Cooperative activation of PI3K by Ras and Rho family small GTPases

Mol Cell. 2012 Jul 27;47(2):281-90. doi: 10.1016/j.molcel.2012.05.007. Epub 2012 Jun 7.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Catalytic Domain
  • Cell Movement
  • Cell Polarity
  • Chemotaxis
  • Enzyme Activation
  • Gene Expression Regulation, Enzymologic*
  • Humans
  • Mice
  • Models, Biological
  • NIH 3T3 Cells
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein Structure, Tertiary
  • Signal Transduction
  • Time Factors
  • cdc42 GTP-Binding Protein / metabolism
  • ras Proteins / metabolism*
  • rho GTP-Binding Proteins / metabolism*


  • Phosphatidylinositol 3-Kinases
  • cdc42 GTP-Binding Protein
  • ras Proteins
  • rho GTP-Binding Proteins