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J. Biol. Chem., Vol. 283, Issue 41, 27973-27981, October 10, 2008

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Receptor Tyrosine Kinase Ror2 Mediates Wnt5a-induced Polarized Cell Migration by Activating c-Jun N-terminal Kinase via Actin-binding Protein Filamin A^*

Akira Nomachi¹, Michiru Nishita², Daisuke Inaba, Masahiro Enomoto, Mayumi Hamasaki, and Yasuhiro Minami³

From the Departments of Physiology and Cell Biology and Pediatrics, Graduate School of Medicine, Kobe University, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan

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. Taken together, our findings indicate that Wnt5a/Ror2 activates JNK, through a process involving filamin A and PKC, to regulate polarized cell migration.

Received for publication, March 25, 2008 , and in revised form, July 23, 2008.

^* This work was supported in part by a Grant-in-Aid for Scientific Research in Priority Areas, a Grant-in-Aid for Scientific Research (B), and a Grant-in-Aid for Young Scientists (B) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan, the Uehara Memorial Foundation, the Naito Foundation, the Hyogo Science and Technology Association, and the Astellas Foundation for Research on Metabolic Disorders. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ A research fellow of the Japan Society for the Promotion of Sciences.

² To whom correspondence may be addressed. Tel.: 81-78-382-5561; Fax: 81-78-382-5579; E-mail: nishita{at}med.kobe-u.ac.jp.

³ To whom correspondence may be addressed. Tel.: 81-78-382-5560; Fax: 81-78-382-5579; E-mail: minami{at}kobe-u.ac.jp.

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