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  • Integration of protein phosphorylation, acetylation, and methylation data sets to outline lung cancer signaling networks
    Sci. Signal. (IF 6.494) Pub Date : 2018-05-22
    Mark Grimes, Benjamin Hall, Lauren Foltz, Tyler Levy, Klarisa Rikova, Jeremiah Gaiser, William Cook, Ekaterina Smirnova, Travis Wheeler, Neil R. Clark, Alexander Lachmann, Bin Zhang, Peter Hornbeck, Avi Ma’ayan, Michael Comb

    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 cell signaling pathways were outlined by clustering patterns in PTMs. We used the t-distributed stochastic neighbor embedding (t-SNE) method to identify PTM clusters and then integrated each with known protein-protein interactions (PPIs) to elucidate functional cell signaling pathways. The CFN identified known and previously unknown cell signaling pathways in lung cancer cells that were not present in normal lung epithelial tissue. In various proteins modified by more than one type of PTM, the incidence of those PTMs exhibited inverse relationships, suggesting that molecular exclusive “OR” gates determine a large number of signal transduction events. We also showed that the acetyltransferase EP300 appears to be a hub in the network of pathways involving different PTMs. In addition, the data shed light on the mechanism of action of geldanamycin, an HSP90 inhibitor. Together, the findings reveal that cell signaling pathways mediated by acetylation, methylation, and phosphorylation regulate the cytoskeleton, membrane traffic, and RNA binding protein–mediated control of gene expression.

    更新日期:2018-05-23
  • Tuning ITAM multiplicity on T cell receptors can control potency and selectivity to ligand density
    Sci. Signal. (IF 6.494) Pub Date : 2018-05-22
    John R. James

    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 into an intracellular signal. This manifested as an increase in the fraction of cells that became activated in response to antigen, and a more synchronous initiation of TCR-proximal signaling, rather than direct amplification of the intracellular signals. Exploiting these findings, the potency and selectivity of chimeric antigen receptors targeted against cancer were substantially enhanced by modulating the number of encoded ITAMs.

    更新日期:2018-05-23
  • How Treg cells stay true
    Sci. Signal. (IF 6.494) Pub Date : 2018-05-22
    Erin R. Williams

    Human Treg cells maintain their cellular identity through changes in their protein expression signature.

    更新日期:2018-05-23
  • The DUF1669 domain of FAM83 family proteins anchor casein kinase 1 isoforms
    Sci. Signal. (IF 6.494) Pub Date : 2018-05-22
    Luke J. Fulcher, Polyxeni Bozatzi, Theresa Tachie-Menson, Kevin Z. L. Wu, Timothy D. Cummins, Joshua C. Bufton, Daniel M. Pinkas, Karen Dunbar, Sabin Shrestha, Nicola T. Wood, Simone Weidlich, Thomas J. Macartney, Joby Varghese, Robert Gourlay, David G. Campbell, Kevin S. Dingwell, James C. Smith, Alex N. Bullock, Gopal P. Sapkota

    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 with the α and α-like isoforms of CK1; FAM83A, FAM83B, FAM83E, and FAM83H also interacted with the δ and ε isoforms of CK1. We detected no interaction between any FAM83 member and the related CK1γ1, CK1γ2, and CK1γ3 isoforms. Each FAM83 protein exhibited a distinct pattern of subcellular distribution and colocalized with the CK1 isoform(s) to which it bound. The interaction of FAM83 proteins with CK1 isoforms was mediated by the conserved domain of unknown function 1669 (DUF1669) that characterizes the FAM83 family. Mutations in FAM83 proteins that prevented them from binding to CK1 interfered with the proper subcellular localization and cellular functions of both the FAM83 proteins and their CK1 binding partners. On the basis of its function, we propose that DUF1669 be renamed the polypeptide anchor of CK1 domain.

    更新日期:2018-05-23
  • New connections: Kinases and phosphatases in control of mitosis
    Sci. Signal. (IF 6.494) Pub Date : 2018-05-15
    Leslie K. Ferrarelli

    Two studies in this week’s issue of Science Signaling reveal coordinated regulation of kinases and phosphatases during cell cycle progression.

    更新日期:2018-05-16
  • Global assessment of its network dynamics reveals that the kinase Plk1 inhibits the phosphatase PP6 to promote Aurora A activity
    Sci. Signal. (IF 6.494) Pub Date : 2018-05-15
    Arminja N. Kettenbach, Kate A. Schlosser, Scott P. Lyons, Isha Nasa, Jiang Gui, Mark E. Adamo, Scott A. Gerber

    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 protected from phosphatase opposition or was unopposed, resulting in persistent interaction of the substrate with Plk1. This subset includes phosphoprotein phosphatase 6 (PP6), whose activity toward Aurora kinase A (Aurora A) was inhibited by Plk1. Our data suggest that this Plk1-PP6 interaction generates a feedback loop that coordinates and reinforces the activities of Plk1 and Aurora A during mitotic entry and is terminated by the degradation of Plk1 during mitotic exit. Thus, we have identified a mechanism for the previously puzzling observation of the Plk1-dependent regulation of Aurora A.

    更新日期:2018-05-16
  • IRE1α prevents hepatic steatosis by processing and promoting the degradation of select microRNAs
    Sci. Signal. (IF 6.494) Pub Date : 2018-05-15
    Jie-Mei Wang, Yining Qiu, Zhao Yang, Hyunbae Kim, Qingwen Qian, Qinghua Sun, Chunbin Zhang, Lei Yin, Deyu Fang, Sung Hong Back, Randal J. Kaufman, Ling Yang, Kezhong Zhang

    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 subset of precursor miRNAs in the liver, including those of the miR-200 and miR-34 families, such that IRE1α promoted their degradation through the process of regulated IRE1-dependent decay (RIDD). A high-fat diet in mice or hepatic steatosis in patients was associated with the S-nitrosylation of IRE1α and inactivation of its endoribonuclease activity. This resulted in an increased abundance of these miRNA families in the liver and, consequently, a decreased abundance of their targets, which included peroxisome proliferator–activated receptor α (PPARα) and the deacetylase sirtuin 1 (SIRT1), regulators of fatty acid oxidation and triglyceride lipolysis. IRE1α deficiency exacerbated hepatic steatosis in mice. The abundance of the miR-200 and miR-34 families was also increased in cultured, lipid-overloaded hepatocytes and in the livers of patients with hepatic steatosis. Our findings reveal a mechanism by which IRE1α maintains lipid homeostasis through its regulation of miRNAs, a regulatory pathway distinct from the canonical IRE1α-UPR pathway under acute ER stress.

