Integrin and autocrine IGF2 pathways control fasting insulin secretion in β-cells
| Autor: | Karim Bouzakri, Katharina Rickenbach, Caroline Arous, Michel Pinget, Bernhard Wehrle-Haller, Maria L. Mizgier |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Proto-Oncogene Proteins c-akt/antagonists & inhibitors/genetics/metabolism
0301 basic medicine Integrins insulin secretion medicine.medical_treatment AKT2 Integrins/metabolism Focal Adhesion Kinase 1/metabolism Biochemistry Mice Insulin-Secreting Cells Signal Transduction/drug effects Akt PKB Cell Adhesion/drug effects RNA Small Interfering Rho-Associated Kinases/metabolism rho-Associated Kinases biology Chemistry IGF2 Tyrphostins Glucose/pharmacology RhoA GTP-Binding Protein/metabolism Cell biology Autocrine Communication Insulin-Like Growth Factor II/metabolism Actins/metabolism Insulin-Secreting Cells/cytology/metabolism IGF1 receptor signaling insulin/insulin-like growth factor 1 (IGF1)-receptor signaling RNA Interference Signal transduction Signal Transduction Receptor insulin Insulin/metabolism integrin Small Interfering/metabolism Integrin Focal adhesion 03 medical and health sciences Insulin-Like Growth Factor II Tyrphostins/pharmacology Cell Adhesion medicine Animals ddc:612 Autocrine signalling Molecular Biology Paxillin beta cell (B-cell) 030102 biochemistry & molecular biology Insulin Actin remodeling Insulin Secretion/drug effects Cell Biology insulin-like growth factor (IGF) Actins Receptor Insulin Rats insulin receptor signaling Glucose 030104 developmental biology Focal Adhesion Kinase 1 AKT isoform biology.protein RNA rhoA GTP-Binding Protein Proto-Oncogene Proteins c-akt |
| Zdroj: | Journal of Biological Chemistry, Vol. 295, No 49 (2020) pp. 16510-16528 The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| Popis: | Elevated levels of fasting insulin release and insufficient glucose-stimulated insulin secretion (GSIS) are hallmarks of diabetes. Studies have established cross-talk between integrin signaling and insulin activity, but more details of how integrin-dependent signaling impacts the pathophysiology of diabetes are needed. Here, we dissected integrin-dependent signaling pathways involved in the regulation of insulin secretion in β-cells and studied their link to the still debated autocrine regulation of insulin secretion by insulin/insulin-like growth factor (IGF) 2–AKT signaling. We observed for the first time a cooperation between different AKT isoforms and focal adhesion kinase (FAK)–dependent adhesion signaling, which either controlled GSIS or prevented insulin secretion under fasting conditions. Indeed, β-cells form integrin-containing adhesions, which provide anchorage to the pancreatic extracellular matrix and are the origin of intracellular signaling via FAK and paxillin. Under low-glucose conditions, β-cells adopt a starved adhesion phenotype consisting of actin stress fibers and large peripheral focal adhesion. In contrast, glucose stimulation induces cell spreading, actin remodeling, and point-like adhesions that contain phospho-FAK and phosphopaxillin, located in small protrusions. Rat primary β-cells and mouse insulinomas showed an adhesion remodeling during GSIS resulting from autocrine insulin/IGF2 and AKT1 signaling. However, under starving conditions, the maintenance of stress fibers and the large adhesion phenotype required autocrine IGF2-IGF1 receptor signaling mediated by AKT2 and elevated FAK-kinase activity and ROCK-RhoA levels but low levels of paxillin phosphorylation. This starved adhesion phenotype prevented excessive insulin granule release to maintain low insulin secretion during fasting. Thus, deregulation of the IGF2 and adhesion-mediated signaling may explain dysfunctions observed in diabetes. |
| Databáze: | OpenAIRE |
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