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The IRS (Insulin receptor substrate) proteins IRS-1, IRS-2, IRS-3, and IRS-4 are major substrates of the insulin receptor tyrosine kinase and the insulin-like growth factor-1 receptor. IRS proteins contain an N-terminal pleckstrin homology (PH) domain, an ATP-binding domain, and multiple tyrosine phosphorylation sites in the C-terminus. Following insulin receptor ligation, IRS-1 binds to the juxtamembrane region of the receptor and is tyrosine phosphorylated. This facilitates its interaction with SH2 domain-containing signaling proteins, such as PI3 kinase, fyn, Grb2, and PTP1D. Phosphorylation dramatically reduces the affinity of IRS-1 for the insulin receptor, indicating that dissociation from the receptor and subsequent subcellular translocation are important to IRS-1 function in the pleiotropic effects induced by insulin. In support of this, IRS-1-null mice are viable, but exhibit growth retardation and abnormal glucose metabolism. In cases of reduced IRS-1 expression, certain IRS-1 functions can be assumed by the related IRS-2 protein, while other activities linked to IRS-1 are inhibited. Thus, IRS-1 is an essential component of insulin induced signal transduction.Immunofluorescence, Western Blotting
