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MAPKAPK-2-mediated LIM-kinase activation is critical for VEGF-induced actin remodeling and cell migration.

Vascular endothelial growth factor-A (VEGF-A) induces actin reorganization and migration of endothelial cells through a p38 mitogen-activated protein kinase (MAPK) pathway. LIM-kinase 1 (LIMK1) induces actin remodeling by phosphorylating and inactivating cofilin, an actin-depolymerizing factor. In this study, we demonstrate that activation of LIMK1 by MAPKAPK-2 (MK2; a downstream kinase of p38 MAPK) represents a novel signaling pathway in VEGF-A-induced cell migration. VEGF-A induced LIMK1 activation and cofilin phosphorylation, and this was inhibited by the p38 MAPK inhibitor SB203580. Although p38 phosphorylated LIMK1 at Ser-310, it failed to activate LIMK1 directly; however, MK2 activated LIMK1 by phosphorylation at Ser-323. Expression of a Ser-323-non-phosphorylatable mutant of LIMK1 suppressed VEGF-A-induced stress fiber formation and cell migration; however, expression of a Ser-323-phosphorylation-mimic mutant enhanced these processes. Knockdown of MK2 by siRNA suppressed VEGF-A-induced LIMK1 activation, stress fiber formation, and cell migration. Expression of kinase-dead LIMK1 suppressed VEGF-A-induced tubule formation. These findings suggest that MK2-mediated LIMK1 phosphorylation/activation plays an essential role in VEGF-A-induced actin reorganization, migration, and tubule formation of endothelial cells.

Pubmed ID: 16456544


  • Kobayashi M
  • Nishita M
  • Mishima T
  • Ohashi K
  • Mizuno K


The EMBO journal

Publication Data

February 22, 2006

Associated Grants


Mesh Terms

  • Actins
  • Amino Acid Substitution
  • Cell Movement
  • Cofilin 1
  • Endothelial Cells
  • Enzyme Inhibitors
  • Humans
  • Imidazoles
  • Intracellular Signaling Peptides and Proteins
  • Lim Kinases
  • MAP Kinase Signaling System
  • Mutagenesis, Site-Directed
  • Phosphorylation
  • Point Mutation
  • Protein Kinases
  • Protein Processing, Post-Translational
  • Protein-Serine-Threonine Kinases
  • Pyridines
  • RNA, Small Interfering
  • Tubulin
  • Vascular Endothelial Growth Factor A
  • p38 Mitogen-Activated Protein Kinases