The microRNA miR-7a-5p ameliorates ischemic brain damage by repressing {alpha}-synuclein
Ischemic stroke, which is caused by a clot that blocks blood flow to the brain, can be severely disabling and sometimes fatal. We previously showed that transient focal ischemia in a rat model induces extensive temporal changes in the expression of cerebral microRNAs, with a sustained decrease in the abundance of miR-7a-5p (miR-7). Here, we evaluated the therapeutic efficacy of a miR-7 mimic oligonucleotide after cerebral ischemia in rodents according to the Stroke Treatment Academic Industry Roundtable (STAIR) criteria. Rodents were injected locally or systemically with miR-7 mimic before or after transient middle cerebra...
Source: Signal Transduction Knowledge Environment - December 11, 2018 Category: Science Authors: Kim, T., Mehta, S. L., Morris-Blanco, K. C., Chokkalla, A. K., Chelluboina, B., Lopez, M., Sullivan, R., Kim, H. T., Cook, T. D., Kim, J. Y., Kim, H., Kim, C., Vemuganti, R. Tags: STKE Research Articles Source Type: news

Crk adaptor proteins mediate actin-dependent T cell migration and mechanosensing induced by the integrin LFA-1
T cell entry into inflamed tissue involves firm adhesion, spreading, and migration of the T cells across endothelial barriers. These events depend on "outside-in" signals through which engaged integrins direct cytoskeletal reorganization. We investigated the molecular events that mediate this process and found that T cells from mice lacking expression of the adaptor protein Crk exhibited defects in phenotypes induced by the integrin lymphocyte function–associated antigen 1 (LFA-1), namely, actin polymerization, leading edge formation, and two-dimensional cell migration. Crk protein was an essential mediator...
Source: Signal Transduction Knowledge Environment - December 11, 2018 Category: Science Authors: Roy, N. H., MacKay, J. L., Robertson, T. F., Hammer, D. A., Burkhardt, J. K. Tags: STKE Research Articles Source Type: news

Targeting PD-1
Loss of an E3 ubiquitin ligase that targets PD-1 for degradation leads to inefficient antitumor responses by T cells. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - December 11, 2018 Category: Science Authors: Foley, J. F. Tags: STKE Editors ' Choice Source Type: news

The {beta}4 subunit of Cav1.2 channels is required for an optimal interferon response in cardiac muscle cells
The auxiliary β4 subunit of the cardiac Cav1.2 channel plays a poorly understood role in gene transcription. Here, we characterized the regulatory effects of the β4 subunit in H9c2 rat cardiac cells on the abundances of Ifnb mRNA [which encodes interferon-β (IFN-β)] and of the IFN-β–related genes Ddx58, Ifitm3, Irf7, Stat2, Ifih1, and Mx1, as well as on the abundances of the antiviral proteins DDX58, IRF7, STAT2, and IFITM3. Knocking down the β4 subunit in H9c2 cells reduced the expression of IFN-β–stimulated genes. In response to inhibition of the kinase JAK1, the abundances ...
Source: Signal Transduction Knowledge Environment - December 11, 2018 Category: Science Authors: Tammineni, E. R., Carrillo, E. D., Soto-Acosta, R., Angel-Ambrocio, A. H., Garcia, M. C., Bautista-Carbajal, P., del Angel, R. M., Sanchez, J. A. Tags: STKE Research Articles Source Type: news

Restricting mitochondrial GRK2 post-ischemia confers cardioprotection by reducing myocyte death and maintaining glucose oxidation
Increased abundance of GRK2 [G protein–coupled receptor (GPCR) kinase 2] is associated with poor cardiac function in heart failure patients. In animal models, GRK2 contributes to the pathogenesis of heart failure after ischemia-reperfusion (IR) injury. In addition to its role in down-regulating activated GPCRs, GRK2 also localizes to mitochondria both basally and post-IR injury, where it regulates cellular metabolism. We previously showed that phosphorylation of GRK2 at Ser670 is essential for the translocation of GRK2 to the mitochondria of cardiomyocytes post-IR injury in vitro and that this localization promotes c...
Source: Signal Transduction Knowledge Environment - December 11, 2018 Category: Science Authors: Sato, P. Y., Chuprun, J. K., Grisanti, L. A., Woodall, M. C., Brown, B. R., Roy, R., Traynham, C. J., Ibetti, J., Lucchese, A. M., Yuan, A., Drosatos, K., Tilley, D. G., Gao, E., Koch, W. J. Tags: STKE Research Articles Source Type: news

