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, Heimo Riedel

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Abstract

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 Cb1, 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.

Original languageEnglish (US)
Pages (from-to)39311-39322
Number of pages12
JournalJournal of Biological Chemistry
Volume278
Issue number41
DOIs
StatePublished - Oct 10 2003

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Phosphatidylinositol 3-Kinase
Growth Factor Receptors
Carrier Proteins
Insulin
Insulin Receptor Substrate Proteins
Insulin Receptor
src Homology Domains
Association reactions
70-kDa Ribosomal Protein S6 Kinases
Glycogen Synthase Kinases
Dissection
Glycogen Synthase
Lipogenesis
p38 Mitogen-Activated Protein Kinases
Ligases
Ubiquitin
Glycogen
Adipocytes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Growth factor receptor-binding protein 10 (Grb10) as a partner of phosphatidylinositol 3-kinase in metabolic insulin action. / Deng, Youping; Bhattacharya, Sujoy; Swamy, O. Rama; Tandon, Ruchi; Wang, Yong; Janda, Robert; Riedel, Heimo.

In: Journal of Biological Chemistry, Vol. 278, No. 41, 10.10.2003, p. 39311-39322.

Research output: Contribution to journalArticle

Deng, Youping ; Bhattacharya, Sujoy ; Swamy, O. Rama ; Tandon, Ruchi ; Wang, Yong ; Janda, Robert ; Riedel, Heimo. / Growth factor receptor-binding protein 10 (Grb10) as a partner of phosphatidylinositol 3-kinase in metabolic insulin action. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 41. pp. 39311-39322.
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AU - Riedel, Heimo

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