Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Base Sequence
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Dishevelled Proteins
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Frizzled Receptors
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L Cells
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Mice
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Multiprotein Complexes
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Neuropeptides / metabolism
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Phosphoproteins / chemistry
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Phosphoproteins / metabolism*
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Protein Interaction Domains and Motifs
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Protein Multimerization
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RNA, Small Interfering / genetics
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Receptor Tyrosine Kinase-like Orphan Receptors / chemistry
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Receptor Tyrosine Kinase-like Orphan Receptors / genetics
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Receptor Tyrosine Kinase-like Orphan Receptors / metabolism*
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Receptors, G-Protein-Coupled / antagonists & inhibitors
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Receptors, G-Protein-Coupled / chemistry
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / metabolism*
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Signal Transduction
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Transcription Factor AP-1 / metabolism*
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Wnt Proteins / metabolism*
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Wnt-5a Protein
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rac GTP-Binding Proteins / metabolism
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rac1 GTP-Binding Protein
Substances
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Adaptor Proteins, Signal Transducing
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Dishevelled Proteins
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Frizzled Receptors
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Fzd7 protein, mouse
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Multiprotein Complexes
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Neuropeptides
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Phosphoproteins
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RNA, Small Interfering
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Rac1 protein, mouse
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Receptors, G-Protein-Coupled
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Recombinant Proteins
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Transcription Factor AP-1
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Wnt Proteins
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Wnt-5a Protein
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Wnt5a protein, mouse
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Receptor Tyrosine Kinase-like Orphan Receptors
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Ror2 protein, mouse
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rac GTP-Binding Proteins
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rac1 GTP-Binding Protein