Cardiomyocyte glucocorticoid and mineralocorticoid receptors directly and antagonistically regulate heart disease in mice
Stress is increasingly associated with heart dysfunction and is linked to higher mortality rates in patients with cardiometabolic disease. Glucocorticoids are primary stress hormones that regulate homeostasis through two nuclear receptors, the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), both of which are present in cardiomyocytes. To examine the specific and coordinated roles that these receptors play in mediating the direct effects of stress on the heart, we generated mice with cardiomyocyte-specific deletion of GR (cardioGRKO), MR (cardioMRKO), or both GR and MR (cardioGRMRdKO). The cardioGRKO mice ...
Source: Signal Transduction Knowledge Environment - April 16, 2019 Category: Science Authors: Oakley, R. H., Cruz-Topete, D., He, B., Foley, J. F., Myers, P. H., Xu, X., Gomez-Sanchez, C. E., Chambon, P., Willis, M. S., Cidlowski, J. A. Tags: STKE Research Articles Source Type: news

Corticosteroid receptor balance regulates life and death in cardiomyocytes
Mineralocorticoid receptor (MR) antagonists are effective at treating heart failure. In this issue of Science Signaling, Oakley et al. provide new insight into their cardioprotective actions and highlight the importance of the opposing relationship between the MR and the related glucocorticoid receptor (GR) in the response to cardiomyocyte injury. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - April 16, 2019 Category: Science Authors: Chapman, K. E. Tags: STKE Focus Source Type: news

FGFR inhibitors get to nuclear PTEN
FGFR inhibitors block DNA repair coordinated by PTEN, enhancing radiotherapy in glioblastoma. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - April 16, 2019 Category: Science Authors: Ferrarelli, L. K. Tags: STKE Editors ' Choice Source Type: news

Cooperation between T cell receptor and Toll-like receptor 5 signaling for CD4+ T cell activation
CD4+ T cells recognize antigens through their T cell receptors (TCRs); however, additional signals involving costimulatory receptors, for example, CD28, are required for proper T cell activation. Alternative costimulatory receptors have been proposed, including members of the Toll-like receptor (TLR) family, such as TLR5 and TLR2. To understand the molecular mechanism underlying a potential costimulatory role for TLR5, we generated detailed molecular maps and logical models for the TCR and TLR5 signaling pathways and a merged model for cross-interactions between the two pathways. Furthermore, we validated the resulting mod...
Source: Signal Transduction Knowledge Environment - April 16, 2019 Category: Science Authors: Rodriguez-Jorge, O., Kempis-Calanis, L. A., Abou-Jaoude, W., Gutierrez-Reyna, D. Y., Hernandez, C., Ramirez-Pliego, O., Thomas-Chollier, M., Spicuglia, S., Santana, M. A., Thieffry, D. Tags: STKE Research Articles Source Type: news

Phosphotyrosine-dependent interaction between the kinases PKC{theta} and Zap70 promotes proximal TCR signaling
Protein kinase C- (PKC) is an important component of proximal T cell receptor (TCR) signaling. We previously identified the amino-terminal C2 domain of PKC as a phosphotyrosine (pTyr)–binding domain. Using a mutant form of PKC that cannot bind pTyr (PKCHR2A), we showed that pTyr binding by PKC was required for TCR-induced T cell activation, proliferation, and TH2 cell differentiation but not for T cell development. Using tandem mass spectrometry and coimmunoprecipitation, we identified the kinase -associated protein kinase of 70 kDa (Zap70) as a binding partner of the PKC pTyr-binding pocket. Tyr126 of Zap70 directly...
Source: Signal Transduction Knowledge Environment - April 16, 2019 Category: Science Authors: Xie, J., Han, X., Zhao, C., Canonigo-Balancio, A. J., Yates, J. R., Li, Y., Lillemeier, B. F., Altman, A. Tags: STKE Research Articles Source Type: news

TRPM7 channels mediate spontaneous Ca2+ fluctuations in growth plate chondrocytes that promote bone development
During endochondral ossification of long bones, the proliferation and differentiation of chondrocytes cause them to be arranged into layered structures constituting the epiphyseal growth plate, where they secrete the cartilage matrix that is subsequently converted into trabecular bone. Ca2+ signaling has been implicated in chondrogenesis in vitro. Through fluorometric imaging of bone slices from embryonic mice, we demonstrated that live growth plate chondrocytes generated small, cell-autonomous Ca2+ fluctuations that were associated with weak and intermittent Ca2+ influx. Several genes encoding Ca2+-permeable channels were...
Source: Signal Transduction Knowledge Environment - April 9, 2019 Category: Science Authors: Qian, N., Ichimura, A., Takei, D., Sakaguchi, R., Kitani, A., Nagaoka, R., Tomizawa, M., Miyazaki, Y., Miyachi, H., Numata, T., Kakizawa, S., Nishi, M., Mori, Y., Takeshima, H. Tags: STKE Research Articles Source Type: news