Regulated proteolysis of p62/SQSTM1 enables differential control of autophagy and nutrient sensing
The multidomain scaffold protein p62 (also called sequestosome-1) is involved in autophagy, antimicrobial immunity, and oncogenesis. Mutations in SQSTM1, which encodes p62, are linked to hereditary inflammatory conditions such as Paget’s disease of the bone, frontotemporal dementia (FTD), amyotrophic lateral sclerosis, and distal myopathy with rimmed vacuoles. Here, we report that p62 was proteolytically trimmed by the protease caspase-8 into a stable protein, which we called p62TRM. We found that p62TRM, but not full-length p62, was involved in nutrient sensing and homeostasis through the mechanistic target of rapam...
Source: Signal Transduction Knowledge Environment - December 4, 2018 Category: Science Authors: Sanchez-Garrido, J., Sancho-Shimizu, V., Shenoy, A. R. Tags: STKE Research Articles Source Type: news

FZD5 is a G{alpha}q-coupled receptor that exhibits the functional hallmarks of prototypical GPCRs
Frizzleds (FZDs) are a group of seven transmembrane–spanning (7TM) receptors that belong to class F of the G protein–coupled receptor (GPCR) superfamily. FZDs bind WNT proteins to stimulate diverse signaling cascades involved in embryonic development, stem cell regulation, and adult tissue homeostasis. Frizzled 5 (FZD5) is one of the most studied class F GPCRs that promote the functional inactivation of the β-catenin destruction complex in response to WNTs. However, whether FZDs function as prototypical GPCRs has been heavily debated and, in particular, FZD5 has not been shown to activate heterotrimeric G ...
Source: Signal Transduction Knowledge Environment - December 4, 2018 Category: Science Authors: Wright, S. C., Canizal, M. C. A., Benkel, T., Simon, K., Le Gouill, C., Matricon, P., Namkung, Y., Lukasheva, V., König, G. M., Laporte, S. A., Carlsson, J., Kostenis, E., Bouvier, M., Schulte, G., Hoffmann, C. Tags: STKE Research Articles Source Type: news

A division of labor in mTORC1 signaling and autophagy
In human cells, the p62 protein acts as an adaptor in various signaling pathways as well as a receptor for selective autophagy. In this issue of Science Signaling, Sanchez-Garrido et al. show that proteolytic cleavage of p62 by caspase-8 determines whether p62 functions as an mTORC1 signaling adaptor or autophagy receptor. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - December 4, 2018 Category: Science Authors: Martens, S. Tags: STKE Focus Source Type: news

ERAD suppresses the starvation response
Endoplasmic reticulum–associated protein degradation suppresses the production of the fasting-associated hepatokine Fgf21. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - December 4, 2018 Category: Science Authors: VanHook, A. M. Tags: STKE Editors ' Choice Source Type: news

Functional selectivity profiling of the angiotensin II type 1 receptor using pathway-wide BRET signaling sensors
G protein–coupled receptors (GPCRs) are important therapeutic targets that exhibit functional selectivity (biased signaling), in which different ligands or receptor variants elicit distinct downstream signaling. Understanding all the signaling events and biases that contribute to both the beneficial and adverse effects of GPCR stimulation by given ligands is important for drug discovery. Here, we report the design, validation, and use of pathway-selective bioluminescence resonance energy transfer (BRET) biosensors that monitor the engagement and activation of signaling effectors downstream of G proteins, including pr...
Source: Signal Transduction Knowledge Environment - December 4, 2018 Category: Science Authors: Namkung, Y., LeGouill, C., Kumar, S., Cao, Y., Teixeira, L. B., Lukasheva, V., Giubilaro, J., Simoes, S. C., Longpre, J.-M., Devost, D., Hebert, T. E., Pineyro, G., Leduc, R., Costa-Neto, C. M., Bouvier, M., Laporte, S. A. Tags: STKE Research Resources Source Type: news

Hippocampal mGluR1-dependent long-term potentiation requires NAADP-mediated acidic store Ca2+ signaling
Acidic organelles, such as endosomes and lysosomes, store Ca2+ that is released in response to intracellular increases in the second messenger nicotinic acid adenine dinucleotide phosphate (NAADP). In neurons, NAADP and Ca2+ signaling contribute to synaptic plasticity, a process of activity-dependent long-term potentiation (LTP) [or, alternatively, long-term depression (LTD)] of synaptic strength and neuronal transmission that is critical for neuronal function and memory formation. We explored the function of and mechanisms regulating acidic Ca2+ store signaling in murine hippocampal neurons. We found that metabotropic glu...
Source: Signal Transduction Knowledge Environment - November 27, 2018 Category: Science Authors: Foster, W. J., Taylor, H. B. C., Padamsey, Z., Jeans, A. F., Galione, A., Emptage, N. J. Tags: STKE Research Articles Source Type: news

