Dishevelled2 Negatively Regulates Cell‐Surface Ror1 Abundance Through Lysosomal Degradation

ABSTRACT Receptor tyrosine kinase‐like orphan receptor 1 (Ror1) mediates Wnt5a‐dependent noncanonical Wnt signaling and promotes lung adenocarcinoma progression. Dishevelled (Dvl) proteins are central mediators of Wnt signaling and have also been implicated in its negative regulation and receptor turnover. However, whether Dvl2 contributes to negative regulation of Wnt5a–Ror1 signaling remains unclear. Here, we show that Dvl2 depletion selectively increased the cell surface‐associated 130‐kDa Ror1 species without affecting Ror1 mRNA levels. Wnt5a depletion similarly increased Ror1 abundance, which was reverted by an addition of recombinant Wnt5a. Dvl2 promoted degradation of the 130‐kDa Ror1 species through a lysosomal rather than proteasomal pathway, and CK1 inhibition stabilized the receptor. Dvl2 interacted with the intracellular C‐terminal region of Ror1 via its DEP domain, and CK1 inhibition enhanced this interaction. Furthermore, both the intracellular C‐terminal region and extracellular cysteine‐rich domain of Ror1 were required for Dvl2‐mediated receptor destabilization. These findings reveal a previously unrecognized role for Dvl2 in regulating Ror1 turnover and suggest that Dvl2‐mediated lysosomal degradation of Ror1 may provide a negative‐feedback mechanism that limits Wnt5a–Ror1 signaling.