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Science Signaling

Bohumil Fafilek, Lukas Balek, Michaela Kunova Bosakova, Miroslav Varecha, Alexandru Nita, Tomas Gregor, Iva Gudernova, Jitka Krenova, Somadri Ghosh, Martin Piskacek, Lucie Jonatova, Nicole H Cernohorsky, Jennifer T Zieba, Michal Kostas, Ellen Margrethe Haugsten, Jørgen Wesche, Christophe Erneux, Lukas Trantirek, Deborah Krakow, Pavel Krejci
Sustained activation of extracellular signal-regulated kinase (ERK) drives pathologies caused by mutations in fibroblast growth factor receptors (FGFRs). We previously identified the inositol phosphatase SHIP2 (also known as INPPL1) as an FGFR-interacting protein and a target of the tyrosine kinase activities of FGFR1, FGFR3, and FGFR4. We report that loss of SHIP2 converted FGF-mediated sustained ERK activation into a transient signal and rescued cell phenotypes triggered by pathologic FGFR-ERK signaling. Mutant forms of SHIP2 lacking phosphoinositide phosphatase activity still associated with FGFRs and did not prevent FGF-induced sustained ERK activation, demonstrating that the adaptor rather than the catalytic activity of SHIP2 was required...
September 18, 2018: Science Signaling
Chengdong Liu, Yi Xin, Yan Bai, Grant Lewin, Gen He, Kangsen Mai, Cunming Duan
The phenotype gap is a challenge for genetically dissecting redundant endocrine signaling pathways, such as the six isoforms in the insulin-like growth factor binding protein (IGFBP) family. Although overexpressed IGFBPs can inhibit or potentiate IGF actions or have IGF-independent actions, mutant mice lacking IGFBP-encoding genes do not exhibit major phenotypes. We found that although zebrafish deficient in igfbp5a did not show overt phenotypes when raised in Ca2+ -rich solutions, they died prematurely in low Ca2+ conditions...
September 18, 2018: Science Signaling
Masataka Yanagawa, Michio Hiroshima, Yuichi Togashi, Mitsuhiro Abe, Takahiro Yamashita, Yoshinori Shichida, Masayuki Murata, Masahiro Ueda, Yasushi Sako
G protein-coupled receptors (GPCRs) are major drug targets. Developing a method to measure the activities of GPCRs is essential for pharmacology and drug screening. However, it is difficult to measure the effects of a drug by monitoring the receptor on the cell surface; thus, changes in the concentrations of downstream signaling molecules, which depend on the signaling pathway selectivity of the receptor, are often used as an index of receptor activity. We show that single-molecule imaging analysis provides an alternative method for assessing the effects of ligands on GPCRs...
September 18, 2018: Science Signaling
Maja Semanjski, Elsa Germain, Katrin Bratl, Andreas Kiessling, Kenn Gerdes, Boris Macek
The bacterial serine-threonine protein kinase HipA promotes multidrug tolerance by phosphorylating the glutamate-tRNA ligase (GltX), leading to a halt in translation, inhibition of growth, and induction of a physiologically dormant state (persistence). The HipA variant HipA7 substantially increases persistence despite being less efficient at inhibiting cell growth. We postulated that this phenotypic difference was caused by differences in the substrates targeted by both kinases. We overproduced HipA and HipA7 in Escherichia coli and identified their endogenous substrates by SILAC-based quantitative phosphoproteomics...
September 11, 2018: Science Signaling
Teresa Purzner, James Purzner, Taylor Buckstaff, Giorgio Cozza, Sharareh Gholamin, Jessica M Rusert, Tom A Hartl, John Sanders, Nicholas Conley, Xuecai Ge, Marc Langan, Vijay Ramaswamy, Lauren Ellis, Ulrike Litzenburger, Sara Bolin, Johanna Theruvath, Ryan Nitta, Lin Qi, Xiao-Nan Li, Gordon Li, Michael D Taylor, Robert J Wechsler-Reya, Lorenzo A Pinna, Yoon-Jae Cho, Margaret T Fuller, Joshua E Elias, Matthew P Scott
A major limitation of targeted cancer therapy is the rapid emergence of drug resistance, which often arises through mutations at or downstream of the drug target or through intrinsic resistance of subpopulations of tumor cells. Medulloblastoma (MB), the most common pediatric brain tumor, is no exception, and MBs that are driven by sonic hedgehog (SHH) signaling are particularly aggressive and drug-resistant. To find new drug targets and therapeutics for MB that may be less susceptible to common resistance mechanisms, we used a developmental phosphoproteomics approach in murine granule neuron precursors (GNPs), the developmental cell of origin of MB...
