, the PTPs PTP1B and TCPTP are activated and posttranslationally modified in infected macrophages, and we identify an essential role for PTP1B in the in vivo progression of Leishmania infection. The mechanism underlying PTP modulation involves the proteolytic activity of the Leishmania surface protease GP63. Access of GP63 to macrophage PTP1B, TCPTP, and SHP-1 is mediated in part by a lipid raft-dependent mechanism, resulting in PTP cleavage and stimulation of phosphatase activity. Collectively, our data present a mechanism of cleavage-dependent activation of macrophage PTPs by an obligate intracellular pathogen and show that internalization of GP63, a key Leishmania virulence factor, into host macrophages is a strategy the parasite uses to interact and ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2858103 Sun, 04 Oct 2009 15:52:02 +0100 2858103 http://www.medworm.com/index.php?rid=2858102&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%3D19797269%26dopt%3DAbstract Authors: Ikeda M, Kawata A, Nishikawa M, Tateishi Y, Yamaguchi M, Nakagawa K, Hirabayashi S, Bao Y, Hidaka S, Hirata Y, Hata Y The Hippo pathway restricts cell growth and proliferation and promotes apoptosis to control organ size. The Drosophila melanogaster isoform of RASSF (Ras association domain family; dRASSF) antagonizes proapoptotic Hippo signaling by inhibiting the binding of the adaptor protein Salvador to the kinase Hippo. Paradoxically, however, dRASSF also functions as a tumor suppressor. In mammals, RASSF1A induces apoptosis by stimulating the mammalian Ste20-like kinases (MSTs) 1 and 2, which are Hippo homologs. Here, we characterize the interaction between MST2 and another mammalian RASSF isoform, RASSF6. When bound to MST2, RASSF6 inhibited MST2 activity to antagonize Hi... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2858102 Sun, 04 Oct 2009 15:52:02 +0100 2858102 http://www.medworm.com/index.php?rid=2858101&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%3D19797270%26dopt%3DAbstract Authors: Rudolph TK, Freeman BA Over the last 50 years, the posttranslational modification (PTM) of proteins has emerged as a central mechanism for cells to regulate metabolism, growth, differentiation, cell-cell interactions, and immune responses. By influencing protein structure and function, PTM leads to a multiplication of proteome diversity. Redox-dependent PTMs, mediated by environmental and endogenously generated reactive species, induce cell signaling responses and can have toxic effects in organisms. PTMs induced by the electrophilic by-products of redox reactions most frequently occur at protein thiols; other nucleophilic amino acids serve as less favorable targets. Advances in mass spectrometry and affinity-chemistry strategies have improved the detection of electrophile-ind... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2858101 Sun, 04 Oct 2009 15:52:02 +0100 2858101 http://www.medworm.com/index.php?rid=2858100&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%3D19797271%26dopt%3DAbstract Authors: Danen EH Integrin transmembrane receptors orchestrate signaling cascades by recruiting cytoskeletal linker proteins and enzymes to sites of cell adhesion. A proteomics-based view of such integrin-associated signaling networks is now available. Besides the usual suspects, the interactomes contain several proteins that were not previously connected to integrins. One of these, regulator of chromosome condensation-2 (RCC2), represents an unexpected molecular connection between integrins and the cell-migration machinery. PMID: 19797271 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2858100 Sun, 04 Oct 2009 15:52:02 +0100 2858100 http://www.medworm.com/index.php?rid=2858099&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%3D19797272%26dopt%3DAbstract Authors: Stahl PD, Wainszelbaum MJ The identification and characterization of human-specific genes and the cellular processes that the encoded proteins control have the potential to help us understand at the molecular level what makes humans different from other species. The sequencing of the human genome and the genomes of closely related primates has revealed the presence of a small number of human- or human-lineage-specific genes that have no orthologs in lower species. Human-specific and human-lineage-specific genes are likely to function as regulators of cell signaling events, and by fine-tuning pathways, the encoded proteins may contribute to human-specific characteristics and behaviors. In addition, human-specific genes may represent biomarkers for examining human-specific chara... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2858099 Sun, 04 Oct 2009 15:52:02 +0100 2858099 http://www.medworm.com/index.php?rid=2858098&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%3D19797273%26dopt%3DAbstract Authors: Finger C, Escher C, Schneider D Transmembrane signaling by receptor tyrosine kinases typically involves a dynamic receptor monomer-dimer equilibrium in which ligand binding to soluble extracellular domains triggers receptor dimerization and subsequent signaling events. Although the role in signal transduction of the single transmembrane helices of individual receptors, which connect the extracellular with the intracellular protein domains, is not understood in detail, we show here that the single transmembrane domains of all 58 human receptor tyrosine kinases alone have an intrinsic propensity to form stable dimeric structures within a membrane. Thus, defined interactions of the transmembrane domains are most likely generally involved in signaling by all human receptor tyrosin... