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https://www.readbyqxmd.com/read/28430987/rab32-subfamily-small-gtpases-pleiotropic-rabs-in-endosomal-trafficking
#1
Norihiko Ohbayashi, Mitsunori Fukuda, Yasunori Kanaho
Rab small GTPases, well-known regulators of membrane trafficking pathways in eukaryotic cells, comprise approximately 60 different members in mammals. During the past decade, our understanding of the functions of mammalian Rab32 subfamily members (Rab32 and Rab38) have deepened, especially on the biogenesis of lysosome-related organelles, such as melanosomes, and the protection mechanisms against several pathogenic microbial infections. Endosome-mediated membrane trafficking by Rab32 subfamily members plays pivotal roles in these events...
April 14, 2017: Journal of Biochemistry
https://www.readbyqxmd.com/read/28426288/post-translational-modifications-of-rab-gtpases
#2
Swapnil Rohidas Shinde, Subbareddy Maddika
Rab GTPases, the highly conserved members of Ras GTPase superfamily are central players in the vesicular trafficking. They are critically involved in intracellular trafficking pathway, beginning from formation of vesicles on donor membranes, defining trafficking specificity to facilitating vesicle docking on target membranes. Given the dynamic roles of Rabs during different stages of vesicular trafficking, mechanisms for their spatial and temporal regulation are crucial for normal cellular function. Regulation of Rab GTPase activity, localization and function has always been focused in and around the association of GDP dissociation inhibitor (GDI), Guanine nucleotide Exchange Factor (GEFs) and GTPase accelerating protein (GAP) to Rabs...
February 28, 2017: Small GTPases
https://www.readbyqxmd.com/read/28420712/sec71-functions-as-a-gef-for-the-small-gtpase-arf1-to-govern-dendrite-pruning-of-drosophila-sensory-neurons
#3
Yan Wang, Heng Zhang, Meng Shi, Yih-Cherng Liou, Lei Lu, Fengwei Yu
Pruning, whereby neurons eliminate their exuberant neurites, is central for the maturation of the nervous system. In Drosophila, sensory neurons, ddaCs, selectively prune their larval dendrites without affecting their axons during metamorphosis. However, it is unknown whether the secretory pathway plays a role in dendrite pruning. Here, we show that the small GTPase Arf1, an important regulator of secretory pathway, is specifically required for dendrite pruning of ddaC/D/E sensory neurons but dispensable for apoptosis of ddaF neurons...
April 18, 2017: Development
https://www.readbyqxmd.com/read/28418645/brain-region-and-isoform-specific-phosphorylation-alters-kalirin-sh2-domain-interaction-sites-and-calpain-sensitivity
#4
Megan B Miller, Yan Yan, Kazuya Machida, Drew D Kiraly, Aaron D Levy, Yi I Wu, TuKiet Tan Lam, Thomas Abbott, Anthony John Koleske, Betty A Eipper, Richard E Mains
Kalirin7 (Kal7), a postsynaptic Rho GDP/GTP exchange factor (RhoGEF), plays a crucial role in long term potentiation and in the effects of cocaine on behavior and spine morphology. The KALRN gene has been linked to schizophrenia and other disorders of synaptic function. Mass spectrometry was used to quantify phosphorylation at 26 sites in Kal7 from individual adult rat nucleus accumbens and prefrontal cortex before and after exposure to acute or chronic cocaine. Region- and isoform-specific phosphorylation was observed along with region-specific effects of cocaine on Kal7 phosphorylation...
April 18, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28416080/molecular-identification-and-immunological-characteristics-of-goose-suppressor-of-cytokine-signaling-1-socs-1-in-vitro-and-vivo-following-dtmuv-challenge
#5
Wei Zhang, Shun Chen, Jingyue Zhang, Zhen Wu, Mingshu Wang, Renyong Jia, Dekang Zhu, Mafeng Liu, Kunfeng Sun, Qiao Yang, Ying Wu, Xiaoyue Chen, Anchun Cheng
Purpose suppressor of cytokine signaling 1 (SOCS-1) is inducible feedback inhibitors of cytokine signaling and involved in viral infection through regulation of both innate and adaptive immunity. In this study, we firstly cloned SOCS-1 (goSOCS-1) from duck Tembusu virus (DTMUV) infected goose. The full-length sequence of goSOCS-1 ORF is 624bp and encoded 108 amino acids. Structurally, the mainly functional regions (KIR, SH2, SOCS-box) were conserved between avian and mammalian. The tissues distribution data showed SOCS-1 highly expressed in immune related tissues (SP, LU, HG) of both gosling and adult goose...
