Activation of Syk protein tyrosine kinase through interaction with integrin beta cytoplasmic domains

Syk protein tyrosine kinase is essential for immune system development and function [1] and for the maintenance of vascular integrity [2, 3]. In leuko cytes, Syk is activated by binding to diphosphorylated immune receptor tyro sine-based activation motifs (pITAMs) [1]. Syk can also be activated by int egrin adhesion receptors [4, 5], but the mechanism of its activation is unk nown. Here we report a novel mechanism for Syk's recruitment and activation , which requires that Syk bind to the integrin beta3 cytoplasmic tail. We f ound that both Syk and the related kinase ZAP-70 bound the beta3 cytoplasmi c tail through their tandem SH2 domains. However, unlike Syk binding to pIT AMs, this interaction was independent of tyrosine phosphorylation and of th e phosphotyrosine binding function of Syk's tandem SH2 domains. Deletion of the four C-terminal residues of the beta3 cytoplasmic tail [beta3(759X)] d ecreased Syk binding and disrupted its physical association with integrin a lpha IIb beta3. Furthermore, cells expressing alpha IIbp3(759X) failed to e xhibit Syk activation or lamellipodia formation upon cell adhesion to the a lpha IIb beta3 ligand, fibrinogen. In contrast, FAK phosphorylation and foc al adhesion formation were unimpaired by this mutation. Thus, the direct bi nding of Syk kinase to the integrin beta3 cytoplasmic tail is a novel and f unctionally significant mechanism for the regulation of this important non- receptor tyrosine kinase.