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Published online 13 November 2006. doi:10.1083/jcb.200607127
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 175, Number 4, 555-562
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Filopodia formation mediated by receptor tyrosine kinase Ror2 is required for Wnt5a-induced cell migration



Michiru Nishita1, Sa Kan Yoo1, Akira Nomachi1, Shuichi Kani1, Nagako Sougawa1, Yasutaka Ohta2, Shinji Takada3,4, Akira Kikuchi5, and Yasuhiro Minami1

1 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
2 Hematology Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115
3 Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, and 4 Department of Molecular Biomechanics, Graduate University for Advanced Studies (SOKENDAI), 38 Nishigonaka, Myodaiji, Okazaki, Aichi 444-8787, Japan
5 Department of Biochemistry, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan

Correspondence to Yasuhiro Minami: minami{at}kobe-u.ac.jp

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 ß-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.

Abbreviations used in this paper: CE, convergent extension; CM, conditioned medium; CRD, cysteine-rich domain; HEK, human embryonic kidney; MEF, mouse embryonic fibroblast; PRD, proline-rich domain.


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