期刊
MOLECULAR AND CELLULAR ENDOCRINOLOGY
卷 364, 期 1-2, 页码 65-70出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2012.08.010
关键词
beta-Cell mass; Incretin; GLP-1; c-Src; beta-Arrestin; Proliferation
资金
- Canadian Institutes of Health Research
Glucagon-like peptide-1 (GLP-1), a glucoincretin hormone secreted by intestinal L cells, is a potent growth factor for the pancreatic beta-cell. The development of GLP-1 mimetics and enhancers as a novel class of anti-diabetes medications underpins the importance of elucidating the molecular basis of GLP-1 signaling. In the present study, we sought to test the hypothesis that beta-arrestin-mediated recruitment of c-Src underlies the proliferative action of GLP-1 in beta-cells. Our results show that GLP-1 increased c-Src phosphorylation in INS832/13 cells, an effect inhibited by siRNA-mediated beta-arrestin1 knockdown. Pharmacological inhibition of c-Src and overexpression of a dominant-negative c-Src mutant protein curtailed GLP-1-induced beta-cell proliferation. Co-immunoprecipitation experiments showed a physical association between c-Src and both beta-arrestin1 and GLP-1R upon GLP-1 treatment. Moreover, expression of beta-arrestin1 mutants that lack the ability to bind c-Src blunted GLP-1-induced proliferation. Conversely, expression of a beta-arrestin1 mutant that fails to target G protein-coupled receptors to clathrin-coated pits for sequestration/degradation maximally increased beta-cell proliferation. We propose that the formation of a signaling complex comprising the agonist-stimulated GLP-1 R, beta-arrestin1 and c-Src is required for the action of GLP-1 on beta-cell mass. (C) 2012 Elsevier Ireland Ltd. All rights reserved.
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