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

The EMBO journal | Feb 22, 2006

http://www.ncbi.nlm.nih.gov/pubmed/16456544

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 RIS Download

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