β-Arrestin1-mediated recruitment of c-Src underlies the proliferative action of glucagon-like peptide-1 in pancreatic β INS832/13 cells
Autor: | Erik Joly, Marc Prentki, Jean Buteau, Jason Talbot |
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Rok vydání: | 2012 |
Předmět: |
Adult
endocrine system medicine.medical_specialty Arrestins medicine.medical_treatment Mutant 030209 endocrinology & metabolism Biology Biochemistry 03 medical and health sciences 0302 clinical medicine Endocrinology Mutant protein Glucagon-Like Peptide 1 Internal medicine Insulin-Secreting Cells medicine Receptors Glucagon Humans Immunoprecipitation Phosphorylation RNA Small Interfering Receptor Molecular Biology beta-Arrestins 030304 developmental biology Aged Cell Proliferation 0303 health sciences Gene knockdown Growth factor digestive oral and skin physiology Middle Aged Protein-Tyrosine Kinases Clathrin 3. Good health Cell biology Gene Expression Regulation Gene Knockdown Techniques Mutation hormones hormone substitutes and hormone antagonists Intestinal L Cells Proto-oncogene tyrosine-protein kinase Src Protein Binding Signal Transduction |
Zdroj: | Molecular and cellular endocrinology. 364(1-2) |
ISSN: | 1872-8057 |
Popis: | 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. |
Databáze: | OpenAIRE |
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