Ror2/Frizzled complex mediates Wnt5a-induced AP-1 activation by regulating Dishevelled polymerization.
The receptor tyrosine kinase Ror2 acts as a receptor or coreceptor for Wnt5a to mediate Wnt5a-induced activation of the Wnt/JNK pathway and inhibition of the beta-catenin-dependent canonical Wnt pathway. However, little is known about how Ror2 cooperates with another receptor component(s) to mediate Wnt5a signaling. We show here that Ror2 regulates Wnt5a-induced polymerization of Dishevelled (Dvl) and that this Ror2-mediated regulation of Dvl is independent of the cytoplasmic region of Ror2. Ror2 can associate with Frizzled7 (Fz7) via its extracellular cysteine-rich domain to form a receptor complex that is required for the regulation of Dvl and activation of the AP-1 promoter after Wnt5a stimulation. Suppressed expression of Fz7 indeed results in the inhibition of Wnt5a-induced polymerization of Dvl and AP-1 activation. Interestingly, both the DIX and the DEP domains of Dvl are indispensable for Dvl polymerization and subsequent AP-1 activation after Wnt5a stimulation. We further show that polymerized Dvl is colocalized with Rac1 and that suppressed expression of Rac1 inhibits Wnt5a-induced AP-1 activation. Collectively, our results indicate that Ror2/Fz receptor complex plays an important role in the Wnt5a/Rac1/AP-1 pathway by regulating the polymerization of Dvl.
Nishita
Michiru
M
Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. nishita@med.kobe-u.ac.jp
Itsukushima
Sumiyo
S
Nomachi
Akira
A
Endo
Mitsuharu
M
Wang
ZhiChao
Z
Inaba
Daisuke
D
Qiao
Sen
S
Takada
Shinji
S
Kikuchi
Akira
A
Minami
Yasuhiro
Y
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D000072261:Dishevelled Proteins; D051157:Frizzled Receptors; D007739:L Cells; D051379:Mice; D046912:Multiprotein Complexes; D009479:Neuropeptides / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D034741:RNA, Small Interfering / Q000235:genetics; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D000071818:Wnt-5a Protein; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein
D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; D051157:Frizzled Receptors; C492041:Fzd7 protein, mouse; D046912:Multiprotein Complexes; D009479:Neuropeptides; D010750:Phosphoproteins; D034741:RNA, Small Interfering; C484602:Rac1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; C477010:Ror2 protein, mouse; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein
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