The DUF1669 domain of FAM83 family proteins anchor casein kinase 1 isoforms
Members of the casein kinase 1 (CK1) family of serine-threonine protein kinases are implicated in the regulation of many cellular processes, including the cell cycle, circadian rhythms, and Wnt and Hedgehog signaling. Because these kinases exhibit constitutive activity in biochemical assays, it is likely that their activity in cells is controlled by subcellular localization, interactions with inhibitory proteins, targeted degradation, or combinations of these mechanisms. We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A to FAM83H) interacted wit...
Source: Signal Transduction Knowledge Environment - May 22, 2018 Category: Science Authors: Fulcher, L. J., Bozatzi, P., Tachie-Menson, T., Wu, K. Z. L., Cummins, T. D., Bufton, J. C., Pinkas, D. M., Dunbar, K., Shrestha, S., Wood, N. T., Weidlich, S., Macartney, T. J., Varghese, J., Gourlay, R., Campbell, D. G., Dingwell, K. S., Smith, J. C., B Tags: STKE Research Articles Source Type: news

How Treg cells stay true
Human Treg cells maintain their cellular identity through changes in their protein expression signature. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - May 22, 2018 Category: Science Authors: Williams, E. R. Tags: STKE Editors ' Choice Source Type: news

Tuning ITAM multiplicity on T cell receptors can control potency and selectivity to ligand density
The T cell antigen receptor (TCR) recognizes peptides from pathogenic proteins bound in the major histocompatibility complex (MHC). To convert this binding event into downstream signaling, the TCR complex contains immunoreceptor tyrosine-based activation motifs (ITAMs) that act as docking sites for the cytoplasmic tyrosine kinase ZAP-70. Unique among antigen receptors, the TCR complex uses 10 ITAMs to transduce peptide-MHC binding to the cell interior. Using synthetic, drug-inducible receptor-ligand pairs, it was found that greater ITAM multiplicity primarily enhanced the efficiency with which ligand binding was converted ...
Source: Signal Transduction Knowledge Environment - May 22, 2018 Category: Science Authors: James, J. R. Tags: STKE Research Articles Source Type: news

Integration of protein phosphorylation, acetylation, and methylation data sets to outline lung cancer signaling networks
Protein posttranslational modifications (PTMs) have typically been studied independently, yet many proteins are modified by more than one PTM type, and cell signaling pathways somehow integrate this information. We coupled immunoprecipitation using PTM-specific antibodies with tandem mass tag (TMT) mass spectrometry to simultaneously examine phosphorylation, methylation, and acetylation in 45 lung cancer cell lines compared to normal lung tissue and to cell lines treated with anticancer drugs. This simultaneous, large-scale, integrative analysis of these PTMs using a cluster-filtered network (CFN) approach revealed that ce...
Source: Signal Transduction Knowledge Environment - May 22, 2018 Category: Science Authors: Grimes, M., Hall, B., Foltz, L., Levy, T., Rikova, K., Gaiser, J., Cook, W., Smirnova, E., Wheeler, T., Clark, N. R., Lachmann, A., Zhang, B., Hornbeck, P., Maayan, A., Comb, M. Tags: STKE Research Resources Source Type: news

Aurora B opposes PP1 function in mitosis by phosphorylating the conserved PP1-binding RVxF motif in PP1 regulatory proteins
Protein phosphatase 1 (PP1) is a highly conserved protein phosphatase that performs most of the serine- and threonine-dephosphorylation reactions in eukaryotes and opposes the actions of a diverse set of serine and threonine (Ser-Thr) protein kinases. PP1 gains substrate specificity through binding to a large number (>200) of regulatory proteins that control PP1 localization, activity, and interactions with substrates. PP1 recognizes the well-characterized RVxF binding motif that is present in many of these regulatory proteins, thus generating a multitude of distinct PP1 holoenzymes. We showed that a subset of the RVxF ...
Source: Signal Transduction Knowledge Environment - May 15, 2018 Category: Science Authors: Nasa, I., Rusin, S. F., Kettenbach, A. N., Moorhead, G. B. Tags: STKE Research Articles Source Type: news

A DGK{zeta}-FoxO-ubiquitin proteolytic axis controls fiber size during skeletal muscle remodeling
Skeletal muscle rapidly remodels in response to various stresses, and the resulting changes in muscle mass profoundly influence our health and quality of life. We identified a diacylglycerol kinase (DGK)–mediated pathway that regulated muscle mass during remodeling. During mechanical overload, DGK abundance was increased and required for effective hypertrophy. DGK not only augmented anabolic responses but also suppressed ubiquitin-proteasome system (UPS)–dependent proteolysis. We found that DGK inhibited the transcription factor FoxO that promotes the induction of the UPS. This function was mediated through a m...
Source: Signal Transduction Knowledge Environment - May 15, 2018 Category: Science Authors: You, J.-S., Dooley, M. S., Kim, C.-R., Kim, E.-J., Xu, W., Goodman, C. A., Hornberger, T. A. Tags: STKE Research Articles Source Type: news

