Receptor tyrosine kinase Ror2 mediates Wnt5a-induced polarized cell migration by activating c-Jun N-terminal kinase via actin-binding protein filamin A.
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 PKCzeta. Taken together, our findings indicate that Wnt5a/Ror2 activates JNK, through a process involving filamin A and PKCzeta, to regulate polarized cell migration.
Nomachi
Akira
A
Physiology and Cell Biology, Kobe University, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Nishita
Michiru
M
Physiology and Cell Biology, Kobe University, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Electronic address: nishita@med.kobe-u.ac.jp.
Inaba
Daisuke
D
Physiology and Cell Biology, Kobe University, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Enomoto
Masahiro
M
Physiology and Cell Biology, Kobe University, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan; Pediatrics, Graduate School of Medicine, Kobe University, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Hamasaki
Mayumi
M
Physiology and Cell Biology, Kobe University, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Minami
Yasuhiro
Y
Physiology and Cell Biology, Kobe University, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Electronic address: minami@kobe-u.ac.jp.
D000199:Actins / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D016764:Cell Polarity / Q000502:physiology*; D003285:Contractile Proteins / Q000378:metabolism*; D064448:Filamins; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D022101:Microtubule-Organizing Center / Q000378:metabolism; D041681:NIH 3T3 Cells; D011493:Protein Kinase C / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D051153:Wnt Proteins / Q000378:metabolism*; D000071818:Wnt-5a Protein; D014945:Wound Healing / Q000502:physiology; D000099221:Protein Kinase C zeta
D000199:Actins; D003285:Contractile Proteins; D064448:Filamins; D048031:JNK Mitogen-Activated Protein Kinases; D008840:Microfilament Proteins; D011493:Protein Kinase C; D020794:Receptor Protein-Tyrosine Kinases; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D000099221:Protein Kinase C zeta; C438615:Wnt5a protein, mouse; C477010:Ror2 protein, mouse