The kinase TNIK is an essential activator of Wnt target genes

Tokameh Mahmoudi, Vivian S.W. Li, Ser Sue Ng, Nadia Taouatas, Robert G.J. Vries, Shabaz Mohammed, Albert J. Heck, Hans Clevers

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

156 Citaten (Scopus)


Wnt signalling maintains the undifferentiated state of intestinal crypt/progenitor cells through the TCF4/Β-catenin-activating transcriptional complex. In colorectal cancer, activating mutations in Wnt pathway components lead to inappropriate activation of the TCF4/Β-catenin transcriptional programme and tumourigenesis. The mechanisms by which TCF4/Β-catenin activate key target genes are not well understood. Using a proteomics approach, we identified Tnik, a member of the germinal centre kinase family as a Tcf4 interactor in the proliferative crypts of mouse small intestine. Tnik is recruited to promoters of Wnt target genes in mouse crypts and in Ls174T colorectal cancer cells in a Β-catenin-dependent manner. Depletion of TNIK and expression of TNIK kinase mutants abrogated TCF-LEF transcription, highlighting the essential function of the kinase activity in Wnt target gene activation. In vitro binding and kinase assays show that TNIK directly binds both TCF4 and Β-catenin and phosphorylates TCF4. siRNA depletion of TNIK followed by expression array analysis showed that TNIK is an essential, specific activator of Wnt transcriptional programme. This kinase may present an attractive candidate for drug targeting in colorectal cancer.

Originele taal-2Engels
Pagina's (van-tot)3329-3340
Aantal pagina's12
TijdschriftEMBO Journal
Nummer van het tijdschrift21
StatusGepubliceerd - nov. 2009
Extern gepubliceerdJa


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