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

Ji Min Lee1, Ik Soo Kim, Hyunkyung Kim

  • 1Department of Biological Sciences, Creative Research Initiative Center for Chromatin Dynamics, Seoul National University, Seoul 151-742, South Korea.

Molecular Cell
|February 4, 2010
PubMed

Insights

RORalpha phosphorylation by Wnt5a/PKCalpha inhibits canonical Wnt/beta-catenin signaling in colon cancer. Reduced RORalpha phosphorylation in tumors suggests therapeutic potential for colorectal cancer.

Area of Science:

  • Molecular biology
  • Oncology
  • Cell signaling

Background:

  • Wnt signaling pathways are crucial in development and disease.
  • Noncanonical Wnt ligands can inhibit canonical Wnt signaling via unknown mechanisms.
  • Understanding Wnt antagonism is vital for cancer therapy.

Purpose of the Study:

  • To elucidate the mechanism of orphan nuclear receptor RORalpha-mediated inhibition of canonical Wnt signaling in colon cancer.
  • To investigate the role of Wnt5a/PKCalpha-dependent RORalpha phosphorylation in Wnt pathway regulation.
  • To assess the clinical relevance of RORalpha phosphorylation in colorectal tumors.

Main Methods:

  • Investigated Wnt5a/PKCalpha-dependent phosphorylation of RORalpha at serine 35.
  • Analyzed the link between RORalpha phosphorylation and Wnt/beta-catenin signaling.
  • Examined the expression of Wnt/beta-catenin target genes.
  • Compared RORalpha phosphorylation levels in colorectal tumor tissues and normal counterparts.

Main Results:

  • Wnt5a/PKCalpha-dependent phosphorylation of RORalpha at serine 35 links it to Wnt/beta-catenin signaling.
  • Phosphorylated RORalpha inhibits the expression of Wnt/beta-catenin target genes.
  • RORalpha phosphorylation is significantly reduced in colorectal tumors compared to normal tissues.

Conclusions:

  • RORalpha acts as a crucial mediator at the intersection of canonical and noncanonical Wnt signaling.
  • RORalpha's transrepression of Wnt/beta-catenin target genes offers new therapeutic strategies for cancer.
  • Targeting RORalpha phosphorylation may provide novel approaches for human cancer treatment.

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