INTEGRIN-MEDIATED TYROSINE PHOSPHORYLATION OF SHPS-1 AND ITS ASSOCIATION WITH SHP-2 - ROLES OF FAK AND SRC FAMILY KINASES

SHPS-1 is a receptor-like glycoprotein that undergoes tyrosine phospho rylation and binds SHP-2, an Src homology 2 domain containing protein tyrosine phosphatase, in response to various mitogens. Cell adhesion t o extracellular matrix proteins such as fibronectin and laminin also i nduced the tyrosine phosphorylation of SHPS-1 and its association with SHP-2. These responses were markedly reduced in cells overexpressing the Csk kinase or in cells that lack focal adhesion kinase or the Src family kinases Src or Fyn. However, unlike Src, focal adhesion kinase did not catalyze phosphorylation of the cytoplasmic domain of SHPS-1 i n vitro. Overexpression of a catalytically inactive SHP-2 markedly inh ibited activation of mitogen-activated protein (MAP) kinase in respons e to fibronectin stimulation without affecting the extent of tyrosine phosphorylation of focal adhesion kinase or its interaction with the d ocking protein Grb2. Overexpression of wild-type SHPS-1 did not enhanc e fibronectin-induced activation of MAP kinase, These results indicate that the binding of integrins to the extracellular matrix induces tyr osine phosphorylation of SHPS-1 and its association with SHP-2, and th at such phosphorylation of SHPS-1 requires both focal adhesion kinase and an Src family kinase, In addition to its role in receptor tyrosine kinase-mediated MAP kinase activation, SHP-2 may play an important ro le, partly through its interaction with SHPS-1, in the activation of M AP kinase in response to the engagement of integrins by the extracellu lar matrix.