    更新日期:2018-05-16
  • A DGKζ-FoxO-ubiquitin proteolytic axis controls fiber size during skeletal muscle remodeling
    Sci. Signal. (IF 6.494) Pub Date : 2018-05-15
    Jae-Sung You, Matthew S. Dooley, Chan-Ran Kim, Eui-Jun Kim, Wei Xu, Craig A. Goodman, Troy A. Hornberger

    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 ζ (DGKζ)–mediated pathway that regulated muscle mass during remodeling. During mechanical overload, DGKζ abundance was increased and required for effective hypertrophy. DGKζ not only augmented anabolic responses but also suppressed ubiquitin-proteasome system (UPS)–dependent proteolysis. We found that DGKζ inhibited the transcription factor FoxO that promotes the induction of the UPS. This function was mediated through a mechanism that was independent of kinase activity but dependent on the nuclear localization of DGKζ. During denervation, DGKζ abundance was also increased and was required for mitigating the activation of FoxO-UPS and the induction of atrophy. Conversely, overexpression of DGKζ prevented fasting-induced atrophy. Therefore, DGKζ is an inhibitor of the FoxO-UPS pathway, and interventions that increase its abundance could prevent muscle wasting.

    更新日期:2018-05-16
  • Aurora B opposes PP1 function in mitosis by phosphorylating the conserved PP1-binding RVxF motif in PP1 regulatory proteins
    Sci. Signal. (IF 6.494) Pub Date : 2018-05-15
    Isha Nasa, Scott F. Rusin, Arminja N. Kettenbach, Greg B. Moorhead

    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 binding motifs, in which x is a phosphorylatable amino acid (RV[S/T]F), was phosphorylated specifically during mitosis and that this phosphorylation event abrogated the interaction of PP1 with the regulatory protein. We determined that this phosphorylation was primarily governed by the mitotic protein kinase Aurora B and that high phosphorylation site stoichiometry of these sites maintained the phosphorylation of PP1 substrates during mitosis by disrupting the assembly of PP1 holoenzymes. We generated an antibody that recognizes the phosphorylated form of the RV[S/T]F motif (RVp[S/T]F) and used it to identify known PP1 regulatory proteins (KNL1, CDCA2, and RIF1) and multiple proteins that could potentially act as PP1 binding partners (UBR5, ASPM, SEH1, and ELYS) governed by this mechanism. Together, these data suggest a general regulatory mechanism by which the coordinated activities of Aurora B and PP1 control mitotic progression.

    更新日期:2018-05-16
  • How to recruit a GRK
    Sci. Signal. (IF 6.494) Pub Date : 2018-05-08
    John F. Foley

    The dopamine D2 receptor recruits and activates the kinase GRK2 without the need for G protein activation.

    更新日期:2018-05-09
  • Chemical synapses without synaptic vesicles: Purinergic neurotransmission through a CALHM1 channel-mitochondrial signaling complex
    Sci. Signal. (IF 6.494) Pub Date : 2018-05-08
    Roman A. Romanov, Robert S. Lasher, Brigit High, Logan E. Savidge, Adam Lawson, Olga A. Rogachevskaja, Haitian Zhao, Vadim V. Rogachevsky, Marina F. Bystrova, Gleb D. Churbanov, Igor Adameyko, Tibor Harkany, Ruibiao Yang, Grahame J. Kidd, Philippe Marambaud, John C. Kinnamon, Stanislav S. Kolesnikov, Thomas E. Finger

    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 showed that the CALHM1 channels were consistently associated with distinctive, large (1- to 2-μm) mitochondria spaced 20 to 40 nm from the presynaptic membrane. Pharmacological disruption of the mitochondrial respiratory chain limited the ability of taste cells to release ATP, suggesting that the immediate source of released ATP was the mitochondrion rather than a cytoplasmic pool of ATP. These large mitochondria may serve as both a reservoir of releasable ATP and the site of synthesis. The juxtaposition of the large mitochondria to areas of membrane displaying CALHM1 also defines a restricted compartment that limits the influx of Ca2+ upon opening of the nonselective CALHM1 channels. These findings reveal a distinctive organelle signature and functional organization for regulated, focal release of purinergic signals in the absence of synaptic vesicles.

    更新日期:2018-05-09
  • CCR5 adopts three homodimeric conformations that control cell surface delivery
    Sci. Signal. (IF 6.494) Pub Date : 2018-05-08
    Jun Jin, Fanny Momboisse, Gaelle Boncompain, Florian Koensgen, Zhicheng Zhou, Nelia Cordeiro, Fernando Arenzana-Seisdedos, Franck Perez, Bernard Lagane, Esther Kellenberger, Anne Brelot

    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 maraviroc stabilized a third state. We found that CCR5 dimerization was required for targeting the receptor to the plasma membrane. These data suggest that dimerization contributes to the conformational diversity of inactive class A GPCRs and may provide new opportunities to investigate the cellular entry of HIV-1 and mechanisms for its inhibition.

    更新日期:2018-05-09
  • The receptor tyrosine kinase TrkB signals without dimerization at the plasma membrane
    Sci. Signal. (IF 6.494) Pub Date : 2018-05-08
    Eitan Erez Zahavi, Noam Steinberg, Topaz Altman, Michael Chein, Yuvraj Joshi, Tal Gradus-Pery, Eran Perlson

    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 endocytosis of TrkB-BDNF was required for the effective activation of the kinase AKT but not of the kinase ERK1/2. Thus, we report a previously uncharacterized mode of monomeric signaling for an RTK and a specific role for the endosome in TrkB homodimerization.

    更新日期:2018-05-09
  • Highlight: A tasteful conversation with atypical mitochondria at atypical synapses
    Sci. Signal. (IF 6.494) Pub Date : 2018-05-08
    George R. Dubyak

    Atypical mitochondria produce ATP used as a neurotransmitter by type II taste cells to transduce sweet, bitter, or savory flavors.

    更新日期:2018-05-09
  • Gene expression kinetics governs stimulus-specific decoration of the Salmonella outer membrane
    Sci. Signal. (IF 6.494) Pub Date : 2018-05-08
    Xinyu Hong, H. Deborah Chen, Eduardo A. Groisman

    Lipid A is the innermost component of the lipopolysaccharide (LPS) molecules that occupy the outer leaflet of the outer membrane in Gram-negative bacteria. Lipid A is recognized by the host immune system and targeted by cationic antimicrobial compounds. In Salmonella enterica serovar Typhimurium, the phosphates of lipid A are chemically modified by enzymes encoded by targets of the transcriptional regulator PmrA. These modifications increase resistance to the cationic peptide antibiotic polymyxin B by reducing the negative charge of the LPS. 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 incorporation of l-Ara4N. By contrast, a mildly acidic pH favored modification of the lipid A phosphates with a mixture of l-Ara4N and phosphoethanolamine (pEtN) by simultaneously inducing the PhoP-activated lpxT and PmrA-activated pmrR genes. Although l-Ara4N reduces the LPS negative charge more than does pEtN, modification of lipid A phosphates solely with l-Ara4N required a prior transient increase in lipid A negative charge. Our findings demonstrate how bacteria tailor their cell surface to different stresses, such as those faced inside phagocytes.

    更新日期:2018-05-09
  • When ER stress is bad for cancer
    Sci. Signal. (IF 6.494) Pub Date : 2018-05-01
    Wei Wong

    A low-protein diet enhances tumor immunosurveillance in multiple cancer types.

    更新日期:2018-05-01
  • The interaction between IKKα and LC3 promotes type I interferon production through the TLR9-containing LAPosome
    Sci. Signal. (IF 6.494) Pub Date : 2018-05-01
    Kachiko Hayashi, Manabu Taura, Akiko Iwasaki

    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 stimulation of TLR9 by CpG oligonucleotides, the autophagy protein LC3 and the kinase IKKα were recruited to endosomes that contained TLR9. The recruitment of IKKα and LC3 to such signaling endosomes was not stimulated by catalysts of classical autophagosome formation but involved LAP formation, which required ATG5 but not FIP200. In addition, we found that the LC3-IKKα complex further associated with both TRAF3 and IRF7. We identified three putative LC3-interacting regions (LIRs) in IKKα, and mutagenesis suggested that two of these were critical for direct binding to LC3. Moreover, mutation of the same LIR sequences failed to rescue type I IFN production in IKKα-deficient dendritic cells upon reconstitution. Together, these data suggest a direct link between LAP formation and IKKα recruitment downstream of TLR9 activation that is necessary to facilitate type I IFN production.

    更新日期:2018-05-01
  • VEGF–neuropilin-2 signaling promotes stem-like traits in breast cancer cells by TAZ-mediated repression of the Rac GAP β2-chimaerin
    Sci. Signal. (IF 6.494) Pub Date : 2018-05-01
    Ameer L. Elaimy, Santosh Guru, Cheng Chang, Jianhong Ou, John J. Amante, Lihua Julie Zhu, Hira Lal Goel, Arthur M. Mercurio

    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 is associated with breast CSCs and confers stem cell–like properties. We found that VEGF-NRP2 signaling contributed to the activation of TAZ in various breast cancer cells, which mediated a positive feedback loop that promoted mammosphere formation. VEGF-NRP2 signaling activated the GTPase Rac1, which inhibited the Hippo kinase LATS, thus leading to TAZ activity. In a complex with the transcription factor TEAD, TAZ then bound and repressed the promoter of the gene encoding the Rac GTPase-activating protein (Rac GAP) β2-chimaerin. By activating GTP hydrolysis, Rac GAPs effectively turn off Rac signaling; hence, the TAZ-mediated repression of β2-chimaerin resulted in sustained Rac1 activity in CSCs. Depletion of β2-chimaerin in non-CSCs increased Rac1 activity, TAZ abundance, and mammosphere formation. Analysis of a breast cancer patient database revealed an inverse correlation between β2-chimaerin and TAZ expression in tumors. Our findings highlight an unexpected role for β2-chimaerin in a feed-forward loop of TAZ activation and the acquisition of CSC properties.

    更新日期:2018-05-01
  • Nuclear PTEN enhances the maturation of a microRNA regulon to limit MyD88-dependent susceptibility to sepsis
    Sci. Signal. (IF 6.494) Pub Date : 2018-05-01
    Flavia Sisti, Soujuan Wang, Stephanie L. Brandt, Nicole Glosson-Byers, Lindsey D. Mayo, Young Min Son, Sarah Sturgeon, Luciano Filgueiras, Sonia Jancar, Hector Wong, Charles S. Dela Cruz, Nathaniel Andrews, Jose Carlos Alves-Filho, Fernando Q. Cunha, C. Henrique Serezani

    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, which depended on enhanced myeloid differentiation primary response gene 88 (MyD88) abundance and resulted in mortality. PTEN-mediated induction of the microRNAs (miRNAs) miR125b and miR203b reduced the abundance of MyD88. Loss- and gain-of-function assays demonstrated that PTEN induced miRNA production by associating with and facilitating the nuclear localization of Drosha-Dgcr8, part of the miRNA-processing complex. Reconstitution of PTEN-deficient mouse embryonic fibroblasts with a mutant form of PTEN that does not localize to the nucleus resulted in retention of Drosha-Dgcr8 in the cytoplasm and impaired production of mature miRNAs. Thus, we identified a regulatory pathway involving nuclear PTEN–mediated miRNA generation that limits the production of MyD88 and thereby limits sepsis-associated mortality.

    更新日期:2018-05-01
  • Glycerol monolaurate induces filopodia formation by disrupting the association between LAT and SLP-76 microclusters
    Sci. Signal. (IF 6.494) Pub Date : 2018-05-01
    Michael S. Zhang, Phuong M. Tran, Alexander J. Wolff, Mikaela M. Tremblay, Micaela G. Fosdick, Jon C. D. Houtman

    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 developed numerous inappropriate actin-mediated filopodia. The formation of these filopodia was not due to disruption of TCR-proximal regulators of actin or microtubule polymerization. Instead, total internal reflection fluorescence microscopy demonstrated mislocalization of actin nucleation protein Arp2 microclusters, but not those containing the adaptor proteins SLP-76 and WASp, or the actin nucleation protein ARPC3, which are necessary for TCR-induced actin rearrangement. Additionally, SLP-76 microclusters colocalized with WASp and WAVE microclusters but not with LAT. Together, our data suggest that GML alters actin cytoskeletal rearrangements and identify diverse functions for GML as a T cell–suppressive agent.

    更新日期:2018-05-01
  • Parkin mediates mitophagy during beige-to-white fat conversion
    Sci. Signal. (IF 6.494) Pub Date : 2018-04-24
    Shireen A. Sarraf, Richard J. Youle

    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.

    更新日期:2018-04-25
  • A defect in KCa3.1 channel activity limits the ability of CD8+ T cells from cancer patients to infiltrate an adenosine-rich microenvironment
    Sci. Signal. (IF 6.494) Pub Date : 2018-04-24
    Ameet A. Chimote, Andras Balajthy, Michael J. Arnold, Hannah S. Newton, Peter Hajdu, Julianne Qualtieri, Trisha Wise-Draper, Laura Conforti

    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 on HNSCC CD8+ T cells than on healthy donor (HD) CD8+ T cells. This response correlated with the inability of CD8+ T cells to infiltrate tumors. The effect of adenosine was mimicked by an A2AR agonist and prevented by an A2AR antagonist. We found no differences in A2AR expression, 3′,5′-cyclic adenosine monophosphate abundance, or protein kinase A type 1 activity between HNSCC and HD CD8+ T cells. We instead detected a decrease in KCa3.1 channel activity, but not expression, in HNSCC CD8+ T cells. Activation of KCa3.1 channels by 1-EBIO restored the ability of HNSCC CD8+ T cells to chemotax in the presence of adenosine. Our data highlight the mechanism underlying the increased sensitivity of HNSCC CD8+ T cells to adenosine and the potential therapeutic benefit of KCa3.1 channel activators, which could increase infiltration of these T cells into tumors.

    更新日期:2018-04-25
  • Transient inflammatory signaling promotes beige adipogenesis
    Sci. Signal. (IF 6.494) Pub Date : 2018-04-24
    Kai Sun, Zhanguo Gao, Mikhail G. Kolonin

    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.

