The kinase TNIK is an essential activator of Wnt target genes

Mahmoudi, Tokameh; Li, Vivian; Ng, Soon Seng; Taouatas, Nadia; Vries, Robert G.J.; Mohammed, Shabaz; Heck, Albert J. R.; Clevers, Hans

doi:10.1038/emboj.2009.285

Cited by 183 publications

(221 citation statements)

References 30 publications

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“…In fact, undifferentiated cells at the bottom of the intestinal crypts accumulate nuclear β-catenin (41). Mahmoudi and colleagues showed that TNIK interacted with and phosphorylated β-catenin as well as TCF4 (21). We further showed that TNIK phosphorylated the S154 residue of TCF4 ( Fig.…”

Section: Discussionsupporting

confidence: 63%

“…Here, we report that colorectal cancer cells are highly dependent on the expression and kinase activity of TNIK for proliferation in vitro and in vivo. During the preparation of this article, Mahmoudi and colleagues also identified Tnik as a protein interacting with Tcf4 in the mouse intestinal crypt (21). Their data overlapped partly with ours: TNIK is an activating kinase for the TCF4 and β-catenin transcriptional complex.…”

Section: Introductionsupporting

confidence: 57%

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Traf2- and Nck-Interacting Kinase Is Essential for Wnt Signaling and Colorectal Cancer Growth

Shitashige¹,

Satow²,

Jigami³

et al. 2010

Cancer Research

111

131

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T-cell factor-4 (TCF4) is a transcription factor essential for maintaining the undifferentiated status and selfrenewal of intestinal epithelial cells. It has therefore been considered that constitutive activation of TCF4 by aberrant Wnt signaling is a major force driving colorectal carcinogenesis. We previously identified Traf2-and Nck-interacting kinase (TNIK) as one of the proteins that interact with TCF4 in colorectal cancer cells, but its functional significance has not been elucidated. Here, we report that TNIK is an activating kinase for TCF4 and essential for colorectal cancer growth. TNIK, but not its catalytically inactive mutant, phosphorylated the conserved serine 154 residue of TCF4. Small interfering RNA targeting TNIK inhibited the proliferation of colorectal cancer cells and the growth of tumors produced by injecting colorectal cancer cells s.c. into immunodeficient mice. The growth inhibition was abolished by restoring the catalytic domain of TNIK, thus confirming that its enzyme activity is essential for the maintenance of colorectal cancer growth. Several ATP-competing kinase inhibitors have been applied to cancer treatment and have shown significant activity. Our findings suggest TNIK as a feasible target for pharmacologic intervention to ablate aberrant Wnt signaling in colorectal cancer. Cancer Res; 70(12); 5024-33. ©2010 AACR.

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Section: Discussionsupporting

confidence: 63%

Section: Introductionsupporting

confidence: 57%

Traf2- and Nck-Interacting Kinase Is Essential for Wnt Signaling and Colorectal Cancer Growth

Shitashige¹,

Satow²,

Jigami³

et al. 2010

Cancer Research

111

131

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“…This hypothesis is consistent with the aforementioned finding that the interaction of NFAT with Dvl is induced by Ca 2ϩ signals in the nucleus. To test this hypothesis, LS174T cells that contain oncogenic mutation of ␤-catenin gene (37,38) and Caco-2 or SW480 cells which contain mutated adenomatous polyposis coli (APC) (39) were used to examine the effect of Ca 2ϩ signaling/NFAT on Wnt reporter activity. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Nuclear Factor of Activated T Cells (NFAT) Proteins Repress Canonical Wnt Signaling via Its Interaction with Dishevelled (Dvl) Protein and Participate in Regulating Neural Progenitor Cell Proliferation and Differentiation