IRE1{alpha} prevents hepatic steatosis by processing and promoting the degradation of select microRNAs
Obesity or a high-fat diet represses the endoribonuclease activity of inositol-requiring enzyme 1α (IRE1α), a transducer of the unfolded protein response (UPR) in cells under endoplasmic reticulum (ER) stress. An impaired UPR is associated with hepatic steatosis and nonalcoholic fatty liver disease (NAFLD), which is caused by lipid accumulation in the liver. We found that IRE1α was critical to maintaining lipid homeostasis in the liver by repressing the biogenesis of microRNAs (miRNAs) that regulate lipid mobilization. In mice fed normal chow, the endoribonuclease function of IRE1α processed a subse...
Source: Signal Transduction Knowledge Environment - May 15, 2018 Category: Science Authors: Wang, J.-M., Qiu, Y., Yang, Z., Kim, H., Qian, Q., Sun, Q., Zhang, C., Yin, L., Fang, D., Back, S. H., Kaufman, R. J., Yang, L., Zhang, K. Tags: STKE Research Articles Source Type: news

Global assessment of its network dynamics reveals that the kinase Plk1 inhibits the phosphatase PP6 to promote Aurora A activity
Polo-like kinase 1 (Plk1) is an essential protein kinase that promotes faithful mitotic progression in eukaryotes. The subcellular localization and substrate interactions of Plk1 are tightly controlled and require its binding to phosphorylated residues. To identify phosphorylation-dependent interactions within the Plk1 network in human mitotic cells, we performed quantitative proteomics on HeLa cells cultured with kinase inhibitors or expressing a Plk1 mutant that was deficient in phosphorylation-dependent substrate binding. We found that many interactions were abolished upon kinase inhibition; however, a subset was protec...
Source: Signal Transduction Knowledge Environment - May 15, 2018 Category: Science Authors: Kettenbach, A. N., Schlosser, K. A., Lyons, S. P., Nasa, I., Gui, J., Adamo, M. E., Gerber, S. A. Tags: STKE Research Articles Source Type: news

New connections: Kinases and phosphatases in control of mitosis
Two studies in this week’s issue of Science Signaling reveal coordinated regulation of kinases and phosphatases during cell cycle progression. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - May 15, 2018 Category: Science Authors: Ferrarelli, L. K. Tags: STKE Editors ' Choice Source Type: news

Gene expression kinetics governs stimulus-specific decoration of the Salmonella outer membrane
We report the mechanism by which Salmonella produces different lipid A profiles when PmrA is activated by low Mg2+ versus a mildly acidic pH. Low Mg2+ favored modification of the lipid A phosphates with 4-amino-4-deoxy-l-aminoarabinose (l-Ara4N) by activating the regulatory protein PhoP, which initially increased the LPS negative charge by promoting transcription of lpxT, encoding an enzyme that adds an additional phosphate group to lipid A. Later, PhoP activated PmrA posttranslationally, resulting in expression of PmrA-activated genes, including those encoding the LpxT inhibitor PmrR and enzymes responsible for the incorp...
Source: Signal Transduction Knowledge Environment - May 8, 2018 Category: Science Authors: Hong, X., Chen, H. D., Groisman, E. A. Tags: STKE Research Articles Source Type: news

Highlight: A tasteful conversation with atypical mitochondria at atypical synapses
Atypical mitochondria produce ATP used as a neurotransmitter by type II taste cells to transduce sweet, bitter, or savory flavors. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - May 8, 2018 Category: Science Authors: Dubyak, G. R. Tags: STKE Editors ' Choice Source Type: news

The receptor tyrosine kinase TrkB signals without dimerization at the plasma membrane
Tropomyosin-related tyrosine kinase B (TrkB) is the receptor for brain-derived neurotrophic factor (BDNF) and provides critical signaling that supports the development and function of the mammalian nervous system. Like other receptor tyrosine kinases (RTKs), TrkB is thought to signal as a dimer. Using cell imaging and biochemical assays, we found that TrkB acted as a monomeric receptor at the plasma membrane regardless of its binding to BDNF and initial activation. Dimerization occurred only after the internalization and accumulation of TrkB monomers within BDNF-containing endosomes. We further showed that dynamin-mediated...
Source: Signal Transduction Knowledge Environment - May 8, 2018 Category: Science Authors: Zahavi, E. E., Steinberg, N., Altman, T., Chein, M., Joshi, Y., Gradus-Pery, T., Perlson, E. Tags: STKE Research Articles Source Type: news