Chromatin serotonylation limits differentiation
Modification of histone H3 with the neurotransmitter serotonin impairs neuronal development. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - April 9, 2019 Category: Science Authors: Williams, E. R. Tags: STKE Editors ' Choice Source Type: news

Pivotal role of STIM2, but not STIM1, in IL-4 production by IL-3-stimulated murine basophils
Basophils have nonredundant roles in various immune responses that require Ca2+ influx. Here, we examined the role of two Ca2+ sensors, stromal interaction molecule 1 and 2 (STIM1 and STIM2), in basophil activation. We found that loss of STIM1, but not STIM2, impaired basophil IL-4 production after stimulation with immunoglobulin E (IgE)–containing immune complexes. In contrast, when basophils were stimulated with IL-3, loss of STIM2, but not STIM1, reduced basophil IL-4 production. This difference in STIM proteins was associated with distinct time courses of Ca2+ influx and transcription of the Il4 gene that were el...
Source: Signal Transduction Knowledge Environment - April 9, 2019 Category: Science Authors: Yoshikawa, S., Oh-hora, M., Hashimoto, R., Nagao, T., Peters, L., Egawa, M., Ohta, T., Miyake, K., Adachi, T., Kawano, Y., Yamanishi, Y., Karasuyama, H. Tags: STKE Research Articles Source Type: news

Stepping out of the shadow: STIM2 promotes IL-3-induced cytokine release
Basophils are a small population of innate immune cells, but their release of the cytokine interleukin-4 (IL-4) is important for mounting an efficient immune response against distinct parasites. Yoshikawa et al. (in the 9 April 2019 issue) showed that whereas STIM1 is essential for IL-4 release after stimulation of FcRI, STIM2 mediates a delayed IL-3/IL-33–induced IL-4 release independent of STIM1. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - April 9, 2019 Category: Science Authors: Alansary, D., Niemeyer, B. A. Tags: STKE Focus Source Type: news

Proteomics profiling of arginine methylation defines PRMT5 substrate specificity
Protein arginine methyltransferases (PRMTs) catalyze arginine methylation on both chromatin-bound and cytoplasmic proteins. Accumulating evidence supports the involvement of PRMT5, the major type II PRMT, in cell survival and differentiation pathways that are important during development and in tumorigenesis. PRMT5 is an attractive drug target in various cancers, and inhibitors are currently in oncological clinical trials. Nonetheless, given the complex biology of PRMT5 and its multiple nonhistone substrates, it is paramount to fully characterize these dynamic changes in methylation and to link them to the observed antican...
Source: Signal Transduction Knowledge Environment - April 2, 2019 Category: Science Authors: Musiani, D., Bok, J., Massignani, E., Wu, L., Tabaglio, T., Ippolito, M. R., Cuomo, A., Ozbek, U., Zorgati, H., Ghoshdastider, U., Robinson, R. C., Guccione, E., Bonaldi, T. Tags: STKE Research Resources Source Type: news

Cholesterol and Alzheimers disease
Inhibiting the accumulation of cholesterol in iPSC-derived neurons prevents the accumulation of both β-amyloid and tau. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - April 2, 2019 Category: Science Authors: VanHook, A. M. Tags: STKE Editors ' Choice Source Type: news

TRPV1 promotes opioid analgesia during inflammation
Pain and inflammation are inherently linked responses to injury, infection, or chronic diseases. Given that acute inflammation in humans or mice enhances the analgesic properties of opioids, there is much interest in determining the inflammatory transducers that prime opioid receptor signaling in primary afferent nociceptors. Here, we found that activation of the transient receptor potential vanilloid type 1 (TRPV1) channel stimulated a mitogen-activated protein kinase (MAPK) signaling pathway that was accompanied by the shuttling of the scaffold protein β-arrestin2 to the nucleus. The nuclear translocation of β-...
Source: Signal Transduction Knowledge Environment - April 2, 2019 Category: Science Authors: Basso, L., Aboushousha, R., Fan, C. Y., Iftinca, M., Melo, H., Flynn, R., Agosti, F., Hollenberg, M. D., Thompson, R., Bourinet, E., Trang, T., Altier, C. Tags: STKE Research Articles Source Type: news

Agonist-selective NOP receptor phosphorylation correlates in vitro and in vivo and reveals differential post-activation signaling by chemically diverse agonists
Agonists of the nociceptin/orphanin FQ opioid peptide (NOP) receptor, a member of the opioid receptor family, are under active investigation as novel analgesics, but their modes of signaling are less well characterized than those of other members of the opioid receptor family. Therefore, we investigated whether different NOP receptor ligands showed differential signaling or functional selectivity at the NOP receptor. Using newly developed phosphosite-specific antibodies to the NOP receptor, we found that agonist-induced NOP receptor phosphorylation occurred primarily at four carboxyl-terminal serine (Ser) and threonine (Th...
Source: Signal Transduction Knowledge Environment - March 26, 2019 Category: Science Authors: Mann, A., Mouledous, L., Froment, C., ONeill, P. R., Dasgupta, P., Günther, T., Brunori, G., Kieffer, B. L., Toll, L., Bruchas, M. R., Zaveri, N. T., Schulz, S. Tags: STKE Research Articles Source Type: news

