RORα Attenuates Wnt/β-Catenin Signaling by PKCα-Dependent Phosphorylation in Colon Cancer

Wnt family members play diverse roles in development and disease. Noncanonical Wnt ligands can inhibit canonical Wnt signaling depending on the cellular context; however, the underlying mechanism of this antagonism remains poorly understood. Here we identify a specific mechanism of orphan nuclear receptor ROR alpha-mediated inhibition of canonical Wnt signaling in colon cancer. Wnt5a/PKC alpha-dependent phosphorylation on serine residue 35 of ROR alpha is crucial to link ROR alpha to Wnt/beta-catenin signaling, which exerts inhibitory function of the expression of Wnt/beta-catenin target genes. Intriguingly, there is a significant correlation of reduction of ROR alpha phosphorylation in colorectal tumor cases compared to their normal counterpart, providing the clinical relevance of the findings. Our data provide evidence for a role of ROR alpha, functioning at the crossroads between the canonical and the noncanonical Wnt signaling pathways, in mediating transrepression of the Wnt/beta-catenin target genes, thereby providing new approaches for the development of therapeutic agents for human cancers.