September 11, 2018: Science Signaling
Pierre Jean Le Reste, Eric Chevet
Translational medicine has been nurtured by the creation of M.D.-Ph.D. programs, a system that now needs to reinvent itself. Now, clinically oriented training programs targeting nonphysician scientists have opened new avenues to improve transdisciplinary approaches in health sciences.
September 11, 2018: Science Signaling
Thijs J Hagenbeek, Joshua D Webster, Noelyn M Kljavin, Matthew T Chang, Trang Pham, Ho-June Lee, Christiaan Klijn, Allen G Cai, Klara Totpal, Buvana Ravishankar, Naiying Yang, Da-Hye Lee, Kevin B Walsh, Georgia Hatzivassiliou, Cecile C de la Cruz, Stephen E Gould, Xiumin Wu, Wyne P Lee, Shuqun Yang, Zhixiang Zhang, Qingyang Gu, Qunsheng Ji, Erica L Jackson, Dae-Sik Lim, Anwesha Dey
The Hippo signaling pathway regulates organ size and plays critical roles in maintaining tissue growth, homeostasis, and regeneration. Dysregulated in a wide spectrum of cancers, in mammals, this pathway is regulated by two key effectors, YAP and TAZ, that may functionally overlap. We found that TAZ promoted liver inflammation and tumor development. The expression of TAZ, but not YAP, in human liver tumors positively correlated with the expression of proinflammatory cytokines. Hyperactivated TAZ induced substantial myeloid cell infiltration into the liver and the secretion of proinflammatory cytokines through a TEAD-dependent mechanism...
September 11, 2018: Science Signaling
Rafael Gil de Rubio, Richard F Ransom, Sundeep Malik, David I Yule, Arun Anantharam, Alan V Smrcka
Phospholipase C (PLC) enzymes hydrolyze the plasma membrane (PM) lipid phosphatidylinositol 4,5-bisphosphate (PI4,5P2 ) to generate the second messengers inositol trisphosphate (IP3 ) and diacylglycerol (DAG) in response to receptor activation in almost all mammalian cells. We previously found that stimulation of G protein-coupled receptors (GPCRs) in cardiac cells leads to the PLC-dependent hydrolysis of phosphatidylinositol 4-phosphate (PI4P) at the Golgi, a process required for the activation of nuclear protein kinase D (PKD) during cardiac hypertrophy...
September 11, 2018: Science Signaling
Erin Sheffels, Nancy E Sealover, Chenyue Wang, Do Hyung Kim, Isabella A Vazirani, Elizabeth Lee, Elizabeth M Terrell, Deborah K Morrison, Ji Luo, Robert L Kortum
About a third of tumors have activating mutations in HRAS , NRAS , or KRAS , genes encoding guanosine triphosphatases (GTPases) of the RAS family. In these tumors, wild-type RAS cooperates with mutant RAS to promote downstream effector activation and cell proliferation and transformation, suggesting that upstream activators of wild-type RAS are important modulators of mutant RAS-driven oncogenesis. The guanine nucleotide exchange factor (GEF) SOS1 mediates KRAS-driven proliferation, but little is understood about the role of SOS2...
September 4, 2018: Science Signaling
Michael D Onken, Carol M Makepeace, Kevin M Kaltenbronn, Stanley M Kanai, Tyson D Todd, Shiqi Wang, Thomas J Broekelmann, Prabakar Kumar Rao, John A Cooper, Kendall J Blumer
Constitutively active G protein α subunits cause cancer, cholera, Sturge-Weber syndrome, and other disorders. Therapeutic intervention by targeted inhibition of constitutively active Gα subunits in these disorders has yet to be achieved. We found that constitutively active Gαq in uveal melanoma (UM) cells was inhibited by the cyclic depsipeptide FR900359 (FR). FR allosterically inhibited guanosine diphosphate-for-guanosine triphosphate (GDP/GTP) exchange to trap constitutively active Gαq in inactive, GDP-bound Gαβγ heterotrimers...
