RESUMO
Glucagon-like peptide-1 (GLP-1), a glucoincretin hormone secreted by intestinal L cells, is a potent growth factor for the pancreatic ß-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 ß-arrestin-mediated recruitment of c-Src underlies the proliferative action of GLP-1 in ß-cells. Our results show that GLP-1 increased c-Src phosphorylation in INS832/13 cells, an effect inhibited by siRNA-mediated ß-arrestin1 knockdown. Pharmacological inhibition of c-Src and overexpression of a dominant-negative c-Src mutant protein curtailed GLP-1-induced ß-cell proliferation. Co-immunoprecipitation experiments showed a physical association between c-Src and both ß-arrestin1 and GLP-1R upon GLP-1 treatment. Moreover, expression of ß-arrestin1 mutants that lack the ability to bind c-Src blunted GLP-1-induced proliferation. Conversely, expression of a ß-arrestin1 mutant that fails to target G protein-coupled receptors to clathrin-coated pits for sequestration/degradation maximally increased ß-cell proliferation. We propose that the formation of a signaling complex comprising the agonist-stimulated GLP-1R, ß-arrestin1 and c-Src is required for the action of GLP-1 on ß-cell mass.