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2858098 Sun, 04 Oct 2009 15:52:02 +0100 2858098 http://www.medworm.com/index.php?rid=2858097&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%3D19797274%26dopt%3DAbstract Authors: Llanos S, Cuadrado A, Serrano M Mitogen- and stress-activated kinase 2 (MSK2) inhibits the transcription factor p53, and we investigate here the mechanisms underlying this inhibition. In the absence of stress stimuli, MSK2 selectively suppressed the expression of a subset of p53 target genes. This basal inhibition of p53 by MSK2 occurred independently of its kinase activity and of upstream mitogen-activated protein kinase signaling to MSK2. Furthermore, MSK2 interacted with and inhibited the p53 coactivator p300 and associated with the Noxa promoter. Apoptotic stimuli promoted the degradation of MSK2, thus relieving its inhibition of p53 and enabling efficient p53-dependent transactivation of Noxa, which contributed to apoptosis. Together, these findings constitute a new mecha... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2858097 Sun, 04 Oct 2009 15:52:02 +0100 2858097 http://www.medworm.com/index.php?rid=2804719&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%3D19755707%26dopt%3DAbstract Authors: Weaver AM Reactive oxygen species (ROS) are increasingly recognized as important signaling regulators. The family of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox's) is responsible for the production of most signaling ROS in cells. An emerging paradigm is that individual Nox family members are organized and activated at distinct subcellular locations for specific functions. Tyrosine kinase substrate (Tks) family adaptor proteins have now been identified as Nox organizer proteins that enhance the production of ROS at invadopodia and podosomes, which are subcellular adhesion structures associated with extracellular matrix degradation. ROS production is also shown to be required for invadopodia and podosome formation. These findings broaden... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2804719 Fri, 18 Sep 2009 02:28:05 +0100 2804719 http://www.medworm.com/index.php?rid=2804718&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%3D19755708%26dopt%3DAbstract Authors: Christie MJ, Mallet C Endocannabinoids produced in the spinal cord can enhance pain by dampening the synapses of inhibitory interneurons that usually prevent the perception of innocuous stimuli as painful. This mechanism promotes pain responsiveness to normally innocuous mechanical stimuli in the skin surrounding a site of injury in both animals and humans subjected to sustained stimulation of pain-sensing nerves. The pain-promoting action of endocannabinoids wanes during the development of chronic pain that is induced by inflammation or nerve injury. This finding may partially explain why, in human trials, cannabinoid drugs have been negative for treatment of most types of acute and postsurgical pain but are effective for some chronic pain states. PMID: 19755708 [PubMed -... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2804718 Fri, 18 Sep 2009 02:28:05 +0100 2804718 http://www.medworm.com/index.php?rid=2804717&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%3D19755709%26dopt%3DAbstract Authors: Diaz B, Shani G, Pass I, Anderson D, Quintavalle M, Courtneidge SA Invadopodia are actin-rich membrane protrusions of cancer cells that facilitate pericellular proteolysis and invasive behavior. We show here that reactive oxygen species (ROS) generated by the NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase (Nox) system are necessary for invadopodia formation and function. Knockdown of the invadopodia protein Tks5 [tyrosine kinase substrate with five Src homology 3 (SH3) domains], which is structurally related to the Nox component p47(phox), reduces total ROS abundance in cancer cells. Furthermore, Tks5 and p22(phox) can associate with each other, suggesting that Tks5 is part of the Nox complex. Tyrosine phosphorylation of Tks5 and Tks4, but not othe... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2804717 Fri, 18 Sep 2009 02:28:05 +0100 2804717 http://www.medworm.com/index.php?rid=2804716&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%3D19755710%26dopt%3DAbstract Authors: Gianni D, Diaz B, Taulet N, Fowler B, Courtneidge SA, Bokoch GM The mechanisms that determine localized formation of reactive oxygen species (ROS) through NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase (Nox) family members in nonphagocytic cells are unknown. We show that the c-Src substrate proteins Tks4 (tyrosine kinase substrate with four SH3 domains) and Tks5 are functional members of a p47(phox)-related organizer superfamily. Tks proteins selectively support Nox1 and Nox3 (and not Nox2 and Nox4) activity in reconstituted cellular systems and interact with the NoxA1 activator protein through an Src homology 3 domain-mediated interaction. Endogenous Tks4 is required for Rac guanosine triphosphatase- and Nox1-dependent ROS production by DLD1 colon... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2804716 Fri, 18 Sep 2009 02:28:05 +0100 2804716 http://www.medworm.com/index.php?rid=2804715&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%3D19755711%26dopt%3DAbstract Authors: Makarenkova HP, Hoffman MP, Beenken A, Eliseenkova AV, Meech R, Tsau C, Patel VN, Lang RA, Mohammadi M The developmental activities of morphogens depend on the gradients that they form in the extracellular matrix. Here, we show that differences in the binding of fibroblast growth factor 7 (FGF7) and FGF10 to heparan sulfate (HS) underlie the formation of different gradients that dictate distinct activities during branching morphogenesis. Reducing the binding affinity of FGF10 for HS by mutating a single residue in its HS-binding pocket converted FGF10 into a functional mimic of FGF7 with respect to gradient formation and regulation of branching morphogenesis. In particular, the mutant form of FGF10 caused lacrimal and salivary gland epithelium buds to branch rather than to elo... