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The Insulin-Like Growth Factor I Receptor-Induced Interaction of Insulin Receptor Substrate-4 and Crk-II

Clinical Endocrinology Branch (M.K., A.P.K., D.L.), NIDDK, National Institutes of Health, Bethesda, Maryland 20892-1758; and Department of Molecular and Cell Biology (Y.Z.), The Weizmann Institute of Science, Rehovot 76100, Israel

Address all correspondence and requests for reprints to: Derek LeRoith, NIH, NIDDK, CEB, Building 10/Room 8D12, 10 Center Drive, MSC 1758, Bethesda, Maryland 20892-1758. E-mail: derek{at}helix.nih.gov

Stimulation of the insulin or insulin-like growth factor (IGF)-I receptor results in activation of several signaling pathways. Proteins of the insulin receptor substrate (IRS) family play important roles in mediating these signaling cascades. To date, four members of the IRS family of docking proteins have been characterized. Recently, we have reported that stimulation of the IGF-I receptor in 293 HEK cells regulates interaction of the newly discovered IRS-4 molecule with the Crk family of proteins. In the present study, we characterize the molecular basis of these interactions. C- and N termini truncation analysis of IRS-4 demonstrated that the region between amino acids 678 and 800 of the IRS-4 molecule is involved in this interaction. This region contains a cluster of four tyrosines (Y⁷⁰⁰, Y⁷¹⁷, Y⁷⁴³, and Y⁷⁷⁹). We hypothesize that one or more of these tyrosines are involved in the interaction between the SH2 domain of the Crk-II molecule when IRS-4 is phosphorylated upon IGF-I receptor activation. Additional mutational analyses confirmed this hypothesis. Interestingly, none of these four tyrosines was individually critical for the interaction between Crk-II and IRS-4, but when all four tyrosines were simultaneously mutated to phenylalanine, the IGF-I induced interaction between these molecules was abolished. Taken together, these results suggest a novel mechanism of Crk-II binding to tyrosine phosphorylated proteins.

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