HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 278, Issue 41, 39311-39322, October 10, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/41/39311    most recent M304599200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted 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 Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Deng, Y. Articles by Riedel, H. Search for Related Content PubMed PubMed Citation Articles by Deng, Y. Articles by Riedel, H. Social Bookmarking                      What's this?

Growth Factor Receptor-binding Protein 10 (Grb10) as a Partner of Phosphatidylinositol 3-Kinase in Metabolic Insulin Action^*

Youping Deng , Sujoy Bhattacharya , O. Rama Swamy, Ruchi Tandon, Yong Wang, Robert Janda and Heimo Riedel ¶

From the Department of Biological Sciences, Wayne State University, Detroit, Michigan 48202

The regulation of the metabolic insulin response by mouse growth factor receptor-binding protein 10 (Grb10) has been addressed in this report. We find mouse Grb10 to be a critical component of the insulin receptor (IR) signaling complex that provides a functional link between IR and p85 phosphatidylinositol (PI) 3-kinase and regulates PI 3-kinase activity. This regulatory mechanism parallels the established link between IR and p85 via insulin receptor substrate (IRS) proteins. A direct association was demonstrated between Grb10 and p85 but was not observed between Grb10 and IRS proteins. In addition, no effect of mouse Grb10 was observed on the association between IRS-1 and p85, on IRS-1-associated PI 3-kinase activity, or on insulin-mediated activation of IR or IRS proteins. A critical role of mouse Grb10 was observed in the regulation of PI 3-kinase activity and the resulting metabolic insulin response. Dominant-negative Grb10 domains, in particular the SH2 domain, eliminated the metabolic response to insulin in differentiated 3T3-L1 adipocytes. This was consistently observed for glycogen synthesis, glucose and amino acid transport, and lipogenesis. In parallel, the same metabolic responses were substantially elevated by increased levels of Grb10. A similar role of Grb10 was confirmed in mouse L6 cells. In addition to the SH2 domain, the Pro-rich amino-terminal region of Grb10 was implicated in the regulation of PI 3-kinase catalytic activity. These regulatory roles of Grb10 were extended to specific insulin mediators downstream of PI 3-kinase including PKB/Akt, glycogen synthase kinase, and glycogen synthase. In contrast, a regulatory role of Grb10 in parallel insulin response pathways including p70 S6 kinase, ubiquitin ligase Cbl, or mitogen-activated protein kinase p38 was not observed. The dissection of the interaction of mouse Grb10 with p85 and the resulting regulation of PI 3-kinase activity should help elucidate the complexity of the IR signaling mechanism.

Received for publication, May 12, 2003

^* This work was supported in part by the National Science Foundation Grant MCB-9808795, American Diabetes Association Grant 7-02-RA-76, National Institutes of Health Grant R01 CA77873, and Juvenile Diabetes Foundation International Grant 197048 (to H. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Division of Biology, Kansas State University, Manhattan, KS 66506-4901.

Present address: Dept. of Molecular Sciences, University of Tennessee Health Science Center, Memphis, TN 38163.

^¶ Member, Barbara Ann Karmanos Cancer Institute. To whom correspondence should be addressed: Dept. of Biological Sciences, Wayne State University, Detroit, MI 48202-3917. Tel.: 313-577-7870 or 8338; Fax: 313-577-6891; E-mail: hriedel{at}sun.science.wayne.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				H. Shiura, K. Nakamura, T. Hikichi, T. Hino, K. Oda, R. Suzuki-Migishima, T. Kohda, T. Kaneko-Ishino, and F. Ishino Paternal deletion of Meg1/Grb10 DMR causes maternalization of the Meg1/Grb10 cluster in mouse proximal Chromosome 11 leading to severe pre- and postnatal growth retardation Hum. Mol. Genet., April 15, 2009; 18(8): 1424 - 1438. [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. M. Smith, L. J. Holt, A. S. Garfield, M. Charalambous, F. Koumanov, M. Perry, R. Bazzani, S. A. Sheardown, B. D. Hegarty, R. J. Lyons, et al. Mice with a Disruption of the Imprinted Grb10 Gene Exhibit Altered Body Composition, Glucose Homeostasis, and Insulin Signaling during Postnatal Life Mol. Cell. Biol., August 15, 2007; 27(16): 5871 - 5886. [Abstract] [Full Text] [PDF]

				R. Di Paola, E. Ciociola, W. Boonyasrisawat, D. Nolan, J. Duffy, G. Miscio, C. Cisternino, G. Fini, V. Tassi, A. Doria, et al. Association of hGrb10 Genetic Variations With Type 2 Diabetes in Caucasian Subjects Diabetes Care, May 1, 2006; 29(5): 1181 - 1183. [Full Text] [PDF]

				M. Kwon, Y. Ling, L. A. Maile, J. Badley-Clark, and D. R. Clemmons Recruitment of the Tyrosine Phosphatase Src Homology 2 Domain Tyrosine Phosphatase-2 to the p85 Subunit of Phosphatidylinositol-3 (PI-3) Kinase Is Required for Insulin-Like Growth Factor-I-Dependent PI-3 Kinase Activation in Smooth Muscle Cells Endocrinology, March 1, 2006; 147(3): 1458 - 1465. [Abstract] [Full Text] [PDF]

				C. Cutcliffe, D. Kersey, C.-C. Huang, Y. Zeng, D. Walterhouse, E. J. Perlman, and for the Renal Tumor Committee of the Children's On Clear Cell Sarcoma of the Kidney: Up-regulation of Neural Markers with Activation of the Sonic Hedgehog and Akt Pathways Clin. Cancer Res., November 15, 2005; 11(22): 7986 - 7994. [Abstract] [Full Text] [PDF]

				S. Urschel, F. Bassermann, R.-Y. Bai, S. Munch, C. Peschel, and J. Duyster Phosphorylation of Grb10 Regulates Its Interaction with 14-3-3 J. Biol. Chem., April 29, 2005; 280(17): 16987 - 16993. [Abstract] [Full Text] [PDF]

				M. Nishi, E. D. Werner, B.-C. Oh, J. D. Frantz, S. Dhe-Paganon, L. Hansen, J. Lee, and S. E. Shoelson Kinase Activation through Dimerization by Human SH2-B Mol. Cell. Biol., April 1, 2005; 25(7): 2607 - 2621. [Abstract] [Full Text] [PDF]

				J. Murdaca, C. Treins, M.-N. Monthouel-Kartmann, R. Pontier-Bres, S. Kumar, E. Van Obberghen, and S. Giorgetti-Peraldi Grb10 Prevents Nedd4-mediated Vascular Endothelial Growth Factor Receptor-2 Degradation J. Biol. Chem., June 18, 2004; 279(25): 26754 - 26761. [Abstract] [Full Text] [PDF]

				P. Langlais, L. Q. Dong, F. J. Ramos, D. Hu, Y. Li, M. J. Quon, and F. Liu Negative Regulation of Insulin-Stimulated Mitogen-Activated Protein Kinase Signaling By Grb10 Mol. Endocrinol., February 1, 2004; 18(2): 350 - 358. [Abstract] [Full Text] [PDF]