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| Subject Categories: Signal Transduction |
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| The EMBO Journal
(2006) 25, 713–726, doi:10.1038/sj.emboj.7600973 Published online 2 February 2006 |
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| MAPKAPK-2-mediated LIM-kinase activation is critical for VEGF-induced actin remodeling and cell migration |
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| Miho Kobayashi, Michiru Nishita, Toshiaki Mishima, Kazumasa Ohashi and Kensaku Mizuno |
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Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi, Japan To whom correspondence should be addressed Kensaku Mizuno, Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan. Tel.: +81 22 795 6676; Fax: +81 22 795 6678; E-mail: kmizuno@biology.tohoku.ac.jp Received 2 September 2005; Accepted 9 January 2006; Published online 2 February 2006. |
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| Abstract |
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| 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. |
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| Keywords: endothelial cell migration, LIM-kinase, MAPKAPK-2, p38 MAPK, VEGF-A |
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