CELL BIOLOGY AND METABOLISM
Tyr624 and Tyr628 in Insulin Receptor Substrate-2 Mediate Its Association with the Insulin Receptor*

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In addition to the pleckstrin homology domain and the phosphotyrosine binding domain in insulin receptor substrate (IRS)-1 and IRS-2, a region between amino acids 591 and 786 in IRS-2 (IRS-2-(591–786)) binds to the insulin receptor. Based on peptide competition studies, this region interacts with the phosphorylated regulatory loop of the insulin receptor; we designate this region the kinase regulatory loop binding (KRLB) domain. Two tyrosine residues in the KRLB domain at positions 624 and 628 are crucial for this interaction. Phosphorylation of tyrosine residues in the KRLB domain by the insulin receptor inhibits the binding to the receptor. These results reveal a novel mechanism regulating the interaction of the insulin receptor and IRS-2 that may distinguish the signal of IRS-2 from IRS-1.

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The research performed in INSERM U145 was supported in part by Institut National de la Santé et de la Recherche Médicale, Association pour la Recherche sur le Cancer (Grant 6432), Université de Nice-Sophia Antipolis, La Ligue contre le Cancer, and Groupe LIPHA (Lyon, France, contract 93123).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Supported by National Institutes of Health Grants DK 43808 and DK 38712.

© 1997 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.