CCR5 adopts three homodimeric conformations that control cell surface delivery
Biophysical methods and x-ray crystallography have revealed that class A G protein–coupled receptors (GPCRs) can form homodimers. We combined computational approaches with receptor cross-linking, energy transfer, and a newly developed functional export assay to characterize the residues involved in the dimerization interfaces of the chemokine receptor CCR5, the major co-receptor for HIV-1 entry into cells. We provide evidence of three distinct CCR5 dimeric organizations, involving residues of transmembrane helix 5. Two dimeric states corresponded to unliganded receptors, whereas the binding of the inverse agonist mar...
Source: Signal Transduction Knowledge Environment - May 8, 2018 Category: Science Authors: Jin, J., Momboisse, F., Boncompain, G., Koensgen, F., Zhou, Z., Cordeiro, N., Arenzana-Seisdedos, F., Perez, F., Lagane, B., Kellenberger, E., Brelot, A. Tags: STKE Research Articles Source Type: news

Chemical synapses without synaptic vesicles: Purinergic neurotransmission through a CALHM1 channel-mitochondrial signaling complex
Conventional chemical synapses in the nervous system involve a presynaptic accumulation of neurotransmitter-containing vesicles, which fuse with the plasma membrane to release neurotransmitters that activate postsynaptic receptors. In taste buds, type II receptor cells do not have conventional synaptic features but nonetheless show regulated release of their afferent neurotransmitter, ATP, through a large-pore, voltage-gated channel, CALHM1. Immunohistochemistry revealed that CALHM1 was localized to points of contact between the receptor cells and sensory nerve fibers. Ultrastructural and super-resolution light microscopy ...
Source: Signal Transduction Knowledge Environment - May 8, 2018 Category: Science Authors: Romanov, R. A., Lasher, R. S., High, B., Savidge, L. E., Lawson, A., Rogachevskaja, O. A., Zhao, H., Rogachevsky, V. V., Bystrova, M. F., Churbanov, G. D., Adameyko, I., Harkany, T., Yang, R., Kidd, G. J., Marambaud, P., Kinnamon, J. C., Kolesnikov, S. S. Tags: STKE Research Articles Source Type: news

How to recruit a GRK
The dopamine D2 receptor recruits and activates the kinase GRK2 without the need for G protein activation. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - May 8, 2018 Category: Science Authors: Foley, J. F. Tags: STKE Editors ' Choice Source Type: news

Glycerol monolaurate induces filopodia formation by disrupting the association between LAT and SLP-76 microclusters
Glycerol monolaurate (GML) is a monoglyceride with potent antimicrobial properties that suppresses T cell receptor (TCR)–induced signaling and T cell effector function. Actin rearrangement is needed for the interaction of T cells with antigen-presenting cells and for migration to sites of infection. Because of the critical role actin rearrangement plays in T cell effector function, we analyzed the effect of GML on the rearrangement of the actin cytoskeleton after TCR activation. We found that GML-treated human T cells were less adherent than untreated T cells and did not form actin ring structures but instead develop...
Source: Signal Transduction Knowledge Environment - May 1, 2018 Category: Science Authors: Zhang, M. S., Tran, P. M., Wolff, A. J., Tremblay, M. M., Fosdick, M. G., Houtman, J. C. D. Tags: STKE Research Articles Source Type: news

Nuclear PTEN enhances the maturation of a microRNA regulon to limit MyD88-dependent susceptibility to sepsis
Sepsis-induced organ damage is caused by systemic inflammatory response syndrome (SIRS), which results in substantial comorbidities. Therefore, it is of medical importance to identify molecular brakes that can be exploited to dampen inflammation and prevent the development of SIRS. We investigated the role of phosphatase and tensin homolog (PTEN) in suppressing SIRS, increasing microbial clearance, and preventing lung damage. Septic patients and mice with sepsis exhibited increased PTEN expression in leukocytes. Myeloid-specific Pten deletion in an animal model of sepsis increased bacterial loads and cytokine production, w...
Source: Signal Transduction Knowledge Environment - May 1, 2018 Category: Science Authors: Sisti, F., Wang, S., Brandt, S. L., Glosson-Byers, N., Mayo, L. D., Son, Y. M., Sturgeon, S., Filgueiras, L., Jancar, S., Wong, H., Dela Cruz, C. S., Andrews, N., Alves-Filho, J. C., Cunha, F. Q., Serezani, C. H. Tags: STKE Research Articles Source Type: news

VEGF-neuropilin-2 signaling promotes stem-like traits in breast cancer cells by TAZ-mediated repression of the Rac GAP {beta}2-chimaerin
The role of vascular endothelial growth factor (VEGF) signaling in cancer is not only well known in the context of angiogenesis but also important in the functional regulation of tumor cells. Autocrine VEGF signaling mediated by its co-receptors called neuropilins (NRPs) appears to be essential for sustaining the proliferation and survival of cancer stem cells (CSCs), which are implicated in mediating tumor growth, progression, and drug resistance. Therefore, understanding the mechanisms involved in VEGF-mediated support of CSCs is critical to successfully treating cancer patients. The expression of the Hippo effector TAZ ...
Source: Signal Transduction Knowledge Environment - May 1, 2018 Category: Science Authors: Elaimy, A. L., Guru, S., Chang, C., Ou, J., Amante, J. J., Zhu, L. J., Goel, H. L., Mercurio, A. M. Tags: STKE Research Articles Source Type: news