Aspirin ameliorates experimental autoimmune encephalomyelitis through interleukin-11-mediated protection of regulatory T cells
Multiple sclerosis (MS) is a human disease that results from autoimmune T cells targeting myelin protein that is expressed within the central nervous system. In MS, the number of FoxP3-expressing regulatory T cells (Tregs) is reduced, which facilitates the activation of autoreactive T cells. Because aspirin (acetylsalicylic acid) is the most widely used nonsteroidal anti-inflammatory drug, we examined its immunomodulatory effect in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We found that low-dose aspirin suppressed the clinical symptoms of EAE in mouse models of both relapsing-remitti...
Source: Signal Transduction Knowledge Environment - November 27, 2018 Category: Science Authors: Mondal, S., Jana, M., Dasarathi, S., Roy, A., Pahan, K. Tags: STKE Research Articles Source Type: news

{beta}-Barrel outer membrane proteins suppress mTORC2 activation and induce autophagic responses
The outer membranes of Gram-negative bacteria and mitochondria contain proteins with a distinct β-barrel tertiary structure that could function as a molecular pattern recognized by the innate immune system. Here, we report that purified outer membrane proteins (OMPs) from different bacterial and mitochondrial sources triggered the induction of autophagy-related endosomal acidification, LC3B lipidation, and p62 degradation. Furthermore, OMPs reduced the phosphorylation and therefore activation of the multiprotein complex mTORC2 and its substrate Akt in macrophages and epithelial cells. The cell surface receptor SlamF8 ...
Source: Signal Transduction Knowledge Environment - November 27, 2018 Category: Science Authors: Chaudhary, A., Kamischke, C., Leite, M., Altura, M. A., Kinman, L., Kulasekara, H., Blanc, M.-P., Wang, G., Terhorst, C., Miller, S. I. Tags: STKE Research Articles Source Type: news

Thinking through acidic Ca2+ stores
Glutamate signaling regulates neuronal activity and synaptic plasticity, which underlies learning and memory. In this issue of Science Signaling, Foster et al. found that metabotropic glutamate receptors mediate long-term potentiation in hippocampal neurons by mobilizing acidic endolysosomal Ca2+ stores through the intracellular messenger NAADP. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - November 27, 2018 Category: Science Authors: Patel, S., Brailoiu, E. Tags: STKE Focus Source Type: news

Priming the liver for a feast after famine
Food perception activates a hypothalamus-to-liver pathway that prepares the liver for nutrient influx. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - November 27, 2018 Category: Science Authors: Wong, W. Tags: STKE Editors ' Choice Source Type: news

Erratum for the Research Article: "The costimulatory molecule CD226 signals through VAV1 to amplify TCR signals and promote IL-17 production by CD4+ T cells" by G. Gaud, R. Roncagalli, K. Chaoui, I. Bernard, J. Familiades, C. Colacios, S. Kassem, B. Monsarrat, O. Burlet-Schiltz, A. G. de Peredo, B. Malissen, A. Saoudi
(Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - November 27, 2018 Category: Science Tags: STKE Errata Source Type: news

IFN-{gamma}-inducible antiviral responses require ULK1-mediated activation of MLK3 and ERK5
It is well established that activation of the transcription factor signal transducer and activator of transcription 1 (STAT1) is required for the interferon- (IFN-)–mediated antiviral response. Here, we found that IFN- receptor stimulation also activated Unc-51–like kinase 1 (ULK1), an initiator of Beclin-1–mediated autophagy. Furthermore, the interaction between ULK1 and the mitogen-activated protein kinase kinase kinase MLK3 (mixed lineage kinase 3) was necessary for MLK3 phosphorylation and downstream activation of the kinase ERK5. This autophagy-independent activity of ULK1 promoted the transcription ...
Source: Signal Transduction Knowledge Environment - November 20, 2018 Category: Science Authors: Saleiro, D., Blyth, G. T., Kosciuczuk, E. M., Ozark, P. A., Majchrzak-Kita, B., Arslan, A. D., Fischietti, M., Reddy, N. K., Horvath, C. M., Davis, R. J., Fish, E. N., Platanias, L. C. Tags: STKE Research Articles Source Type: news

Erratum for the Focus Article: "Arid5a makes the IL-17A/F-responsive pathway less arid" by A. Puel and J.-L. Casanova
(Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - November 20, 2018 Category: Science Tags: STKE Errata Source Type: news

Integrated proximal proteomics reveals IRS2 as a determinant of cell survival in ALK-driven neuroblastoma
Oncogenic anaplastic lymphoma kinase (ALK) is one of the few druggable targets in neuroblastoma, and therapy resistance to ALK-targeting tyrosine kinase inhibitors (TKIs) comprises an inevitable clinical challenge. Therefore, a better understanding of the oncogenic signaling network rewiring driven by ALK is necessary to improve and guide future therapies. Here, we performed quantitative mass spectrometry–based proteomics on neuroblastoma cells treated with one of three clinically relevant ALK TKIs (crizotinib, LDK378, or lorlatinib) or an experimentally used ALK TKI (TAE684) to unravel aberrant ALK signaling pathway...
Source: Signal Transduction Knowledge Environment - November 20, 2018 Category: Science Authors: Emdal, K. B., Pedersen, A.-K., Bekker-Jensen, D. B., Lundby, A., Claeys, S., De Preter, K., Speleman, F., Francavilla, C., Olsen, J. V. Tags: STKE Research Resources Source Type: news

