MODIFICATION OF PHOSPHATIDYLINOSITOL 3-KINASE SH2 DOMAIN BINDING-PROPERTIES BY ABL-MEDIATED OR LCK-MEDIATED TYROSINE PHOSPHORYLATION AT TYR-688

In cells expressing the oncogenic Bcr-Abl tyrosine kinase, the regulat ory p85 subunit of phosphatidylinositol 3-kinase is phosphorylated on tyrosine residues. We report that this phosphorylation event is readil y catalyzed by the Abl and Lck protein-tyrosine kinases in vitro, by B cr-Abl or a catalytically activated Lck-Y505F in cotransfected COS cel ls, and by endogenous kinases in transfected Jurkat T cells upon trigg ering of their T cen antigen receptor, Using these systems, we have ma pped a major phosphorylation site to Tyr-688 in the C-terminal. SH2 do main of p85. Tyrosine phosphorylation of p85 in vitro or in vivo was n ot associated with detectable change in the enzymatic activity of the phosphatidylinositol 3-kinase heterodimer, but correlated with a stron g reduction in the binding of same, but not all, phosphoproteins to th e SH2 domains of p85, This provides tan additional candidate to the li st of SH2 domains regulated by tyrosine phosphorylation and mag explai n why association of phosphatidylinositol 3-kinase with same cellular ligands is transient or of lower stoichiometry than anticipated.