Cooperative Activation of PI3K by Ras and Rho Family Small GTPases

• DOI: 10.1016/j.molcel.2012.05.007
• Publication Date: 2012-06-07T15:46:04Z
• Authors: Hee Won Yang; Min-Gyoung Shin; Sangkyu Lee; Jeong-Rae Kim; Wei Sun Park; Kwang-Hyun Cho; Tobias Meyer; Won Do Heo
• Keywords: rho GTP-Binding Proteins; 0303 health sciences; 571; Time Factors; Chemotaxis; Cell Polarity; Cell Biology; PHOSPHOINOSITIDE 3-KINASE; NEUTROPHIL CHEMOTAXIS; ACTIN CYTOSKELETON; EXCHANGE FACTORS; POLARITY; KINASE; GROWTH; CELLS; PI(3,4,5)P-3; POLARIZATION; Models, Biological; Gene Expression Regulation, Enzymologic; Protein Structure, Tertiary; Enzyme Activation; Mice; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Cell Movement; Catalytic Domain; NIH 3T3 Cells; ras Proteins; Animals; Humans; cdc42 GTP-Binding Protein; Molecular Biology; Signal Transduction

Phosphoinositide 3-kinases (PI3Ks) and Ras and Rho family small GTPases are key regulators of cell polarization, motility, and chemotaxis. They influence each other's activities by direct and indirect feedback processes that are only partially understood. Here, we show that 21 small GTPase homologs activate PI3K. Using a microscopy-based binding assay, we show that K-Ras, H-Ras, and five homologous Ras family small GTPases function upstream of PI3K by directly binding the PI3K catalytic subunit, p110. In contrast, several Rho family small GTPases activated PI3K by an indirect cooperative positive feedback that required a combination of Rac, CDC42, and RhoG small GTPase activities. Thus, a distributed network of Ras and Rho family small GTPases induces and reinforces PI3K activity, explaining past challenges to elucidate the specific relevance of different small GTPases in regulating PI3K and controlling cell polarization and chemotaxis.