Abstract

Insulin signal transduction is a multiple-step process and defects in insulin signaling in cells might result in insulin resistance, as occurs in NIDDM. The overall goal of this proposal is to learn more about the proteins involved in insulin signal transduction and regulation, while focusing on the newly identified insulin receptor binding protein Grb-IR (for Insulin Receptor associated Growth factor receptor binding protein) and its Pleckstrin-homology (PH) domain-containing isoform Grb-IRPH. Of interest are the observations that only Grb-IRPH undergoes insulin-stimulated phosphorylation and that the expression of Grb-IR in cells inhibits insulin signaling, suggesting isoform-specific differences on insulin signal transduction.
Aim 1 is to determine the roles of the Grb-IR isoforms in insulin signaling.
Aim 2 is to characterize insulin-stimulated Grb-IRPH phosphorylation.
Aim 3 is to identify and characterize proteins interacting with Grb-IR isoforms.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052933-04
Application #
6178158
Study Section
Endocrinology Study Section (END)
Program Officer
Margolis, Ronald N
Project Start
1997-09-16
Project End
2002-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
4
Fiscal Year
2000
Total Cost
$169,989
Indirect Cost

  Institution

Name
University of Texas Health Science Center San Antonio
Department
Pharmacology
Type
Other Domestic Higher Education
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229

  Publications

Li, Ling; Li, Xiaowen; Zhu, Yunxia et al. (2013) Growth receptor binding protein 10 inhibits glucose-stimulated insulin release from pancreatic ?-cells associated with suppression of the insulin/insulin-like growth factor-1 signalling pathway. Clin Exp Pharmacol Physiol 40:841-7
Kikani, Chintan K; Verona, Erik V; Ryu, Jiyoon et al. (2012) Proliferative and antiapoptotic signaling stimulated by nuclear-localized PDK1 results in oncogenesis. Sci Signal 5:ra80
Wang, Lixin; Balas, Bogdan; Christ-Roberts, Christine Y et al. (2007) Peripheral disruption of the Grb10 gene enhances insulin signaling and sensitivity in vivo. Mol Cell Biol 27:6497-505
Mao, Xuming; Kikani, Chintan K; Riojas, Ramon A et al. (2006) APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function. Nat Cell Biol 8:516-23
Langlais, Paul; Wang, Changhua; Dong, Lily Q et al. (2005) Phosphorylation of Grb10 by mitogen-activated protein kinase: identification of Ser150 and Ser476 of human Grb10zeta as major phosphorylation sites. Biochemistry 44:8890-7
Li, Yang; Langlais, Paul; Gamper, Nikita et al. (2004) Dual phosphorylations underlie modulation of unitary KCNQ K(+) channels by Src tyrosine kinase. J Biol Chem 279:45399-407
McClung, James P; Roneker, Carol A; Mu, Weipeng et al. (2004) Development of insulin resistance and obesity in mice overexpressing cellular glutathione peroxidase. Proc Natl Acad Sci U S A 101:8852-7
Langlais, Paul; Dong, Lily Q; Ramos, Fresnida J et al. (2004) Negative regulation of insulin-stimulated mitogen-activated protein kinase signaling by Grb10. Mol Endocrinol 18:350-8
Wick, KeriLyn R; Werner, Eric D; Langlais, Paul et al. (2003) 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. J Biol Chem 278:8460-7
Wick, M J; Dong, L Q; Hu, D et al. (2001) Insulin receptor-mediated p62dok tyrosine phosphorylation at residues 362 and 398 plays distinct roles for binding GTPase-activating protein and Nck and is essential for inhibiting insulin-stimulated activation of Ras and Akt. J Biol Chem 276:42843-50

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