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
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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