The interaction between IKK{alpha} and LC3 promotes type I interferon production through the TLR9-containing LAPosome
Toll-like receptor 9 (TLR9) recognizes DNA in endosomes and activates distinct signaling pathways to stimulate the production of proinflammatory cytokines and type I interferons (IFNs). The assembly of signaling platforms on microtubule-associated proteins 1A/1B–light chain 3 (LC3)–decorated endosomal vesicles is required to transduce TLR9 signals that stimulate the production of IFN but not interleukin-12 p40 (IL-12p40). LC3-associated phagocytosis (LAP), a form of noncanonical autophagy, is critical for the activation of interferon regulatory factor 7 (IRF7) and for IFN synthesis. We showed that after the sti...
Source: Signal Transduction Knowledge Environment - May 1, 2018 Category: Science Authors: Hayashi, K., Taura, M., Iwasaki, A. Tags: STKE Research Articles Source Type: news

When ER stress is bad for cancer
A low-protein diet enhances tumor immunosurveillance in multiple cancer types. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - May 1, 2018 Category: Science Authors: Wong, W. Tags: STKE Editors ' Choice Source Type: news

New connections: Ewings sarcomas driver is its Achilles heel
Several studies identify drug combinations that target or exploit the EWS-FLI1 fusion protein to kill Ewing’s sarcoma cells. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - April 24, 2018 Category: Science Authors: Ferrarelli, L. K. Tags: STKE Editors ' Choice Source Type: news

Mitophagy controls beige adipocyte maintenance through a Parkin-dependent and UCP1-independent mechanism
Beige adipocytes are an inducible form of mitochondria-enriched thermogenic adipocytes that emerge in response to external stimuli, such as chronic cold exposure. We have previously shown that after the withdrawal of external stimuli, beige adipocytes directly acquire a white fat–like phenotype through autophagy-mediated mitochondrial degradation. We investigated the upstream pathway that mediates mitochondrial clearance and report that Parkin-mediated mitophagy plays a key role in the beige-to-white adipocyte transition. Mice genetically deficient in Park2 showed reduced mitochondrial degradation and retained thermo...
Source: Signal Transduction Knowledge Environment - April 24, 2018 Category: Science Authors: Lu, X., Altshuler-Keylin, S., Wang, Q., Chen, Y., Henrique Sponton, C., Ikeda, K., Maretich, P., Yoneshiro, T., Kajimura, S. Tags: STKE Research Articles Source Type: news

Jak-TGF{beta} cross-talk links transient adipose tissue inflammation to beige adipogenesis
The transient activation of inflammatory networks is required for adipose tissue remodeling including the "browning" of white fat in response to stimuli such as β3-adrenergic receptor activation. In this process, white adipose tissue acquires thermogenic characteristics through the recruitment of so-called beige adipocytes. We investigated the downstream signaling pathways impinging on adipocyte progenitors that promote de novo formation of adipocytes. We showed that the Jak family of kinases controlled TGFβ signaling in the adipose tissue microenvironment through Stat3 and thereby adipogenic commitment...
Source: Signal Transduction Knowledge Environment - April 24, 2018 Category: Science Authors: Babaei, R., Schuster, M., Meln, I., Lerch, S., Ghandour, R. A., Pisani, D. F., Bayindir-Buchhalter, I., Marx, J., Wu, S., Schoiswohl, G., Billeter, A. T., Krunic, D., Mauer, J., Lee, Y.-H., Granneman, J. G., Fischer, L., Müller-Stich, B. P., Amri, Tags: STKE Research Articles Source Type: news

Transient inflammatory signaling promotes beige adipogenesis
Inflammatory signaling has been implicated in adipose tissue remodeling and metabolism. In this issue of Science Signaling, Babaei et al. report that lipolysis induced by β3-adrenergic signaling triggers transient inflammation that directs progenitor cells toward beige adipogenesis. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - April 24, 2018 Category: Science Authors: Sun, K., Gao, Z., Kolonin, M. G. Tags: STKE Focus Source Type: news

A defect in KCa3.1 channel activity limits the ability of CD8+ T cells from cancer patients to infiltrate an adenosine-rich microenvironment
The limited ability of cytotoxic T cells to infiltrate solid tumors hampers immune surveillance and the efficacy of immunotherapies in cancer. Adenosine accumulates in solid tumors and inhibits tumor-specific T cells. Adenosine inhibits T cell motility through the A2A receptor (A2AR) and suppression of KCa3.1 channels. We conducted three-dimensional chemotaxis experiments to elucidate the effect of adenosine on the migration of peripheral blood CD8+ T cells from head and neck squamous cell carcinoma (HNSCC) patients. The chemotaxis of HNSCC CD8+ T cells was reduced in the presence of adenosine, and the effect was greater o...
Source: Signal Transduction Knowledge Environment - April 24, 2018 Category: Science Authors: Chimote, A. A., Balajthy, A., Arnold, M. J., Newton, H. S., Hajdu, P., Qualtieri, J., Wise-Draper, T., Conforti, L. Tags: STKE Research Articles Source Type: news

