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Novel mechanistic link between focal adhesion remodeling and glucose-stimulated insulin secretion

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Published in Journal of Biological Chemistry. 2012, vol. 287, no. 4, p. 2423-36
Abstract Actin cytoskeleton remodeling is well known to be positively involved in glucose-stimulated pancreatic β cell insulin secretion. We have observed glucose-stimulated focal adhesion remodeling at the β cell surface and have shown this to be crucial for glucose-stimulated insulin secretion. However, the mechanistic link between such remodeling and the insulin secretory machinery remained unknown and was the major aim of this study. MIN6B1 cells, a previously validated model of primary β cell function, were used for all experiments. Total internal reflection fluorescence microscopy revealed the glucose-responsive co-localization of focal adhesion kinase (FAK) and paxillin with integrin β1 at the basal cell surface after short term stimulation. In addition, blockade of the interaction between β1 integrins and the extracellular matrix with an anti-β1 integrin antibody (Ha2/5) inhibited short term glucose-induced phosphorylation of FAK (Tyr-397), paxillin (Tyr-118), and ERK1/2 (Thr-202/Tyr-204). Pharmacological inhibition of FAK activity blocked glucose-induced actin cytoskeleton remodeling and glucose-induced disruption of the F-actin/SNAP-25 association at the plasma membrane as well as the distribution of insulin granules to regions in close proximity to the plasma membrane. Furthermore, FAK inhibition also completely blocked short term glucose-induced activation of the Akt/AS160 signaling pathway. In conclusion, these results indicate 1) that glucose-induced activation of FAK, paxillin, and ERK1/2 is mediated by β1 integrin intracellular signaling, 2) a mechanism whereby FAK mediates glucose-induced actin cytoskeleton remodeling, hence allowing docking and fusion of insulin granules to the plasma membrane, and 3) a possible functional role for the Akt/AS160 signaling pathway in the FAK-mediated regulation of glucose-stimulated insulin secretion.
Keywords Actins/genetics/metabolismAnimalsAntigens, CD29/genetics/metabolismCell Line, TumorCytoskeleton/genetics/metabolismFocal Adhesion Kinase 1/genetics/metabolismFocal Adhesions/genetics/metabolismGTPase-Activating Proteins/genetics/metabolismGlucose/pharmacologyInsulin/genetics/secretionInsulin-Secreting Cells/cytology/metabolismMitogen-Activated Protein Kinase 3/genetics/metabolismPaxillin/genetics/metabolismProto-Oncogene Proteins c-akt/genetics/metabolismRatsSignal Transduction/drug effects/geneticsSweetening Agents/pharmacologySynaptosomal-Associated Protein 25/genetics/metabolism
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PMID: 22139838
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Structures
Research group Fonction de l'îlot de Langerhans (324)
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RONDAS, Dieter et al. Novel mechanistic link between focal adhesion remodeling and glucose-stimulated insulin secretion. In: Journal of Biological Chemistry, 2012, vol. 287, n° 4, p. 2423-36. https://archive-ouverte.unige.ch/unige:25163

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Deposited on : 2013-01-09

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