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      Intermolecular steric inhibition of Ephexin4 is relieved by Elmo1

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          Abstract

          Ephexin4, a guanine nucleotide-exchange factor for RhoG, promotes engulfment of apoptotic cells and cancer cell migration in a RhoG-dependent manner, which is synergistically augmented by Elmo1, an Ephexin4-interacting protein. However, the underlying molecular mechanism remains elusive. Here, we report a mechanism by which Elmo1 cooperates with Ephexin4 to activate RhoG. We found that Ephexin4 activity was increased by elimination of its SH3 domain which intermolecularly interacts with the N20 region of Ephexin4. This interaction prevented RhoG from binding to Ephexin4 and thus inhibited RhoG activation. Moreover, we also found that Elmo1 associated with the SH3 domain as well as the N20 region and competed with the SH3 domain for binding to the N20 region, interrupting the interaction of the SH3 domain with the N20 region and thereby promoting RhoG binding to Ephexin4. In addition, the activity of Ephexin4 lacking the SH3 domain was comparable to that of Ephexin4 with Elmo1. Taken together, the data suggest that Elmo1 relieves the steric hindrance of Ephexin4 generated by the intermolecular interaction of the SH3 domain and makes Ephexin4 more accessible to RhoG.

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          CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration.

          Tina Gumienny, Enrico Brugnera, Annie-Carole Tosello-Trampont … (2001)
          The C. elegans genes ced-2, ced-5, and ced-10, and their mammalian homologs crkII, dock180, and rac1, mediate cytoskeletal rearrangements during phagocytosis of apoptotic cells and cell motility. Here, we describe an additional member of this signaling pathway, ced-12, and its mammalian homologs, elmo1 and elmo2. In C. elegans, CED-12 is required for engulfment of dying cells and for cell migrations. In mammalian cells, ELMO1 functionally cooperates with CrkII and Dock180 to promote phagocytosis and cell shape changes. CED-12/ELMO-1 binds directly to CED-5/Dock180; this evolutionarily conserved complex stimulates a Rac-GEF, leading to Rac1 activation and cytoskeletal rearrangements. These studies identify CED-12/ELMO as an upstream regulator of Rac1 that affects engulfment and cell migration from C. elegans to mammals.
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            SH3 domains: complexity in moderation.

            B Mayer (2001)
            The SH3 domain is perhaps the best-characterized member of the growing family of protein-interaction modules. By binding with moderate affinity and selectivity to proline-rich ligands, these domains play critical roles in a wide variety of biological processes ranging from regulation of enzymes by intramolecular interactions, increasing the local concentration or altering the subcellular localization of components of signaling pathways, and mediating the assembly of large multiprotein complexes. SH3 domains and their binding sites have cropped up in many hundreds of proteins in species from yeast to man, which suggests that they provide the cell with an especially handy and adaptable means of bringing proteins together. The wealth of genetic, biochemical and structural information available provides an intimate and detailed portrait of the domain, serving as a framework for understanding other modular protein-interaction domains. Processes regulated by SH3 domains also raise important questions about the nature of specificity and the overall logic governing networks of protein interactions.
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              Phosphatidylserine receptor BAI1 and apoptotic cells as new promoters of myoblast fusion

              Amelia Hochreiter-Hufford, Chang Sup Lee, Jason M. Kinchen … (2013)
              Skeletal muscle arises from the fusion of precursor myoblasts into multinucleated myofibers 1,2 . While conserved transcription factors and signaling proteins involved in myogenesis have been identified, upstream regulators are less well understood. Here, we report an unexpected discovery that the membrane protein BAI1, previously linked to recognition of apoptotic cells by phagocytes 3 , promotes myoblast fusion. Endogenous BAI1 expression increased during myoblast fusion, and BAI1 overexpression enhanced myoblast fusion via signaling through ELMO/Dock180/Rac1 proteins 4 . During myoblast fusion, a fraction of myoblasts underwent apoptosis and exposed phosphatidylserine (PtdSer), an established ligand for BAI1 3 . Blocking apoptosis potently impaired myoblast fusion, and adding back apoptotic myoblasts restored fusion. Furthermore, primary human myoblasts could be induced to form myotubes by adding apoptotic myoblasts, even under normal growth conditions. In vivo, myofibers from Bai1−/− mice are smaller than wild-type littermates. Muscle regeneration after injury was also impaired in Bai1−/− mice, highlighting a role for BAI1 in mammalian myogenesis. Collectively, these data identify signaling via the phosphatidylserine receptor BAI1 and apoptotic cells as novel promoters of myoblast fusion, with significant implications for muscle development and repair.
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                Author and article information

                Contributors
                Daeho Park: daehopark@gist.ac.kr
                Journal
                Journal ID (nlm-ta): Sci Rep
                Journal ID (iso-abbrev): Sci Rep
                Title: Scientific Reports
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2045-2322
                Publication date (Electronic): 30 June 2017
                Publication date PMC-release: 30 June 2017
                Publication date Collection: 2017
                Volume: 7
                Electronic Location Identifier: 4404
                Affiliations
                [1 ]ISNI 0000 0001 1033 9831, GRID grid.61221.36, School of Life Sciences and Aging Research Institute, , Gwangju Institute of Science and Technology, ; Gwangju, 61005 Korea
                [2 ]ISNI 0000 0001 2171 7754, GRID grid.255649.9, Research Center for Cellular Homeostasis, , Ewha Womans University, ; Seoul, 03760 Korea
                [3 ]ISNI 0000 0001 0356 9399, GRID grid.14005.30, Department of Internal Medicine, , Chonnam National University Medical School, ; Gwangju, 61469 Korea
                [4 ]ISNI 0000 0001 1033 9831, GRID grid.61221.36, Department of Biomedical Science and Engineering, , Gwangju Institute of Science and Technology, ; Gwangju, 61005 Korea
                Article
                Publisher ID: 4810
                DOI: 10.1038/s41598-017-04810-6
                PMC ID: 5493634
                PubMed ID: 28667327
                SO-VID: 21c60aff-0253-4be2-996e-6ae1b5e775bc
                Copyright © © The Author(s) 2017
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 22 February 2017
                Date accepted : 19 May 2017
                Categories
                Subject: Article
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                issue-copyright-statement © The Author(s) 2017

                ScienceOpen disciplines: Uncategorized
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