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PKM2 Tyrosine Phosphorylation and Glutamine Metabolism Signal a Different View of the Warburg Effect.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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...
Source: Science Signaling - November 20, 2009 Category: Biomedical Science Authors: Dang CV Tags: Sci Signal Source Type: journals

Acetylation Goes Global: The Emergence of Acetylation Biology.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 qua...
Source: Science Signaling - November 20, 2009 Category: Biomedical Science Authors: Norris KL, Lee JY, Yao TP Tags: Sci Signal Source Type: journals

Tyrosine Phosphorylation Inhibits PKM2 to Promote the Warburg Effect and Tumor Growth.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 active, tetrameric PKM2 by disrupting binding of t...
Source: Science Signaling - November 20, 2009 Category: Biomedical Science 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 Tags: Sci Signal Source Type: journals

Trypanosoma cruzi Targets Akt in Host Cells as an Intracellular Antiapoptotic Strategy.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 elicit...
Source: Science Signaling - November 20, 2009 Category: Biomedical Science Authors: Chuenkova MV, Pereiraperrin M Tags: Sci Signal Source Type: journals

Focus Issue: Coping with Cellular Stress.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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)
Source: Science Signaling - November 12, 2009 Category: Biomedical Science Authors: Wong W Tags: Sci Signal Source Type: journals

Science Signaling Podcast: 10 November 2009.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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)
Source: Science Signaling - November 12, 2009 Category: Biomedical Science Authors: Snyder SH, Vanhook AM Tags: Sci Signal Source Type: journals

Aiming Straight for the Heart: Prolyl Hydroxylases Set the BAR.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 expectat...
Source: Science Signaling - November 12, 2009 Category: Biomedical Science Authors: Garcia JA Tags: Sci Signal Source Type: journals

A New Mechanism of Phosphoregulation in Signal Transduction Pathways.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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)
Source: Science Signaling - November 12, 2009 Category: Biomedical Science Authors: Jung K, Jung H Tags: Sci Signal Source Type: journals

A Gluconeogenic Tryst in the Nucleus, with ER Stress as the Third Wheel.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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...
Source: Science Signaling - November 12, 2009 Category: Biomedical Science Authors: Rutkowski DT Tags: Sci Signal Source Type: journals

FBXO31: A New Player in the Ever-Expanding DNA Damage Response Orchestra.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 geno...
Source: Science Signaling - November 12, 2009 Category: Biomedical Science Authors: Shiloh Y Tags: Sci Signal Source Type: journals

Nutrition-Minded Cell Cycle.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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...
Source: Science Signaling - November 12, 2009 Category: Biomedical Science Authors: Shiozaki K Tags: Sci Signal Source Type: journals

H2S Signals Through Protein S-Sulfhydration.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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:...
Source: Science Signaling - November 12, 2009 Category: Biomedical Science Authors: Mustafa AK, Gadalla MM, Sen N, Kim S, Mu W, Gazi SK, Barrow RK, Yang G, Wang R, Snyder SH Tags: Sci Signal Source Type: journals

The Hippo tumor suppressor pathway: a brainstorming workshop.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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)
Source: Science Signaling - November 7, 2009 Category: Biomedical Science Authors: Blandino G, Shaul Y, Strano S, Sudol M, Yaffe M Tags: Sci Signal Source Type: journals

In with the TRP channels: intracellular functions for TRPM1 and TRPM2.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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)
Source: Science Signaling - November 7, 2009 Category: Biomedical Science Authors: Patel S, Docampo R Tags: Sci Signal Source Type: journals

The Rfx4 transcription factor modulates Shh signaling by regional control of ciliogenesis.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 ...
Source: Science Signaling - November 7, 2009 Category: Biomedical Science Authors: Ashique AM, Choe Y, Karlen M, May SR, Phamluong K, Solloway MJ, Ericson J, Peterson AS Tags: Sci Signal Source Type: journals

Activation of a bacterial virulence protein by the GTPase RhoA.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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...
Source: Science Signaling - November 7, 2009 Category: Biomedical Science Authors: Christen M, Coye LH, Hontz JS, LaRock DL, Pfuetzner RA, Megha , Miller SI Tags: Sci Signal Source Type: journals

Confronting morphogen gradients: how important are they for growth?Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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)
Source: Science Signaling - October 30, 2009 Category: Biomedical Science Authors: Hamaratoglu F, Basler K, Affolter M Tags: Sci Signal Source Type: journals

P-REX2a driving tumorigenesis by PTEN inhibition.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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-d...
Source: Science Signaling - October 30, 2009 Category: Biomedical Science Authors: Leslie NR Tags: Sci Signal Source Type: journals