Parkin mediates mitophagy during beige-to-white fat conversion
In this issue of Science Signaling, Lu et al. reveal a role for Parkin-mediated mitophagy in beige-to-white adipocyte transition. In the absence of Parkin, mitochondria in thermogenic beige adipocytes are preserved even after the elimination of cold mimetic stimuli—in contrast to their typical elimination during the white transition. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - April 24, 2018 Category: Science Authors: Sarraf, S. A., Youle, R. J. Tags: STKE Focus Source Type: news

Estrogen receptor {alpha} contributes to T cell-mediated autoimmune inflammation by promoting T cell activation and proliferation
It has long been appreciated that most autoimmune disorders are characterized by increased prevalence in females, suggesting a potential role for sex hormones in the etiology of autoimmunity. To study how estrogen receptor α (ERα) contributes to autoimmune diseases, we generated mice in which ERα was deleted specifically in T lymphocytes. We found that ERα deletion in T cells reduced their pathogenic potential in a mouse model of colitis and correlated with transcriptomic changes that affected T cell activation. ERα deletion in T cells contributed to multiple aspects of T cell function, includ...
Source: Signal Transduction Knowledge Environment - April 17, 2018 Category: Science Authors: Mohammad, I., Starskaia, I., Nagy, T., Guo, J., Yatkin, E., Väänänen, K., Watford, W. T., Chen, Z. Tags: STKE Research Articles Source Type: news

Revisiting PD-1 signaling
The protective effect of anti-PD1 therapy in cancer may not require the phosphatase Ptpn11. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - April 17, 2018 Category: Science Authors: Williams, E. Tags: STKE Editors ' Choice Source Type: news

Interleukin-2 shapes the cytotoxic T cell proteome and immune environment-sensing programs
Interleukin-2 (IL-2) and Janus kinases (JAKs) regulate transcriptional programs and protein synthesis to promote the differentiation of effector CD8+ cytotoxic T lymphocytes (CTLs). Using high-resolution mass spectrometry, we generated an in-depth characterization of how IL-2 and JAKs configure the CTL proteome to control CTL function. We found that IL-2 signaling through JAK1 and JAK3 (JAK1/3) increased the abundance of a key subset of proteins to induce the accumulation of critical cytokines and effector molecules in T cells. Moreover, IL-2 maintained the concentration of proteins that support core metabolic processes es...
Source: Signal Transduction Knowledge Environment - April 17, 2018 Category: Science Authors: Rollings, C. M., Sinclair, L. V., Brady, H. J. M., Cantrell, D. A., Ross, S. H. Tags: STKE Research Resources Source Type: news

Truncation- and motif-based pan-cancer analysis reveals tumor-suppressing kinases
A major challenge in cancer genomics is identifying "driver" mutations from the many neutral "passenger" mutations within a given tumor. To identify driver mutations that would otherwise be lost within mutational noise, we filtered genomic data by motifs that are critical for kinase activity. In the first step of our screen, we used data from the Cancer Cell Line Encyclopedia and The Cancer Genome Atlas to identify kinases with truncation mutations occurring within or before the kinase domain. The top 30 tumor-suppressing kinases were aligned, and hotspots for loss-of-function (LOF) mutations were ident...
Source: Signal Transduction Knowledge Environment - April 17, 2018 Category: Science Authors: Hudson, A. M., Stephenson, N. L., Li, C., Trotter, E., Fletcher, A. J., Katona, G., Bieniasz-Krzywiec, P., Howell, M., Wirth, C., Furney, S., Miller, C. J., Brognard, J. Tags: STKE Research Articles Source Type: news

A switch-variant model integrates the functions of an autoimmune variant of the phosphatase PTPN22
The R620W polymorphism in protein tyrosine phosphatase nonreceptor type 22 (PTPN22) predisposes carriers to several autoimmune diseases. Two papers in Science Immunology and Science Signaling on this human disease–associated variant lead us to propose a new "switch-of-function" model. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - April 17, 2018 Category: Science Authors: Vang, T., Nielsen, J., Burn, G. L. Tags: STKE Focus Source Type: news

New connections: The complexity of simple signaling systems
Bacterial two-component systems are efficient and versatile but not always simple. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - April 10, 2018 Category: Science Authors: VanHook, A. M. Tags: STKE Editors ' Choice Source Type: news

mTORC1 controls lysosomal Ca2+ release through the two-pore channel TPC2
Two-pore segment channel 2 (TPC2) is a ubiquitously expressed, lysosomally targeted ion channel that aids in terminating autophagy and is inhibited upon its association with mechanistic target of rapamycin (mTOR). It is controversial whether TPC2 mediates lysosomal Ca2+ release or selectively conducts Na+ and whether the binding of nicotinic acid adenine dinucleotide phosphate (NAADP) or phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] is required for the activity of this ion channel. We show that TPC2 is required for intracellular Ca2+ signaling in response to NAADP or to mTOR inhibition by rapamycin. In pulmonary arteri...
Source: Signal Transduction Knowledge Environment - April 10, 2018 Category: Science Authors: Ogunbayo, O. A., Duan, J., Xiong, J., Wang, Q., Feng, X., Ma, J., Zhu, M. X., Evans, A. M. Tags: STKE Research Articles Source Type: news