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2804715 Fri, 18 Sep 2009 02:28:05 +0100 2804715 http://www.medworm.com/index.php?rid=2781655&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%3D19738199%26dopt%3DAbstract Authors: Sidhu SS, Vanhook AM This is a conversation with Sachdev Sidhu about a Research Article published in the 8 September 2009 issue of Science Signaling. PMID: 19738199 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2781655 Thu, 10 Sep 2009 18:04:02 +0100 2781655 http://www.medworm.com/index.php?rid=2781654&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%3D19738200%26dopt%3DAbstract Authors: Ernst A, Sazinsky SL, Hui S, Currell B, Dharsee M, Seshagiri S, Bader GD, Sidhu SS Multicellular organisms rely on complex, fine-tuned protein networks to respond to environmental changes. We used in vitro evolution to explore the role of domain mutation and expansion in the evolution of network complexity. Using random mutagenesis to facilitate family expansion, we asked how versatile and robust the binding site must be to produce the rich functional diversity of the natural PDZ domain family. From a combinatorial protein library, we analyzed several hundred structured domain variants and found that one-quarter were functional for carboxyl-terminal ligand recognition and that our variant repertoire was as specific and diverse as the natural family. Our results show that ligan... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2781654 Thu, 10 Sep 2009 18:04:02 +0100 2781654 http://www.medworm.com/index.php?rid=2781653&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%3D19738201%26dopt%3DAbstract Authors: Humphries JD, Byron A, Bass MD, Craig SE, Pinney JW, Knight D, Humphries MJ The binding of integrin adhesion receptors to their extracellular matrix ligands controls cell morphology, movement, survival, and differentiation in various developmental, homeostatic, and disease processes. Here, we report a methodology to isolate complexes associated with integrin adhesion receptors, which, like other receptor-associated signaling complexes, have been refractory to proteomic analysis. Quantitative, comparative analyses of the proteomes of two receptor-ligand pairs, alpha(4)beta(1)-vascular cell adhesion molecule-1 and alpha(5)beta(1)-fibronectin, defined both core and receptor-specific components. Regulator of chromosome condensation-2 (RCC2) was detected in the alpha(5)beta(1)-fibr... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2781653 Thu, 10 Sep 2009 18:04:02 +0100 2781653 http://www.medworm.com/index.php?rid=2781651&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%3D19738202%26dopt%3DAbstract Authors: Itoh T, Hasegawa J, Tsujita K, Kanaho Y, Takenawa T Phosphatidic acid (PA), which can be produced by phospholipase D (PLD), is involved in various signaling events, such as cell proliferation, survival, and migration. However, the molecular mechanisms that link PA to cell migration are largely unknown. Here, we show that PA binds to the tyrosine kinase Fer and enhances its ability to phosphorylate cortactin, a protein that promotes actin polymerization. We found that a previously unknown lipid-binding module in Fer adjacent to the F-BAR [Fes-Cdc42-interacting protein 4 (CIP4) homology (FCH) and bin-amphiphysin-Rvs] domain mediated PA binding. We refer to this lipid-binding domain as the FX (F-BAR extension) domain. Overexpression of Fer enhanced lamellipodia formation and cell... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2781651 Thu, 10 Sep 2009 18:04:02 +0100 2781651 http://www.medworm.com/index.php?rid=2781650&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%3D19738203%26dopt%3DAbstract Authors: Huang PH, Xu AM, White FM The epidermal growth factor receptor (EGFR) is a primary contributor to glioblastoma (GBM) initiation and progression. Here, we examine how EGFR and key downstream signaling networks contribute to the hallmark characteristics of GBM such as rapid cancer cell proliferation and diffused invasion. Additionally, we discuss current therapeutic options for GBM patients and elaborate on the mechanisms through which EGFR promotes chemoresistance. We conclude by offering a perspective on how the potential of integrative systems biology may be harnessed to develop safe and effective treatment strategies for this disease. PMID: 19738203 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2781650 Thu, 10 Sep 2009 18:04:02 +0100 2781650 http://www.medworm.com/index.php?rid=2766808&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%3D19724060%26dopt%3DAbstract Authors: Shaw RJ The LKB1 serine-threonine kinase is a tumor suppressor that is inactivated in a large number of sporadic human lung non-small cell carcinomas (NSCLCs) and cervical cancers. Genetic deletion of LKB1 in various mouse tissues results in tumorigenesis, and loss of LKB1 increases metastasis in a mouse model of NSCLC. LKB1 directly activates a family of 14 kinases related to AMPK [adenosine monophosphate (AMP)-activated protein kinase] to control cell metabolism, growth, and polarity, though which of these are critical to its tumor suppressor functions remain undefined. The LKB1-dependent kinase SIK1 (salt-inducible kinase 1) has now been identified as a key modulator of anoikis (apoptosis induced by cell detachment) and transformation in culture, and its modulation of the t... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2766808 Sat, 05 Sep 2009 05:50:02 +0100 2766808 http://www.medworm.com/index.php?rid=2766807&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%3D19724061%26dopt%3DAbstract Authors: Firaguay G, Nunès JA Many proteins involved in cell signaling are phosphorylated. To determine the phosphorylation status of these signaling molecules at the single-cell level, we present a protocol for using state-specific antibodies to detect target phosphoproteins with fluorescence measurements by flow cytometry. To improve the signal intensity, a sandwich-labeling method for the analysis of signaling proteins is performed. By comparing the phosphorylation state of proteins in the presence and absence of sodium pervanadate, a nonspecific tyrosine phosphatase inhibitor, we determined the relative amount of tyrosine-phosphorylated protein in the samples, which reflects the activity of the signaling pathway. This dynamic approach, in combination with the signal amplificat... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2766807 Sat, 05 Sep 2009 05:50:02 +0100 2766807 http://www.medworm.com/index.php?rid=2766806&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%3D19724062%26dopt%3DAbstract Authors: Jerde TJ, Bushman W Chronic inflammation and reactivation of developmental signaling pathways are both hallmarks of adenocarcinomas. However, developmental and inflammatory processes are generally thought of as distinct and are believed to represent separate paths to carcinogenesis. Here, we show that the inflammatory cytokine interleukin-1alpha (IL-1alpha) plays a critical role in prostate development by activating insulin-like growth factor (IGF) signaling; this process is reiterated during inflammatory reactive hyperplasia to elicit epithelial proliferation. The appearance of developmental signals during hyperplasia supports the hypothesis that reactivation of developmental signaling plays a role in the hyperplasic reaction to inflammation and suggests that there may be a c... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2766806 Sat, 05 Sep 2009 05:50:02 +0100 2766806 http://www.medworm.com/index.php?rid=2766805&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%3D19724063%26dopt%3DAbstract Authors: Prager EM, Johnson LR As the key neuron-to-neuron interface, the synapse is involved in learning and memory, including traumatic memories during times of stress. However, the signal transduction mechanisms by which stress mediates its lasting effects on synapse transmission and on memory are not fully understood. A key component of the stress response is the increased secretion of adrenal steroids. Adrenal steroids (e.g., cortisol) bind to genomic mineralocorticoid and glucocorticoid receptors (gMRs and gGRs) in the cytosol. In addition, they may act through membrane receptors (mMRs and mGRs), and signal transduction through these receptors may allow for rapid modulation of synaptic transmission as well as modulation of membrane ion currents. mMRs increase synaptic and neurona... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2766805 Sat, 05 Sep 2009 05:50:02 +0100 2766805 http://www.medworm.com/index.php?rid=2741949&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%3D19706869%26dopt%3DAbstract Authors: Yaffe MB PMID: 19706869 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2741949 Fri, 28 Aug 2009 21:34:03 +0100 2741949 http://www.medworm.com/index.php?rid=2741948&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%3D19706870%26dopt%3DAbstract Authors: Mikkola ML The organization and renewal capacity of teeth vary greatly among vertebrates. Mammals have only one row of teeth that are renewed at most once, whereas many nonmammalian species have multirowed dentitions and show remarkable capacity to replace their teeth throughout life. Although knowledge on the genetic basis of tooth morphogenesis has increased exponentially over the past 20 years, little is known about the molecular mechanisms controlling sequential initiation of multiple tooth rows or restricting tooth development to one row in mammals. Mouse genetics has revealed a pivotal role for the transcription factor Osr2 in this process. Loss of Osr2 caused expansion of the expression domain of Bmp4, a well-known activator of tooth development, leading to the inductio... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2741948 Fri, 28 Aug 2009 21:34:03 +0100 2741948 http://www.medworm.com/index.php?rid=2741947&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%3D19706871%26dopt%3DAbstract Authors: Hinke SA Sulfonylurea drugs are used in type 2 diabetes mellitus therapy to induce release of endogenous insulin from pancreatic beta cells. They act on sulfonylurea receptors, which are the regulatory subunits of adenosine triphosphate (ATP)-sensitive potassium ion (K(ATP)) channels and cause channel closure to trigger exocytosis. Epac2 was identified as an intracellular target for sulfonylurea drugs, providing a potential nonelectrogenic signaling component to the mechanism of action for these agents. Commonly used sulfonylureas such as tolbutamide and glibenclamide induced Epac2 activation with distinct kinetic profiles. Epac2(-/-) mice failed to respond to sulfonylureas, suggesting that both sulfonylurea receptors and Epac2 are necessary for the action of these drugs. Thes... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2741947 Fri, 28 Aug 2009 21:34:03 +0100 2741947 http://www.medworm.com/index.php?rid=2741946&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%3D19706872%26dopt%3DAbstract Authors: Grillet N, Kazmierczak P, Xiong W, Schwander M, Reynolds A, Sakaguchi H, Tokita J, Kachar B, Müller U Mechanotransduction, the conversion of mechanical force into an electrochemical signal, allows living organisms to detect touch, hear, register movement and gravity, and sense changes in cell volume and shape. Hair cells in the vertebrate inner ear are mechanoreceptor cells specialized for the detection of sound and head movement. Each hair cell contains, at the apical surface, rows of stereocilia that are connected by extracellular filaments to form an exquisitely organized bundle. Mechanotransduction channels, localized near the tips of the stereocilia, are gated by the gating spring, an elastic element that is stretched upon stereocilia deflection and mediates rapid ch... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2741946 Fri, 28 Aug 2009 21:34:03 +0100 2741946 http://www.medworm.com/index.php?rid=2741945&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%3D19706873%26dopt%3DAbstract Authors: Ren D, Kim H, Tu HC, Westergard TD, Fisher JK, Rubens JA, Korsmeyer SJ, Hsieh JJ, Cheng EH The proapoptotic proteins BAX and BAK constitute the mitochondrial apoptotic gateway that executes cellular demise after integrating death signals. The lethal BAK is kept in check by voltage-dependent anion channel 2 (VDAC2), a mammalian-restricted VDAC isoform. Here, we provide evidence showing a critical role for the VADC2-BAK complex in determining thymocyte survival in vivo. Genetic depletion of Vdac2 in the thymus resulted in excessive cell death and hypersensitivity to diverse death stimuli including engagement of the T cell receptor. These phenotypes were completely rescued by the concurrent deletion of Bak but not that of Bax. Thus, the VDAC2-BAK axis provides a mechanism that go... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2741945 Fri, 28 Aug 2009 21:34:03 +0100 2741945 http://www.medworm.com/index.php?rid=2741944&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%3D19706874%26dopt%3DAbstract Authors: Gough NR Learning the peer-review process by trial and error may not be the most effective way to train the next generation of scientists in how to be effective reviewers. Here are some suggestions from an editor's perspective. PMID: 19706874 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2741944 Fri, 28 Aug 2009 21:34:03 +0100 2741944 http://www.medworm.com/index.php?rid=2720114&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%3D19690328%26dopt%3DAbstract Authors: Chan EY High nutrient availability stimulates the mammalian target of rapamycin complex 1 (mTORC1) to coordinately activate anabolic processes, such as protein synthesis, while inhibiting the cellular catabolism of autophagy. Positive regulation of protein synthesis through the mTORC1 substrates p70 ribosomal S6 kinase (p70S6K) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1) has been well characterized. The complementary inhibitory mechanism in which mTORC1 phosphorylates the autophagy regulatory complex containing unc-51-like kinase 1 (ULK1), the mammalian Atg13 protein, and focal adhesion kinase interacting protein of 200 kD (FIP200) has also been elucidated. PMID: 19690328 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2720114 Fri, 21 Aug 2009 13:18:11 +0100 2720114 http://www.medworm.com/index.php?rid=2720113&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%3D19690329%26dopt%3DAbstract Authors: Rougvie AE MicroRNAs (miRNAs) posttranscriptionally regulate gene expression, but the factors that direct transcription of miRNAs are not well characterized. Activation versus repression of key developmental miRNAs in Caenorhabditis elegans is directly mediated by ligand occupancy of a nuclear hormone receptor that acts to couple nutrient availability to developmental programs. PMID: 19690329 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2720113 Fri, 21 Aug 2009 13:18:11 +0100 2720113 http://www.medworm.com/index.php?rid=2720112&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%3D19690330%26dopt%3DAbstract Authors: Chen Z, Carracedo A, Lin HK, Koutcher JA, Behrendt N, Egia A, Alimonti A, Carver BS, Gerald W, Teruya-Feldstein J, Loda M, Pandolfi PP One reported function of the tumor suppressor p19(Arf) is to stabilize p53, providing a critical checkpoint in the response to oncogenic insults. Acute loss of Pten leads to an increase in the abundance of p19(Arf), p53, and p21 proteins as part of a fail-safe senescence response. Here, we report that loss of p19(Arf) in prostate epithelium does not accelerate-but rather partially inhibits-the prostate cancer phenotype of Pten-deficient mice. Moreover, cellular senescence and a further decrease in the number of pre-neoplastic glands were observed in prostates of the Pten-p19(Arf) double-mutant mice. In both prostate epithelium and primary mouse... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2720112 Fri, 21 Aug 2009 13:18:11 +0100 2720112 http://www.medworm.com/index.php?rid=2720111&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%3D19690331%26dopt%3DAbstract Authors: Miller G, Schlauch K, Tam R, Cortes D, Torres MA, Shulaev V, Dangl JL, Mittler R Cell-to-cell communication and long-distance signaling play a key role in the response of plants to pests, mechanical wounding, and extreme environmental conditions. Here, we report on a rapid systemic signal in Arabidopsis thaliana that traveled at a rate of 8.4 centimeters per minute and was dependent on the respiratory burst oxidase homolog D (RbohD) gene. Signal propagation was accompanied by the accumulation of reactive oxygen species (ROS) in the extracellular spaces between cells and was inhibited by the suppression of ROS accumulation at locations distant from the initiation site. The rapid systemic signal was triggered by wounding, heat, cold, high-intensity light, and salinity stresses. ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2720111 Fri, 21 Aug 2009 13:18:11 +0100 2720111 http://www.medworm.com/index.php?rid=2720110&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%3D19690332%26dopt%3DAbstract Authors: Mayya V, Lundgren DH, Hwang SI, Rezaul K, Wu L, Eng JK, Rodionov V, Han DK Protein phosphorylation events during T cell receptor (TCR) signaling control the formation of complexes among proteins proximal to the TCR, the activation of kinase cascades, and the activation of transcription factors; however, the mode and extent of the influence of phosphorylation in coordinating the diverse phenomena associated with T cell activation are unclear. Therefore, we used the human Jurkat T cell leukemia cell line as a model system and performed large-scale quantitative phosphoproteomic analyses of TCR signaling. We identified 10,665 unique phosphorylation sites, of which 696 showed TCR-responsive changes. In addition, we analyzed broad trends in phosphorylation data sets to uncover under... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2720110 Fri, 21 Aug 2009 13:18:11 +0100 2720110 http://www.medworm.com/index.php?rid=2720109&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%3D19690333%26dopt%3DAbstract Authors: Yasukawa K, Oshiumi H, Takeda M, Ishihara N, Yanagi Y, Seya T, Kawabata S, Koshiba T The innate immune response to viral infection involves the activation of multiple signaling steps that culminate in the production of type I interferons (IFNs). Mitochondrial antiviral signaling (MAVS), a mitochondrial outer membrane adaptor protein, plays an important role in this process. Here, we report that mitofusin 2 (Mfn2), a mediator of mitochondrial fusion, interacts with MAVS to modulate antiviral immunity. Overexpression of Mfn2 resulted in the inhibition of retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA-5), two cytosolic sensors of viral RNA, as well as of MAVS-mediated activation of the transcription factors interferon regulatory factor ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2720109 Fri, 21 Aug 2009 13:18:11 +0100 2720109 http://www.medworm.com/index.php?rid=2696601&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%3D19671926%26dopt%3DAbstract Authors: Arnold DB Neuronal proteins are transported to either the axon or dendrites through the action of kinesin motors; however, understanding of how cytoskeletal elements steer these cargo-motor complexes to one compartment or the other has remained elusive. Three recent developments-the discovery of an actin-based filter within the axon initial segment, the identification of the pivotal role played by myosin motors in dendritic targeting, and the determination of the properties of a kinesin motor that cause it to prefer axonal to dendritic microtubules-have now provided a structural framework for understanding polarized targeting in neurons. PMID: 19671926 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2696601 Fri, 14 Aug 2009 05:02:02 +0100 2696601 http://www.medworm.com/index.php?rid=2696600&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%3D19671927%26dopt%3DAbstract Authors: Huppert SS, Magnuson MA The differentiation of hepatic and pancreatic progenitor cells during embryogenesis is determined by inductive factors secreted by neighboring cells. These factors stimulate and repress the expression of key regulatory genes in progenitor cells, thereby establishing unique genetic programs that determine cell fate. The signaling network that controls liver and pancreas development is highly dynamic with respect to both concentration and timing of exposure to several key inductive factors. Not only do large changes occur within short time frames, multiple signaling pathways also converge on the same target genes. Given the intense effort under way to generate certain differentiated cell types from both embryonic and induced pluripotent stem cells, greate... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2696600 Fri, 14 Aug 2009 05:02:02 +0100 2696600 http://www.medworm.com/index.php?rid=2696599&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%3D19671928%26dopt%3DAbstract Authors: Fu Y, Ren M, Feng H, Chen L, Altun ZF, Rubin CS Ubiquitously expressed protein kinase D (PKD) isoforms are poised to disseminate signals carried by diacylglycerol (DAG). However, the in vivo regulation and functions of PKDs are poorly understood. We show that the Caenorhabditis elegans gene, dkf-2, encodes not just DKF-2A, but also a second previously unknown isoform, DKF-2B. Whereas DKF-2A is present mainly in intestine, we show that DKF-2B is found in neurons. Characterization of dkf-2 null mutants and transgenic animals expressing DKF-2B, DKF-2A, or both isoforms revealed that PKDs couple DAG signals to regulation of sodium ion (Na+)-induced learning. EGL-8 (a phospholipase Cbeta4 homolog) and TPA-1 (a protein kinase Cdelta homolog) are upstream regulators of DKF-2 isoforms... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2696599 Fri, 14 Aug 2009 05:02:02 +0100 2696599 http://www.medworm.com/index.php?rid=2696598&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%3D19671929%26dopt%3DAbstract Authors: Martínez-Martín N, Risueño RM, Morreale A, Zaldívar I, Fernández-Arenas E, Herranz F, Ortiz AR, Alarcón B The CD3epsilon subunit of the T cell receptor (TCR) complex undergoes a conformational change upon ligand binding that is thought to be important for the activation of T cells. To study this process, we built a molecular dynamics model of the transmission of the conformational change within the ectodomains of CD3. The model showed that the CD3 dimers underwent a stiffening effect that was funneled to the base of the CD3epsilon subunit. Mutation of two relevant amino acid residues blocked transmission of the conformational change and the differentiation and activation of T cells. Furthermore, this inhibition occurred even in the presence of exc... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2696598 Fri, 14 Aug 2009 05:02:02 +0100 2696598 http://www.medworm.com/index.php?rid=2674950&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%3D19654413%26dopt%3DAbstract Authors: Margolis RN, Moore DD, Willson TM, Guy RK The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) sponsored a workshop, "Chemical Approaches to Nuclear Receptors and Metabolism," in April 2009 to explore how chemical and molecular biology and physiology can be exploited to further our understanding of nuclear receptor structure, function, and role in disease. Signaling cascades involving nuclear receptors are more complex and interrelated than once thought. Nuclear receptors continue to be attractive targets for drug discovery. The overall goal of this workshop was to identify gaps in our understanding of the complexity of ligand activities and begin to address them by (i) increasing the collaboration of investigators from different disciplines, (ii) devel... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2674950 Thu, 06 Aug 2009 19:08:04 +0100 2674950 http://www.medworm.com/index.php?rid=2674949&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%3D19654414%26dopt%3DAbstract Authors: Bader JS The best-studied signaling pathways still hold secrets. Recent studies have now applied a new wave of technologies encompassing computational approaches and experimental techniques to the mitogen-activated protein kinase pathway in yeast and have provided new knowledge of pathway connections, components, and dynamics. The computational algorithms build on advances in network science motivated by studies of large-scale social and WWW networks. Experimental techniques permit exploration of the frequency-space response, describing biological signaling networks in the language of control theory. Together, these technologies are revealing the design choices made by evolution, and they provide a framework for building new biological circuits to order. PMID: 19654414 [Pu... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2674949 Thu, 06 Aug 2009 19:08:04 +0100 2674949 http://www.medworm.com/index.php?rid=2674948&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%3D19654415%26dopt%3DAbstract Authors: Schleicher M, Yu J, Murata T, Derakhshan B, Atochin D, Qian L, Kashiwagi S, Di Lorenzo A, Harrison KD, Huang PL, Sessa WC Akt1 is critical for many in vivo functions; however, the cell-specific substrates responsible remain to be defined. Here, we examine the importance of endothelial nitric oxide synthase (eNOS) as an Akt1 substrate by generating Akt1-deficient mice (Akt1(-/-) mice) carrying knock-in mutations (serine to aspartate or serine to alanine substitutions) of the critical Akt1 phosphorylation site on eNOS (serine 1176) that render the enzyme "constitutively active" or "less active." The eNOS mutations did not influence several phenotypes in Akt1(-/-) mice; however, the defective postnatal angiogenesis characteristic of Akt1(-/-) mice was rescued by crossing the Akt1... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2674948 Thu, 06 Aug 2009 19:08:04 +0100 2674948 http://www.medworm.com/index.php?rid=2658632&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%3D19638609%26dopt%3DAbstract Authors: Gough NR, Foley JF The biochemical processes that control the responses of cells to changes in their internal or external environments form a complex interconnected network. The molecules that participate in these processes are diverse and dynamic, and the networks themselves are affected by the flow of information through them. With this appreciation of the complexity in signaling networks, Science Signaling highlights computational and experimental approaches to understanding both the macroscopic cellular response and the microscopic signaling network and its constituents and dynamics. PMID: 19638609 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2658632 Sat, 01 Aug 2009 06:22:03 +0100 2658632 http://www.medworm.com/index.php?rid=2658631&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%3D19638611%26dopt%3DAbstract We describe recent advances in the analysis of modularity in biological networks, focusing on the increasing realization that a dynamic perspective is essential to grouping molecules into modules and determining their collective function. PMID: 19638611 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2658631 Sat, 01 Aug 2009 06:22:03 +0100 2658631 http://www.medworm.com/index.php?rid=2658630&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%3D19638612%26dopt%3DAbstract Authors: Flick K, Kaiser P Dynamic changes in the posttranslational modification of proteins govern most cellular signaling pathways. Work over the past decade has connected many of these processes with the covalent attachment of the small ubiquitin-like modifier (SUMO) protein to target proteins, but a global view of the dynamics of SUMOylation was missing. A system-level proteomics approach has now been used to describe quantitative changes in protein modification with the SUMO-2 paralog during the response to heat shock. The SUMOylation status of more than 700 proteins was monitored in HeLa cells during the induction of hyperthermic stress and the recovery period. A massive redistribution of SUMO-2 was observed that affected many biological pathways that are important for the heat s... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2658630 Sat, 01 Aug 2009 06:22:03 +0100 2658630 http://www.medworm.com/index.php?rid=2658629&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%3D19638613%26dopt%3DAbstract Authors: Hlavacek WS, Faeder JR Cell signaling systems respond to multiple inputs, such as ligands of cell-surface receptors; and produce multiple outputs, such as changes in gene expression and cellular activities, including motility, proliferation, and death. This "macroscopic" input-output behavior is generated by a web of molecular interactions that can be viewed as taking place at a lower, "microscopic" level. These interactions prominently involve posttranslational modification of proteins and the nucleation of protein complexes. Behaviors at both the micro- and macroscopic levels are complex and must be probed systematically and characterized quantitatively as a prelude to the development of a predictive understanding of a cell signaling system. We must also have a theoretical f... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2658629 Sat, 01 Aug 2009 06:22:03 +0100 2658629 http://www.medworm.com/index.php?rid=2658628&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%3D19638614%26dopt%3DAbstract Authors: Kobayashi T, Kageyama R Signaling through the transcription factor nuclear factor kappaB (NF-kappaB) regulates various physiological processes, including immune responses and inflammation. An analysis of NF-kappaB dynamics suggests that the oscillation frequency of NF-kappaB activation determines which downstream genes are expressed, enabling a single pathway to respond to diverse stimuli in distinct ways. PMID: 19638614 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2658628 Sat, 01 Aug 2009 06:22:03 +0100 2658628 http://www.medworm.com/index.php?rid=2658627&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%3D19638615%26dopt%3DAbstract Authors: Kiel C, Serrano L We generated 17 c-Raf (RAF proto-oncogene serine-threonine protein kinase) mutants with altered Ras-Raf association and dissociation rates to investigate the role of electrostatically driven Ras-Raf association rates on epidermal growth factor (EGF)-activated mitogen-activated protein kinase (MAPK) signal transduction. Some of these mutants had compensating changes in association and dissociation rates, enabling the effects of changes in association rate to be distinguished from those of changes in affinity. In rabbit kidney (RK13) cells, these mutants affected downstream signaling, with changes in Ras-c-Raf association rates having a greater effect on MAPK signaling than did similar changes in dissociation rates. Mutants with compensating decreases in both a... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2658627 Sat, 01 Aug 2009 06:22:03 +0100 2658627 http://www.medworm.com/index.php?rid=2658626&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%3D19638616%26dopt%3DAbstract Authors: Tan CS, Bodenmiller B, Pasculescu A, Jovanovic M, Hengartner MO, Jørgensen C, Bader GD, Aebersold R, Pawson T, Linding R Protein kinases enable cellular information processing. Although numerous human phosphorylation sites and their dynamics have been characterized, the evolutionary history and physiological importance of many signaling events remain unknown. Using target phosphoproteomes determined with a similar experimental and computational pipeline, we investigated the conservation of human phosphorylation events in distantly related model organisms (fly, worm, and yeast). With a sequence-alignment approach, we identified 479 phosphorylation events in 344 human proteins that appear to be positionally conserved over approximately 600 million years of evolution and hen... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2658626 Sat, 01 Aug 2009 06:22:03 +0100 2658626 http://www.medworm.com/index.php?rid=2658625&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%3D19638617%26dopt%3DAbstract We present a technique, based on the Steiner tree problem, that uses previously reported protein-protein and protein-DNA interactions to determine how these hits are organized into functionally coherent pathways, revealing many components of the cellular response that are not readily apparent in the original data. Applied simultaneously to phosphoproteomic and transcriptional data for the yeast pheromone response, it identifies changes in diverse cellular processes that extend far beyond the expected pathways. PMID: 19638617 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2658625 Sat, 01 Aug 2009 06:22:03 +0100 2658625 http://www.medworm.com/index.php?rid=2635009&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%3D19622828%26dopt%3DAbstract Authors: Wong W Neurodegenerative diseases exact a tremendous toll on afflicted individuals and their families. Understanding the underlying signaling cascades that are perturbed by or contribute to neurodegeneration may identify new therapeutic targets or improve current therapies. The pieces in this Focus Issue of Science Signaling discuss molecular mechanisms and signaling pathways implicated in the pathologies of Parkinson's, Alzheimer's, and Huntington's diseases. PMID: 19622828 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2635009 Fri, 24 Jul 2009 21:10:02 +0100 2635009 http://www.medworm.com/index.php?rid=2635008&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%3D19622830%26dopt%3DAbstract Authors: Klann E In a mouse model of Parkinson's disease, new evidence shows that l-DOPA, which is used to treat the symptoms of the disease but also causes dyskinesia, results in a persistent activation of the protein kinase mTOR (mammalian target of rapamycin) in a subset of striatal medium spiny neurons. Moreover, blockade of a specific type of mTOR signaling (mTORC1) prevents the development of dyskinesia, but not the antiakinetic benefits produced by l-DOPA. Thus, mTORC1 may be a viable therapeutic target for dyskinesia caused by l-DOPA treatment in patients with Parkinson's disease. PMID: 19622830 [PubMed - in process] (Source: Science Signaling) Science Signaling journals http://www.medworm.com/rss/comments.php?id=2635008 Fri, 24 Jul 2009 21:10:02 +0100 2635008 http://www.medworm.com/index.php?rid=2635007&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%3D19622831%26dopt%3DAbstract Authors: Badtke MP, Hammer ND, Chapman MR Amyloids have traditionally been associated with misfolded protein aggregates and debilitating neurodegenerative diseases. However, a growing number of functional amyloids have now been described that demonstrate that amyloid formation can be an integral part of normal cellular physiology. Functional amyloid production is highly regulated, and the resulting fibers serve a variety of roles for the cells that produce them. A new role for amyloid as storage reservoirs for peptide hormones within mammalian secretory granules has been discovered. More than 30 different peptide hormones have been found to form amyloids in vitro, and both rats and mice have been shown to store hormone amyloid deposits in secretory granules. Thus, the emerging evidence... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2635007 Fri, 24 Jul 2009 21:10:02 +0100 2635007 http://www.medworm.com/index.php?rid=2635006&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%3D19622832%26dopt%3DAbstract Authors: Cheng H, Liu P, Wang ZC, Zou L, Santiago S, Garbitt V, Gjoerup OV, Iglehart JD, Miron A, Richardson AL, Hahn WC, Zhao JJ Resistance to anoikis, the subtype of apoptosis triggered by lack of adhesion, contributes to malignant transformation and the development of metastasis. Although several lines of evidence suggest that p53 plays a critical role in anoikis, the pathway(s) that connect cell detachment to p53 remain undefined. Here, through the use of a kinome-wide loss-of-function screen, we identify the serine-threonine kinase SIK1 (salt-inducible kinase 1) as a regulator of p53-dependent anoikis. Inactivation of SIK1 compromised p53 function in anoikis and allowed cells to grow in an anchorage-independent manner. In vivo, SIK1 loss facilitated metastatic spread and survival ... Science Signaling journals http://www.medworm.com/rss/comments.php?id=2635006 Fri, 24 Jul 2009 21:10:02 +0100 2635006