An atypical CNG channel activated by a single cGMP molecule controls sperm chemotaxis.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 ...
Source: Science Signaling - October 30, 2009 Category: Biomedical Science Authors: Bönigk W, Loogen A, Seifert R, Kashikar N, Klemm C, Krause E, Hagen V, Kremmer E, Strünker T, Kaupp UB Tags: Sci Signal Source Type: journals

Increased MKK4 abundance with replicative senescence is linked to the joint reduction of multiple microRNAs.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 in...
Source: Science Signaling - October 30, 2009 Category: Biomedical Science Authors: Marasa BS, Srikantan S, Masuda K, Abdelmohsen K, Kuwano Y, Yang X, Martindale JL, Rinker-Schaeffer CW, Gorospe M Tags: Sci Signal Source Type: journals

To co-author or not to co-author: how to write, publish, and negotiate issues of authorship with undergraduate research students.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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. Ou...
Source: Science Signaling - October 30, 2009 Category: Biomedical Science Authors: Burks RL, Chumchal MM Tags: Sci Signal Source Type: journals

Focus issue: addressing complicated questions in neuroscience.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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)
Source: Science Signaling - October 23, 2009 Category: Biomedical Science Authors: Gough NR Tags: Sci Signal Source Type: journals

Emerging miniaturized proteomic technologies to study cell signaling in clinical samples.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 a...
Source: Science Signaling - October 23, 2009 Category: Biomedical Science Authors: Gujral TS, Macbeath G Tags: Sci Signal Source Type: journals

Schizophrenia: The "BLOC" May Be in the Endosomes.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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....
Source: Science Signaling - October 23, 2009 Category: Biomedical Science Authors: Ryder PV, Faundez V Tags: Sci Signal Source Type: journals

A Noisy Paracrine Signal Determines the Cellular NF-{kappa}B Response to Lipopolysaccharide.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 l...
Source: Science Signaling - October 23, 2009 Category: Biomedical Science Authors: Lee TK, Denny EM, Sanghvi JC, Gaston JE, Maynard ND, Hughey JJ, Covert MW Tags: Sci Signal Source Type: journals

Two Mechanistically and Temporally Distinct NF-{kappa}B Activation Pathways in IL-1 Signaling.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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...
Source: Science Signaling - October 23, 2009 Category: Biomedical Science Authors: Yamazaki K, Gohda J, Kanayama A, Miyamoto Y, Sakurai H, Yamamoto M, Akira S, Hayashi H, Su B, Inoue J Tags: Sci Signal Source Type: journals

STIM2 Regulates Capacitive Ca2+ Entry in Neurons and Plays a Key Role in Hypoxic Neuronal Cell Death.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 essen...
Source: Science Signaling - October 23, 2009 Category: Biomedical Science Authors: Berna-Erro A, Braun A, Kraft R, Kleinschnitz C, Schuhmann MK, Stegner D, Wultsch T, Eilers J, Meuth SG, Stoll G, Nieswandt B Tags: Sci Signal Source Type: journals

G Protein-Coupled Receptors, Cholinergic Dysfunction, and A{beta} Toxicity in Alzheimer's Disease.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 to...
Source: Science Signaling - October 23, 2009 Category: Biomedical Science Authors: Thathiah A, De Strooper B Tags: Sci Signal Source Type: journals

Science signaling podcast: 13 october 2009.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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)
Source: Science Signaling - October 15, 2009 Category: Biomedical Science Authors: Meyn MA, Vanhook AM Tags: Sci Signal Source Type: journals

IL-17 Receptor Signaling: Ubiquitin Gets In On the Act.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 as...
Source: Science Signaling - October 15, 2009 Category: Biomedical Science Authors: Levin SD Tags: Sci Signal Source Type: journals

MicroRNAs Differentially Regulated by Akt Isoforms Control EMT and Stem Cell Renewal in Cancer Cells.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 b...
Source: Science Signaling - October 15, 2009 Category: Biomedical Science Authors: Iliopoulos D, Polytarchou C, Hatziapostolou M, Kottakis F, Maroulakou IG, Struhl K, Tsichlis PN Tags: Sci Signal Source Type: journals

Act1, a U-box E3 Ubiquitin Ligase for IL-17 Signaling.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 o...
Source: Science Signaling - October 15, 2009 Category: Biomedical Science Authors: Liu C, Qian W, Qian Y, Giltiay NV, Lu Y, Swaidani S, Misra S, Deng L, Chen ZJ, Li X Tags: Sci Signal Source Type: journals