April 13, 2017: Cytokine
https://www.readbyqxmd.com/read/28389580/mgcracgap-s-sxip-motif-tethers-centralspindlin-to-microtubule-plus-ends
#6
Elaina B Breznau, Megan Murt, T Lynne Blasius, Kristen J Verhey, Ann L Miller
Centralspindlin, a complex of the kinesin-6 MKLP1 and MgcRacGAP, is required for cytokinesis and cell-cell junctions. During anaphase, Centralspindlin accumulates at overlapping central spindle microtubules and directs contractile ring formation by recruiting the GEF Ect2 to the cell equator to activate RhoA. We found that MgcRacGAP localized to plus ends of equatorial astral microtubules during cytokinesis in Xenopus laevis embryos. How MgcRacGAP is stabilized at microtubule plus ends is unknown. We identified an SxIP motif in X...
April 7, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28373025/early-life-febrile-seizures-worsen-adult-phenotypes-in-scn1a-mutants
#7
Stacey B B Dutton, Karoni Dutt, Ligia A Papale, Sandra Helmers, Alan L Goldin, Andrew Escayg
Mutations in the voltage-gated sodium channel (VGSC) gene SCN1A, encoding the Nav1.1 channel, are responsible for a number of epilepsy disorders including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS). Patients with SCN1A mutations often experience prolonged early-life febrile seizures (FSs), raising the possibility that these events may influence epileptogenesis and lead to more severe adult phenotypes. To test this hypothesis, we subjected 21-23-day-old mice expressing the human SCN1A GEFS+ mutation R1648H to prolonged hyperthermia, and then examined seizure and behavioral phenotypes during adulthood...
March 31, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28370940/-molecular-activity-painting-switch-like-light-controlled-perturbations-inside-living-cells
#8
Xi Chen, Muthukumaran Venkatachalapathy, Dominic Kamps, Simone Weigel, Ravi Kumar, Michael Orlich, Ruben Garrecht, Michael Hirtz, Christof M Niemeyer, Yao-Wen Wu, Leif Dehmelt
Acute subcellular protein targeting is a powerful tool to study biological networks. However, signaling at the plasma membrane is highly dynamic, making it difficult to study in space and time. In particular, sustained local control of molecular function is challenging owing to the lateral diffusion of plasma membrane targeted molecules. Herein we present "molecular-activity painting" (MAP), a novel technology which combines photoactivatable chemically induced dimerization (pCID) with immobilized artificial receptors...
March 29, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28362242/arf-gaps-a-family-of-proteins-with-disparate-functions-that-converge-on-a-common-structure-the-integrin-adhesion-complex
#9
Teresa Vitali, Sofia Girald-Berlingeri, Paul A Randazzo, Pei-Wen Chen
ADP-ribosylation factors (Arfs) are members of the Ras GTPase superfamily. The function of Arfs is dependent on GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs), which allow Arfs to cycle between the GDP-bound and GTP-bound forms. Arf GAPs have been shown to be present in integrin adhesion complexes, which include focal adhesions. Integrin adhesion complexes are composed of integrins, scaffolding proteins and signaling proteins and regulate cell proliferation, survival, differentiation and migration...
March 31, 2017: Small GTPases
https://www.readbyqxmd.com/read/28356423/phosphorylated-cortactin-recruits-vav2-guanine-nucleotide-exchange-factor-to-activate-rac3-and-promote-invadopodial-function-in-invasive-breast-cancer-cells
#10
Brian J Rosenberg, Hava Gil-Henn, Christopher C Mader, Tiffany Halo, Taofei Yin, John Condeelis, Kazuya Machida, Yi I Wu, Anthony J Koleske
Breast carcinoma cells use specialized, actin-rich protrusions called invadopodia to degrade and invade through the extracellular matrix. Phosphorylation of the actin nucleation promoting factor and actin stabilizing protein cortactin downstream of the EGF receptor-Src-Arg kinase cascade is known to be a critical trigger for invadopodium maturation and subsequent cell invasion in breast cancer cells. The functions of cortactin phosphorylation in this process, however, are not completely understood. We identified the Rho-family guanine nucleotide exchange factor (GEF) Vav2 in a comprehensive screen for human SH2 domains that bind selectively to phosphorylated cortactin...
