Differential signaling by insulin receptor substrate 1 (IRS-1) and IRS-2 in IRS-1-deficient cells.

摘要: Mice made insulin receptor substrate 1 (IRS-1) deficient by targeted gene knockout exhibit growth retardation and abnormal glucose metabolism due to resistance the actions of insulin-like factor (IGF-1) (E. Araki et al., Nature 372:186-190, 1994; H. Tamemoto 372:182-186, 1994). Embryonic fibroblasts 3T3 cell lines derived from IRS-1-deficient embryos no IGF-1-stimulated IRS-1 phosphorylation or IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity but normal IRS-2 Shc IRS-2-associated PI activity. deficiency results in a 70 80% reduction parallel decreases S-phase entry, activity, induction immediate-early genes c-fos egr-1 unaltered activation mitogen-activated protein kinases ERK 2. Expression cells retroviral transduction restores mitogenesis, activation, proportion level reconstitution. Increasing these using retrovirus reconstitutes IGF-1 expression same degree as IRS-1; however, overexpression has only minor effect on stimulation cycle progression. These indicate that is not necessary for 2 sufficient egr-1. data also provide evidence are functionally interchangeable signaling intermediates mitogenesis despite their highly conserved structure many common functions such activating early expression.