Chemical Genetics Identifies c-Src as an Activator of Primitive Ectoderm Formation in Murine Embryonic Stem Cells.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 ...
Source: Science Signaling - October 15, 2009 Category: Biomedical Science Authors: Meyn MA, Smithgall TE Tags: Sci Signal Source Type: journals

Apoptosis: calling time on apoptosome activity.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 li...
Source: Science Signaling - October 10, 2009 Category: Biomedical Science Authors: Adrain C, Martin SJ Tags: Sci Signal Source Type: journals

Snapshots form a big picture of guanine nucleotide exchange.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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...
Source: Science Signaling - October 10, 2009 Category: Biomedical Science Authors: Rittinger K Tags: Sci Signal Source Type: journals

Wingless promotes proliferative growth in a gradient-independent manner.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 exogen...
Source: Science Signaling - October 10, 2009 Category: Biomedical Science Authors: Baena-Lopez LA, Franch-Marro X, Vincent JP Tags: Sci Signal Source Type: journals

Coordinated responses to oxygen and sugar deficiency allow rice seedlings to tolerate flooding.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 producti...
Source: Science Signaling - October 10, 2009 Category: Biomedical Science Authors: Lee KW, Chen PW, Lu CA, Chen S, Ho TH, Yu SM Tags: Sci Signal Source Type: journals

Focus issue: the long and short of redox signaling.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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)
Source: Science Signaling - October 4, 2009 Category: Biomedical Science Authors: Gough NR Tags: Sci Signal Source Type: journals

Sending ROS on a bullet train.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 din...
Source: Science Signaling - October 4, 2009 Category: Biomedical Science Authors: Wong HL, Shimamoto K Tags: Sci Signal Source Type: journals

STAT3 revs up the powerhouse.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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)
Source: Science Signaling - October 4, 2009 Category: Biomedical Science Authors: Reich NC Tags: Sci Signal Source Type: journals

Leishmania GP63 alters host signaling through cleavage-activated protein tyrosine phosphatases.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 obliga...
Source: Science Signaling - October 4, 2009 Category: Biomedical Science Authors: Gomez MA, Contreras I, Hallé M, Tremblay ML, McMaster RW, Olivier M Tags: Sci Signal Source Type: journals

Hippo pathway-dependent and -independent roles of RASSF6.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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, RASS...
Source: Science Signaling - October 4, 2009 Category: Biomedical Science Authors: Ikeda M, Kawata A, Nishikawa M, Tateishi Y, Yamaguchi M, Nakagawa K, Hirabayashi S, Bao Y, Hidaka S, Hirata Y, Hata Y Tags: Sci Signal Source Type: journals

Transduction of redox signaling by electrophile-protein reactions.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 ...
Source: Science Signaling - October 4, 2009 Category: Biomedical Science Authors: Rudolph TK, Freeman BA Tags: Sci Signal Source Type: journals

Integrin proteomes reveal a new guide for cell motility.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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)
Source: Science Signaling - October 4, 2009 Category: Biomedical Science Authors: Danen EH Tags: Sci Signal Source Type: journals

Human-specific genes may offer a unique window into human cell signaling.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 huma...
Source: Science Signaling - October 4, 2009 Category: Biomedical Science Authors: Stahl PD, Wainszelbaum MJ Tags: Sci Signal Source Type: journals

The single transmembrane domains of human receptor tyrosine kinases encode self-interactions.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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...
Source: Science Signaling - October 4, 2009 Category: Biomedical Science Authors: Finger C, Escher C, Schneider D Tags: Sci Signal Source Type: journals

MSK2 inhibits p53 activity in the absence of stress.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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...
Source: Science Signaling - October 4, 2009 Category: Biomedical Science Authors: Llanos S, Cuadrado A, Serrano M Tags: Sci Signal Source Type: journals

Regulation of cancer invasion by reactive oxygen species and Tks family scaffold proteins.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 assoc...
Source: Science Signaling - September 18, 2009 Category: Biomedical Science Authors: Weaver AM Tags: Sci Signal Source Type: journals

Endocannabinoids can open the pain gate.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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 negat...
Source: Science Signaling - September 18, 2009 Category: Biomedical Science Authors: Christie MJ, Mallet C Tags: Sci Signal Source Type: journals

Tks5-dependent, nox-mediated generation of reactive oxygen species is necessary for invadopodia formation.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
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...
Source: Science Signaling - September 18, 2009 Category: Biomedical Science Authors: Diaz B, Shani G, Pass I, Anderson D, Quintavalle M, Courtneidge SA Tags: Sci Signal Source Type: journals