Nishita Michiru, Yoo Sa Kan, Nomachi Akira, Kani Shuichi, Sougawa Nagako, Ohta Yasutaka, Takada Shinji, Kikuchi Akira, Minami Yasuhiro
Department of Genome Sciences, Faculty of Medical Sciences, Graduate School of Medicine, Kobe University, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
J Cell Biol. 2006 Nov 20;175(4):555-62. doi: 10.1083/jcb.200607127. Epub 2006 Nov 13.
The receptor tyrosine kinase Ror2 plays important roles in developmental morphogenesis. It has recently been shown that Ror2 mediates Wnt5a-induced noncanonical Wnt signaling by activating the Wnt-JNK pathway and inhibiting the beta-catenin-TCF pathway. However, the function of Ror2 in noncanonical Wnt signaling leading to cell migration is largely unknown. We show, using genetically different or manipulated cultured cells, that Ror2 is critical for Wnt5a-induced, but not Wnt3a-induced, cell migration. Ror2-mediated cell migration requires the extracellular cysteine-rich domain (CRD), which is the binding site for Wnt5a, and the cytoplasmic proline-rich domain (PRD) of Ror2. Furthermore, Ror2 can mediate filopodia formation via actin reorganization, irrespective of Wnt5a, and this Ror2-mediated filopodia formation requires the actin-binding protein filamin A, which associates with the PRD of Ror2. Intriguingly, disruption of filopodia formation by suppressing the expression of either Ror2 or filamin A inhibits Wnt5a-induced cell migration, indicating that Ror2-mediated filopodia formation is essential for Wnt5a-induced cell migration.
受体酪氨酸激酶Ror2在发育形态发生中发挥重要作用。最近研究表明，Ror2通过激活Wnt-JNK途径并抑制β-连环蛋白-TCF途径来介导Wnt5a诱导的非经典Wnt信号传导。然而，Ror2在导致细胞迁移的非经典Wnt信号传导中的功能在很大程度上尚不清楚。我们利用基因不同或经过操作的培养细胞表明，Ror2对Wnt5a诱导而非Wnt3a诱导的细胞迁移至关重要。Ror2介导的细胞迁移需要细胞外富含半胱氨酸的结构域（CRD），它是Wnt5a的结合位点，以及Ror2的细胞质富含脯氨酸的结构域（PRD）。此外，Ror2可通过肌动蛋白重组介导丝状伪足形成，与Wnt5a无关，并且这种Ror2介导的丝状伪足形成需要肌动蛋白结合蛋白细丝蛋白A，它与Ror2的PRD相关联。有趣的是，通过抑制Ror2或细丝蛋白A的表达来破坏丝状伪足形成会抑制Wnt5a诱导的细胞迁移，这表明Ror2介导的丝状伪足形成对Wnt5a诱导的细胞迁移至关重要。