Dephosphorylation of protamine 2 at serine 56 is crucial for murine sperm maturation in vivo
The posttranslational modification of histones is crucial in spermatogenesis, as in other tissues; however, during spermiogenesis, histones are replaced with protamines, which are critical for the tight packaging of the DNA in sperm cells. Protamines are also posttranslationally modified by phosphorylation and dephosphorylation, which prompted our investigation of the underlying mechanisms and biological consequences of their regulation. On the basis of a screen that implicated the heat shock protein Hspa4l in spermatogenesis, we generated mice deficient in Hspa4l (Hspa4l-null mice), which showed male infertility and the m...
Source: Signal Transduction Knowledge Environment - March 26, 2019 Category: Science Authors: Itoh, K., Kondoh, G., Miyachi, H., Sugai, M., Kaneko, Y., Kitano, S., Watanabe, H., Maeda, R., Imura, A., Liu, Y., Ito, C., Itohara, S., Toshimori, K., Fujita, J. Tags: STKE Research Articles Source Type: news

Activating cGAS at the right time and place
Plasma membrane localization and acetylation ensure the appropriate activation of the DNA sensor cGAS. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - March 26, 2019 Category: Science Authors: Wong, W. Tags: STKE Editors ' Choice Source Type: news

Enzymatically oxidized phospholipids assume center stage as essential regulators of innate immunity and cell death
Enzymatically oxidized phospholipids (eoxPLs) are formed through regulated processes by which eicosanoids or prostaglandins are attached to phospholipids (PLs) in immune cells. These eoxPLs comprise structurally diverse families of biomolecules with potent bioactivities, and they have important immunoregulatory roles in both health and disease. The formation of oxPLs through enzymatic pathways and their signaling capabilities are emerging concepts. This paradigm is changing our understanding of eicosanoid, prostaglandin, and PL biology in health and disease. eoxPLs have roles in cellular events such as ferroptosis, apoptos...
Source: Signal Transduction Knowledge Environment - March 26, 2019 Category: Science Authors: ODonnell, V. B., Aldrovandi, M., Murphy, R. C., Krönke, G. Tags: STKE Reviews Source Type: news

Regulation of type I interferon: Its HIP to be K2
Uncontrolled expression of type I interferon (IFN-I) drives autoimmunity, necessitating the need for tight regulation. In this issue, Cao et al. reveal a role for the kinase HIPK2 in the transcriptional control of IFN-I during antiviral immune responses. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - March 19, 2019 Category: Science Authors: Best, S. M., Ponia, S. S. Tags: STKE Focus Source Type: news

Direct targeting of G{alpha}q and G{alpha}11 oncoproteins in cancer cells
Somatic gain-of-function mutations of GNAQ and GNA11, which encode α subunits of heterotrimeric Gαq/11 proteins, occur in about 85% of cases of uveal melanoma (UM), the most common cancer of the adult eye. Molecular therapies to directly target these oncoproteins are lacking, and current treatment options rely on radiation, surgery, or inhibition of effector molecules downstream of these G proteins. A hallmark feature of oncogenic Gαq/11 proteins is their reduced intrinsic rate of hydrolysis of guanosine triphosphate (GTP), which results in their accumulation in the GTP-bound, active state. Here, we repor...
Source: Signal Transduction Knowledge Environment - March 19, 2019 Category: Science Authors: Annala, S., Feng, X., Shridhar, N., Eryilmaz, F., Patt, J., Yang, J., Pfeil, E. M., Cervantes-Villagrana, R. D., Inoue, A., Häberlein, F., Slodczyk, T., Reher, R., Kehraus, S., Monteleone, S., Schrage, R., Heycke, N., Rick, U., Engel, S., Pfeifer, Tags: STKE Research Articles Source Type: news

HIPK2 is necessary for type I interferon-mediated antiviral immunity
Precise control of interferons (IFNs) is crucial to maintain immune homeostasis. Here, we demonstrated that homeodomain-interacting protein kinase 2 (HIPK2) was required for the production of type I IFNs in response to RNA virus infection. HIPK2 deficiency markedly impaired IFN production in macrophages after vesicular stomatitis virus (VSV) infection, and HIPK2-deficient mice were more susceptible to lethal VSV disease than were wild-type mice. After VSV infection, HIPK2 was cleaved by active caspases, which released a hyperactive, N-terminal fragment that translocated to the nucleus and further augmented antiviral respon...
Source: Signal Transduction Knowledge Environment - March 19, 2019 Category: Science Authors: Cao, L., Yang, G., Gao, S., Jing, C., Montgomery, R. R., Yin, Y., Wang, P., Fikrig, E., You, F. Tags: STKE Research Articles Source Type: news

