Grb10 inhibits insulin-stimulated insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase/Akt signaling pathway by disrupting the association of IRS-1/IRS-2 with the insulin receptor

Keri Lyn R. Wick, Eric D. Werner, Paul Langlais, Fresnida J. Ramos, Lily Q. Dong, Steven E. Shoelson, Feng Liu

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

Abstract

Grb10 has been proposed to inhibit or activate insulin signaling, depending on cellular context. We have investigated the mechanism by which full-length hGrb10γ inhibits signaling through the insulin receptor substrate (IRS) proteins. Overexpression of hGrb10γ in CHO/IR cells and in differentiated adipocytes significantly reduced insulin-stimulated tyrosine phosphorylation of IRS-1 and IRS-2. Inhibition occurred rapidly and was sustained for 60 min during insulin stimulation. In agreement with inhibited signaling through the IRS/PI 3-kinase pathway, we found hGrb10γ to both delay and reduce phosphorylation of Akt at Thr308 and Ser473 in response to insulin stimulation. Decreased phosphorylation of IRS-1/2 may arise from impaired catalytic activity of the receptor, since hGrb10γ directly associates with the IR kinase regulatory loop. However, yeast tri-hybrid studies indicated that full-length Grb10 blocks association between IRS proteins and IR, and that this requires the SH2 domain of Grb10. In cells, hGrb10γ inhibited insulin-stimulated IRS-1 tyrosine phosphorylation in a dose-dependent manner, but did not affect IR catalytic activity toward Tyr972 in the juxtamembrane region and Tyr1158/1162/1163 in the regulatory domain. We conclude that binding of hGrb10γ to IR decreases signaling through the IRS/PI 3-kinase/AKT pathway by physically blocking IRS access to IR.

Original languageEnglish (US)
Pages (from-to)8460-8467
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number10
DOIs
StatePublished - Mar 7 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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