SHP-1 regulates Lck-induced phosphatidylinositol 3-kinase phosphorylation and activity

Ligation of the T cell antigen receptor (TCR) activates the Src family tyro sine kinase p56 Lck, which, in turn, phosphorylates a variety of intracellu lar substrates. The phosphatidylinositol 3-kinase (PI3K) and the tyrosine p hosphatase SHP-1 are two Lck substrates that have been implicated in TGR si gnaling. In this study, we demonstrate that SHP-1 co-immunoprecipitates wit h the p85 regulatory subunit of PI3K in Jurkat T cells, and that this assoc iation is increased by ligation of the TCR complex. Go-expression of SHP-1 and PI3K with a constitutively activated form of Lck in COS7 cells demonstr ated the carboxyl-terminal SH2 domain of PI3K to inducibly associate with t he full-length SHP-1 protein. By contrast, a truncated SHP-1 mutant lacking the Lck phosphorylation site (Tyr(564)) failed to bind p85. Wild-type but not catalytically inactive SHP-1 induced dephosphorylation of p85, Furtherm ore, expression of SHP-1 decreased PI3K enzyme activity in anti-phosphotyro sine immunoprecipitates and phosphorylation of serine 473 in Akt, a process dependent on PI3K activity. These results indicate the presence of a funct ional interaction between PI3K and SHP-1 and suggest that PI3K signaling, w hich has been implicated in cell proliferation, apoptosis, cytoskeletal reo rganization, and many other biological activities, can be regulated by SHP- 1 in T lymphocytes.