The HDAC3-SMARCA4-miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood with an unmet clinical need for decades. A single oncogenic fusion gene is associated with treatment resistance and a 40 to 45% decrease in overall survival. We previously showed that expression of this PAX3:FOXO1 fusion oncogene in alveolar RMS (aRMS) mediates tolerance to chemotherapy and radiotherapy and that the class I–specific histone deacetylase (HDAC) inhibitor entinostat reduces PAX3:FOXO1 protein abundance. Here, we established the antitumor efficacy of entinostat with chemotherapy in various preclinical cell and mouse models and fou...
Source: Signal Transduction Knowledge Environment - November 20, 2018 Category: Science Authors: Bharathy, N., Berlow, N. E., Wang, E., Abraham, J., Settelmeyer, T. P., Hooper, J. E., Svalina, M. N., Ishikawa, Y., Zientek, K., Bajwa, Z., Goros, M. W., Hernandez, B. S., Wolff, J. E., Rudek, M. A., Xu, L., Anders, N. M., Pal, R., Harrold, A. P., Davies Tags: STKE Research Articles Source Type: news

Phosphoproteome and gene expression profiling of ALK inhibition in neuroblastoma cell lines reveals conserved oncogenic pathways
In this study, we established both phosphoproteomic and gene expression profiles of ALK activity in neuroblastoma cells exposed to first- and third-generation ALK TKIs, to identify the underlying molecular mechanisms and identify relevant biomarkers, signaling networks, and new therapeutic targets. This analysis has unveiled various important leads for novel combinatorial treatment strategies for patients with neuroblastoma and an increased understanding of ALK signaling involved in this disease. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - November 20, 2018 Category: Science Authors: Van den Eynden, J., Umapathy, G., Ashouri, A., Cervantes-Madrid, D., Szydzik, J., Ruuth, K., Koster, J., Larsson, E., Guan, J., Palmer, R. H., Hallberg, B. Tags: STKE Research Resources Source Type: news

The two faces of cGAS in cancer and immunity
Cytosolic DNA sensing by cGAS promotes immunity, but its nuclear localization can promote tumorigenesis. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - November 20, 2018 Category: Science Authors: Ferrarelli, L. K. Tags: STKE Editors ' Choice Source Type: news

Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission-associated myocardial senescence
Defective mitochondrial dynamics through aberrant interactions between mitochondria and actin cytoskeleton is increasingly recognized as a key determinant of cardiac fragility after myocardial infarction (MI). Dynamin-related protein 1 (Drp1), a mitochondrial fission–accelerating factor, is activated locally at the fission site through interactions with actin. Here, we report that the actin-binding protein filamin A acted as a guanine nucleotide exchange factor for Drp1 and mediated mitochondrial fission–associated myocardial senescence in mice after MI. In peri-infarct regions characterized by mitochondrial hy...
Source: Signal Transduction Knowledge Environment - November 13, 2018 Category: Science Authors: Nishimura, A., Shimauchi, T., Tanaka, T., Shimoda, K., Toyama, T., Kitajima, N., Ishikawa, T., Shindo, N., Numaga-Tomita, T., Yasuda, S., Sato, Y., Kuwahara, K., Kumagai, Y., Akaike, T., Ide, T., Ojida, A., Mori, Y., Nishida, M. Tags: STKE Research Articles Source Type: news

The transmembrane adaptor protein NTAL limits mast cell chemotaxis toward prostaglandin E2
Chemotaxis of mast cells is one of the crucial steps in their development and function. Non–T cell activation linker (NTAL) is a transmembrane adaptor protein that inhibits the activation of mast cells and B cells in a phosphorylation-dependent manner. Here, we studied the role of NTAL in the migration of mouse mast cells stimulated by prostaglandin E2 (PGE2). Although PGE2 does not induce the tyrosine phosphorylation of NTAL, unlike IgE immune complex antigens, we found that loss of NTAL increased the chemotaxis of mast cells toward PGE2. Stimulation of mast cells that lacked NTAL with PGE2 enhanced the phosphorylat...
Source: Signal Transduction Knowledge Environment - November 13, 2018 Category: Science Authors: Halova, I., Bambouskova, M., Draberova, L., Bugajev, V., Draber, P. Tags: STKE Research Articles Source Type: news

