REGULATION OF THE PP72(SYK) PROTEIN-TYROSINE KINASE BY PLATELET INTEGRIN ALPHA(IIB)BETA(3)

pp72(syk) is essential for development and function of several hematop oietic cells, and it becomes activated through tandem SH2 interaction with ITAM motifs in immune response receptors. Since Syk is also activ ated through integrins, which do not contain ITAMs, a CHO cell model s ystem was used to study Syk activation by the platelet integrin, alpha (IIb)beta(3). As in platelets, Syk underwent tyrosine phosphorylation and activation during CHO cell adhesion to alpha(IIb)beta(3) ligands, including fibrinogen. This involved Syk autophosphorylation and the ty rosine kinase activity of Src, and it exhibited two novel features. Fi rstly, unlike alpha(IIb)beta(3)-mediated activation of pp125(FAK), Syk activation could be triggered by the binding of soluble fibrinogen an d abolished by truncation of the alpha(IIb) or beta(3) cytoplasmic tai l, and it was resistant to inhibition by cytochalasin D. Secondly, it did not require phosphorylated ITAMs since it was unaffected by disrup tion of an ITAM-interaction motif in the SH2(C) domain of Syk or by si multaneous overexpression of the tandem SH2 domains. These studies dem onstrate that Syk is a proximal component in alpha(IIb)beta(3) signali ng and is regulated as a consequence of intimate functional relationsh ips with the alpha(IIb)beta(3) cytoplasmic tails and with Src or a clo sely related kinase. Furthermore, there are fundamental differences in the activation of Syk by alpha(IIb)beta(3) and immune response recept ors, suggesting a unique role for integrins in Syk function.