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PXD020478

PXD020478 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleRNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer
DescriptionWnt/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.
HostingRepositoryPRIDE
AnnounceDate2020-08-14
AnnouncementXMLSubmission_2020-09-25_03:01:08.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterKaterina Hanakova
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListbiotinylated residue; phosphorylated residue
InstrumentLTQ Orbitrap Elite
Dataset History
RevisionDatetimeStatusChangeLog Entry
02020-07-21 17:49:45ID requested
12020-08-13 22:15:45announced
22020-09-25 03:01:09announced2020-09-25: Updated publication reference for PubMed record(s): 32965059.
Publication List
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]
Keyword List
submitter keyword: cancer mutations, human colon organoids, PORCN inhibitors, RNF 43, Wnt signaling, LC-MS/MS
Contact List
Zbynek Zdrahal
contact affiliationCEITEC—Central European Institute of Technology, Masaryk University, Brno, Czech Republic
contact emailzdrahal@sci.muni.cz
lab head
Katerina Hanakova
contact affiliationCEITEC MU
contact emailkaterina.hanak@gmail.com
dataset submitter
Full Dataset Link List
Dataset FTP location
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PRIDE project URI
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