A cytoskeletal anchor connects ischemic mitochondrial fission to myocardial senescence
The interplay between the actin cytoskeleton and mitochondria has been implicated in cell and tissue homeostasis and physiological function. In this issue of Science Signaling, Nishimura et al. demonstrate that inhibiting the interaction of filamin A, an actin cytoskeleton regulator, with Drp1, a modulator of mitochondrial dynamics, attenuates mitochondrial hyperfission and cardiomyocyte senescence after myocardial infarction. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - November 13, 2018 Category: Science Authors: Boyer, M. J., Eguchi, S. Tags: STKE Focus Source Type: news

The basics of mechanotransduction
Basic residues in the transmembrane domain of the T cell receptor α chain promote its association with CD3 signaling chains. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - November 13, 2018 Category: Science Authors: Williams, E. R. Tags: STKE Editors ' Choice Source Type: news

Distinct control of PERIOD2 degradation and circadian rhythms by the oncoprotein and ubiquitin ligase MDM2
The circadian clock relies on posttranslational modifications to set the timing for degradation of core regulatory components, which drives clock progression. Ubiquitin-modifying enzymes that target clock components for degradation mainly recognize phosphorylated substrates. Degradation of the circadian clock component PERIOD 2 (PER2) is mediated by its phospho-specific recognition by β-transducin repeat–containing proteins (β-TrCPs), which are F-box–containing proteins that function as substrate recognition subunits of the SCFβ-TRCP ubiquitin ligase complex. However, this mode of regulating PER2...
Source: Signal Transduction Knowledge Environment - November 13, 2018 Category: Science Authors: Liu, J., Zou, X., Gotoh, T., Brown, A. M., Jiang, L., Wisdom, E. L., Kim, J. K., Finkielstein, C. V. Tags: STKE Research Articles Source Type: news

New connections: Taking advantage of bias
Biased chemokine receptor agonists and antagonists that target specific signaling pathways may provide therapeutic benefit. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - November 6, 2018 Category: Science Authors: Foley, J. F. Tags: STKE Editors ' Choice Source Type: news

Mammalian pigmentation is regulated by a distinct cAMP-dependent mechanism that controls melanosome pH
The production of melanin increases skin pigmentation and reduces the risk of skin cancer. Melanin production depends on the pH of melanosomes, which are more acidic in lighter-skinned than in darker-skinned people. We showed that inhibition of soluble adenylyl cyclase (sAC) controlled pigmentation by increasing the pH of melanosomes both in cells and in vivo. Distinct from the canonical melanocortin 1 receptor (MC1R)–dependent cAMP pathway that controls pigmentation by altering gene expression, we found that inhibition of sAC increased pigmentation by increasing the activity of tyrosinase, the rate-limiting enzyme i...
Source: Signal Transduction Knowledge Environment - November 6, 2018 Category: Science Authors: Zhou, D., Ota, K., Nardin, C., Feldman, M., Widman, A., Wind, O., Simon, A., Reilly, M., Levin, L. R., Buck, J., Wakamatsu, K., Ito, S., Zippin, J. H. Tags: STKE Research Articles Source Type: news

Engineering allosteric regulation in protein kinases
Phosphoregulation, in which the addition of a negatively charged phosphate group modulates protein activity, enables dynamic cellular responses. To understand how new phosphoregulation might be acquired, we mutationally scanned the surface of a prototypical yeast kinase (Kss1) to identify potential regulatory sites. The data revealed a set of spatially distributed "hotspots" that might have coevolved with the active site and preferentially modulated kinase activity. By engineering simple consensus phosphorylation sites at these hotspots, we rewired cell signaling in yeast. Using the same approach with a homolog y...
Source: Signal Transduction Knowledge Environment - November 6, 2018 Category: Science Authors: Pincus, D., Pandey, J. P., Feder, Z. A., Creixell, P., Resnekov, O., Reynolds, K. A. Tags: STKE Research Articles Source Type: news

Biased agonists of the chemokine receptor CXCR3 differentially control chemotaxis and inflammation
This study demonstrates that biased agonists of CXCR3 produce distinct physiological effects, suggesting discrete roles for different endogenous CXCR3 ligands and providing evidence that biased signaling can affect the clinical utility of drugs targeting CXCR3 and other chemokine receptors. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - November 6, 2018 Category: Science Authors: Smith, J. S., Nicholson, L. T., Suwanpradid, J., Glenn, R. A., Knape, N. M., Alagesan, P., Gundry, J. N., Wehrman, T. S., Atwater, A. R., Gunn, M. D., MacLeod, A. S., Rajagopal, S. Tags: STKE Research Articles Source Type: news

Pathogen-driven vascularization
A cell wall component of mycobacteria stimulates vascularization of granulomas. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - October 30, 2018 Category: Science Authors: VanHook, A. M. Tags: STKE Editors ' Choice Source Type: news

