Negative Regulation of Insulin-Stimulated Mitogen-Activated Protein Kinase Signaling by Grb10

Paul R Langlais, Lily Q. Dong, Fresnida J. Ramos, Derong Hu, Yunhua Li, Michael J. Quon, Feng Liu

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Grb10 is a Pleckstrin homology and Src homology 2 (SH2) domain-containing protein that binds to the tyrosine-phosphorylated insulin receptor in response to insulin stimulation. Loss of Grb10 function in mice results in fetal and placental overgrowth; however, the molecular mechanism remains unknown. In the present study, we show that overexpression of Grb10 in Chinese hamster ovary cells expressing the insulin receptor or in 3T3-L1 adlpocytes reduced insulin-stimulated phosphorylation of MAPK. Overexpression of Grb10 in rat primary adipocytes also inhibited insulin-stimulated phosphorylation of the MAPK downstream substrate Elk1. To determine the mechanism by which Grb10 inhibited insulin-stimulated MAPK signaling, we examined whether Grb10 affects the phosphorylation of MAPK upstream signaling components. We found that overexpression of Grb10 inhibited the insulin-stimulated phosphorylation of Shc, a positive regulator of the MAPK signaling pathway. The inhibitory effect was diminished when the SH2 domain of Grb10 was deleted. The negative role of Grb10 in insulin signaling was established by suppression of endogenous Grb10 by RNA interference in HeLa cells overexpressing the insulin receptor, which enhanced insulin-stimulated phosphorylation of MAPK, Shc, and Akt. Taken together, our findings suggest that Grb10O functions as a negative regulator in the insulin-stimulated MAPK signaling pathway. In addition, the inhibitory effect of Grb10 on the MAPK pathway is most likely due to a direct block of insulin-stimulated Shc tyrosine phosphorylation.

Original languageEnglish (US)
Pages (from-to)350-358
Number of pages9
JournalMolecular Endocrinology
Volume18
Issue number2
DOIs
StatePublished - Feb 2004
Externally publishedYes

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Mitogen-Activated Protein Kinases
Insulin
Phosphorylation
Insulin Receptor
src Homology Domains
Tyrosine
RNA Interference
Cricetulus
HeLa Cells
Adipocytes
Ovary

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

Langlais, P. R., Dong, L. Q., Ramos, F. J., Hu, D., Li, Y., Quon, M. J., & Liu, F. (2004). Negative Regulation of Insulin-Stimulated Mitogen-Activated Protein Kinase Signaling by Grb10. Molecular Endocrinology, 18(2), 350-358. https://doi.org/10.1210/me.2003-0117

Negative Regulation of Insulin-Stimulated Mitogen-Activated Protein Kinase Signaling by Grb10. / Langlais, Paul R; Dong, Lily Q.; Ramos, Fresnida J.; Hu, Derong; Li, Yunhua; Quon, Michael J.; Liu, Feng.

In: Molecular Endocrinology, Vol. 18, No. 2, 02.2004, p. 350-358.

Research output: Contribution to journalArticle

Langlais, PR, Dong, LQ, Ramos, FJ, Hu, D, Li, Y, Quon, MJ & Liu, F 2004, 'Negative Regulation of Insulin-Stimulated Mitogen-Activated Protein Kinase Signaling by Grb10', Molecular Endocrinology, vol. 18, no. 2, pp. 350-358. https://doi.org/10.1210/me.2003-0117
Langlais, Paul R ; Dong, Lily Q. ; Ramos, Fresnida J. ; Hu, Derong ; Li, Yunhua ; Quon, Michael J. ; Liu, Feng. / Negative Regulation of Insulin-Stimulated Mitogen-Activated Protein Kinase Signaling by Grb10. In: Molecular Endocrinology. 2004 ; Vol. 18, No. 2. pp. 350-358.
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