title: Phosphatidylinositol 3-kinase: inhibition of intrinsic protein-serine kinase activity by phosphoinositides, and of lipid kinase activity by Mn2+.
abstract: Phosphatidylinositol (PI) 3-kinase is composed of 110 kDa catalytic and 85 kDa regulatory subunits. The 110 kDa subunit has two intrinsic kinase activities, i.e., Mn(2+)-dependent protein-serine kinase and Mg(2+)-dependent lipid kinase activities. These intrinsic kinases have been reported 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 phosphoinositides can selectively inhibit the protein-serine kinase activity of PI 3-kinase without affecting lipid kinase activity. This inhibition depends on the phosphorylation status of the phosphoinositides, i.e., PI 4,5-bisphosphate > PI 4-phosphate >> PI. Mn2+ (2 mM) protected protein kinase activity from phosphoinositides-mediated inhibition if added prior to interaction of PI 3-kinase with phosphoinositides. On the other hand, Mn2+ (2 mM) inhibited lipid kinase activity independent of its effect on the protein kinase activity of PI 3-kinase. The present study suggests that the protein-serine kinase and the lipid kinase activities of PI 3-kinase can be selectively inhibited by phosphoinositides and Mn2+ respectively.
authors.affiliation: N.Y.S. Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
authors.forename: V P
authors.initials: VP
authors.lastname: Chauhan
authors.forename: S S
authors.initials: SS
authors.lastname: Singh
authors.forename: A
authors.initials: A
authors.lastname: Chauhan
authors.forename: H
authors.initials: H
authors.lastname: Brockerhoff
mesh_terms: D000818:Animals; D008099:Liver / Q000201:enzymology; D008345:Manganese / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases; D010716:Phosphatidylinositols / Q000494:pharmacology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats
chemical_list: D008345:Manganese; D019869:Phosphatidylinositol 3-Kinases; D010716:Phosphatidylinositols; D017853:Phosphotransferases (Alcohol Group Acceptor); D017346:Protein Serine-Threonine Kinases