    更新日期:2018-04-25
  • Jak-TGFβ cross-talk links transient adipose tissue inflammation to beige adipogenesis
    Sci. Signal. (IF 6.494) Pub Date : 2018-04-24
    Rohollah Babaei, Maximilian Schuster, Irina Meln, Sarah Lerch, Rayane A. Ghandour, Didier F. Pisani, Irem Bayindir-Buchhalter, Julia Marx, Shuang Wu, Gabriele Schoiswohl, Adrian T. Billeter, Damir Krunic, Jan Mauer, Yun-Hee Lee, James G. Granneman, Lars Fischer, Beat P. Müller-Stich, Ez-Zoubir Amri, Erin E. Kershaw, Mathias Heikenwälder, Stephan Herzig, Alexandros Vegiopoulos

    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, a function that was required for beige adipocyte differentiation of murine and human progenitors. Jak/Stat3 inhibited TGFβ signaling to the transcription factors Srf and Smad3 by repressing local Tgfb3 and Tgfb1 expression before the core transcriptional adipogenic cascade was activated. This pathway cross-talk was triggered in stromal cells by ATGL-dependent adipocyte lipolysis and a transient wave of IL-6 family cytokines at the onset of adipose tissue remodeling induced by β3-adrenergic receptor stimulation. Our results provide insight into the activation of adipocyte progenitors and are relevant for the therapeutic targeting of adipose tissue inflammatory pathways.

    更新日期:2018-04-25
  • Mitophagy controls beige adipocyte maintenance through a Parkin-dependent and UCP1-independent mechanism
    Sci. Signal. (IF 6.494) Pub Date : 2018-04-24
    Xiaodan Lu, Svetlana Altshuler-Keylin, Qiang Wang, Yong Chen, Carlos Henrique Sponton, Kenji Ikeda, Pema Maretich, Takeshi Yoneshiro, Shingo Kajimura

    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 thermogenic beige adipocytes even after the withdrawal of external stimuli. Norepinephrine signaling through the PKA pathway inhibited the recruitment of Parkin protein to mitochondria in beige adipocytes. However, mitochondrial proton uncoupling by uncoupling protein 1 (UCP1) was dispensable for Parkin recruitment and beige adipocyte maintenance. These results suggest a physiological mechanism by which external cues control mitochondrial homeostasis in thermogenic fat cells through mitophagy.

    更新日期:2018-04-25
  • New connections: Ewing’s sarcoma’s driver is its Achilles’ heel
    Sci. Signal. (IF 6.494) Pub Date : 2018-04-24
    Leslie K. Ferrarelli

    Several studies identify drug combinations that target or exploit the EWS-FLI1 fusion protein to kill Ewing’s sarcoma cells.

    更新日期:2018-04-25
  • A switch-variant model integrates the functions of an autoimmune variant of the phosphatase PTPN22
    Sci. Signal. (IF 6.494) Pub Date : 2018-04-17
    Torkel Vang, Jimmi Nielsen, Garth L. Burn

    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.

    更新日期:2018-04-18
  • Truncation- and motif-based pan-cancer analysis reveals tumor-suppressing kinases
    Sci. Signal. (IF 6.494) Pub Date : 2018-04-17
    Andrew M. Hudson, Natalie L. Stephenson, Cynthia Li, Eleanor Trotter, Adam J. Fletcher, Gitta Katona, Patrycja Bieniasz-Krzywiec, Matthew Howell, Chris Wirth, Simon Furney, Crispin J. Miller, John Brognard

    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 identified on the basis of amino acid conservation and mutational frequency. The functional consequences of new LOF mutations were biochemically validated, and the top 15 hotspot LOF residues were used in a pan-cancer analysis to define the tumor-suppressing kinome. A ranked list revealed MAP2K7, an essential mediator of the c-Jun N-terminal kinase (JNK) pathway, as a candidate tumor suppressor in gastric cancer, despite its mutational frequency falling within the mutational noise for this cancer type. The majority of mutations in MAP2K7 abolished its catalytic activity, and reactivation of the JNK pathway in gastric cancer cells harboring LOF mutations in MAP2K7 or the downstream kinase JNK suppressed clonogenicity and growth in soft agar, demonstrating the functional relevance of inactivating the JNK pathway in gastric cancer. Together, our data highlight a broadly applicable strategy to identify functional cancer driver mutations and define the JNK pathway as tumor-suppressive in gastric cancer.

    更新日期:2018-04-18
  • Interleukin-2 shapes the cytotoxic T cell proteome and immune environment–sensing programs
    Sci. Signal. (IF 6.494) Pub Date : 2018-04-17
    Christina M. Rollings, Linda V. Sinclair, Hugh J. M. Brady, Doreen A. Cantrell, Sarah H. Ross

    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 essential for cellular fitness. One fundamental insight was the dominant role for IL-2 in stimulating effector T cells to detect microenvironmental cues. IL-2–JAK1/3 signaling pathways thus increased the abundance of nutrient transporters, nutrient sensors, and critical oxygen-sensing molecules. These data provide key insights into how IL-2 promotes T cell function and highlight signaling mechanisms and transcription factors that integrate oxygen sensing to transcriptional control of CD8+ T cell differentiation.

    更新日期:2018-04-18
  • Revisiting PD-1 signaling
    Sci. Signal. (IF 6.494) Pub Date : 2018-04-17
    Erin Williams

    The protective effect of anti-PD1 therapy in cancer may not require the phosphatase Ptpn11.

    更新日期:2018-04-18
  • Estrogen receptor α contributes to T cell–mediated autoimmune inflammation by promoting T cell activation and proliferation
    Sci. Signal. (IF 6.494) Pub Date : 2018-04-17
    Imran Mohammad, Inna Starskaia, Tamas Nagy, Jitao Guo, Emrah Yatkin, Kalervo Väänänen, Wendy T. Watford, Zhi Chen

    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, including reducing T cell activation and proliferation and increasing the expression of Foxp3, which encodes a critical transcription factor for the differentiation and function of regulatory T cells. Thus, these data demonstrate that ERα in T cells plays an important role in inflammation and suggest that ERα-targeted immunotherapies could be used to treat autoimmune disorders.

    更新日期:2018-04-18
  • Architecture of the complete oxygen-sensing FixL-FixJ two-component signal transduction system
    Sci. Signal. (IF 6.494) Pub Date : 2018-04-10
    Gareth S. A. Wright, Akane Saeki, Takaaki Hikima, Yoko Nishizono, Tamao Hisano, Misaki Kamaya, Kohei Nukina, Hideo Nishitani, Hiro Nakamura, Masaki Yamamoto, Svetlana V. Antonyuk, S. Samar Hasnain, Yoshitsugu Shiro, Hitomi Sawai

    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 fixation. We purified full-length B. japonicum FixL and FixJ proteins and defined their structures individually and in complex using small-angle x-ray scattering, crystallographic, and in silico modeling techniques. Comparison of active and inactive forms of FixL suggests that intramolecular signal transduction is driven by local changes in the sensor domain and in the coiled-coil region connecting the sensor and histidine kinase domains. We also found that FixJ exhibits conformational plasticity not only in the monomeric state but also in tetrameric complexes with FixL during phosphotransfer. This structural characterization of a complete TCS contributes both a mechanistic and evolutionary understanding to TCS signal relay, specifically in the context of the control of nitrogen fixation in root nodules.

