Wnt5a uses CD146 as a receptor to regulate cell motility and convergent extension

Area of Science:

• Cell Biology
• Developmental Biology
• Molecular Biology

Background:

• Wnt signaling pathways are crucial for development and disease.
• Non-canonical Wnt signaling, involving planar cell polarity proteins, regulates cell migration and convergent extension.
• The precise mechanisms governing non-canonical Wnt signaling remain incompletely understood.

Purpose of the Study:

• To investigate the role of CD146 as a receptor for Wnt5a.
• To elucidate the mechanisms by which Wnt5a, via CD146, regulates cell migration and embryonic development.
• To determine the interplay between CD146-mediated non-canonical Wnt signaling and the canonical Wnt pathway.

Main Methods:

• Investigated Wnt5a-CD146 binding affinity and Wnt5a-induced activation of Dishevelled (Dvl) and c-jun amino-terminal kinase (JNK).
• Utilized mutational analysis of the Dvl2-binding region to assess its role in JNK activation, cell migration, and cell protrusion formation.
• Employed knockdown of Dvls to evaluate their necessity for CD146-induced cell migration.
• Examined the effect of CD146 on canonical Wnt signaling and beta-catenin degradation.

Main Results:

• CD146 binds Wnt5a with high affinity, activating Dvl and JNK.
• Wnt5a treatment enhances the CD146-Dvl2 interaction.
• Disruption of Dvl2 binding impairs JNK activation, cell migration, and protrusion formation.
• CD146 mediates Wnt5a-induced cell migration and zebrafish embryonic convergent extension.
• CD146 inhibits canonical Wnt signaling by promoting beta-catenin degradation.

Conclusions:

• CD146 functions as a high-affinity receptor for Wnt5a in regulating cell migration and convergent extension.
• The CD146-Wnt5a axis activates non-canonical Wnt signaling through Dvl and JNK.
• CD146 plays a dual role by promoting non-canonical signaling and suppressing canonical Wnt signaling via beta-catenin degradation.