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      The Intermolecular Interaction of Ephexin4 Leads to Autoinhibition by Impeding Binding of RhoG

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          Abstract

          Ephexin4 is a guanine nucleotide-exchange factor (GEF) for RhoG and is involved in various RhoG-related cellular processes such as phagocytosis of apoptotic cells and migration of cancer cells. Ephexin4 forms an oligomer via an intermolecular interaction, and its GEF activity is increased in the presence of Elmo, an Ephexin4-interacting protein. However, it is uncertain if and how Ephexin4 is autoinhibited. Here, using an Ephexin4 mutant that abrogated the intermolecular interaction, we report that this interaction impeded binding of RhoG to Ephexin4 and thus inhibited RhoG activation. Mutation of the glutamate residue at position 295, which is a highly conserved residue located in the region of Ephexin4 required for the intermolecular interaction, to alanine (Ephexin4 E295A) disrupted the intermolecular interaction and increased binding of RhoG, resulting in augmented RhoG activation. In addition, phagocytosis of apoptotic cells and formation of membrane ruffles were increased more by expression of Ephexin4 E295A than by expression of wild-type Ephexin4. Taken together, our data suggest that Ephexin4 is autoinhibited through its intermolecular interaction, which impedes binding of RhoG.

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          Most cited references 29

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          Rho GTPases in cell biology.

          Rho GTPases are molecular switches that control a wide variety of signal transduction pathways in all eukaryotic cells. They are known principally for their pivotal role in regulating the actin cytoskeleton, but their ability to influence cell polarity, microtubule dynamics, membrane transport pathways and transcription factor activity is probably just as significant. Underlying this biological complexity is a simple biochemical idea, namely that by switching on a single GTPase, several distinct signalling pathways can be coordinately activated. With spatial and temporal activation of multiple switches factored in, it is not surprising to find Rho GTPases having such a prominent role in eukaryotic cell biology.
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            Rho GTPases: biochemistry and biology.

            Approximately one percent of the human genome encodes proteins that either regulate or are regulated by direct interaction with members of the Rho family of small GTPases. Through a series of complex biochemical networks, these highly conserved molecular switches control some of the most fundamental processes of cell biology common to all eukaryotes, including morphogenesis, polarity, movement, and cell division. In the first part of this review, we present the best characterized of these biochemical pathways; in the second part, we attempt to integrate these molecular details into a biological context.
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              GEFs and GAPs: critical elements in the control of small G proteins.

              Guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) regulate the activity of small guanine nucleotide-binding (G) proteins to control cellular functions. In general, GEFs turn on signaling by catalyzing the exchange from G-protein-bound GDP to GTP, whereas GAPs terminate signaling by inducing GTP hydrolysis. GEFs and GAPs are multidomain proteins that are regulated by extracellular signals and localized cues that control cellular events in time and space. Recent evidence suggests that these proteins may be potential therapeutic targets for developing drugs to treat various diseases, including cancer.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                15 November 2018
                November 2018
                : 7
                : 11
                Affiliations
                [1 ]School of Life Sciences and Aging Research Institute, Gwangju Institute of Science and Technology, Gwangju 61005, Korea; khkim0409@ 123456gist.ac.kr (K.K.); iris260@ 123456gist.ac.kr (J.L.); hjmoon311@ 123456gist.ac.kr (H.M.); sanga03@ 123456gist.ac.kr (S.-A.L.); po7322@ 123456gist.ac.kr (D.K.); susuminy@ 123456gist.ac.kr (S.Y.); gwangroglee@ 123456gist.ac.kr (G.L.)
                [2 ]Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 03760, Korea
                [3 ]Department of Oncology, College of Medicine, Korea University, Seoul 08308, Korea; neogene@ 123456korea.ac.kr
                Author notes
                [* ]Correspondence: daehopark@ 123456gist.ac.kr ; Tel.: +82-62-715-2890
                Article
                cells-07-00211
                10.3390/cells7110211
                6262623
                30445756
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                Categories
                Article

                interaction, autoinhibition, rhog, gef, ephexin, ephexin4

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