    更新日期:2018-04-11
  • The nuclear translocation of the kinases p38 and JNK promotes inflammation-induced cancer
    Sci. Signal. (IF 6.494) Pub Date : 2018-04-10
    Galia Maik-Rachline, Elder Zehorai, Tamar Hanoch, John Blenis, Rony Seger

    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 of their nuclear (but not cytoplasmic) substrates. Through these effects, the PERY peptide reduced the proliferation of several (but not all) cancer cell lines in culture and inhibited the growth of a human breast cancer xenograft in mice. In addition, the PERY peptide substantially inhibited inflammation in mice, as manifested in models of colitis and colitis-associated colon cancer. The PERY peptide more effectively prevented colon cancer development than did a commercial p38 inhibitor. In vivo analysis further suggested that this effect was mediated by PERY peptide–induced prevention of the nuclear translocation of p38 in macrophages. Together, these results support the use of the nuclear translocation of p38 and JNK as a novel drug target to treat various cancers and inflammation-induced diseases.

    更新日期:2018-04-11
  • A nanoscale reorganization of the IL-15 receptor is triggered by NKG2D in a ligand-dependent manner
    Sci. Signal. (IF 6.494) Pub Date : 2018-04-10
    Štefan Bálint, Filipa B. Lopes, Daniel M. Davis

    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 receptor subunit for both interleukin-2 (IL-2) and IL-15 (IL-2/IL-15Rβ), such that these cytokine receptor subunits coalesced with nanoclusters of NKG2D. Functionally, the response of NK cells activated by ULBP2 was augmented by an interaction between ULBP2-bound NKG2D and IL-15R ligated by IL-15 (trans-presented by IL-15Rα–coated surfaces). These data suggest that NKG2DLs are not equivalent in their capacity to activate NKG2D and establish a previously unknown paradigm in how ligand-induced changes to the nanoscale organization of the cell surface can affect immune responses.

    更新日期:2018-04-11
  • mTORC1 controls lysosomal Ca2+ release through the two-pore channel TPC2
    Sci. Signal. (IF 6.494) Pub Date : 2018-04-10
    Oluseye A. Ogunbayo, Jingxian Duan, Jian Xiong, Qiaochu Wang, Xinghua Feng, Jianjie Ma, Michael X. Zhu, A. Mark Evans

    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 arterial myocytes, rapamycin and NAADP evoked global Ca2+ transients that were blocked by depletion of lysosomal Ca2+ stores. Preincubation of cells with high concentrations of rapamycin resulted in desensitization and blocked NAADP-evoked Ca2+ signals. Moreover, rapamycin and NAADP did not evoke discernable Ca2+ transients in myocytes derived from Tpcn2 knockout mice, which showed normal responses to other Ca2+-mobilizing signals. In HEK293 cells stably overexpressing human TPC2, shRNA-mediated knockdown of mTOR blocked rapamycin- and NAADP-evoked Ca2+ signals. Confocal imaging of a genetically encoded Ca2+ indicator fused to TPC2 demonstrated that rapamycin-evoked Ca2+ signals localized to lysosomes and were in close proximity to TPC2. Therefore, inactivation of mTOR may activate TPC2 and consequently lysosomal Ca2+ release.

    更新日期:2018-04-11
  • New connections: The complexity of simple signaling systems
    Sci. Signal. (IF 6.494) Pub Date : 2018-04-10
    Annalisa M. VanHook

    Bacterial two-component systems are efficient and versatile but not always simple.

    更新日期:2018-04-11
  • A hierarchy of affinities between cytokine receptors and the common gamma chain leads to pathway cross-talk
    Sci. Signal. (IF 6.494) Pub Date : 2018-04-03
    Pauline Gonnord, Bastian R. Angermann, Kaitlyn Sadtler, Erin Gombos, Pascal Chappert, Martin Meier-Schellersheim, Rajat Varma

    Cytokines belonging to the common gamma chain (γc) family depend on the shared γc receptor subunit for signaling. We report the existence of a fast, cytokine-induced pathway cross-talk acting at the receptor level, resulting from a limiting amount of γc on the surface of T cells. We found that this limited abundance of γc 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 γc molecules even before stimulation with cytokine. Upon exposure of T cells to IL-7, the high affinity of the IL-7Rα:IL-7 complex for γc further reduced the amount of free γc in a manner dependent on the concentration of IL-7. Measurements of bioluminescence resonance energy transfer (BRET) between IL-4Rα and γc were reduced when IL-7Rα was overexpressed. Furthermore, in a system expressing IL-7Rα, IL-4Rα, and γc, BRET between IL-4Rα and γc increased after IL-4 binding and decreased when cells were preexposed to IL-7, supporting the assumption that IL-7Rα and the IL-7Rα:IL-7 complex limit the accessibility of γc for other cytokine receptor complexes. We propose that in complex inflammatory environments, such asymmetric cross-talk establishes a hierarchy of cytokine responsiveness.

    更新日期:2018-04-04
  • Mutant and wild-type p53 form complexes with p73 upon phosphorylation by the kinase JNK
    Sci. Signal. (IF 6.494) Pub Date : 2018-04-03
    Eric R. Wolf, Ciarán P. McAtarsney, Kristin E. Bredhold, Amber M. Kline, Lindsey D. Mayo

    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 predicted that phosphorylation of Thr81 exposes the DNA-binding domain in p53 to enable its binding to p73. The dimerization of wild-type p53 with p73 facilitated the expression of apoptotic target genes [such as those encoding p53–up-regulated modulator of apoptosis (PUMA) and Bcl-2-associated X protein (BAX)] and, subsequently, the induction of apoptosis in response to JNK activation by cell stress in various cells. Thus, JNK phosphorylation of mutant and wild-type p53 promotes the formation of a p53/p73 complex that determines cell fate: apoptosis in the context of wild-type p53 or cell survival in the context of the mutant. These findings refine our current understanding of both the mechanistic links between p53 and p73 and the functional role for Thr81 phosphorylation.

    更新日期:2018-04-04
  • The nociceptin receptor inhibits axonal regeneration and recovery from spinal cord injury
    Sci. Signal. (IF 6.494) Pub Date : 2018-04-03
    Yuichi Sekine, Chad S. Siegel, Tomoko Sekine-Konno, William B. J. Cafferty, Stephen M. Strittmatter

    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 glycosylation and surface expression of NgR1 in HEK293T and Neuro2A cells and primary neurons. ORL1 overexpression inhibited cortical neuron axon regeneration independently of NgR1. Furthermore, regeneration was inhibited by an ORL1 agonist and enhanced by the ORL1 antagonist J113397 through a ROCK-dependent mechanism. Mice treated with J113397 after dorsal hemisection of the mid-thoracic spinal cord recovered greater locomotor function and exhibited lumbar raphespinal axon sprouting. These effects were further enhanced by combined Ngr1 deletion and ORL1 inhibition. Thus, ORL1 limits neural repair directly and indirectly by enhancing NgR1 maturation, and ORL1 antagonists enhance recovery from traumatic CNS injuries in wild-type and Ngr1 null mice.

    更新日期:2018-04-04
  • New connections: Cytokines learn to share
    Sci. Signal. (IF 6.494) Pub Date : 2018-04-03
    John F. Foley

    Computational modeling provides insights into the consequences for T cells of having a shared receptor subunit for different cytokines.

