Novel Mechanistic Link between Focal Adhesion Remodeling and Glucose-stimulated Insulin Secretion
File(s)
Published version
OA Location
Author(s)
Rondas, D
Tomas, A
Soto-Ribeiro, M
Wehrle-Haller, B
Halban, PA
Type
Journal Article
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.
Date Issued
2011-12-02
Date Acceptance
2011-12-02
Citation
Journal of Biological Chemistry, 2011, 287 (4), pp.2423-2436
ISSN
1083-351X
Publisher
American Society for Biochemistry and Molecular Biology
Start Page
2423
End Page
2436
Journal / Book Title
Journal of Biological Chemistry
Volume
287
Issue
4
Copyright Statement
© 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
Subjects
Actins
Animals
Antigens, CD29
Cell Line, Tumor
Cytoskeleton
Focal Adhesion Kinase 1
Focal Adhesions
GTPase-Activating Proteins
Glucose
Insulin
Insulin-Secreting Cells
Mitogen-Activated Protein Kinase 3
Paxillin
Proto-Oncogene Proteins c-akt
Rats
Signal Transduction
Sweetening Agents
Synaptosomal-Associated Protein 25
Biochemistry & Molecular Biology
06 Biological Sciences
11 Medical And Health Sciences
03 Chemical Sciences
Publication Status
Published