Apoptosis Inhibitor Protein Causes a Ruckus with PI3K Activity

Apoptosis is an exquisitely regulated process in cells. Shifting the balance of apoptotic regulation can result in aberrant proliferation or excessive cell death. The phosphatidylinositol 3-kinase (PI3K) signal pathway is important in the prevention of cellular apoptosis. However, PI3K's function is attenuated by PTEN, a lipid phosphatase that regulates PI3K signaling indirectly by dephosphorylating phosphoinositides. Gout et al. have identified a protein, Ruk, that directly inhibits PI3K activity. Despite the ability of Ruk's proline-rich region to bind the SH3 domain of p85α and the NH₂-terminal SH3 domain of Grb2 in vitro, only the interaction with p85α could be confirmed in vivo. In Sf9 cells, overexpressed Ruk immunoprecipitated with PI3K holoenzyme complexes containing the p85α but not the p85β or p55 noncatalytic subunits, suggesting that Ruk only interacts with p85α-containing PI3K complexes. Overexpressed Ruk decreased PI3K activity as measured by phosphatidylinositol 3-phosphate production in vitro. Additionally, overexpression of Ruk in cultured neurons led to increased apoptosis. Thus, PI3K activity can be controlled indirectly, by decreasing the amounts of its phospholipid products, and directly, by attenuating its enzymatic activity.

Gout, I., Middleton, G., Adu, J., Ninkina, N.N., Drobot, L.B., Filonenko,V., Matsuka, G., Davies, A.M., Waterfield, M., and Buchman, V.L. (2000) Negative regulation of PI 3-kinase by Ruk, a novel adaptor protein. EMBO J. 19: 4015-4025. [Abstract] [Full Text]