RORalpha attenuates Wnt/beta-catenin signaling by PKCalpha-dependent phosphorylation in colon cancer

Mol Cell. 2010 Jan 29;37(2):183-95. doi: 10.1016/j.molcel.2009.12.022.


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 RORalpha-mediated inhibition of canonical Wnt signaling in colon cancer. Wnt5a/PKCalpha-dependent phosphorylation on serine residue 35 of RORalpha is crucial to link RORalpha 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 RORalpha 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 RORalpha, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma / metabolism*
  • Cell Line
  • Colonic Neoplasms / metabolism*
  • Gene Expression Regulation
  • Humans
  • Nuclear Receptor Subfamily 1, Group F, Member 1 / chemistry
  • Nuclear Receptor Subfamily 1, Group F, Member 1 / metabolism
  • Nuclear Receptor Subfamily 1, Group F, Member 1 / physiology*
  • Phosphorylation
  • Protein Kinase C-alpha / metabolism*
  • Wnt Proteins / metabolism*
  • beta Catenin / metabolism*


  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • RORA protein, human
  • Wnt Proteins
  • beta Catenin
  • Protein Kinase C-alpha