MAPKAPK-2-mediated LIM-kinase activation is critical for VEGF-induced actin remodeling and cell migration
MAPKAPK-2-mediated LIM-kinase activation is critical for VEGF-induced actin remodeling and cell migration
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DOI：
10.1038/sj.emboj.7600973
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发表时间：
2006-02-22
期刊：
影响因子：
11.4
通讯作者：
Mizuno, K
中科院分区：
文献类型：
--
作者：
Kobayashi, M;Nishita, M;Mizuno, K
血管内皮生长因子-A(VEGF-A)通过p38丝裂原活化蛋白激酶(MAPK)途径诱导内皮细胞肌动蛋白重组和迁移。Lim-kinase1(LIMK1)通过磷酸化和失活肌动蛋白解聚因子cofilin来诱导肌动蛋白重塑。在这项研究中，我们证明了MAPKAPK-2(MK2，p38MAPK的下游激酶)激活LIMK1是血管内皮生长因子-A诱导细胞迁移的一条新的信号通路。血管内皮生长因子-A诱导LIMK1活化和cofilin磷酸化，这一作用可被p38 MAPK抑制剂SB203580抑制。虽然p38在Ser-310处使LIMK1磷酸化，但不能直接激活LIMK1，而MK2通过在Ser-323处磷酸化来激活LIMK1。LIMK1的Ser-323非磷酸化突变体的表达抑制了VEGF-A诱导的应激纤维的形成和细胞迁移；然而，Ser-323磷酸化模拟突变体的表达促进了这些过程。通过siRNA敲除MK2可以抑制血管内皮生长因子-A诱导的LIMK1的激活、应力纤维的形成和细胞迁移。蛋白激酶LIMK1的表达抑制了血管内皮生长因子-A诱导的小管形成。这些结果表明，MK2介导的LIMK1磷酸化/激活在血管内皮生长因子-A诱导的肌动蛋白重组、迁移和微管形成中起重要作用。
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.