A nanoscale reorganization of the IL-15 receptor is triggered by NKG2D in a ligand-dependent manner
Natural killer group 2D (NKG2D), an activating receptor on natural killer (NK) cells and a subset of T cells, recognizes stress-inducible proteins, including MICA and ULBP2, which are present on infected or transformed cells. Whether each NKG2D ligand (NKG2DL) has a distinct biological role is not clear. Using superresolution microscopy, we found that NKG2D is constitutively arranged in nanoclusters at the surface of human primary NK cells. Nanoclusters of NKG2D became smaller upon ligation with MICA but became larger upon activation by ULBP2. In addition, ULBP2 induced the reorganization of nanoclusters of the cytokine re...
Source: Signal Transduction Knowledge Environment - April 10, 2018 Category: Science Authors: Balint, S., Lopes, F. B., Davis, D. M. Tags: STKE Research Articles Source Type: news

The nuclear translocation of the kinases p38 and JNK promotes inflammation-induced cancer
The stimulated nuclear translocation of signaling proteins, such as MAPKs, is a necessity for the initiation and regulation of their physiological functions. Previously, we determined that nuclear translocation of the MAPKs p38 and JNK involves binding to heterodimers comprising importin 3 and either importin 7 or importin 9. Here, we identified the importin-binding region in p38 and JNK and developed a myristoylated peptide targeting this site that we called PERY. The PERY peptide specifically blocked the interaction of p38 and JNK with the importins, restricted their nuclear translocation, and inhibited phosphorylation o...
Source: Signal Transduction Knowledge Environment - April 10, 2018 Category: Science Authors: Maik-Rachline, G., Zehorai, E., Hanoch, T., Blenis, J., Seger, R. Tags: STKE Research Articles Source Type: news

Architecture of the complete oxygen-sensing FixL-FixJ two-component signal transduction system
The symbiotic nitrogen-fixing bacterium Bradyrhizobium japonicum is critical to the agro-industrial production of soybean because it enables the production of high yields of soybeans with little use of nitrogenous fertilizers. The FixL and FixJ two-component system (TCS) of this bacterium ensures that nitrogen fixation is only stimulated under conditions of low oxygen. When it is not bound to oxygen, the histidine kinase FixL undergoes autophosphorylation and transfers phosphate from adenosine triphosphate (ATP) to the response regulator FixJ, which, in turn, stimulates the expression of genes required for nitrogen fixatio...
Source: Signal Transduction Knowledge Environment - April 10, 2018 Category: Science Authors: Wright, G. S. A., Saeki, A., Hikima, T., Nishizono, Y., Hisano, T., Kamaya, M., Nukina, K., Nishitani, H., Nakamura, H., Yamamoto, M., Antonyuk, S. V., Hasnain, S. S., Shiro, Y., Sawai, H. Tags: STKE Research Articles Source Type: news

Structural basis for the preference of the Arabidopsis thaliana phosphatase RLPH2 for tyrosine-phosphorylated substrates
Despite belonging to the phosphoserine- and phosphothreonine-specific phosphoprotein phosphatase (PPP) family, Arabidopsis thaliana Rhizobiales-like phosphatase 2 (RLPH2) strongly prefers substrates bearing phosphorylated tyrosine residues. We solved the structures of RLPH2 crystallized in the presence or absence of sodium tungstate. These structures revealed the presence of a central domain that forms a binding site for two divalent metal ions that closely resembles that of other PPP-family enzymes. Unique structural elements from two flanking domains suggest a mechanism for the selective dephosphorylation of phosphotyros...
Source: Signal Transduction Knowledge Environment - April 3, 2018 Category: Science Authors: Labandera, A.-M., Uhrig, R. G., Colville, K., Moorhead, G. B., Ng, K. K. S. Tags: STKE Research Articles Source Type: news

New connections: Cytokines learn to share
Computational modeling provides insights into the consequences for T cells of having a shared receptor subunit for different cytokines. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - April 3, 2018 Category: Science Authors: Foley, J. F. Tags: STKE Editors ' Choice Source Type: news

