期刊
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
卷 32, 期 3, 页码 533-541出版社
KARGER
DOI: 10.1159/000354457
关键词
nm23-H1; Pancreatic beta-cell; Insulin secretion; Rac1 and Arf6
资金
- Merit Review award [1BX000469]
- Department of Veterans Affairs
- Office of Research and Development [Biomedical Laboratory Research and Development]
- National Institutes of Health [DK074921, CA159871]
- Department of VA
- NATIONAL CANCER INSTITUTE [R01CA159871] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK074921, P30DK020572] Funding Source: NIH RePORTER
- Veterans Affairs [I01BX000469] Funding Source: NIH RePORTER
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-nm23H1 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 beta-cells. Copyright (C) 2013 S. Karger AG, Basel
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