INVOLVEMENT OF SRC-HOMOLOGY-2-DOMAIN-CONTAINING PROTEIN-TYROSINE-PHOSPHATASE-2 IN T-CELL ACTIVATION

Activation of resting T lymphocytes by ligands to the complex of T cel l antigen receptor (TCR) and CD3 is initiated by a series of critical tyrosine phosphorylation and dephosphorylation events. Protein-tyrosin e kinases of the Syk, Src and Csk families and the CD45 protein-tyrosi ne phosphatase (PTPase) are known to be involved in these early bioche mical reactions. We have found that one of the two T-cell-expressed SH 2-domain-containing PTPases, SHPTP2, is rapidly phosphorylated on tyro sine upon addition of anti-CD3 mAbs. This response was absent in cells lacking the Src family kinase Lck. Concomitantly with tyrosine phosph orylation, SHPTP2 co-immunoprecipitated with two unphosphorylated cell ular proteins: phosphatidylinositol 3-kinase p85 and Grb2. Binding of SHPTP2 to Grb2 occurred through the SH2 domain of Grb2, while the asso ciation between SHPTP2 and p85 seemed to be mediated through Grb2 as a n intermediate. In addition, many other molecules associate with Grb2 and may thereby become juxtaposed to SHPTP2. Our results indicate that SHPTP2 participates actively at an early stage in TCR signaling and t hat its phosphorylation on tyrosine may direct a Grb2-dependent associ ation with selected substrates.