Activating mutations in MEK1 enhance homodimerization and promote tumorigenesis
RAS-RAF-MEK-ERK signaling has a well-defined role in cancer biology. Although aberrant pathway activation occurs mostly upstream of the kinase MEK, mutations in MEK are prevalent in some cancer subsets. Here, we found that cancer-related, activating mutations in MEK can be classified into two groups: those that relieve inhibitory interactions with the helix A region and those that are in-frame deletions of the β3-αC loop, which enhance MEK1 homodimerization. The former, helix A–associated mutants, are inhibited by traditional MEK inhibitors. However, we found that the increased homodimerization associated ...
Source: Signal Transduction Knowledge Environment - October 30, 2018 Category: Science Authors: Yuan, J., Ng, W. H., Tian, Z., Yap, J., Baccarini, M., Chen, Z., Hu, J. Tags: STKE Research Articles Source Type: news

Modulation of Cl- signaling and ion transport by recruitment of kinases and phosphatases mediated by the regulatory protein IRBIT
IRBIT is a multifunctional protein that controls the activity of various epithelial ion transporters including NBCe1-B. Interaction with IRBIT increases NBCe1-B activity and exposes two cryptic Cl–-sensing GXXXP sites that enable regulation of NBCe1-B by intracellular Cl– (Cl–in). Here, phosphoproteomic analysis revealed that IRBIT controlled five phosphorylation sites in NBCe1-B that determined both the active conformation of the transporter and its regulation by Cl–in. Mutational analysis suggested that the phosphorylation status of Ser232, Ser233, and Ser235 was regulated by IRBIT and determined ...
Source: Signal Transduction Knowledge Environment - October 30, 2018 Category: Science Authors: Vachel, L., Shcheynikov, N., Yamazaki, O., Fremder, M., Ohana, E., Son, A., Shin, D. M., Yamazaki-Nakazawa, A., Yang, C.-R., Knepper, M. A., Muallem, S. Tags: STKE Research Articles Source Type: news

RSK2 contributes to myogenic vasoconstriction of resistance arteries by activating smooth muscle myosin and the Na+/H+ exchanger
Smooth muscle contraction is triggered when Ca2+/calmodulin-dependent myosin light chain kinase (MLCK) phosphorylates the regulatory light chain of myosin (RLC20). However, blood vessels from Mlck-deficient mouse embryos retain the ability to contract, suggesting the existence of additional regulatory mechanisms. We showed that the p90 ribosomal S6 kinase 2 (RSK2) also phosphorylated RLC20 to promote smooth muscle contractility. Active, phosphorylated RSK2 was present in mouse resistance arteries under normal basal tone, and phosphorylation of RSK2 increased with myogenic vasoconstriction or agonist stimulation. Resistance...
Source: Signal Transduction Knowledge Environment - October 30, 2018 Category: Science Authors: Artamonov, M. V., Sonkusare, S. K., Good, M. E., Momotani, K., Eto, M., Isakson, B. E., Le, T. H., Cope, E. L., Derewenda, Z. S., Derewenda, U., Somlyo, A. V. Tags: STKE Research Articles Source Type: news

The RAS-ERK pathway: A route for couples
Data accumulated over more than three decades demonstrate that the assembly of macrocomplexes, mainly of dimers, is widespread among the members of the different tiers that constitute the RAS-ERK pathway. In this issue of Science Signaling, Yuan et al. report that MEK1 homodimerization is necessary for signal transduction through the RAF-ERK pathway and that cancer-related MEK1 mutations confer enhanced dimerization and resistance to MEK inhibitors. These findings endorse interference with RAS-ERK pathway–component dimerization as a potential therapeutic strategy in cancer patients. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - October 30, 2018 Category: Science Authors: Santos, E., Crespo, P. Tags: STKE Focus Source Type: news

Flipping in a kinase fold for AMPylation
The pseudokinase SelO mediates AMPylation instead of phosphorylation due to the flipped orientation of ATP in the active site. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - October 23, 2018 Category: Science Authors: Wong, W. Tags: STKE Editors ' Choice Source Type: news

Erratum for the Research Article: "Identification of Toll-like receptor signaling inhibitors based on selective activation of hierarchically acting signaling proteins" by S. K. Ippagunta, J. A. Pollock, N. Sharma, W. Lin, T. Chen, K. Tawaratsumida, A. A. High, J. Min, Y. Chen, R. K. Guy, V. Redecke, J. A. Katzenellenbogen, H. Häcker
(Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - October 23, 2018 Category: Science Tags: STKE Errata Source Type: news

The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation
Fgr is a member of the Src family of nonreceptor tyrosine kinases, which are overexpressed and constitutively active in many human cancers. Fgr expression is restricted to myeloid hematopoietic cells and is markedly increased in a subset of bone marrow samples from patients with acute myeloid leukemia (AML). Here, we investigated the oncogenic potential of Fgr using Rat-2 fibroblasts that do not express the kinase. Expression of either wild-type or regulatory tail-mutant constructs of Fgr promoted cellular transformation (inferred from colony formation in soft agar), which was accompanied by phosphorylation of the Fgr acti...
Source: Signal Transduction Knowledge Environment - October 23, 2018 Category: Science Authors: Shen, K., Moroco, J. A., Patel, R. K., Shi, H., Engen, J. R., Dorman, H. R., Smithgall, T. E. Tags: STKE Research Articles Source Type: news

