Nm23-H1 Regulates Glucose-Stimulated Insulin Secretion in Pancreatic β-Cells via Arf6-Rac1 Signaling Axis

Cellular Physiology and Biochemistry

关键词: nm23-H1;    Pancreatic β-cell;    Insulin secretion;    Rac1 and Arf6;   

DOI  :  10.1159/000354457

学科分类：分子生物学，细胞生物学和基因

来源: S Karger AG

【 摘 要 】

Background A growing body of evidence implicates novel roles for nm23-like proteins in the regulation of cellular functions. However, roles of these proteins in islet function and glucose-stimulated insulin secretion (GSIS) remain largely unknown. Methods siRNA-nm23-H1 and nucleoside diphosphate kinase and histidine kinase-deficient mutants of nm23-H1 (K12Q and H118F) were used to assess roles of nm23-H1 in GSIS. Results siRNA-mediated knockdown of the expression of nm23-H1 markedly inhibited GSIS in INS-1 832/13 cells. Nm23-H1 knockdown also resulted in significant inhibition of glucose-mediated activation of Arf6, a small G-protein, which has been implicated in GSIS. Expression of K12Q and H118F mutants of nm23-H1 in INS-1 832/13 cells led to inhibition of glucose-induced translocation and membrane association of Rac1, another small G-protein, which is downstream to Arf6 in the signaling events leading to GSIS. A significant inhibition of GSIS was also seen in these cells expressing K12Q and H118F. Conclusions We conclude that the nm23-H1 activation step is upstream of Arf6 activation in signaling events leading to GSIS. NDP kinase and histidine kinase functions of nm23-H1 are necessary for glucose-induced membrane association of Rac1 and ensuing insulin secretion. We present the first evidence for regulation of GSIS by nm23-H1 in pancreatic β-cells.

【 授权许可】

CC BY-NC-ND