Design of a light-gated proton channel based on the crystal structure of Coccomyxa rhodopsin
In this study, solving crystal structure of CsR at 2.0-Å resolution enabled us to identify distinct features of the membrane protein that determine ion transport directivity and voltage sensitivity. A specific hydrogen bond between the highly conserved Arg83 and the nearby nonconserved tyrosine (Tyr14) guided our structure-based transformation of CsR into an operational light-gated proton channel (CySeR) that could potentially be used in optogenetic assays. Time-resolved electrophysiological and spectroscopic measurements distinguished pump currents from channel currents in a single protein and emphasized the necessi...
Source: Signal Transduction Knowledge Environment - March 19, 2019 Category: Science Authors: Fudim, R., Szczepek, M., Vierock, J., Vogt, A., Schmidt, A., Kleinau, G., Fischer, P., Bartl, F., Scheerer, P., Hegemann, P. Tags: STKE Research Articles Source Type: news

Diverse bacterial nucleotide signals
Bacterial enzymes synthesize a range of different cyclic nucleotides that activate distinct host cell receptors. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - March 19, 2019 Category: Science Authors: Foley, J. F. Tags: STKE Editors ' Choice Source Type: news

Mutations in the NPxxY motif stabilize pharmacologically distinct conformational states of the {alpha}1B- and {beta}2-adrenoceptors
G protein–coupled receptors (GPCRs) convert extracellular stimuli to intracellular responses that regulate numerous physiological processes. Crystallographic and biophysical advances in GPCR structural analysis have aided investigations of structure-function relationships that clarify our understanding of these dynamic receptors, but the molecular mechanisms associated with activation and signaling for individual GPCRs may be more complex than was previously appreciated. Here, we investigated the proposed water-mediated, hydrogen-bonded activation switch between the conserved NPxxY motif on transmembrane helix 7 (TMH...
Source: Signal Transduction Knowledge Environment - March 12, 2019 Category: Science Authors: Ragnarsson, L., Andersson, A., Thomas, W. G., Lewis, R. J. Tags: STKE Research Articles Source Type: news

Eye on ion channels in immune cells
Ion channels facilitate the movement of ions across the plasma and organellar membranes. A recent symposium brought together scientists who study ion channels and transporters in immune cells, which highlighted advances in this emerging field and served to chart new avenues for investigating the roles of ion channels in immunity. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - March 12, 2019 Category: Science Authors: Feske, S., Concepcion, A. R., Coetzee, W. A. Tags: STKE Focus Source Type: news

Manganese promotes the aggregation and prion-like cell-to-cell exosomal transmission of {alpha}-synuclein
The aggregation of α-synuclein (αSyn) is considered a key pathophysiological feature of certain neurodegenerative disorders, collectively termed synucleinopathies. Given that a prion-like, cell-to-cell transfer of misfolded αSyn has been recognized in the spreading of αSyn pathology in synucleinopathies, we investigated the biological mechanisms underlying the propagation of the disease with respect to environmental neurotoxic stress. Considering the potential role of the divalent metal manganese (Mn2+) in protein aggregation, we characterized its effect on αSyn misfolding and transmission in ...
Source: Signal Transduction Knowledge Environment - March 12, 2019 Category: Science Authors: Harischandra, D. S., Rokad, D., Neal, M. L., Ghaisas, S., Manne, S., Sarkar, S., Panicker, N., Zenitsky, G., Jin, H., Lewis, M., Huang, X., Anantharam, V., Kanthasamy, A., Kanthasamy, A. G. Tags: STKE Research Articles Source Type: news

Linking Mn2+, {alpha}-synuclein, and neuroinflammation
Several studies elucidate the molecular links between manganese exposure and Parkinson’s disease. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - March 12, 2019 Category: Science Authors: Ferrarelli, L. K. Tags: STKE Editors ' Choice Source Type: news

Carbohydrate-dependent B cell activation by fucose-binding bacterial lectins
Bacterial lectins are typically multivalent and bind noncovalently to specific carbohydrates on host tissues to facilitate bacterial adhesion. Here, we analyzed the effects of two fucose-binding lectins, BambL from Burkholderia ambifaria and LecB from Pseudomonas aeruginosa, on specific signaling pathways in B cells. We found that these bacterial lectins induced B cell activation, which, in vitro, was dependent on the cell surface expression of the B cell antigen receptor (BCR) and its co-receptor CD19, as well as on spleen tyrosine kinase (Syk) activity. The resulting release of intracellular Ca2+ was followed by an incre...
Source: Signal Transduction Knowledge Environment - March 5, 2019 Category: Science Authors: Wilhelm, I., Levit-Zerdoun, E., Jakob, J., Villringer, S., Frensch, M., Übelhart, R., Landi, A., Müller, P., Imberty, A., Thuenauer, R., Claudinon, J., Jumaa, H., Reth, M., Eibel, H., Hobeika, E., Römer, W. Tags: STKE Research Articles Source Type: news