    更新日期:2018-04-04
  • Structural basis for the preference of the Arabidopsis thaliana phosphatase RLPH2 for tyrosine-phosphorylated substrates
    Sci. Signal. (IF 6.494) Pub Date : 2018-04-03
    Anne-Marie Labandera, R. Glen Uhrig, Keaton Colville, Greg B. Moorhead, Kenneth K. S. Ng

    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 phosphotyrosine residues. Cocrystallization with the phosphate mimetic tungstate also suggests how positively charged residues that are highly conserved in the RLPH2 class form an additional pocket that is specific for a phosphothreonine residue located near the phosphotyrosine residue that is bound to the active site. Site-directed mutagenesis confirmed that this auxiliary recognition element facilitates the recruitment of dual-phosphorylated substrates containing a pTxpY motif.

    更新日期:2018-04-04
  • The p85 isoform of the kinase S6K1 functions as a secreted oncoprotein to facilitate cell migration and tumor growth
    Sci. Signal. (IF 6.494) Pub Date : 2018-03-27
    Jianjun Zhang, Jianping Guo, Xing Qin, Bin Wang, Linli Zhang, Yingnan Wang, Wenjian Gan, Pier Paolo Pandofi, Wantao Chen, Wenyi Wei

    Cancer cells can remodel surrounding microenvironments to facilitate cell growth, invasion, and migration by secreting proteins that educate surrounding stromal cells. 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 which cancer cells remodel their microenvironment by transforming the surrounding cells to drive tumorigenesis.

    更新日期:2018-03-28
  • New connections: Healed by ROS
    Sci. Signal. (IF 6.494) Pub Date : 2018-03-27
    Wei Wong

    ROS generated by Nox2 or mitochondria play critical roles in mammalian tissue repair pathways.

    更新日期:2018-03-28
  • Palmitoylation of δ-catenin promotes kinesin-mediated membrane trafficking of Nav1.6 in sensory neurons to promote neuropathic pain
    Sci. Signal. (IF 6.494) Pub Date : 2018-03-27
    Xiao-Long Zhang, Huan-Huan Ding, Ting Xu, Meng Liu, Chao Ma, Shao-Ling Wu, Jia-You Wei, Cui-Cui Liu, Su-Bo Zhang, Wen-Jun Xin

    Palmitoylation of δ-catenin is critical to synapse plasticity and memory formation. We found that δ-catenin palmitoylation is also instrumental in the development of neuropathic pain. The abundances of palmitoylated δ-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 δ-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 δ-catenin, which was induced by the inflammatory cytokine TNF-α, facilitated its interaction with the voltage-gated sodium channel Nav1.6 and the kinesin motor protein KIF3A, which promoted the trafficking of Nav1.6 to the plasma membrane in DRG neurons and contributed to mechanical hypersensitivity and allodynia in rats. These findings suggest that a palmitoylation-mediated KIF3A/δ-catenin/Nav1.6 complex enhances the transmission of mechanical and nociceptive signals; thus, blocking this mechanism may be therapeutic in patients with neuropathic pain.

    更新日期:2018-03-28
  • Hydrophobic patches on SMAD2 and SMAD3 determine selective binding to cofactors
    Sci. Signal. (IF 6.494) Pub Date : 2018-03-27
    Ken-ichi Miyazono, Saho Moriwaki, Tomoko Ito, Akira Kurisaki, Makoto Asashima, Masaru Tanokura

    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 genes. SMAD2 and SMAD3 may promote or repress target genes depending on whether they form complexes with other transcription factors, coactivators, or corepressors; therefore, the selection of specific cofactors is critical for the appropriate activity of these transcription factors. To reveal the structural basis by which SMAD2 and SMAD3 select cofactors, we determined the crystal structures of SMAD3 in complex with the transcription factor FOXH1 and SMAD2 in complex with the transcriptional corepressor SKI. The structures of the complexes show that the MAD homology 2 (MH2) domains of SMAD2 and SMAD3 have multiple hydrophobic patches on their surfaces. The cofactors tether to various subsets of these patches to interact with SMAD2 and SMAD3 in a cooperative or competitive manner to control the output of TGF-β signaling.

    更新日期:2018-03-28
  • Gain-of-function mutations in the gene encoding the tyrosine phosphatase SHP2 induce hydrocephalus in a catalytically dependent manner
    Sci. Signal. (IF 6.494) Pub Date : 2018-03-20
    Hong Zheng, Wen-Mei Yu, Ronald R. Waclaw, Maria I. Kontaridis, Benjamin G. Neel, Cheng-Kui Qu

    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 on the development of hydrocephalus in the mouse. Targeted pan-neuronal knockin of a Ptpn11 allele encoding the active SHP2 E76K mutant resulted in hydrocephalus due to aberrant development of ependymal cells and their cilia. These pathogenic effects of the E76K mutation were suppressed by the additional mutation C459S, which abolished the catalytic activity of SHP2. Moreover, ependymal cells in NSML mice bearing the inactive SHP2 mutant Y279C were also unaffected. Mechanistically, the SHP2 E76K mutant induced developmental defects in ependymal cells by enhancing dephosphorylation and inhibition of the transcription activator STAT3. Whereas STAT3 activity was reduced in Ptpn11E76K/+ cells, the activities of the kinases ERK and AKT were enhanced, and neural cell–specific Stat3 knockout mice also manifested developmental defects in ependymal cells and cilia. These genetic and biochemical data demonstrate a catalytic-dependent role of SHP2 gain-of-function disease mutants in the pathogenesis of hydrocephalus.

    更新日期:2018-03-22
  • New connections: Amyloid-β in the pathology of Alzheimer’s disease
    Sci. Signal. (IF 6.494) Pub Date : 2018-03-20
    Leslie K. Ferrarelli

    Two studies in this issue of Science Signaling identify how amyloid-β causes various pathological mechanisms in mouse models of Alzheimer’s disease.

    更新日期:2018-03-22
  • Nitrosylation of GAPDH augments pathological tau acetylation upon exposure to amyloid-β
    Sci. Signal. (IF 6.494) Pub Date : 2018-03-20
    Tanusree Sen, Pampa Saha, Nilkantha Sen

    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-phosphate dehydrogenase (GAPDH). S-nitrosylated GAPDH (GAPDH-SNO) promoted the acetylation and activation of the acetyltransferase p300 and facilitated the nitrosylation and inactivation of the deacetylase sirtuin 1 (SIRT1). The abundance of GAPDH-SNO was increased in postmortem brain samples from AD patients. Preventing the increase in GAPDH-SNO abundance in both cultured neurons and mice, either by overexpression of the nitrosylation mutant of GAPDH (GAPDH C150S) or by treatment with the GAPDH nitrosylation inhibitor CGP3466B (also known as omigapil), abrogated Aβ1–42–induced tau acetylation, memory impairment, and locomotor dysfunction in mice, suggesting that this drug might be repurposed to treat patients with AD.

