Ror2/Frizzled complex mediates Wnt5a-induced AP-1 activation by regulating Dishevelled polymerization

Area of Science:

• Cellular Biology
• Molecular Signaling
• Receptor Tyrosine Kinases

Background:

• Ror2 is a receptor tyrosine kinase involved in Wnt5a signaling, mediating JNK pathway activation and canonical Wnt pathway inhibition.
• The precise mechanism of Ror2 cooperation with other receptors in Wnt5a signaling remains unclear.

Purpose of the Study:

• To elucidate the role of Ror2 in Wnt5a signaling pathways.
• To identify cooperating receptor components and downstream effectors in Ror2-mediated Wnt5a signaling.

Main Methods:

• Investigated Ror2's interaction with Frizzled7 (Fz7) using its extracellular domain.
• Assessed the impact of Ror2 and Fz7 on Dishevelled (Dvl) polymerization and AP-1 promoter activation.
• Examined the role of Dvl domains (DIX and DEP) and Rac1 in Wnt5a signaling.

Main Results:

• Ror2 regulates Wnt5a-induced Dishevelled (Dvl) polymerization independently of its cytoplasmic region.
• Ror2 associates with Frizzled7 (Fz7) via its extracellular domain to form a receptor complex essential for Dvl regulation and AP-1 activation.
• Fz7 suppression inhibits Wnt5a-induced Dvl polymerization and AP-1 activation.
• Both DIX and DEP domains of Dvl are critical for polymerization and AP-1 activation.
• Polymerized Dvl colocalizes with Rac1, and Rac1 suppression inhibits Wnt5a-induced AP-1 activation.

Conclusions:

• The Ror2/Fz7 receptor complex is crucial for Wnt5a signaling.
• This complex regulates Dvl polymerization, a key step in the Wnt5a/Rac1/AP-1 pathway.