title: β-Arrestin1-mediated recruitment of c-Src underlies the proliferative action of glucagon-like peptide-1 in pancreatic β INS832/13 cells.
abstract: Glucagon-like peptide-1 (GLP-1), a glucoincretin hormone secreted by intestinal L cells, is a potent growth factor for the pancreatic β-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 β-arrestin-mediated recruitment of c-Src underlies the proliferative action of GLP-1 in β-cells. Our results show that GLP-1 increased c-Src phosphorylation in INS832/13 cells, an effect inhibited by siRNA-mediated β-arrestin1 knockdown. Pharmacological inhibition of c-Src and overexpression of a dominant-negative c-Src mutant protein curtailed GLP-1-induced β-cell proliferation. Co-immunoprecipitation experiments showed a physical association between c-Src and both β-arrestin1 and GLP-1R upon GLP-1 treatment. Moreover, expression of β-arrestin1 mutants that lack the ability to bind c-Src blunted GLP-1-induced proliferation. Conversely, expression of a β-arrestin1 mutant that fails to target G protein-coupled receptors to clathrin-coated pits for sequestration/degradation maximally increased β-cell proliferation. We propose that the formation of a signaling complex comprising the agonist-stimulated GLP-1R, β-arrestin1 and c-Src is required for the action of GLP-1 on β-cell mass.
authors.affiliation: Department of Medicine, Université Laval and CRIUCPQ, Quebec, QC, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Talbot
authors.forename: Erik
authors.initials: E
authors.lastname: Joly
authors.forename: Marc
authors.initials: M
authors.lastname: Prentki
authors.forename: Jean
authors.initials: J
authors.lastname: Buteau
mesh_terms: D000328:Adult; D000368:Aged; D019390:Arrestins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002966:Clathrin / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D006801:Humans; D047468:Immunoprecipitation; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D002966:Clathrin; D034741:RNA, Small Interfering; D018027:Receptors, Glucagon; D000071557:beta-Arrestins; D052216:Glucagon-Like Peptide 1; D011505:Protein-Tyrosine Kinases