This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Langlais, P. Articles by Liu, F. Search for Related Content PubMed PubMed Citation Articles by Langlais, P. Articles by Liu, F. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB L-TYROSINE

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

Department of Biochemistry (P.L., F.L.), Department of Cellular & Structural Biology (L.Q.D.), and Department of Pharmacology (F.J.R., D.H., F.L.), The University of Texas Health Science Center, San Antonio, Texas 78229; and Diabetes Unit, National Center for Complementary and Alternative Medicine (M.J.Q., Y.L.), National Institutes of Health, Bethesda, Maryland 20892-1755

Address all correspondence and requests for reprints to: Feng Liu, Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, Texas 78229. E-mail: liuf{at}uthscsa.edu.

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 adipocytes 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 Grb10 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.

This article has been cited by other articles:

				M. Liu, L. Zhou, A. Xu, K. S. L. Lam, M. D. Wetzel, R. Xiang, J. Zhang, X. Xin, L. Q. Dong, and F. Liu From the Cover: A disulfide-bond A oxidoreductase-like protein (DsbA-L) regulates adiponectin multimerization PNAS, November 25, 2008; 105(47): 18302 - 18307. [Abstract] [Full Text] [PDF]

				E. Rampersaud, C. M. Damcott, M. Fu, H. Shen, P. McArdle, X. Shi, J. Shelton, J. Yin, Y.-P. C. Chang, S. H. Ott, et al. Identification of Novel Candidate Genes for Type 2 Diabetes From a Genome-Wide Association Scan in the Old Order Amish: Evidence for Replication From Diabetes-Related Quantitative Traits and From Independent Populations Diabetes, December 1, 2007; 56(12): 3053 - 3062. [Abstract] [Full Text] [PDF]

				F. J. Ramos, P. R. Langlais, D. Hu, L. Q. Dong, and F. Liu Grb10 mediates insulin-stimulated degradation of the insulin receptor: a mechanism of negative regulation Am J Physiol Endocrinol Metab, June 1, 2006; 290(6): E1262 - E1266. [Abstract] [Full Text] [PDF]

				S. Nambiar, A. Mirmohammadsadegh, R. Doroudi, A. Gustrau, A. Marini, G. Roeder, T. Ruzicka, and U. R. Hengge Signaling Networks in Cutaneous Melanoma Metastasis Identified by Complementary DNA Microarrays Arch Dermatol, February 1, 2005; 141(2): 165 - 173. [Abstract] [Full Text] [PDF]