title: Nm23-H1 regulates glucose-stimulated insulin secretion in pancreatic β-cells via Arf6-Rac1 signaling axis.
abstract: 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.
authors.affiliation: Beta-cell Biochemistry Laboratory, John D. Dingell VA Medical Center, Maryland, USA.
authors.forename: Rajakrishnan
authors.initials: R
authors.lastname: Veluthakal
authors.forename: David
authors.initials: D
authors.lastname: Kaetzel
authors.forename: Anjaneyulu
authors.initials: A
authors.lastname: Kowluru
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D054778:NM23 Nucleoside Diphosphate Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000089982:ADP-Ribosylation Factor 6; D007328:Insulin; D054778:NM23 Nucleoside Diphosphate Kinases; D034741:RNA, Small Interfering; C499134:Rac1 protein, rat; D020727:ADP-Ribosylation Factors; C000715349:Arf6 protein, rat; D020830:rac1 GTP-Binding Protein; D005947:Glucose