PXD020478-2

PXD020478 is an original dataset announced via ProteomeXchange.

Title	RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer
Description	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.
HostingRepository	PRIDE
AnnounceDate	2020-08-14
AnnouncementXML	Submission_2020-09-25_03:01:08.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Katerina Hanakova
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	biotinylated residue; phosphorylated residue
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2020-07-21 17:49:45	ID requested
1	2020-08-13 22:15:45	announced
⏵ 2	2020-09-25 03:01:09	announced	2020-09-25: Updated publication reference for PubMed record(s): 32965059.
3	2024-10-22 05:10:53	announced	2024-10-22: Updated project metadata.

Spit M, Fenderico N, Jordens I, Radaszkiewicz T, Lindeboom RG, Bugter JM, Cristobal A, Ootes L, van Osch M, Janssen E, Boonekamp KE, Hanakova K, Potesil D, Zdrahal Z, Boj SF, Medema JP, Bryja V, Koo BK, Vermeulen M, Maurice MM, RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer. EMBO J, 39(18):e103932(2020) [pubmed]

submitter keyword: cancer mutations, human colon organoids, PORCN inhibitors, RNF 43, Wnt signaling, LC-MS/MS

Zbynek Zdrahal
contact affiliation	CEITEC—Central European Institute of Technology, Masaryk University, Brno, Czech Republic
contact email	zdrahal@sci.muni.cz
lab head
Katerina Hanakova
contact affiliation	CEITEC MU
contact email	katerina.hanak@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD020478
     1. Label: PRIDE project
     2. Name: RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer