Interaction of Insulin Receptor Substrate-2 (IRS-2) with the Insulin and Insulin-like Growth Factor I Receptors

作者：Weimin He, Ann Craparo, Youyan Zhu, Thomas J. O’Neill, Ling-Mei Wang, Jacalyn H. Pierce, Thomas A. Gustafson · 发表于：Journal of Biological Chemistry · 年份：1996 · DOI：10.1074/jbc.271.20.11641 · 被引用次数：137 · 研究领域：Metabolism, Diabetes, and Cancer、PI3K/AKT/mTOR signaling in cancer、Protein Kinase Regulation and GTPase Signaling

Insulin receptor substrate 2 (IRS-2) has recently been shown to be a substrate of the insulin receptor (IR). In this study we utilize the yeast two-hybrid system and assays of in vitro interaction to demonstrate that IRS-2 interacts directly with the IR and the insulin-like growth factor I receptor. We show that, like IRS-1, the region of IRS-2 that contains the putative phosphotyrosine binding and SAIN elements (188-591) is sufficient for receptor interaction and that this interaction is dependent upon the NPX(p)Y (where (p)Y is phosphotyrosine) motifs within the juxtamembrane domains of the receptors. In addition to this amino-terminal NPX(p)Y-binding domain, an additional domain of strong interaction was identified in the central region of IRS-2 and was localized between amino acids 591 and 733. This interaction was found to be dependent upon receptor phosphorylation but was NPX(p)Y-independent. This region does not appear to have either an SH2 or a phosphotyrosine binding domain. Both of the interactions could also be demonstrated in vitro using IRS-2 glutathione S-transferase fusion proteins. We conclude that IRS-2, unlike IRS-1, can interact with tyrosine-phosphorylated receptors such as the IR and insulin-like growth factor I receptor via multiple independent binding motifs. Our findings suggest the existence of a previously unidentified phosphotyrosine-dependent binding domain within the central region of IRS-2.