Excitatory neuron-specific SHP2-ERK signaling network regulates synaptic plasticity and memory
Mutations in RAS signaling pathway components cause diverse neurodevelopmental disorders, collectively called RASopathies. Previous studies have suggested that dysregulation in RAS–extracellular signal–regulated kinase (ERK) activation is restricted to distinct cell types in different RASopathies. Some cases of Noonan syndrome (NS) are associated with gain-of-function mutations in the phosphatase SHP2 (encoded by PTPN11); however, SHP2 is abundant in multiple cell types, so it is unclear which cell type(s) contribute to NS phenotypes. Here, we found that expressing the NS-associated mutant SHP2D61G in excitator...
Source: Signal Transduction Knowledge Environment - March 5, 2019 Category: Science Authors: Ryu, H.-H., Kim, T., Kim, J.-W., Kang, M., Park, P., Kim, Y. G., Kim, H., Ha, J., Choi, J. E., Lee, J., Lim, C.-S., Kim, C.-H., Kim, S. J., Silva, A. J., Kaang, B.-K., Lee, Y.-S. Tags: STKE Research Articles Source Type: news

The RBPomics of viral infection
Systems analysis shows that RNA-binding proteins are critical for Sindbis virus infection. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - March 5, 2019 Category: Science Authors: Williams, E. R. Tags: STKE Editors ' Choice Source Type: news

Desynchronization of the molecular clock contributes to the heterogeneity of the inflammatory response
Heterogeneity in the behavior of genetically and developmentally equivalent cells is becoming increasingly appreciated. There are several sources of cellular heterogeneity, including both intrinsic and extrinsic noise. We found that some aspects of heterogeneity in the response of macrophages to bacterial lipopolysaccharide (LPS) were due to intercellular desynchronization of the molecular clock, a cell-intrinsic oscillator. We found that the ratio of the relative expression of two clock genes, Nfil3 and Dbp, expressed in opposite phases of the clock, determined the fraction of cells that produced the cytokine IL-12p40 in ...
Source: Signal Transduction Knowledge Environment - March 5, 2019 Category: Science Authors: Allen, N. C., Philip, N. H., Hui, L., Zhou, X., Franklin, R. A., Kong, Y., Medzhitov, R. Tags: STKE Research Articles Source Type: news

Chronic TGF-{beta} exposure drives stabilized EMT, tumor stemness, and cancer drug resistance with vulnerability to bitopic mTOR inhibition
Tumors comprise cancer stem cells (CSCs) and their heterogeneous progeny within a stromal microenvironment. In response to transforming growth factor–β (TGF-β), epithelial and carcinoma cells undergo a partial or complete epithelial-mesenchymal transition (EMT), which contributes to cancer progression. This process is seen as reversible because cells revert to an epithelial phenotype upon TGF-β removal. However, we found that prolonged TGF-β exposure, mimicking the state of in vivo carcinomas, promotes stable EMT in mammary epithelial and carcinoma cells, in contrast to the reversible EMT induced ...
Source: Signal Transduction Knowledge Environment - February 26, 2019 Category: Science Authors: Katsuno, Y., Meyer, D. S., Zhang, Z., Shokat, K. M., Akhurst, R. J., Miyazono, K., Derynck, R. Tags: STKE Research Articles Source Type: news

Specificity, versatility, and control of TGF-{beta} family signaling
Encoded in mammalian cells by 33 genes, the transforming growth factor–β (TGF-β) family of secreted, homodimeric and heterodimeric proteins controls the differentiation of most, if not all, cell lineages and many aspects of cell and tissue physiology in multicellular eukaryotes. Deregulation of TGF-β family signaling leads to developmental anomalies and disease, whereas enhanced TGF-β signaling contributes to cancer and fibrosis. Here, we review the fundamentals of the signaling mechanisms that are initiated upon TGF-β ligand binding to its cell surface receptors and the dependence of the sig...
Source: Signal Transduction Knowledge Environment - February 26, 2019 Category: Science Authors: Derynck, R., Budi, E. H. Tags: STKE Reviews Source Type: news

Immunometabolism regulates TCR recycling and iNKT cell functions
Invariant natural killer T (iNKT) cells are innate-like T lymphocytes that express an invariant T cell receptor (TCR), which recognizes glycolipid antigens presented on CD1d molecules. These cells are phenotypically and functionally distinct from conventional T cells. When we characterized the metabolic activity of iNKT cells, consistent with their activated phenotype, we found that they had much less mitochondrial respiratory capacity but increased glycolytic activity in comparison to naìˆve conventional CD4+ T cells. After TCR engagement, iNKT cells further increased aerobic glycolysis, which was important for the expre...
Source: Signal Transduction Knowledge Environment - February 26, 2019 Category: Science Authors: Fu, S., Zhu, S., Tian, C., Bai, S., Zhang, J., Zhan, C., Xie, D., Wang, L., Li, Z., Li, J., Zhang, H., Zhou, R., Tian, Z., Xu, T., Bai, L. Tags: STKE Research Articles Source Type: news

