Journal
EMBO JOURNAL
Volume 28, Issue 21, Pages 3329-3340Publisher
WILEY
DOI: 10.1038/emboj.2009.285
Keywords
beta-catenin; TCF4; TNIK; Wnt
Categories
Funding
- Marie Curie Incoming International Fellowship (MC IIF) [221108]
- Croucher Foundation
- Marie Curie Outgoing International Fellowship [2004 002682]
- Centre for Biomedical Genetics
- Cancer Consortium
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Wnt signalling maintains the undifferentiated state of intestinal crypt/progenitor cells through the TCF4/beta-catenin-activating transcriptional complex. In colorectal cancer, activating mutations in Wnt pathway components lead to inappropriate activation of the TCF4/beta-catenin transcriptional programme and tumourigenesis. The mechanisms by which TCF4/beta-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 beta-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 beta-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. The EMBO Journal (2009) 28, 3329-3340. doi: 10.1038/emboj.2009.285; Published online 8 October 2009
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