INHIBITION OF PHOSPHATIDYLINOSITOL 3-KINASE BY C-ABL IN THE GENOTOXICSTRESS-RESPONSE

Activation of phosphatidylinositol (PI) 3-kinase by growth factors res ults in phosphorylation of phosphatidylinositol lipids at the D3 posit ion. Although PI 3-kinase is essential to cell survival, little is kno wn about mechanisms that negatively regulate this activity. Here we sh ow that the c-Abl tyrosine kinase interacts directly with the p85 subu nit of PI 3-kinase. Activation of c-Abl by ionizing radiation exposure is associated with c-Abl-dependent phosphorylation of PI 3-kinase. We also show that phosphorylation of p85 by c-Abl inhibits PI 3-kinase a ctivity in vitro and in irradiated cells. These findings indicate that c-Abl negatively regulates PI 3-kinase in the stress response to DNA damage.