PHOSPHATIDYLINOSITOL 3-KINASE - INHIBITION OF INTRINSIC PROTEIN-SERINE KINASE-ACTIVITY BY PHOSPHOINOSITIDES, AND OF LIPID KINASE-ACTIVITY BY MN2+

Phosphatidylinositol (PI) 3-kinase is composed of 110 kDa catalytic an d 85 kDa regulatory subunits. The 110 kDa subunit has two intrinsic ki nase activities, i.e., Mn2+-dependent protein-serine kinase and Mg2+-d ependent lipid kinase activities. These intrinsic kinases have been re ported to be interdependent: protein-serine kinase phosphorylates the 85 kDa subunit of PI 3-kinase, which upon phosphorylation inhibits the lipid kinase activity of PI 3-kinase. We report here that phosphoinos itides can selectively inhibit the protein-serine kinase activity of P I 3-kinase without affecting lipid kinase activity. This inhibition de pends on the phosphorylation status of the phosphoinositides, i.e., PI 4,5-bisphosphate > PI 4-phosphate much greater than PI. Mn2+ (2 mM) p rotected protein kinase activity from phosphoinositides-mediated inhib ition if added prior to interaction of PI 3-kinase with phosphoinositi des. On the other hand, Mn2+ (2 mM) inhibited lipid kinase activity in dependent of its effect on the protein kinase activity of PI 3-kinase. The present study suggests that the protein-serine kinase and the lip id kinase activities of PI 3-kinase can be selectively inhibited by ph osphoinositides and Mn2+ respectively.