    更新日期:2018-03-22
  • Pin1 mediates Aβ42-induced dendritic spine loss
    Sci. Signal. (IF 6.494) Pub Date : 2018-03-20
    Nancy R. Stallings, Melissa A. O’Neal, Jie Hu, Ege T. Kavalali, Ilya Bezprozvanny, James S. Malter

    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 Aβ42-calcineurin signaling. In dendritic spines, Pin1 interacted with and was dephosphorylated by calcineurin, which rapidly suppressed its isomerase activity. Knockout of Pin1 or exposure to Aβ42 induced the loss of mature dendritic spines, which was prevented by exogenous Pin1. The calcineurin inhibitor FK506 blocked dendritic spine loss in Aβ42-treated wild-type cells but had no effect on Pin1-null neurons. These data implicate Pin1 in dendritic spine maintenance and synaptic loss in early Alzheimer’s disease.

    更新日期:2018-03-22
  • p38α signaling in Langerhans cells promotes the development of IL-17–producing T cells and psoriasiform skin inflammation
    Sci. Signal. (IF 6.494) Pub Date : 2018-03-13
    Tingting Zheng, Weiheng Zhao, Hongjin Li, Shuxiu Xiao, Ran Hu, Miaomiao Han, Heng Liu, Yeqiang Liu, Kinya Otsu, Xinguang Liu, Gonghua Huang

    Dendritic cells (DCs) contribute to psoriasis pathogenesis. In a mouse model of imiquimod-induced psoriasiform skin inflammation, we found that p38α activity in Langerhans cells (LCs), a skin-resident subset of DCs, promoted the generation of T cells that produce IL-17, a proinflammatory cytokine that is implicated in autoimmune disease. Deletion of p38α in LCs, but not in other skin or circulating DC subsets or T cells, decreased T cell–mediated psoriasiform skin inflammation in mice. The activity of p38α in LCs specifically promoted IL-17 production from γδ and CD4+ T cells by increasing the abundance of IL-23 and IL-6, two cytokines that stimulate IL-17 secretion. Inhibition of p38 activity through either pharmacological inhibition or genetic deletion also reduced the severity of established psoriasiform skin inflammation. Together, our findings indicate a critical role for p38α signaling in LCs in promoting inflammatory responses in the skin and suggest that targeting p38α signaling in LCs may offer an effective therapeutic approach to treat psoriasis.

    更新日期:2018-03-14
  • Skp2-dependent reactivation of AKT drives resistance to PI3K inhibitors
    Sci. Signal. (IF 6.494) Pub Date : 2018-03-13
    Emilie Clement, Hiroyuki Inuzuka, Naoe T. Nihira, Wenyi Wei, Alex Toker

    The PI3K-AKT kinase signaling pathway is frequently deregulated in human cancers, particularly breast cancer, where amplification and somatic mutations of PIK3CA occur with high frequency in patients. Numerous small-molecule inhibitors targeting both PI3K and AKT are under clinical evaluation, but dose-limiting toxicities and the emergence of resistance limit therapeutic efficacy. Various resistance mechanisms to PI3K inhibitors have been identified, including de novo mutations, feedback activation of AKT, or cross-talk pathways. We found a previously unknown resistance mechanism to PI3K pathway inhibition that results in AKT rebound activation. In a subset of triple-negative breast cancer cell lines, treatment with a PI3K inhibitor or depletion of PIK3CA expression ultimately promoted AKT reactivation in a manner dependent on the E3 ubiquitin ligase Skp2, the kinases IGF-1R (insulin-like growth factor 1 receptor) and PDK-1 (phosphoinositide-dependent kinase-1), and the cell growth and metabolism-regulating complex mTORC2 (mechanistic target of rapamycin complex 2), but was independent of PI3K activity or PIP3 production. Resistance to PI3K inhibitors correlated with the increased abundance of Skp2, ubiquitylation of AKT, cell proliferation in culture, and xenograft tumor growth in mice. These findings reveal a ubiquitin signaling feedback mechanism by which PI3K inhibitor resistance may emerge in aggressive breast cancer cells.

    更新日期:2018-03-14
  • Extension of chemotactic pseudopods by nonadherent human neutrophils does not require or cause calcium bursts
    Sci. Signal. (IF 6.494) Pub Date : 2018-03-13
    Emmet A. Francis, Volkmar Heinrich

    Global bursts in free intracellular calcium (Ca2+) are among the most conspicuous signaling events in immune cells. To test the common view that Ca2+ bursts mediate rearrangement of the actin cytoskeleton in response to the activation of G protein–coupled receptors, we combined single-cell manipulation with fluorescence imaging and monitored the Ca2+ concentration in individual human neutrophils during complement-mediated chemotaxis. By decoupling purely chemotactic pseudopod formation from cell-substrate adhesion, we showed that physiological concentrations of anaphylatoxins, such as C5a, induced nonadherent human neutrophils to form chemotactic pseudopods but did not elicit Ca2+ bursts. By contrast, pathological or supraphysiological concentrations of C5a often triggered Ca2+ bursts, but pseudopod protrusion stalled or reversed in such cases, effectively halting chemotaxis, similar to sepsis-associated neutrophil paralysis. The maximum increase in cell surface area during pseudopod extension in pure chemotaxis was much smaller—by a factor of 8—than the known capacity of adherent human neutrophils to expand their surface. Because the measured rise in cortical tension was not sufficient to account for this difference, we attribute the limited deformability to a reduced ability of the cytoskeleton to generate protrusive force in the absence of cell adhesion. Thus, we hypothesize that Ca2+ bursts in neutrophils control a mechanistic switch between two distinct modes of cytoskeletal organization and dynamics. A key element of this switch appears to be the expedient coordination of adhesion-dependent lock or release events of cytoskeletal membrane anchors.

    更新日期:2018-03-14
  • Epigenetic ignition of melanoma
    Sci. Signal. (IF 6.494) Pub Date : 2018-03-13
    Leslie K. Ferrarelli

    The histone demethylases LSD1 and JMJD2C enable premalignant melanocytes to escape oncogene-induced senescence and form aggressive melanomas.

    更新日期:2018-03-14
  • TSLP signaling in CD4+ T cells programs a pathogenic T helper 2 cell state
    Sci. Signal. (IF 6.494) Pub Date : 2018-03-13
    Yrina Rochman, Krista Dienger-Stambaugh, Phoebe K. Richgels, Ian P. Lewkowich, Andrey V. Kartashov, Artem Barski, Gurjit K. Khurana Hershey, Warren J. Leonard, Harinder Singh

    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–programmed TH2 cells had a pathogenic phenotype, producing greater amounts of IL-5 and IL-13 and other proinflammatory cytokines than did TH2 cells stimulated with IL-4 alone. TSLP-mediated TH2 cell induction involved distinct molecular pathways, including activation of the transcription factor STAT5 through the kinase JAK2 and repression of the transcription factor BCL6. Mice that received wild-type CD4+ T cells had exacerbated pathogenic TH2 cell responses upon exposure to house dust mites compared to mice that received TSLP receptor–deficient CD4+ T cells. Transient TSLP signaling stably programmed pathogenic potential in memory TH2 cells. In human CD4+ T cells, TSLP and IL-4 promoted the generation of TH2 cells that produced greater amounts of IL-5 and IL-13. Compared to healthy controls, asthmatic children showed enhancement of such T cell responses in peripheral blood. Our data support a sequential cytokine model for pathogenic TH2 cell differentiation and provide a mechanistic basis for the therapeutic targeting of TSLP signaling in human allergic diseases.

    更新日期:2018-03-14
  • Inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signaling responses to p38 inhibition
    Sci. Signal. (IF 6.494) Pub Date : 2018-03-06
    Douglas S. Jones, Anne P. Jenney, Brian A. Joughin, Peter K. Sorger, Douglas A. Lauffenburger

    Rheumatoid arthritis (RA) is a chronic inflammatory disorder that causes joint pain, swelling, and loss of function. Development of effective new drugs has proven challenging in part because of the complexities and interconnected nature of intracellular signaling networks that complicate the effects of pharmacological interventions. We characterized the kinase signaling pathways that are activated in RA and evaluated the multivariate effects of targeted inhibitors. Synovial fluids from RA patients activated the kinase signaling pathways JAK, JNK, p38, and MEK in synovial fibroblasts (SFs), a stromal cell type that promotes RA progression. Kinase inhibitors enhanced signaling of “off-target” pathways in a manner dependent on stimulatory context. Inhibitors of p38, which have been widely explored in clinical trials for RA, resulted in undesirable increases in nuclear factor κB (NF-κB), JNK, and MEK signaling in SFs in inflammatory, but not mitogenic, contexts. This was mediated by the transcription factor CREB, which functions in part within a negative feedback loop in MAPK signaling. CREB activation was induced predominately by p38 in response to inflammatory stimuli, but by MEK in response to mitogenic stimuli; hence, the effects of drugs targeting p38 or MEK were markedly different in SFs cultured under mitogenic or inflammatory conditions. Together, these findings illustrate how stimulatory context can alter dominance in pathway cross-talk even for a fixed network topology, thereby providing a rationale for why p38 inhibitors deliver limited benefits in RA and demonstrating the need for careful consideration of p38-targeted drugs in inflammation-related disorders.

    更新日期:2018-03-07
  • Splenic leukocytes define the resolution of inflammation in heart failure
    Sci. Signal. (IF 6.494) Pub Date : 2018-03-06
    Ganesh V. Halade, Paul C. Norris, Vasundhara Kain, Charles N. Serhan, Kevin A. Ingle

    Inflammation promotes healing in myocardial infarction but, if unresolved, leads to heart failure. To define the inflammatory and resolving responses, we quantified leukocyte trafficking and specialized proresolving mediators (SPMs) in the infarcted left ventricle and spleen after myocardial infarction, with the goal of distinguishing inflammation from its resolution. Our data suggest that the spleen not only served as a leukocyte reservoir but also was the site where SPMs were actively generated after coronary ligation in mice. Before myocardial infarction, SPMs were more abundant in the spleen than in the left ventricle. At day 1 after coronary ligation, the spleen was depleted of leukocytes, a phenomenon that was associated with greater numbers of leukocytes in the infarcted left ventricle and increased generation of SPMs at the same site, particularly resolvins, maresin, lipoxins, and protectin. In addition, the infarcted left ventricle showed increased expression of genes encoding lipoxygenases and enhanced production of SPMs generated by these enzymes. We found that macrophages were necessary for SPM generation. The abundance of SPMs in the spleen before myocardial infarction and increased SPM concentrations in the infarcted left ventricle within 24 hours after myocardial infarction were temporally correlated with the resolution of inflammation. Thus, the acute inflammatory response coincided with the active resolving phase in post–myocardial infarction and suggests that further investigation into macrophage-derived SPMs in heart failure is warranted.

    更新日期:2018-03-07
  • cAMPr: A single-wavelength fluorescent sensor for cyclic AMP
    Sci. Signal. (IF 6.494) Pub Date : 2018-03-06
    Christopher R. Hackley, Esteban O. Mazzoni, Justin Blau

    Genetically encoded fluorescent sensors enable cell-specific measurements of ions and small molecules in real time. Cyclic adenosine monophosphate (cAMP) is one of the most important signaling molecules in virtually all cell types and organisms. We describe cAMPr, a new single-wavelength cAMP sensor. We developed cAMPr in bacteria and embryonic stem cells and validated the sensor in mammalian neurons in vitro and in Drosophila circadian pacemaker neurons in intact brains. Comparison with other single-wavelength cAMP sensors showed that cAMPr improved the quantitative detection of cAMP abundance. In addition, cAMPr is compatible with both single-photon and two-photon imaging. This enabled us to use cAMPr together with the red fluorescent Ca2+ sensor RCaMP1h to simultaneously monitor Ca2+ and cAMP in Drosophila brains. Thus, cAMPr is a new and versatile genetically encoded cAMP sensor.

    更新日期:2018-03-07
  • Infection alters circadian rhythm
    Sci. Signal. (IF 6.494) Pub Date : 2018-03-06
    Annalisa M. VanHook

    The response to bacterial infection alters the circadian rhythm of Arabidopsis thaliana.

    更新日期:2018-03-07
  • A role for corticotropin-releasing factor signaling in the lateral habenula and its modulation by early-life stress
    Sci. Signal. (IF 6.494) Pub Date : 2018-03-06
    Michael E. Authement, Ludovic D. Langlois, Ryan D. Shepard, Caroline A. Browne, Irwin Lucki, Haifa Kassis, Fereshteh S. Nugent

    Centrally released corticotropin-releasing factor or hormone (extrahypothalamic CRF or CRH) in the brain is involved in the behavioral and emotional responses to stress. The lateral habenula (LHb) is an epithalamic brain region involved in value-based decision-making and stress evasion. Through its inhibition of dopamine-mediated reward circuitry, the increased activity of the LHb is associated with addiction, depression, schizophrenia, and behavioral disorders. We found that extrahypothalamic CRF neurotransmission increased neuronal excitability in the LHb. Through its receptor CRFR1 and subsequently protein kinase A (PKA), CRF application increased the intrinsic excitability of LHb neurons by affecting changes in small-conductance SK-type and large-conductance BK-type K+ channels. CRF also reduced inhibitory γ-aminobutyric acid–containing (GABAergic) synaptic transmission onto LHb neurons through endocannabinoid-mediated retrograde signaling. Maternal deprivation is a severe early-life stress that alters CRF neural circuitry and is likewise associated with abnormal mental health later in life. LHb neurons from pups deprived of maternal care exhibited increased intrinsic excitability, reduced GABAergic transmission, decreased abundance of SK2 channel protein, and increased activity of PKA, without any substantial changes in Crh or Crhr1 expression. Furthermore, maternal deprivation blunted the response of LHb neurons to subsequent, acute CRF exposure. Activating SK channels or inhibiting postsynaptic PKA activity prevented the effects of both CRF and maternal deprivation on LHb intrinsic excitability, thus identifying potential pharmacological targets to reverse central CRF circuit dysregulation in patients with associated disorders.

    更新日期:2018-03-07
  • The cost of being different
    Sci. Signal. (IF 6.494) Pub Date : 2018-02-27
    Wei Wong

    Extensive genetic variations in GPCRs may alter responses to commonly used drugs and incur a high economic burden.

    更新日期:2018-02-27
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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