Nm23-H1 Regulates Glucose-Stimulated Insulin Secretion in Pancreatic β-Cells via Arf6-Rac1 Signaling Axis
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 k...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Cell Physiol Biochem Press GmbH & Co KG
2013-08-01
|
| Series: | Cellular Physiology and Biochemistry |
| Subjects: | |
| Online Access: | http://www.karger.com/Article/FullText/354457 |
| _version_ | 1819095853591166976 |
|---|---|
| author | Rajakrishnan Veluthakal David Kaetzel Anjaneyulu Kowluru |
| author_facet | Rajakrishnan Veluthakal David Kaetzel Anjaneyulu Kowluru |
| author_sort | Rajakrishnan Veluthakal |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T23:49:54Z |
| format | Article |
| id | doaj.art-45635244b0c14bd68c31acff0517867f |
| institution | Directory Open Access Journal |
| issn | 1015-8987 1421-9778 |
| language | English |
| last_indexed | 2024-12-21T23:49:54Z |
| publishDate | 2013-08-01 |
| publisher | Cell Physiol Biochem Press GmbH & Co KG |
| record_format | Article |
| series | Cellular Physiology and Biochemistry |
| spelling | doaj.art-45635244b0c14bd68c31acff0517867f2022-12-21T18:45:57ZengCell Physiol Biochem Press GmbH & Co KGCellular Physiology and Biochemistry1015-89871421-97782013-08-0132353354110.1159/000354457354457Nm23-H1 Regulates Glucose-Stimulated Insulin Secretion in Pancreatic β-Cells via Arf6-Rac1 Signaling AxisRajakrishnan VeluthakalDavid KaetzelAnjaneyulu KowluruBackground: 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.http://www.karger.com/Article/FullText/354457nm23-H1Pancreatic β-cellInsulin secretionRac1 and Arf6 |
| spellingShingle | Rajakrishnan Veluthakal David Kaetzel Anjaneyulu Kowluru Nm23-H1 Regulates Glucose-Stimulated Insulin Secretion in Pancreatic β-Cells via Arf6-Rac1 Signaling Axis Cellular Physiology and Biochemistry nm23-H1 Pancreatic β-cell Insulin secretion Rac1 and Arf6 |
| title | Nm23-H1 Regulates Glucose-Stimulated Insulin Secretion in Pancreatic β-Cells via Arf6-Rac1 Signaling Axis |
| title_full | Nm23-H1 Regulates Glucose-Stimulated Insulin Secretion in Pancreatic β-Cells via Arf6-Rac1 Signaling Axis |
| title_fullStr | Nm23-H1 Regulates Glucose-Stimulated Insulin Secretion in Pancreatic β-Cells via Arf6-Rac1 Signaling Axis |
| title_full_unstemmed | Nm23-H1 Regulates Glucose-Stimulated Insulin Secretion in Pancreatic β-Cells via Arf6-Rac1 Signaling Axis |
| title_short | Nm23-H1 Regulates Glucose-Stimulated Insulin Secretion in Pancreatic β-Cells via Arf6-Rac1 Signaling Axis |
| title_sort | nm23 h1 regulates glucose stimulated insulin secretion in pancreatic β cells via arf6 rac1 signaling axis |
| topic | nm23-H1 Pancreatic β-cell Insulin secretion Rac1 and Arf6 |
| url | http://www.karger.com/Article/FullText/354457 |
| work_keys_str_mv | AT rajakrishnanveluthakal nm23h1regulatesglucosestimulatedinsulinsecretioninpancreaticbcellsviaarf6rac1signalingaxis AT davidkaetzel nm23h1regulatesglucosestimulatedinsulinsecretioninpancreaticbcellsviaarf6rac1signalingaxis AT anjaneyulukowluru nm23h1regulatesglucosestimulatedinsulinsecretioninpancreaticbcellsviaarf6rac1signalingaxis |