Sphingosine 1-phosphate stimulates eyelid closure in the developing rat by stimulating EGFR signaling
In many mammals, the eyelids migrate over the eye and fuse during embryogenesis to protect the cornea from damage during birth and early life. Loss-of-function mutations affecting the epidermal growth factor receptor (EGFR) signaling pathway cause an eyes-open-at-birth (EOB) phenotype in rodents. We identified an insertional mutation in Spinster homolog 2 (Spns2) in a strain of transgenic rats exhibiting the EOB phenotype. Spns2, a sphingosine 1-phosphate (S1P) transporter that releases S1P from cells, was enriched at the tip of developing eyelids in wild-type rat embryos. Spns2 expression or treatment with S1P or any one ...
Source: Signal Transduction Knowledge Environment - October 23, 2018 Category: Science Authors: Bian, G., Yu, C., Liu, L., Fang, C., Chen, K., Ren, P., Zhang, Q., Liu, F., Zhang, K., Xue, Q., Xiang, J., Guo, H., Song, J., Zhao, Y., Wu, W., Chung, S. K., Sun, R., Ju, G., Wang, J. Tags: STKE Research Articles Source Type: news

ER-mitochondria cross-talk is regulated by the Ca2+ sensor NCS1 and is impaired in Wolfram syndrome
Communication between the endoplasmic reticulum (ER) and mitochondria plays a pivotal role in Ca2+ signaling, energy metabolism, and cell survival. Dysfunction in this cross-talk leads to metabolic and neurodegenerative diseases. Wolfram syndrome is a fatal neurodegenerative disease caused by mutations in the ER-resident protein WFS1. Here, we showed that WFS1 formed a complex with neuronal calcium sensor 1 (NCS1) and inositol 1,4,5-trisphosphate receptor (IP3R) to promote Ca2+ transfer between the ER and mitochondria. In addition, we found that NCS1 abundance was reduced in WFS1-null patient fibroblasts, which showed redu...
Source: Signal Transduction Knowledge Environment - October 23, 2018 Category: Science Authors: Angebault, C., Fauconnier, J., Patergnani, S., Rieusset, J., Danese, A., Affortit, C. A., Jagodzinska, J., Megy, C., Quiles, M., Cazevieille, C., Korchagina, J., Bonnet-Wersinger, D., Milea, D., Hamel, C., Pinton, P., Thiry, M., Lacampagne, A., Delprat, B Tags: STKE Research Articles Source Type: news

A call to arms: Unifying the fight against resistance
This Editorial discusses the state of research on drug resistance in the fields of cancer, infectious disease, and agriculture. Reaching across the aisle for a more cross-collaborative approach may lead to exciting breakthroughs toward tackling the challenges of drug resistance in each field. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - October 23, 2018 Category: Science Authors: Kaushansky, A., Hedstrom, L., Goldman, A., Singh, J., Yang, P. L., Rathod, P. K., Cynamon, M., Wodarz, D., Mahadevan, D., Tomaras, A., Navia, M. A., Schiffer, C. A. Tags: STKE Editorial Source Type: news

New connections: VEGF beyond the vasculature
The growth factor VEGF promotes cancer-associated stem cell biology and pain, as well as angiogenesis. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - October 16, 2018 Category: Science Authors: Ferrarelli, L. K. Tags: STKE Editors ' Choice Source Type: news

G protein subtype-specific signaling bias in a series of CCR5 chemokine analogs
Chemokines and some chemical analogs of chemokines prevent cellular HIV-1 entry when bound to the HIV-1 coreceptors C-C chemokine receptor 5 (CCR5) or C-X-C chemokine receptor 4 (CXCR4), which are G protein–coupled receptors (GPCRs). The ideal HIV-1 entry blocker targeting the coreceptors would display ligand bias and avoid activating G protein–mediated pathways that lead to inflammation. We compared CCR5-dependent activation of second messenger pathways in a single cell line. We studied two endogenous chemokines [RANTES (also known as CCL5) and MIP-1α (also known as CCL3)] and four chemokine analogs of R...
Source: Signal Transduction Knowledge Environment - October 16, 2018 Category: Science Authors: Lorenzen, E., Ceraudo, E., Berchiche, Y. A., Rico, C. A., Fürstenberg, A., Sakmar, T. P., Huber, T. Tags: STKE Research Articles Source Type: news

