RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer

EMBO J. 2020 Sep 15;39(18):e103932. doi: 10.15252/embj.2019103932. Epub 2020 Aug 10.


Wnt/β-catenin signaling is a primary pathway for stem cell maintenance during tissue renewal and a frequent target for mutations in cancer. Impaired Wnt receptor endocytosis due to loss of the ubiquitin ligase RNF43 gives rise to Wnt-hypersensitive tumors that are susceptible to anti-Wnt-based therapy. Contrary to this paradigm, we identify a class of RNF43 truncating cancer mutations that induce β-catenin-mediated transcription, despite exhibiting retained Wnt receptor downregulation. These mutations interfere with a ubiquitin-independent suppressor role of the RNF43 cytosolic tail that involves Casein kinase 1 (CK1) binding and phosphorylation. Mechanistically, truncated RNF43 variants trap CK1 at the plasma membrane, thereby preventing β-catenin turnover and propelling ligand-independent target gene transcription. Gene editing of human colon stem cells shows that RNF43 truncations cooperate with p53 loss to drive a niche-independent program for self-renewal and proliferation. Moreover, these RNF43 variants confer decreased sensitivity to anti-Wnt-based therapy. Our data demonstrate the relevance of studying patient-derived mutations for understanding disease mechanisms and improved applications of precision medicine.

Keywords: PORCN inhibitors; RNF43; Wnt signaling; cancer mutations; human colon organoids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Casein Kinase I / genetics
  • Casein Kinase I / metabolism*
  • HEK293 Cells
  • Humans
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Wnt Signaling Pathway*
  • beta Catenin / genetics
  • beta Catenin / metabolism


  • CTNNB1 protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • beta Catenin
  • RNF43 protein, human
  • Ubiquitin-Protein Ligases
  • Casein Kinase I

Associated data

  • GEO/GSE129288