Receptor tyrosine kinase Ror2 mediates Wnt5a-induced polarized cell migration by activating c-Jun N-terminal kinase via actin-binding protein filamin A
Receptor tyrosine kinase Ror2 mediates Wnt5a-induced polarized cell migration by activating c-Jun N-terminal kinase via actin-binding protein filamin A
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DOI：
10.1074/jbc.m802325200
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发表时间：
2008-10-10
影响因子：
4.8
通讯作者：
Minami, Yasuhiro
中科院分区：
文献类型：
--
作者：
Nomachi, Akira;Nishita, Michiru;Minami, Yasuhiro
受体酪氨酸激酶Ror 2最近已被证明作为Wnt 5a的替代受体或辅助受体，并介导Wnt 5a诱导的培养细胞迁移。然而，很少有人知道这个迁移过程的分子机制。在这里，我们通过伤口愈合试验表明，Ror 2通过调节板状伪足的形成和微管组织中心（MTOC）的重新定向在Wnt 5a诱导的细胞迁移中起着关键作用。Wnt 5a刺激以Ror 2依赖性方式诱导伤口边缘的c-Jun N-末端激酶JNK的活化，并且抑制JNK活性消除Wnt 5a诱导的板状伪足形成和MTOC重定向。此外，Ror 2与肌动蛋白结合蛋白细丝蛋白A的关联是Wnt 5a诱导的JNK活化和极化细胞迁移所必需的。我们进一步表明，Wnt 5a诱导的JNK激活和MTOC重定向可以通过抑制PKC ζ来抑制。总之，我们的研究结果表明，Wnt 5a/Ror 2激活JNK，通过一个过程，涉及细丝蛋白A和PKC ζ，调节极化细胞迁移。
The receptor tyrosine kinase Ror2 has recently been shown to act as an alternative receptor or coreceptor for Wnt5a and to mediate Wnt5a-induced migration of cultured cells. However, little is known about the molecular mechanism underlying this migratory process. Here we show by wound-healing assays that Ror2 plays critical roles in Wnt5a-induced cell migration by regulating formation of lamellipodia and reorientation of microtubule-organizing center (MTOC). Wnt5a stimulation induces activation of the c-Jun N-terminal kinase JNK at the wound edge in a Ror2-dependent manner, and inhibiting JNK activity abrogates Wnt5a-induced lamellipodia formation and MTOC reorientation. Additionally, the association of Ror2 with the actin-binding protein filamin A is required for Wnt5a-induced JNK activation and polarized cell migration. We further show that Wnt5a-induced JNK activation and MTOC reorientation can be suppressed by inhibiting PKC zeta. Taken together, our findings indicate that Wnt5a/Ror2 activates JNK, through a process involving filamin A and PKC zeta, to regulate polarized cell migration.