Proteomics

Dataset Information

0

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


ABSTRACT: Wnt/b-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 b-catenin-mediated transcription, despite exhibiting retained Wnt receptor downregulation. These mutations interfere with an 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 b-catenin turnover and propelling ligandindependent 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.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Katerina Hanakova  

LAB HEAD: Zbynek Zdrahal

PROVIDER: PXD020478 | Pride | 2020-08-14

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
RNF-43_BioID_replicate1.mgf Mgf
RNF-43_BioID_replicate1.msf Msf
RNF-43_BioID_replicate1.pep.xml Pepxml
RNF-43_BioID_replicate1.prot.xml Xml
RNF-43_BioID_replicate1.raw Raw
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Publications


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 mut  ...[more]

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