Prickle-1 negatively regulates Wnt/beta-catenin pathway by promoting Dishevelled ubiquitination/degradation in liver cancer

Gastroenterology. 2006 Oct;131(4):1218-27. doi: 10.1053/j.gastro.2006.07.020. Epub 2006 Jul 24.


Background & aims: Aberrant activation of Wnt signaling due to accumulation of beta-catenin has been linked to tumorigenesis. Mutations of beta-catenin, APC, and axins are important but not frequent enough to be accountable for the accumulation of beta-catenin in human hepatocellular carcinoma (HCC). In this study, we characterized the roles of Prickle-1, a Dishevelled (Dvl)-associated protein, in regulation of Wnt/beta-catenin activity in HCC.

Methods: The expression levels of human Prickle-1 and Dvl3 were examined in HCC cell lines and human HCC samples. The interaction and effects of Prickle-1 on Dvl3, the Wnt/beta-catenin pathway, and cell growth were assessed in HCC cell lines.

Results: We showed that Prickle-1 bound with Dvl3 and facilitated Dvl3 ubiquitination/degradation, and this was through its destruction box (D-box) motifs. Enforced expression of Prickle-1 significantly reduced the Wnt/beta-catenin activity and tumorigenic properties of HCC cells. Clinicopathologic analysis showed that underexpression of Prickle-1 was significantly associated with overexpression of Dvl3, beta-catenin accumulation (P = .023), and larger tumor size (P = .030).

Conclusions: Our results have elucidated a novel mechanistic relationship between Prickle-1 and Dvl3 in the Wnt/beta-catenin pathway. The facilitation of Prickle-1 on Dvl3 degradation and the suppression of beta-catenin activity and cell growth suggest that Prickle-1 is a negative regulator of the Wnt/beta-catenin signaling pathway and is a putative tumor suppressor in human HCCs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Sequence
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / physiopathology
  • Cell Division / physiology
  • Cell Line
  • Consensus Sequence
  • Dishevelled Proteins
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kidney / cytology
  • LIM Domain Proteins
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Liver Neoplasms / physiopathology
  • Molecular Sequence Data
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Signal Transduction / physiology*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitin / metabolism
  • Wnt Proteins / metabolism*
  • beta Catenin / metabolism*


  • Adaptor Proteins, Signal Transducing
  • DVL3 protein, human
  • Dishevelled Proteins
  • LIM Domain Proteins
  • PRICKLE1 protein, human
  • Phosphoproteins
  • Tumor Suppressor Proteins
  • Ubiquitin
  • Wnt Proteins
  • beta Catenin