title: A phosphorylation switch controls the spatiotemporal activation of Rho GTPases in directional cell migration.
abstract: Although cell migration plays a central role in development and disease, the underlying molecular mechanism is not fully understood. Here we report that a phosphorylation-mediated molecular switch comprising deleted in liver cancer 1 (DLC1), tensin-3 (TNS3), phosphatase and tensin homologue (PTEN) and phosphoinositide-3-kinase (PI3K) controls the spatiotemporal activation of the small GTPases, Rac1 and RhoA, thereby initiating directional cell migration induced by growth factors. On epidermal growth factor (EGF) or platelet-derived growth factor (PDGF) stimulation, TNS3 and PTEN are phosphorylated at specific Thr residues, which trigger the rearrangement of the TNS3-DLC1 and PTEN-PI3K complexes into the TNS3-PI3K and PTEN-DLC1 complexes. Subsequently, the TNS3-PI3K complex translocates to the leading edge of a migrating cell to promote Rac1 activation, whereas PTEN-DLC1 translocates to the posterior for localized RhoA activation. Our work identifies a core signalling mechanism by which an external motility stimulus is coupled to the spatiotemporal activation of Rac1 and RhoA to drive directional cell migration.
authors.affiliation: 1] Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada N6A 5C1 [2] Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada N6A 5C1.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Kaneko
authors.affiliation: Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada N6A 5C1.
authors.forename: Jenny S
authors.initials: JS
authors.lastname: Li
authors.affiliation: Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: An-Dong
authors.initials: AD
authors.lastname: Liu
authors.affiliation: Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada N6A 5C1.
authors.forename: Courtney
authors.initials: C
authors.lastname: Voss
authors.affiliation: 1] Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada N6A 5C1 [2] Children's Health Research Institute, 800 Commissioners Road East, London, Ontario, Canada N6C 2V5.
authors.forename: Shawn S C
authors.initials: SS
authors.lastname: Li
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D004815:Epidermal Growth Factor; D020690:GTPase-Activating Proteins / Q000235:genetics*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D061986:MCF-7 Cells; D008840:Microfilament Proteins / Q000235:genetics*; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D016297:Mutagenesis, Site-Directed; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor; D015398:Signal Transduction; D000070876:Tensins; D059008:Time-Lapse Imaging; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: C112352:DLC1 protein, human; D020690:GTPase-Activating Proteins; D008840:Microfilament Proteins; D010982:Platelet-Derived Growth Factor; C107953:RAC1 protein, human; C000603370:TNS3 protein, human; D000070876:Tensins; D025521:Tumor Suppressor Proteins; C066737:RHOA protein, human; D004815:Epidermal Growth Factor; D058539:Phosphatidylinositol 3-Kinase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein