Irs-proteins link the receptors for insulin/IGF-1, growth hormones, and several interleukins and interferons to signaling proteins that contain Src homology-2 (SH2). To identify new Irs-1-binding proteins, we screened a mouse embryo expression library with recombinant [P]Irs-1, which revealed a specific association between p59 and Irs-1. The SH2 domain in p59 bound to phosphorylated Tyr and Tyr, which are located in YXX(L/I) motifs. Mutation of p59 at the COOH-terminal tyrosine phosphorylation site (Tyr) enhanced its binding to Irs-1 during insulin stimulation. Binding experiments with various SH2 proteins revealed that Grb-2 was largely excluded from Irs-1 complexes containing p59, whereas Grb-2 and p85 occurred in the same Irs-1 complex. By comparison with the insulin receptor, p59kinase phosphorylated a unique cohort of tyrosine residues in Irs-1. These results outline a role for p59 or other related Src-kinases during insulin and cytokine signaling.

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