September 4, 2018: Science Signaling
Marc Torrent, Guilhem Chalancon, Natalia S de Groot, Arthur Wuster, M Madan Babu
Decoding the information in mRNA during protein synthesis relies on tRNA adaptors, the abundance of which can affect the decoding rate and translation efficiency. To determine whether cells alter tRNA abundance to selectively regulate protein expression, we quantified changes in the abundance of individual tRNAs at different time points in response to diverse stress conditions in Saccharomyces cerevisiae We found that the tRNA pool was dynamic and rearranged in a manner that facilitated selective translation of stress-related transcripts...
September 4, 2018: Science Signaling
Akshay A D'Cruz, Mary Speir, Meghan Bliss-Moreau, Sylvia Dietrich, Shu Wang, Alyce A Chen, Mathilde Gavillet, Arshed Al-Obeidi, Kate E Lawlor, James E Vince, Michelle A Kelliher, Razq Hakem, Manolis Pasparakis, David A Williams, Maria Ericsson, Ben A Croker
Neutrophil extracellular trap (NET) formation can generate short-term, functional anucleate cytoplasts and trigger loss of cell viability. We demonstrated that the necroptotic cell death effector mixed lineage kinase domain-like (MLKL) translocated from the cytoplasm to the plasma membrane and stimulated downstream NADPH oxidase-independent ROS production, loss of cytoplasmic granules, breakdown of the nuclear membrane, chromatin decondensation, histone hypercitrullination, and extrusion of bacteriostatic NETs...
September 4, 2018: Science Signaling
Sebastian Pechmann
Stress conditions curtail the energetically costly process of messenger RNA translation. In this issue of Science Signaling , Torrent et al. report key evidence for a direct link between codon usage and translation regulation in response to stress.
September 4, 2018: Science Signaling
Davinna L Ligons, SuJin Hwang, Adam T Waickman, Joo-Young Park, Megan A Luckey, Jung-Hyun Park
The cytokine receptor subunit γc provides critical signals for T cell survival and differentiation. We investigated the molecular mechanism that controls the cell surface abundance of γc during T cell development in the thymus. We found that the amount of γc was low on CD4+ CD8+ double-positive (DP) thymocytes before their positive selection to become mature T cells. The transcription factor RORγt was abundant in immature DP thymocytes, and its loss resulted in an increase in the abundance of surface γc, specifically on preselection DP cells...
August 28, 2018: Science Signaling
Angeliki Karamitri, Bianca Plouffe, Amélie Bonnefond, Min Chen, Jonathan Gallion, Jean-Luc Guillaume, Alan Hegron, Mathilde Boissel, Mickaël Canouil, Claudia Langenberg, Nicholas J Wareham, Christian Le Gouill, Viktoria Lukasheva, Olivier Lichtarge, Philippe Froguel, Michel Bouvier, Ralf Jockers
Melatonin is produced during the night and regulates sleep and circadian rhythms. Loss-of-function variants in MTNR1B , which encodes the melatonin receptor MT2 , a G protein-coupled receptor (GPCR), are associated with an increased risk of type 2 diabetes (T2D). To identify specific T2D-associated signaling pathway(s), we profiled the signaling output of 40 MT2 variants by monitoring spontaneous (ligand-independent) and melatonin-induced activation of multiple signaling effectors. Genetic association analysis showed that defects in the melatonin-induced activation of Gαi1 and Gαz proteins and in spontaneous β-arrestin2 recruitment to MT2 were the most statistically significantly associated with an increased T2D risk...
August 28, 2018: Science Signaling
Sonja L Joksimovic, Srdjan M Joksimovic, Vesna Tesic, Agustin García-Caballero, Simon Feseha, Gerald W Zamponi, Vesna Jevtovic-Todorovic, Slobodan M Todorovic
Pain-sensing sensory neurons of the dorsal root ganglion (DRG) can become sensitized or hyperexcitable in response to surgically induced peripheral tissue injury. We investigated the potential role and molecular mechanisms of nociceptive ion channel dysregulation in acute pain conditions such as those resulting from skin and soft tissue incision. We used selective pharmacology, electrophysiology, and mouse genetics to link increased current densities arising from the CaV 3.2 isoform of T-type calcium channels (T-channels) to nociceptive sensitization using a clinically relevant rodent model of skin and deep tissue incision...