Linking lysosomes to stem cell differentiation
Lysosomal signaling enables stem cell differentiation by sequestering the transcription factor Tfe3 in the cytoplasm. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - February 26, 2019 Category: Science Authors: VanHook, A. M. Tags: STKE Editors ' Choice Source Type: news

Disabling the G{beta}{gamma}-SNARE interaction disrupts GPCR-mediated presynaptic inhibition, leading to physiological and behavioral phenotypes
G protein–coupled receptors (GPCRs) that couple to Gi/o proteins modulate neurotransmission presynaptically by inhibiting exocytosis. Release of Gβ subunits from activated G proteins decreases the activity of voltage-gated Ca2+ channels (VGCCs), decreasing excitability. A less understood Gβ-mediated mechanism downstream of Ca2+ entry is the binding of Gβ to SNARE complexes, which facilitate the fusion of vesicles with the cell plasma membrane in exocytosis. Here, we generated mice expressing a form of the SNARE protein SNAP25 with premature truncation of the C terminus and that were therefore partially...
Source: Signal Transduction Knowledge Environment - February 19, 2019 Category: Science Authors: Zurawski, Z., Thompson Gray, A. D., Brady, L. J., Page, B., Church, E., Harris, N. A., Dohn, M. R., Yim, Y. Y., Hyde, K., Mortlock, D. P., Jones, C. K., Winder, D. G., Alford, S., Hamm, H. E. Tags: STKE Research Articles Source Type: news

Structure of the C-terminal guanine nucleotide exchange factor module of Trio in an autoinhibited conformation reveals its oncogenic potential
The C-terminal guanine nucleotide exchange factor (GEF) module of Trio (TrioC) transfers signals from the Gαq/11 subfamily of heterotrimeric G proteins to the small guanosine triphosphatase (GTPase) RhoA, enabling Gαq/11-coupled G protein–coupled receptors (GPCRs) to control downstream events, such as cell motility and gene transcription. This conserved signal transduction axis is crucial for tumor growth in uveal melanoma. Previous studies indicate that the GEF activity of the TrioC module is autoinhibited, with release of autoinhibition upon Gαq/11 binding. Here, we determined the crystal structur...
Source: Signal Transduction Knowledge Environment - February 19, 2019 Category: Science Authors: Bandekar, S. J., Arang, N., Tully, E. S., Tang, B. A., Barton, B. L., Li, S., Gutkind, J. S., Tesmer, J. J. G. Tags: STKE Research Articles Source Type: news

Glutathione S-transferases promote proinflammatory astrocyte-microglia communication during brain inflammation
Astrocytes and microglia play critical roles in brain inflammation. Here, we report that glutathione S-transferases (GSTs), particularly GSTM1, promote proinflammatory signaling in astrocytes and contribute to astrocyte-mediated microglia activation during brain inflammation. In vivo, astrocyte-specific knockdown of GSTM1 in the prefrontal cortex attenuated microglia activation in brain inflammation induced by systemic injection of lipopolysaccharides (LPS). Knocking down GSTM1 in astrocytes also attenuated LPS-induced production of the proinflammatory cytokine tumor necrosis factor–α (TNF-α) by microglia...
Source: Signal Transduction Knowledge Environment - February 19, 2019 Category: Science Authors: Kano, S.-i., Choi, E. Y., Dohi, E., Agarwal, S., Chang, D. J., Wilson, A. M., Lo, B. D., Rose, I. V. L., Gonzalez, S., Imai, T., Sawa, A. Tags: STKE Research Articles Source Type: news

Build them up, break them down
Cancer and stromal cells release signals that manipulate the vasculature to promote tumor metastasis or growth. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - February 19, 2019 Category: Science Authors: Wong, W. Tags: STKE Editors ' Choice Source Type: news

An immunoproteomic approach to characterize the CAR interactome and signalosome
Adoptive transfer of T cells that express a chimeric antigen receptor (CAR) is an approved immunotherapy that may be curative for some hematological cancers. To better understand the therapeutic mechanism of action, we systematically analyzed CAR signaling in human primary T cells by mass spectrometry. When we compared the interactomes and the signaling pathways activated by distinct CAR-T cells that shared the same antigen-binding domain but differed in their intracellular domains and their in vivo antitumor efficacy, we found that only second-generation CARs induced the expression of a constitutively phosphorylated form ...
Source: Signal Transduction Knowledge Environment - February 12, 2019 Category: Science Authors: Ramello, M. C., Benzaïd, I., Kuenzi, B. M., Lienlaf-Moreno, M., Kandell, W. M., Santiago, D. N., Pabon-Saldana, M., Darville, L., Fang, B., Rix, U., Yoder, S., Berglund, A., Koomen, J. M., Haura, E. B., Abate-Daga, D. Tags: STKE Research Articles Source Type: news