March 29, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28342870/the-rab-gtpase-rab18-modulates-macroautophagy-and-proteostasis
#11
Anne Feldmann, Fazilet Bekbulat, Heike Huesmann, Sarah Ulbrich, Jörg Tatzelt, Christian Behl, Andreas Kern
Macroautophagy is a conserved degradative pathway and its deterioration is linked to disturbances in cellular proteostasis and multiple diseases. Here, we show that the RAB GTPase RAB18 modulates autophagy in primary human fibroblasts. The knockdown of RAB18 results in a decreased autophagic activity, while its overexpression enhances the degradative pathway. Importantly, this function of RAB18 is dependent on RAB3GAP1 and RAB3GAP2, which might act as RAB GEFs and stimulate the activity of the RAB GTPase. Moreover, the knockdown of RAB18 deteriorates proteostasis and results in the intracellular accumulation of ubiquitinated degradation-prone proteins...
March 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28341448/the-drosophila-dock-family-protein-sponge-is-required-for-development-of-the-air-sac-primordium
#12
Kazushge Morishita, Dang Ngoc Anh Suong, Hideki Yoshida, Masamitsu Yamaguchi
Dedicator of cytokinesis (DOCK) family genes are known as DOCK1-DOCK11 in mammals. DOCK family proteins mainly regulate actin filament polymerization and/or depolymerization and are GEF proteins, which contribute to cellular signaling events by activating small G proteins. Sponge (Spg) is a Drosophila counterpart to mammalian DOCK3/DOCK4, and plays a role in embryonic central nervous system development, R7 photoreceptor cell differentiation, and adult thorax development. In order to conduct further functional analyses on Spg in vivo, we examined its localization in third instar larval wing imaginal discs...
March 21, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28334931/rgf1p-rho1p-gef-is-required-for-double-strand-break-repair-in-fission-yeast
#13
Elvira Manjón, Tomás Edreira, Sofía Muñoz, Yolanda Sánchez
Rho GTPases are conserved molecules that control cytoskeletal dynamics. These functions are expedited by Rho GEFs that stimulate the release of GDP to enable GTP binding, thereby allowing Rho proteins to initiate intracellular signaling. How Rho GEFs and Rho GTPases protect cells from DNA damage is unknown. Here, we explore the extreme sensitivity of a deletion mutation in the Rho1p exchange factor Rgf1p to the DNA break/inducing antibiotic phleomycin (Phl). The Rgf1p mutant cells are defective in reentry into the cell cycle following the induction of severe DNA damage...
March 15, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28331191/identification-of-a-novel-small-molecule-partial-agonist-for-the-cyclic-amp-sensor-epac1
#14
Euan Parnell, Stuart P McElroy, Jolanta Wiejak, Gemma L Baillie, Alison Porter, David R Adams, Holger Rehmann, Brian O Smith, Stephen J Yarwood
Screening of a carefully selected library of 5,195 small molecules identified 34 hit compounds that interact with the regulatory cyclic nucleotide-binding domain (CNB) of the cAMP sensor, EPAC1. Two of these hits (I942 and I178) were selected for their robust and reproducible inhibitory effects within the primary screening assay. Follow-up characterisation by ligand observed nuclear magnetic resonance (NMR) revealed direct interaction of I942 and I178 with EPAC1 and EPAC2-CNBs in vitro. Moreover, in vitro guanine nucleotide exchange factor (GEF) assays revealed that I942 and, to a lesser extent, I178 had partial agonist properties towards EPAC1, leading to activation of EPAC1, in the absence of cAMP, and inhibition of GEF activity in the presence of cAMP...
March 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28318223/high-throughput-dual-screening-method-for-ras-activities-and-inhibitors
#15
Kari Kopra, Arjan J van Adrichem, Outi M H Salo-Ahen, Juha Peltonen, Krister Wennerberg, Harri Härmä
Ras GTPases act as "molecular switches", alternating between inactive GDP-bound and active GTP-bound conformation. Ras-oncogenes were discovered over three decades ago, but there are still no effective therapies for Ras-driven cancers. So far, drug discovery strategies have been unsuccessful, because of a lack of suitable screening methodologies and well-defined binding pockets on the Ras proteins. Here, we addressed the former by introducing a homogeneous quenching resonance energy transfer (QRET) technique-based screening strategy for Ras interfacial and competitive inhibitors...
