Abstract
Syk and ZAP-70 form a subfamily of nonreceptor tyrosine kinases that contain tandem SH2 domains at their N termini. Engagement of these SH2 domains by tyrosine-phosphorylated immunoreceptor tyrosine-based activation motifs leads to kinase activation and downstream signaling. These kinases are also regulated by beta3 integrin-dependent cell adhesion via a phosphorylation-independent interaction with the beta3 integrin cytoplasmic domain. Here, we report that the interaction of integrins with Syk and ZAP-70 depends on the N-terminal SH2 domain and the interdomain A region of the kinase. The N-terminal SH2 domain alone is sufficient for weak binding, and this interaction is independent of tyrosine phosphorylation of the integrin tail. Indeed, phosphorylation of tyrosines within the two conserved NXXY motifs in the integrin beta3 cytoplasmic domain blocks Syk binding. The tandem SH2 domains of these kinases bind to multiple integrin beta cytoplasmic domains with varying affinities (beta3 (Kd = 24 nm) > beta2 (Kd = 38 nm) > beta1 (Kd = 71 nm)) as judged by both affinity chromatography and surface plasmon resonance. Thus, the binding of Syk and ZAP-70 to integrin beta cytoplasmic domains represents a novel phosphotyrosine-independent interaction mediated by their N-terminal SH2 domains.
Highlights
Integrin adhesion receptors bind components of the extracellular matrix or cell surface molecules and transmit signals that regulate processes such as cell proliferation, differentiation, migration, and death
We report that the interaction of integrins with Syk and ZAP-70 depends on the N-terminal SH2 domain and the interdomain A region of the kinase
The N-terminal SH2 domain alone is sufficient for weak binding, and this interaction is independent of tyrosine phosphorylation of the integrin tail
Summary
Integrin adhesion receptors bind components of the extracellular matrix or cell surface molecules and transmit signals that regulate processes such as cell proliferation, differentiation, migration, and death (reviewed in Refs. 1 and 2). Linking the tandem SH2 domains with the kinase domain is the “interdomain B” region This region contains a number of tyrosines that are phosphorylated in vivo and can recruit other signaling/ adaptor molecules such as Src family members [15], Vav-1 [16], and Cbl [17]. Residues 6 –370 in Syk and 1–337 in Zap-70, which contain the tandem SH2 domains and part of the interdomain B region, directly bind the integrin 3 cytoplasmic domain [7]. The interaction between Syk and integrin 3 tails does not require tyrosine phosphorylation of the 3 tail or intact phosphotyrosine-binding sites in the Syk tandem SH2 domains [7]. Phosphotyrosine-independent Binding to Cytoplasmic Domains the Syk/ZAP-70 integrin interaction is mediated by a phosphorylation-independent interaction of an SH2 domain
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