Inflammation, necrosis, and the kinase RIP3 are key mediators of AAG-dependent alkylation-induced retinal degeneration
DNA-alkylating agents are commonly used to kill cancer cells, but the base excision repair (BER) pathway they trigger can also produce toxic intermediates that cause tissue damage, such as retinal degeneration (RD). Apoptosis, a process of programmed cell death, is assumed to be the main mechanism of this alkylation-induced photoreceptor (PR) cell death in RD. Here, we studied the involvement of necroptosis (another programmed cell death process) and inflammation in alkylation-induced RD. Male mice exposed to a methylating agent exhibited a reduced number of PR cell rows, active gliosis, and cytokine induction and macropha...
Source: Signal Transduction Knowledge Environment - February 12, 2019 Category: Science Authors: Allocca, M., Corrigan, J. J., Mazumder, A., Fake, K. R., Samson, L. D. Tags: STKE Research Articles Source Type: news

Mitochondrial reactive oxygen species enable proinflammatory signaling through disulfide linkage of NEMO
A major function of macrophages during infection is initiation of the proinflammatory response, leading to the secretion of cytokines that help to orchestrate the immune response. Here, we identify reactive oxygen species (ROS) as crucial mediators of proinflammatory signaling leading to cytokine secretion in Listeria monocytogenes–infected macrophages. ROS produced by NADPH oxidases (Noxes), such as Nox2, are key components of the macrophage response to invading pathogens; however, our data show that the ROS that mediated proinflammatory signaling were produced by mitochondria (mtROS). We identified the inhibitor of...
Source: Signal Transduction Knowledge Environment - February 12, 2019 Category: Science Authors: Herb, M., Gluschko, A., Wiegmann, K., Farid, A., Wolf, A., Utermöhlen, O., Krut, O., Krönke, M., Schramm, M. Tags: STKE Research Articles Source Type: news

EGFR signaling moves infection
A viral EGF homolog increases the migration of cells infected with vaccinia virus to promote viral spread. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - February 12, 2019 Category: Science Authors: Williams, E. R. Tags: STKE Editors ' Choice Source Type: news

Hypoxic cancer-associated fibroblasts increase NCBP2-AS2/HIAR to promote endothelial sprouting through enhanced VEGF signaling
Intratumoral hypoxia causes the formation of dysfunctional blood vessels, which contribute to tumor metastasis and reduce the efficacy of therapeutic treatments. Blood vessels are embedded in the tumor stroma of which cancer-associated fibroblasts (CAFs) constitute a prominent cellular component. We found that hypoxic human mammary CAFs promoted angiogenesis in CAF-endothelial cell cocultures in vitro. Mass spectrometry–based proteomic analysis of the CAF secretome unraveled that hypoxic CAFs contributed to blood vessel abnormalities by altering their secretion of various pro- and anti-angiogenic factors. Hypoxia ind...
Source: Signal Transduction Knowledge Environment - February 5, 2019 Category: Science Authors: Kugeratski, F. G., Atkinson, S. J., Neilson, L. J., Lilla, S., Knight, J. R. P., Serneels, J., Juin, A., Ismail, S., Bryant, D. M., Markert, E. K., Machesky, L. M., Mazzone, M., Sansom, O. J., Zanivan, S. Tags: STKE Research Articles Source Type: news

Autophagy-independent p62 in metastatic melanoma
By pairing up with RNA-binding proteins, p62 promotes melanoma progression. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - February 5, 2019 Category: Science Authors: Ferrarelli, L. K. Tags: STKE Editors ' Choice Source Type: news

Inhibition of T cell activation and function by the adaptor protein CIN85
T cell activation is initiated by signaling molecules downstream of the T cell receptor (TCR) that are organized by adaptor proteins. CIN85 (Cbl-interacting protein of 85 kDa) is one such adaptor protein. Here, we showed that CIN85 limited T cell responses to TCR stimulation. Compared to activated wild-type (WT) T cells, those that lacked CIN85 produced more IL-2 and exhibited greater proliferation. After stimulation of WT T cells with their cognate antigen, CIN85 was recruited to the TCR signaling complex. Early TCR signaling events, such as phosphorylation of -chain–associated protein kinase 70 (Zap70), Src homolog...
Source: Signal Transduction Knowledge Environment - February 5, 2019 Category: Science Authors: Kong, M. S., Hashimoto-Tane, A., Kawashima, Y., Sakuma, M., Yokosuka, T., Kometani, K., Onishi, R., Carpino, N., Ohara, O., Kurosaki, T., Phua, K. K., Saito, T. Tags: STKE Research Articles Source Type: news

Interrogating B cell signaling pathways: A quest for novel therapies for mantle cell lymphoma
Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma that is largely chemoresistant. Ibrutinib, a drug that inhibits Bruton’s tyrosine kinase (BTK), has improved the overall survival of patients with MCL; however, resistance to ibrutinib has emerged as a decisive, negative factor in the prognosis of MCL. Adopting a more patient-centric therapeutic approach that incorporates applied genomics and interrogation of B cell signaling pathways may offer an alternative route to reach durable remission in patients with MCL. Although targeting genetic variants in MCL is not yet feasible in the clinical setting, the iden...
Source: Signal Transduction Knowledge Environment - February 5, 2019 Category: Science Authors: Ahmed, M., Lorence, E., Wang, J., Jung, D., Zhang, L., Nomie, K., Wang, M. Tags: STKE Reviews Source Type: news

