Cooperative activation of PI3K by Ras and Rho family small GTPases.
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.
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
Hee Won
HW
Yang
Min-Gyoung
MG
Shin
Sangkyu
S
Lee
Jeong-Rae
JR
Kim
Wei Sun
WS
Park
Kwang-Hyun
KH
Cho
Tobias
T
Meyer
Won Do
WD
Heo
D000818:Animals; D020134:Catalytic Domain; D002465:Cell Movement; D016764:Cell Polarity; D002633:Chemotaxis; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013997:Time Factors; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
D019869:Phosphatidylinositol 3-Kinases; D020764:cdc42 GTP-Binding Protein; D018631:ras Proteins; D020741:rho GTP-Binding Proteins