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

Xuan Cao; Tomonori Kaneko; Jenny S Li; An-Dong Liu; Courtney Voss; Shawn S C Li

doi:10.1038/ncomms8721

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.

Authors

Xuan Cao¹, Tomonori Kaneko², Jenny S Li³, An-Dong Liu⁴, Courtney Voss², Shawn S C Li⁵

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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Blotting, Western
Cell Line, Tumor
Cell Movement / genetics*
Epidermal Growth Factor
GTPase-Activating Proteins / genetics*
Gene Knockdown Techniques
HEK293 Cells
HeLa Cells
Humans
Immunoprecipitation
MCF-7 Cells
Microfilament Proteins / genetics*
Microscopy, Confocal
Microscopy, Fluorescence
Mutagenesis, Site-Directed
PTEN Phosphohydrolase / genetics*
Phosphatidylinositol 3-Kinase / genetics*
Phosphorylation
Platelet-Derived Growth Factor
Signal Transduction
Tensins
Time-Lapse Imaging
Tumor Suppressor Proteins / genetics*
rac1 GTP-Binding Protein / metabolism*
rho GTP-Binding Proteins / metabolism
rhoA GTP-Binding Protein / metabolism*

Substances

DLC1 protein, human
GTPase-Activating Proteins
Microfilament Proteins
Platelet-Derived Growth Factor
RAC1 protein, human
TNS3 protein, human
Tensins
Tumor Suppressor Proteins
RHOA protein, human
Epidermal Growth Factor
Phosphatidylinositol 3-Kinase
PTEN Phosphohydrolase
PTEN protein, human
rac1 GTP-Binding Protein
rho GTP-Binding Proteins
rhoA GTP-Binding Protein