Targeting NOTCH activation in small cell lung cancer through LSD1 inhibition
Small cell lung cancer (SCLC) is a recalcitrant, aggressive neuroendocrine-type cancer for which little change to first-line standard-of-care treatment has occurred within the last few decades. Unlike nonsmall cell lung cancer (NSCLC), SCLC harbors few actionable mutations for therapeutic intervention. Lysine-specific histone demethylase 1A (LSD1 also known as KDM1A) inhibitors were previously shown to have selective activity in SCLC models, but the underlying mechanism was elusive. Here, we found that exposure to the selective LSD1 inhibitor ORY-1001 activated the NOTCH pathway, resulting in the suppression of the transcr...
Source: Signal Transduction Knowledge Environment - February 5, 2019 Category: Science Authors: Augert, A., Eastwood, E., Ibrahim, A. H., Wu, N., Grunblatt, E., Basom, R., Liggitt, D., Eaton, K. D., Martins, R., Poirier, J. T., Rudin, C. M., Milletti, F., Cheng, W.-Y., Mack, F., MacPherson, D. Tags: STKE Research Articles Source Type: news

The transcription factor SP3 drives TNF-{alpha} expression in response to Smac mimetics
The controlled production and downstream signaling of the inflammatory cytokine tumor necrosis factor–α (TNF-α) are important for immunity and its anticancer effects. Although chronic stimulation with TNF-α is detrimental to the health of the host in several autoimmune and inflammatory disorders, TNF-α—contrary to what its name implies—leads to cancer formation by promoting cell proliferation and survival. Smac mimetic compounds (SMCs), small-molecule antagonists of inhibitor of apoptosis proteins (IAPs), switch the TNF-α signal from promoting survival to promoting death in c...
Source: Signal Transduction Knowledge Environment - January 29, 2019 Category: Science Authors: Beug, S. T., Cheung, H. H., Sanda, T., St-Jean, M., Beauregard, C. E., Mamady, H., Baird, S. D., LaCasse, E. C., Korneluk, R. G. Tags: STKE Research Articles Source Type: news

Immune suppression with complex III
Loss of mitochondrial complex III in regulatory T cells reduces their suppressive activity without affecting their survival. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - January 29, 2019 Category: Science Authors: Foley, J. F. Tags: STKE Editors ' Choice Source Type: news

The pseudokinase domains of guanylyl cyclase-A and -B allosterically increase the affinity of their catalytic domains for substrate
Natriuretic peptides regulate multiple physiologic systems by activating transmembrane receptors containing intracellular guanylyl cyclase domains, such as GC-A and GC-B, also known as Npr1 and Npr2, respectively. Both enzymes contain an intracellular, phosphorylated pseudokinase domain (PKD) critical for activation of the C-terminal cGMP-synthesizing guanylyl cyclase domain. Because ATP allosterically activates GC-A and GC-B, we investigated how ATP binding to the PKD influenced guanylyl cyclase activity. Molecular modeling indicated that all the residues of the ATP-binding site of the prototypical kinase PKA, except the ...
Source: Signal Transduction Knowledge Environment - January 29, 2019 Category: Science Authors: Edmund, A. B., Walseth, T. F., Levinson, N. M., Potter, L. R. Tags: STKE Research Articles Source Type: news

Transcriptional repressor REST drives lineage stage-specific chromatin compaction at Ptch1 and increases AKT activation in a mouse model of medulloblastoma
In medulloblastomas (MBs), the expression and activity of RE1-silencing transcription factor (REST) is increased in tumors driven by the sonic hedgehog (SHH) pathway, specifically the SHH-α (children 3 to 16 years) and SHH-β (infants) subgroups. Neuronal maturation is greater in SHH-β than SHH-α tumors, but both correlate with poor overall patient survival. We studied the contribution of REST to MB using a transgenic mouse model (RESTTG) wherein conditional NeuroD2-controlled REST transgene expression in lineage-committed Ptch1+/– cerebellar granule neuron progenitors (CGNPs) accelerated tumorig...
Source: Signal Transduction Knowledge Environment - January 22, 2019 Category: Science Authors: Dobson, T. H. W., Tao, R.-H., Swaminathan, J., Maegawa, S., Shaik, S., Bravo-Alegria, J., Sharma, A., Kennis, B., Yang, Y., Callegari, K., Haltom, A. R., Taylor, P., Kogiso, M., Qi, L., Khatua, S., Goldman, S., Lulla, R. R., Fangusaro, J., MacDonald, T. J Tags: STKE Research Articles Source Type: news