The receptor tyrosine kinase Ror2 is involved in non‐canonical Wnt5a/JNK signalling pathway

TLDR

Ror2, an orphan receptor tyrosine kinase of the Ror family, is implicated in developmental morphogenesis but its precise signaling partners remain unclear, with its cysteine‑rich domain resembling Frizzled Wnt‑binding sites suggesting potential Wnt interactions. Our experiments show that Wnt5a binds the CRD of Ror2, Ror2 associates with rFz2, and together they activate the non‑canonical Wnt/JNK pathway, indicating that Ror2 functions as a receptor for Wnt5a.

Abstract

Ror2 is an orphan receptor, belonging to the Ror family of receptor tyrosine kinases. Although Ror2 has been shown to play crucial roles in developmental morphogenesis, the precise signalling events that Ror2 mediates remain elusive. Since Ror2 possesses an extracellular cysteine-rich domain (CRD) that resembles the Wnt-binding sites of the Frizzled (Fz) proteins, it is conceivable that Ror2 interacts with members of the Wnt family.Both Ror2-/- and Wnt5a-/- mice exhibit dwarfism, facial abnormalities, short limbs and tails, dysplasia of lungs and genitals, and ventricular septal defects. In vitro binding assay revealed that Wnt5a binds to the CRD of Ror2. Furthermore, Ror2 associates via its CRD with rFz2, a putative receptor for Wnt5a. Interestingly, Wnt5a and Ror2 activate the non-canonical Wnt pathway, as assessed by activation of JNK in cultured cells and inhibition of convergent extension movements in Xenopus.Our findings indicate that Wnt5a and Ror2 interact physically and functionally. Ror2 may thus act as a receptor for Wnt5a to activate non-canonical Wnt signalling.