Filopodia formation mediated by receptor tyrosine kinase Ror2 is required for Wnt5a-induced cell migration.
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.
Nishita
Michiru
M
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.
Yoo
Sa Kan
SK
Nomachi
Akira
A
Kani
Shuichi
S
Sougawa
Nagako
N
Ohta
Yasutaka
Y
Takada
Shinji
S
Kikuchi
Akira
A
Minami
Yasuhiro
Y
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D003285:Contractile Proteins / Q000737:chemistry; D017077:Culture Media, Conditioned; D003593:Cytoplasm / Q000187:drug effects; D000072261:Dishevelled Proteins; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D064448:Filamins; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000737:chemistry; D010750:Phosphoproteins / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D011554:Pseudopodia / Q000187:drug effects*; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D051153:Wnt Proteins / Q000494:pharmacology*; D000071818:Wnt-5a Protein
D048868:Adaptor Proteins, Signal Transducing; D003285:Contractile Proteins; D017077:Culture Media, Conditioned; D000072261:Dishevelled Proteins; D064448:Filamins; D008840:Microfilament Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; C477010:Ror2 protein, mouse