The nociceptin receptor inhibits axonal regeneration and recovery from spinal cord injury
Axonal growth after traumatic spinal cord injury is limited by endogenous inhibitors, selective blockade of which promotes partial neurological recovery. The partial repair phenotypes suggest that compensatory pathways limit improvement. Gene expression profiles of mice deficient in Ngr1, which encodes a receptor for myelin-associated inhibitors of axonal regeneration such as Nogo, revealed that trauma increased the mRNA expression of ORL1, which encodes the receptor for the opioid-related peptide nociceptin. Endogenous and overexpressed ORL1 coimmunoprecipitated with immature NgR1 protein, and ORL1 enhanced the O-linked g...
Source: Signal Transduction Knowledge Environment - April 3, 2018 Category: Science Authors: Sekine, Y., Siegel, C. S., Sekine-Konno, T., Cafferty, W. B. J., Strittmatter, S. M. Tags: STKE Research Articles Source Type: news

Mutant and wild-type p53 form complexes with p73 upon phosphorylation by the kinase JNK
The transcription factors p53 and p73 are critical to the induction of apoptotic cell death, particularly in response to cell stress that activates c-Jun N-terminal kinase (JNK). Mutations in the DNA-binding domain of p53, which are commonly seen in cancers, result in conformational changes that enable p53 to interact with and inhibit p73, thereby suppressing apoptosis. In contrast, wild-type p53 reportedly does not interact with p73. We found that JNK-mediated phosphorylation of Thr81 in the proline-rich domain (PRD) of p53 enabled wild-type p53, as well as mutant p53, to form a complex with p73. Structural algorithms pre...
Source: Signal Transduction Knowledge Environment - April 3, 2018 Category: Science Authors: Wolf, E. R., McAtarsney, C. P., Bredhold, K. E., Kline, A. M., Mayo, L. D. Tags: STKE Research Articles Source Type: news

A hierarchy of affinities between cytokine receptors and the common gamma chain leads to pathway cross-talk
We report the existence of a fast, cytokine-induced pathway cross-talk acting at the receptor level, resulting from a limiting amount of c on the surface of T cells. We found that this limited abundance of c reduced interleukin-4 (IL-4) and IL-21 responses after IL-7 preexposure but not vice versa. Computational modeling combined with quantitative experimental assays indicated that the asymmetric cross-talk resulted from the ability of the "private" IL-7 receptor subunits (IL-7Rα) to bind to many of the c molecules even before stimulation with cytokine. Upon exposure of T cells to IL-7, the high affinity of...
Source: Signal Transduction Knowledge Environment - April 3, 2018 Category: Science Authors: Gonnord, P., Angermann, B. R., Sadtler, K., Gombos, E., Chappert, P., Meier-Schellersheim, M., Varma, R. Tags: STKE Research Articles Source Type: news

Hydrophobic patches on SMAD2 and SMAD3 determine selective binding to cofactors
The transforming growth factor–β (TGF-β) superfamily of cytokines regulates various biological processes, including cell proliferation, immune responses, autophagy, and senescence. Dysregulation of TGF-β signaling causes various diseases, such as cancer and fibrosis. SMAD2 and SMAD3 are core transcription factors involved in TGF-β signaling, and they form heterotrimeric complexes with SMAD4 (SMAD2-SMAD2-SMAD4, SMAD3-SMAD3-SMAD4, and SMAD2-SMAD3-SMAD4) in response to TGF-β signaling. These heterotrimeric complexes interact with cofactors to control the expression of TGF-β–dependent ...
Source: Signal Transduction Knowledge Environment - March 27, 2018 Category: Science Authors: Miyazono, K.-i., Moriwaki, S., Ito, T., Kurisaki, A., Asashima, M., Tanokura, M. Tags: STKE Research Articles Source Type: news

Palmitoylation of {delta}-catenin promotes kinesin-mediated membrane trafficking of Nav1.6 in sensory neurons to promote neuropathic pain
Palmitoylation of -catenin is critical to synapse plasticity and memory formation. We found that -catenin palmitoylation is also instrumental in the development of neuropathic pain. The abundances of palmitoylated -catenin and the palmitoyl acyltransferase DHHC3 were increased in dorsal root ganglion (DRG) sensory neurons in rat models of neuropathic pain. Inhibiting palmitoyl acyltransferases or decreasing -catenin abundance in the DRG by intrathecal injection of 2-bromopalmitate or shRNA, respectively, alleviated oxaliplatin or nerve injury–induced neuropathic pain in the rats. The palmitoylation of -catenin, which...
Source: Signal Transduction Knowledge Environment - March 27, 2018 Category: Science Authors: Zhang, X.-L., Ding, H.-H., Xu, T., Liu, M., Ma, C., Wu, S.-L., Wei, J.-Y., Liu, C.-C., Zhang, S.-B., Xin, W.-J. Tags: STKE Research Articles Source Type: news

New connections: Healed by ROS
ROS generated by Nox2 or mitochondria play critical roles in mammalian tissue repair pathways. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - March 27, 2018 Category: Science Authors: Wong, W. Tags: STKE Editors ' Choice Source Type: news

The p85 isoform of the kinase S6K1 functions as a secreted oncoprotein to facilitate cell migration and tumor growth
We report that p85S6K1, the longest isoform of S6K (ribosomal protein S6 kinase), but not the shorter isoform p70S6K1 or p56S6K2, was secreted from cancer cells through its HIV TAT-like, N-terminal six-arginine motif. The exogenously produced p85S6K1 protein entered cultured transformed and nontransformed cells to promote or confer malignant behaviors, leading to increased cell growth and migration. When injected into mice, the p85S6K1 protein enhanced the growth of xenografted breast cancer cells and lung metastasis. Hence, our findings reveal a role for p85S6K1 as a secreted oncogenic kinase and provide a mechanism by wh...
Source: Signal Transduction Knowledge Environment - March 27, 2018 Category: Science Authors: Zhang, J., Guo, J., Qin, X., Wang, B., Zhang, L., Wang, Y., Gan, W., Pandofi, P. P., Chen, W., Wei, W. Tags: STKE Research Articles Source Type: news

Pin1 mediates A{beta}42-induced dendritic spine loss
Early-stage Alzheimer’s disease is characterized by the loss of dendritic spines in the neocortex of the brain. This phenomenon precedes tau pathology, plaque formation, and neurodegeneration and likely contributes to synaptic loss, memory impairment, and behavioral changes in patients. Studies suggest that dendritic spine loss is induced by soluble, multimeric amyloid-β (Aβ42), which, through postsynaptic signaling, activates the protein phosphatase calcineurin. We investigated how calcineurin caused spine pathology and found that the cis-trans prolyl isomerase Pin1 was a critical downstream target of A&be...
Source: Signal Transduction Knowledge Environment - March 20, 2018 Category: Science Authors: Stallings, N. R., ONeal, M. A., Hu, J., Kavalali, E. T., Bezprozvanny, I., Malter, J. S. Tags: STKE Research Articles Source Type: news

Nitrosylation of GAPDH augments pathological tau acetylation upon exposure to amyloid-{beta}
Acetylation of the microtubule-associated protein tau promotes its polymerization into neurofibrillary tangles that are implicated in the pathology of Alzheimer’s disease (AD). The gaseous neurotransmitter nitric oxide (NO) regulates cell signaling through the nitrosylation of proteins. We found that NO production and tau acetylation at Lys280 occurred in the brain tissue in mice and in cultured mouse cortical neurons in response to exposure to amyloid-β1–42 (Aβ1–42), a peptide that is also implicated in AD. An increased abundance of NO facilitated the S-nitrosylation (SNO) of glyceraldehyde-3-p...
Source: Signal Transduction Knowledge Environment - March 20, 2018 Category: Science Authors: Sen, T., Saha, P., Sen, N. Tags: STKE Research Articles Source Type: news

New connections: Amyloid-{beta} in the pathology of Alzheimers disease
Two studies in this issue of Science Signaling identify how amyloid-β causes various pathological mechanisms in mouse models of Alzheimer’s disease. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - March 20, 2018 Category: Science Authors: Ferrarelli, L. K. Tags: STKE Editors ' Choice Source Type: news

Gain-of-function mutations in the gene encoding the tyrosine phosphatase SHP2 induce hydrocephalus in a catalytically dependent manner
Catalytically activating mutations in Ptpn11, which encodes the protein tyrosine phosphatase SHP2, cause 50% of Noonan syndrome (NS) cases, whereas inactivating mutations in Ptpn11 are responsible for nearly all cases of the similar, but distinct, developmental disorder Noonan syndrome with multiple lentigines (NSML; formerly called LEOPARD syndrome). However, both types of disease mutations are gain-of-function mutations because they cause SHP2 to constitutively adopt an open conformation. We found that the catalytic activity of SHP2 was required for the pathogenic effects of gain-of-function, disease-associated mutations...
Source: Signal Transduction Knowledge Environment - March 20, 2018 Category: Science Authors: Zheng, H., Yu, W.-M., Waclaw, R. R., Kontaridis, M. I., Neel, B. G., Qu, C.-K. Tags: STKE Research Articles Source Type: news

TSLP signaling in CD4+ T cells programs a pathogenic T helper 2 cell state
Pathogenic T helper 2 (TH2) cells, which produce increased amounts of the cytokines interleukin-5 (IL-5) and IL-13, promote allergic disorders, including asthma. Thymic stromal lymphopoietin (TSLP), a cytokine secreted by epithelial and innate immune cells, stimulates such pathogenic TH2 cell responses. We found that TSLP signaling in mouse CD4+ T cells initiated transcriptional changes associated with TH2 cell programming. IL-4 signaling amplified and stabilized the genomic response of T cells to TSLP, which increased the frequency of T cells producing IL-4, IL-5, and IL-13. Furthermore, the TSLP- and IL-4–programme...
Source: Signal Transduction Knowledge Environment - March 13, 2018 Category: Science Authors: Rochman, Y., Dienger-Stambaugh, K., Richgels, P. K., Lewkowich, I. P., Kartashov, A. V., Barski, A., Khurana Hershey, G. K., Leonard, W. J., Singh, H. Tags: STKE Research Articles Source Type: news