title: PLEKHG3 enhances polarized cell migration by activating actin filaments at the cell front.
abstract: Cells migrate by directing Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division control protein 42 (Cdc42) activities and by polymerizing actin toward the leading edge of the cell. Previous studies have proposed that this polarization process requires a local positive feedback in the leading edge involving Rac small GTPase and actin polymerization with PI3K likely playing a coordinating role. Here, we show that the pleckstrin homology and RhoGEF domain containing G3 (PLEKHG3) is a PI3K-regulated Rho guanine nucleotide exchange factor (RhoGEF) for Rac1 and Cdc42 that selectively binds to newly polymerized actin at the leading edge of migrating fibroblasts. Optogenetic inactivation of PLEKHG3 showed that PLEKHG3 is indispensable both for inducing and for maintaining cell polarity. By selectively binding to newly polymerized actin, PLEKHG3 promotes local Rac1/Cdc42 activation to induce more local actin polymerization, which in turn promotes the recruitment of more PLEKHG3 to induce and maintain cell front. Thus, autocatalytic reinforcement of PLEKHG3 localization to the leading edge of the cell provides a molecular basis for the proposed positive feedback loop that is required for cell polarization and directed migration.
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea;
authors.forename: Trang Thi Thu
authors.initials: TT
authors.lastname: Nguyen
authors.affiliation: Department of Biology, Chungnam National University, Daejeon 34134, Republic of Korea;
authors.forename: Wei Sun
authors.initials: WS
authors.lastname: Park
authors.affiliation: Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34141, Republic of Korea;
authors.forename: Byung Ouk
authors.initials: BO
authors.lastname: Park
authors.affiliation: Graduate School of Nanoscience and Technology, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea;
authors.forename: Cha Yeon
authors.initials: CY
authors.lastname: Kim
authors.affiliation: Institute for Cell Engineering, Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Yohan
authors.initials: Y
authors.lastname: Oh
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea;
authors.forename: Jin Man
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea;
authors.forename: Hana
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea; Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34141, Republic of Korea;
authors.forename: Taeyoon
authors.initials: T
authors.lastname: Kyung
authors.affiliation: Department of Biology, Chungnam National University, Daejeon 34134, Republic of Korea;
authors.forename: Cheol-Hee
authors.initials: CH
authors.lastname: Kim
authors.affiliation: Institute for Cell Engineering, Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Gabsang
authors.initials: G
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
authors.forename: Klaus M
authors.initials: KM
authors.lastname: Hahn
authors.affiliation: Department of Chemical and System Biology, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Tobias
authors.initials: T
authors.lastname: Meyer
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea; Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34141, Republic of Korea; Korea Advanced Institute of Science and Technology Institute for the BioCentury, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea wondo@kaist.ac.kr.
authors.forename: Won Do
authors.initials: WD
authors.lastname: Heo
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism* / Q000648:ultrastructure; D000199:Actins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics*; D016764:Cell Polarity; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D000066449:Human Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D062308:Optogenetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D058105:Polymerization; D011485:Protein Binding; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; C581598:Cdc42 protein, mouse; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D064067:Rho Guanine Nucleotide Exchange Factors; D019869:Phosphatidylinositol 3-Kinases; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein
keywords: F-actin binding; PI3K; PLEKHG3; cell polarity; positive feedback