Huang

Xie

Wang

et al. 2011

Journal of Biological Chemistry

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“…Coimmunoprecipitation was carried out as previously described (53). In short, mouse primary crypt material was prepared as described above for Western blot and qRT-PCR of intestine, and then prepared in PLB buffer (1% Triton X-100, 2 mM EDTA, 1 mM DTT, 5% glycerol in PBS) supplemented with complete protease inhibitor cocktail (Sigma-Aldrich).…”

Section: Discussionmentioning

confidence: 99%

The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer

Diefenbacher¹,

Popov

Blake³

et al. 2014

J. Clin. Invest.

128

141

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R e s e a R c h a R t i c l e3 4 0 7 jci.org Volume 124 Number 8 August 2014 IntroductionThe intestine is made up of repetitive units that consist of a differentiated compartment (the villus) and a proliferative compartment (the crypt). Intestinal stem cells are located in the crypt (1, 2) and produce rapidly proliferating daughter cells, the transit amplifying cells, which subsequently differentiate into 2 main epithelial lineages. The absorptive lineage is composed of all enterocytes, while the secretory lineage is composed of goblet cells (secreting protective mucins), enteroendocrine cells (secreting hormones like serotonin or secretin), and Paneth cells (3, 4). Whether transit amplifying cells differentiate along an absorptive or a secretory lineage is regulated by the Notch pathway (5). Engagement of Notch receptors by Notch ligands, such as Delta or Jagged, induces proteolytic cleavage of the receptor by γ-secretase. The cleaved NOTCH1 receptor (NICD1) translocates into the nucleus, resulting in the formation of an active transcriptional complex composed of RBPJκ (also known as CSL or CBF1) and NICD1. Notch signal activation induces hairy/enhancer of split (Hes) gene expression. Ablation of Notch signaling via genetic deletion of Rbpj results in secretory cell expansion (6). Conversely, in transgenic mice overexpressing NICD1, goblet cells are absent, and the proliferative compartment is expanded (7).The Wnt signaling pathway is a key regulator of intestinal stem cell homeostasis (8), and 2 of the target genes induced by Wnt signaling, c-MYC and c-JUN, encode transcription factors that have oncogenic potential (9, 10). Consequently, aberrant activation of the adenomatous polyposis coli/β-catenin/T cell factor (APC/ β-catenin/TCF) pathway is an initiating event in the majority of human colorectal cancers (11).c-MYC is a transcription factor with key functions in cell differentiation and cancer development (12)(13)(14). In the intestine, c-MYC is required for the altered proliferation and differentiation induced by APC inactivation (15-18). c-MYC is a highly labile protein, and at least 2 ubiquitin ligases, SKP2 and FBW7, can target it for proteasomal degradation (19-21). c-MYC ubiquitination is antagonized by the deubiquitinase USP28, which "piggybacks" on FBW7 and stabilizes c-MYC protein (22). Thus, an E3 ubiquitin ligase and a deubiquitinase, FBW7 and USP28, are together recruited to substrates (22), and a cycle of deubiquitination and ubiquitination controls c-MYC stability.Genomic data from human cancers suggest that most colorectal cancer mutations converge on c-MYC misregulation (23). Due to its key role in tumorigenesis, much recent research has been directed to finding ways to target c-MYC function (24-29). Dominant-negative approaches targeting c-MYC function impair intestinal tumor formation, and c-Myc heterozygous mice show reduced tumor development in the Apc min/+ model (16,17). Transgenic expression of a dominant-negative allele of Myc, OmoMyc, has provided proof of principle that targeting ...

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The kinase TNIK is an essential activator of Wnt target genes

Cited by 183 publications

References 30 publications

Traf2- and Nck-Interacting Kinase Is Essential for Wnt Signaling and Colorectal Cancer Growth

Traf2- and Nck-Interacting Kinase Is Essential for Wnt Signaling and Colorectal Cancer Growth

Nuclear Factor of Activated T Cells (NFAT) Proteins Repress Canonical Wnt Signaling via Its Interaction with Dishevelled (Dvl) Protein and Participate in Regulating Neural Progenitor Cell Proliferation and Differentiation

The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer

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