March 29, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28314177/gintonin-attenuates-depressive-like-behaviors-associated-with-alcohol-withdrawal-in-mice
#16
Hyeon-Joong Kim, Sang-Deuk Park, Ra Mi Lee, Byung-Hwan Lee, Sun-Hye Choi, Sung-Hee Hwang, Hyewhon Rhim, Hyoung-Chun Kim, Seung-Yeol Nah
BACKGROUND: Panax ginseng Meyer extracts have been used to improve mood and alleviate symptoms of depression. However, little is known about the extracts' active ingredients and the molecular mechanisms underlying their reported anti-depressive effects. METHODS: Gintonin is an exogenous lysophosphatidic acid (LPA) receptor ligand isolated from P. ginseng. BON cells, an enterochromaffin cell line, and C57BL/6 mice were used to investigate whether gintonin stimulates serotonin release...
March 9, 2017: Journal of Affective Disorders
https://www.readbyqxmd.com/read/28304276/scaffold-mediated-gating-of-cdc42-signalling-flux
#17
Péter Rapali, Romain Mitteau, Craig Braun, Aurèlie Massoni-Laporte, Caner Ünlü, Laure Bataille, Floriane Saint Arramon, Steven P Gygi, Derek McCusker
Scaffold proteins modulate signalling pathway activity spatially and temporally. In budding yeast, the scaffold Bem1 contributes to polarity axis establishment by regulating the GTPase Cdc42. Although different models have been proposed for Bem1 function, there is little direct evidence for an underlying mechanism. Here, we find that Bem1 directly augments the guanine exchange factor (GEF) activity of Cdc24. Bem1 also increases GEF phosphorylation by the p21-activated kinase (PAK), Cla4. Phosphorylation abrogates the scaffold-dependent stimulation of GEF activity, rendering Cdc24 insensitive to additional Bem1...
March 17, 2017: ELife
https://www.readbyqxmd.com/read/28304230/modular-regulation-of-rho-family-gtpases-in-development
#18
Marlis Denk-Lobnig, Adam C Martin
Rho family GTPase signaling regulates the actin cytoskeleton and is critical for behaviors that range from the cell to tissue-scale. A theme in Rho GTPase biology is that there are many more regulators, such as guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), than GTPases themselves. Here, we review different, modular cases where GEFs and GAPs function together to elicit precise spatial and temporal control of signaling. We focus on examples from metazoan development, where precise regulation of Rho GTPases is critical for proper tissue form and function...
March 17, 2017: Small GTPases
https://www.readbyqxmd.com/read/28301299/differential-role-for-pak1-and-pak4-during-the-invadopodia-lifecycle
#19
Nicole S Nicholas, Aikaterini Pipili, Michaela S Lesjak, Claire M Wells
PAK1 and PAK4 are members of the p-21 activated kinase family of serine/threonine kinases. PAK1 has previously been implicated in both the formation and disassembly of invasive cell protrusions, termed invadopodia. We recently reported a novel role for PAK4 during invadopodia maturation and confirmed a specific role for PAK1 in invadopodia formation; findings we will review here. Moreover, we found that PAK4 induction of maturation is delivered via interaction with the RhoA regulator PDZRho-GEF. We can now reveal that loss of PAK4 expression leads to changes in invadopodia dynamics...
March 16, 2017: Small GTPases
https://www.readbyqxmd.com/read/28298491/cyk-4-regulates-rac-but-not-rho-during-cytokinesis
#20
Yelena Zhuravlev, Sophia M Hirsch, Shawn N Jordan, Julien Dumont, Mimi Shirasu-Hiza, Julie C Canman
Cytokinesis is driven by constriction of an actomyosin contractile ring that is controlled by Rho family small GTPases. Rho, activated by the Guanine-nucleotide Exchange Factor (GEF) ECT-2, is upstream of both myosin-II activation and diaphanous formin-mediated filamentous actin (f-actin) assembly, which drive ring constriction. The role for Rac and its regulators is more controversial but, based on the finding that Rac inactivation can rescue cytokinesis failure when the GTPase Activating Protein (GAP) CYK-4 is disrupted, Rac activity was proposed to be inhibitory to contractile ring constriction and thus specifically inactivated by CYK-4 at the division plane...
March 15, 2017: Molecular Biology of the Cell
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