Loss of the tumor suppressor CYLD enhances Wnt/beta-catenin signaling through K63-linked ubiquitination of Dvl

Mol Cell. 2010 Mar 12;37(5):607-19. doi: 10.1016/j.molcel.2010.01.035.

Abstract

The mechanism by which Wnt receptors transduce signals to activate downstream beta-catenin-mediated target gene transcription remains incompletely understood but involves Frizzled (Fz) receptor-mediated plasma membrane recruitment and activation of the cytoplasmic effector Dishevelled (Dvl). Here, we identify the deubiquitinating enzyme CYLD, the familial cylindromatosis tumor suppressor gene, as a negative regulator of proximal events in Wnt/beta-catenin signaling. Depletion of CYLD from cultured cells markedly enhances Wnt-induced accumulation of beta-catenin and target gene activation. Moreover, we demonstrate hyperactive Wnt signaling in human cylindroma skin tumors that arise from mutations in CYLD. At the molecular level, CYLD interacts with and regulates K63-linked ubiquitination of Dvl. Enhanced ubiquitination of the polymerization-prone DIX domain in CYLD-deficient cells positively links to the signaling activity of Dvl. Together, our results argue that loss of CYLD instigates tumor growth in human cylindromatosis through a mechanism in which hyperubiquitination of polymerized Dvl drives enhancement of Wnt responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Carcinoma, Adenoid Cystic / genetics
  • Carcinoma, Adenoid Cystic / metabolism*
  • Carcinoma, Adenoid Cystic / pathology
  • Carcinoma, Skin Appendage / genetics
  • Carcinoma, Skin Appendage / metabolism*
  • Carcinoma, Skin Appendage / pathology
  • Cell Proliferation
  • Deubiquitinating Enzyme CYLD
  • Dishevelled Proteins
  • HeLa Cells
  • Humans
  • Lysine
  • Mice
  • Mutation
  • NF-kappa B / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Protein Multimerization
  • Protein Processing, Post-Translational*
  • Protein Structure, Tertiary
  • RNA Interference
  • Signal Transduction*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism*
  • Skin Neoplasms / pathology
  • Time Factors
  • Transcriptional Activation
  • Transfection
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitination
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*
  • Wnt3 Protein
  • beta Catenin / genetics
  • beta Catenin / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • CTNNB1 protein, human
  • Dishevelled Proteins
  • NF-kappa B
  • Phosphoproteins
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Proteins
  • Wnt Proteins
  • Wnt3 Protein
  • beta Catenin
  • CYLD protein, human
  • Deubiquitinating Enzyme CYLD
  • Lysine