A phosphorylation switch controls the spatiotemporal activation of Rho GTPases in directional cell migration

  • Nat Commun. 2015 Jul 13:6:7721. doi: 10.1038/ncomms8721.
Xuan Cao  1 ,  Tomonori Kaneko  2 ,  Jenny S Li  3 ,  An-Dong Liu  4 ,  Courtney Voss  2 ,  Shawn S C Li  5
Affiliations
  • 1. 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.
  • 2. Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada N6A 5C1.
  • 3. Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada N6A 5C1.
  • 4. Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 5. 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.
PMID: 26166433 DOI: 10.1038/ncomms8721
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.