August 28, 2018: Science Signaling
Lauren M Browning, Maciej Pietrzak, Michal Kuczma, Colin P Simms, Agnieszka Kurczewska, Justin M Refugia, Dustin J Lowery, Grzegorz Rempala, Dmitriy Gutkin, Leszek Ignatowicz, Pawel Muranski, Piotr Kraj
The cytokines of the transforming growth factor-β (TGF-β) family promote the growth and differentiation of multiple tissues, but the role of only the founding member, TGF-β, in regulating the immune responses has been extensively studied. TGF-β is critical to prevent the spontaneous activation of self-reactive T cells and sustain immune homeostasis. In contrast, in the presence of proinflammatory cytokines, TGF-β promotes the differentiation of effector T helper 17 (TH 17) cells. Abrogating TGF-β receptor signaling prevents the development of interleukin-17 (IL-17)-secreting cells and protects mice from TH 17 cell-mediated autoimmunity...
August 28, 2018: Science Signaling
Minjung Choi, Dean P Staus, Laura M Wingler, Seungkirl Ahn, Biswaranjan Pani, William D Capel, Robert J Lefkowitz
Biased agonists of G protein-coupled receptors (GPCRs), which selectively activate either G protein- or β-arrestin-mediated signaling pathways, are of major therapeutic interest because they have the potential to show improved efficacy and specificity as drugs. Efforts to understand the mechanistic basis of this phenomenon have focused on the hypothesis that G proteins and β-arrestins preferentially couple to distinct GPCR conformations. However, because GPCR kinase (GRK)-dependent receptor phosphorylation is a critical prerequisite for the recruitment of β-arrestins to most GPCRs, GRKs themselves may play an important role in establishing biased signaling...
August 21, 2018: Science Signaling
Alexander I Salter, Richard G Ivey, Jacob J Kennedy, Valentin Voillet, Anusha Rajan, Eva J Alderman, Uliana J Voytovich, Chenwei Lin, Daniel Sommermeyer, Lingfeng Liu, Jeffrey R Whiteaker, Raphael Gottardo, Amanda G Paulovich, Stanley R Riddell
Chimeric antigen receptors (CARs) link an antigen recognition domain to intracellular signaling domains to redirect T cell specificity and function. T cells expressing CARs with CD28/CD3ζ or 4-1BB/CD3ζ signaling domains are effective at treating refractory B cell malignancies but exhibit differences in effector function, clinical efficacy, and toxicity that are assumed to result from the activation of divergent signaling cascades. We analyzed stimulation-induced phosphorylation events in primary human CD8+ CD28/CD3ζ and 4-1BB/CD3ζ CAR T cells by mass spectrometry and found that both CAR constructs activated similar signaling intermediates...
August 21, 2018: Science Signaling
Yoshimitsu Nakanishi, Modong Tan, Takako Ichiki, Asuka Inoue, Jun-Ichi Yoshihara, Naoto Maekawa, Itsuki Takenoshita, Keisuke Yanagida, Shinya Yamahira, Satoshi Yamaguchi, Junken Aoki, Teruyuki Nagamune, Takehiko Yokomizo, Takao Shimizu, Motonao Nakamura
Leukotriene B4 (LTB4 ) receptor type 1 (BLT1) is abundant in phagocytic and immune cells and plays crucial roles in various inflammatory diseases. BLT1 is phosphorylated at several serine and threonine residues upon stimulation with the inflammatory lipid LTB4 Using Phos-tag gel electrophoresis to separate differentially phosphorylated forms of BLT1, we identified two distinct types of phosphorylation, basal and ligand-induced, in the carboxyl terminus of human BLT1. In the absence of LTB4 , the basal phosphorylation sites were modified to various degrees, giving rise to many different phosphorylated forms of BLT1...
August 21, 2018: Science Signaling
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