Role of IRS-1-GRB-2 complexes in insulin signaling - PubMed (original) (raw)

Role of IRS-1-GRB-2 complexes in insulin signaling

M G Myers Jr et al. Mol Cell Biol. 1994 Jun.

Abstract

GRB-2 is a small SH2- and SH3 domain-containing adapter protein that associates with the mammalian SOS homolog to regulate p21ras during growth factor signaling. During insulin stimulation, GRB-2 binds to the phosphorylated Y895VNI motif of IRS-1. Substitution of Tyr-895 with phenylalanine (IRS-1F-895) prevented the IRS-1-GRB-2 association in vivo and in vitro. The myeloid progenitor cell line, 32-D, is insensitive to insulin because it contains few insulin receptors and no IRS-1. Coexpression of IRS-1 or IRS-1F-895 with the insulin receptor was required for insulin-stimulated mitogenesis in 32-D cells, while expression of the insulin receptor alone was sufficient to mediate insulin-stimulated tyrosine phosphorylation of Shc and activation of p21ras and mitogen-activated protein (MAP) kinase. The Shc-GRB-2 complex formed during insulin stimulation is a possible mediator of p21ras and MAP kinase activation in IRS-1-deficient 32-D cells. Interestingly, IRS-1, but not IRS-1F-895, enhanced the stimulation of MAP kinase by insulin in 32-D cells expressing insulin receptors. Thus, IRS-1 contributes to the stimulation of MAP kinase by insulin, probably through formation of the IRS-1-GRB-2 complex at Tyr-895. Our results suggest that the Shc-GRB-2 complex and the activation of p21ras-dependent signaling pathways, including MAP kinase, are insufficient for insulin-stimulated mitogenesis and that the essential function(s) of IRS-1 in proliferative signaling is largely unrelated to IRS-1-GRB-2 complex formation.

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References

    1. Mol Cell Biol. 1990 Jun;10(6):3204-15 - PubMed
    1. Mol Cell Biol. 1993 Dec;13(12):7418-28 - PubMed
    1. Nature. 1991 Jul 4;352(6330):73-7 - PubMed
    1. Methods Enzymol. 1991;201:65-79 - PubMed
    1. Mol Cell Biol. 1991 Dec;11(12):5963-7 - PubMed

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