Decreased abundance of TRESK two-pore domain potassium channels in sensory neurons underlies the pain associated with bone metastasis
Cancer-associated pain is debilitating. Understanding the mechanisms that cause it can inform drug development that may improve quality of life in patients. Here, we found that the reduced abundance of potassium channels called TRESK in dorsal root ganglion (DRG) neurons sensitized nociceptive sensory neurons and cancer-associated pain. Overexpressing TRESK in DRG neurons suppressed tumor-induced neuronal hyperexcitability and pain hypersensitivity in bone metastasis model rats, whereas knocking down TRESK increased neuronal hyperexcitability and pain hypersensitivity in normal rats. Mechanistically, tumor-associated produ...
Source: Signal Transduction Knowledge Environment - October 16, 2018 Category: Science Authors: Yang, Y., Li, S., Jin, Z.-R., Jing, H.-B., Zhao, H.-Y., Liu, B.-H., Liang, Y.-J., Liu, L.-Y., Cai, J., Wan, Y., Xing, G.-G. Tags: STKE Research Articles Source Type: news

Biased antagonism of CXCR4 avoids antagonist tolerance
Repeated dosing of drugs targeting G protein–coupled receptors can stimulate antagonist tolerance, which reduces their efficacy; thus, strategies to avoid tolerance are needed. The efficacy of AMD3100, a competitive antagonist of the chemokine receptor CXCR4 that mobilizes leukemic blasts from the bone marrow into the blood to sensitize them to chemotherapy, is reduced after prolonged treatment. Tolerance to AMD3100 increases the abundance of CXCR4 on the surface of leukemic blasts, which promotes their rehoming to the bone marrow. AMD3100 inhibits both G protein signaling by CXCR4 and β-arrestin1/2–depend...
Source: Signal Transduction Knowledge Environment - October 16, 2018 Category: Science Authors: Hitchinson, B., Eby, J. M., Gao, X., Guite-Vinet, F., Ziarek, J. J., Abdelkarim, H., Lee, Y., Okamoto, Y., Shikano, S., Majetschak, M., Heveker, N., Volkman, B. F., Tarasova, N. I., Gaponenko, V. Tags: STKE Research Articles Source Type: news

Convergence of VEGF and YAP/TAZ signaling: Implications for angiogenesis and cancer biology
Vascular endothelial growth factor (VEGF) stimulates endothelial cells to promote both developmental and pathological angiogenesis. VEGF also directly affects tumor cells and is associated with the initiation, progression, and recurrence of tumors, as well as the emergence and maintenance of cancer stem cells (CSCs). Studies have uncovered the importance of the transcriptional regulators YAP and TAZ in mediating VEGF signaling. For example, VEGF stimulates the GTPase activity of Rho family members and thereby alters cytoskeletal dynamics, which contributes to the activation of YAP and TAZ. In turn, YAP- and TAZ-mediated ch...
Source: Signal Transduction Knowledge Environment - October 16, 2018 Category: Science Authors: Elaimy, A. L., Mercurio, A. M. Tags: STKE Reviews Source Type: news

Neratinib is effective in breast tumors bearing both amplification and mutation of ERBB2 (HER2)
Mutations in ERBB2, the gene encoding epidermal growth factor receptor (EGFR) family member HER2, are common in and drive the growth of "HER2-negative" (not ERBB2 amplified) tumors but are rare in "HER2-positive" (ERBB2 amplified) breast cancer. We analyzed DNA-sequencing data from HER2-positive patients and used cell lines and a patient-derived xenograft model to test the consequence of HER2 mutations on the efficacy of anti-HER2 agents such as trastuzumab, lapatinib, and neratinib, an irreversible pan-EGFR inhibitor. HER2 mutations were present in ~7% of HER2-positive tumors, all of which were metasta...
Source: Signal Transduction Knowledge Environment - October 9, 2018 Category: Science Authors: Cocco, E., Javier Carmona, F., Razavi, P., Won, H. H., Cai, Y., Rossi, V., Chan, C., Cownie, J., Soong, J., Toska, E., Shifman, S. G., Sarotto, I., Savas, P., Wick, M. J., Papadopoulos, K. P., Moriarty, A., Cutler, R. E., Avogadri-Connors, F., Lalani, A. Tags: STKE Research Articles Source Type: news

Arid5a makes the IL-17A/F-responsive pathway less arid
The cytokine interleukin-17A/F (IL-17A/F) not only protects the skin and mucosae against Candida albicans infection in mice and humans but also promotes autoimmunity and autoinflammation in mice. In this issue of Science Signaling, Amatya et al. report that the RNA binding protein Arid5a promotes responses to IL-17A/F through multiple mechanisms. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - October 9, 2018 Category: Science Authors: Puel, A., Casanova, J.-L. Tags: STKE Focus Source Type: news

Promoting cytokine production
The helicase DHX9 is required for production of the cytokine IL-6 in response to Toll-like receptor stimulation. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - October 9, 2018 Category: Science Authors: Foley, J. F. Tags: STKE Editors ' Choice Source Type: news