The rho guanosine 5'-triphosphatase, cell division cycle 42, is required for insulin-induced actin remodeling and glucagon-like peptide-1 secretion in the intestinal endocrine L cell

Endocrinology. 2009 Dec;150(12):5249-61. doi: 10.1210/en.2009-0508. Epub 2009 Oct 9.


Rho GTPases, such as cell division cycle 42 (Cdc42) and ras-related C3 botulinum toxin substrate 1 (Rac1), have been identified as regulators of F-actin dynamics and hormone release from endocrine cells; however, their role in secretion of the incretin hormone, glucagon-like peptide-1 (GLP-1), from the enteroendocrine L cell is unknown. Insulin induced a 1.4-fold increase in L cell GLP-1 release; however, secretion was potentiated to 2.1-fold in the presence of the F-actin depolymerizing agent, latrunculin B, suggesting that F-actin functions as a permissive barrier. In murine GLUTag L cells, insulin stimulated F-actin depolymerization and Cdc42 activation simultaneously, and these events occurred prior to detectable increases in insulin-induced GLP-1 release. After insulin treatment, Cdc42-dependent p21-activated kinase-1 (PAK1) activation was also detected, and transfection of small-interfering RNA against Cdc42 or of dominant-negative Cdc42(T17N) impaired insulin-stimulated PAK1 activation, actin remodeling, and GLP-1 secretion. Overexpression of kinase-dead PAK1(K299R) or PAK1 small interfering RNA similarly attenuated insulin-induced GLP-1 secretion. Knockdown or inhibition of Cdc42 and PAK1 activities also prevented activation of MAPK/ERK (MEK)-1/2-ERK1/2 by insulin, which was previously identified as a critical pathway for insulin-regulated GLP-1 release. Taken together, these data identify a novel signaling pathway in the endocrine L cell, whereby Cdc42 regulates actin remodeling, activation of the cannonical 1/2-ERK1/2 pathway and PAK1, and GLP-1 secretion in response to insulin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism*
  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cytoskeleton / drug effects
  • Cytoskeleton / metabolism
  • Enteroendocrine Cells / cytology
  • Enteroendocrine Cells / drug effects*
  • Enteroendocrine Cells / metabolism
  • Enzyme Activation / drug effects
  • Glucagon-Like Peptide 1 / metabolism*
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Insulin / pharmacology*
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • RNA Interference
  • Signal Transduction / drug effects
  • Time Factors
  • cdc42 GTP-Binding Protein / genetics
  • cdc42 GTP-Binding Protein / metabolism*
  • p21-Activated Kinases / genetics
  • p21-Activated Kinases / metabolism
  • rho GTP-Binding Proteins / genetics
  • rho GTP-Binding Proteins / metabolism*


  • Actins
  • Insulin
  • Glucagon-Like Peptide 1
  • PAK1 protein, human
  • p21-Activated Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • cdc42 GTP-Binding Protein
  • rho GTP-Binding Proteins