Tyr624 and Tyr628 in Insulin Receptor Substrate-2 Mediate Its Association with the Insulin Receptor*

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 regula-tory loop of the insulin receptor; we designate this re-gion the kinase regulatory loop binding (KRLB) domain. Two tyrosine residues in the KRLB domain at positions 624 and 628 are crucial for this interaction. Phosphoryl-ation 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. The insulin receptor (IR)1 mediates tyrosine phosphorylatio