The enormous influence of TNIK knockdown on intracellular signals and cell survival

Gui, Jianian; Yang, Baotian; Wu, Jinyun; Zhou, Xiumei

doi:10.1007/s13577-011-0023-2

Cited by 20 publications

(15 citation statements)

References 22 publications

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“…However, TNIK is a multifunctional protein1920, and its function is not limited to regulation of Wnt signalling or colorectal carcinogenesis. Recently, amplification of TNIK has been reported in 7% (8/106) of gastric cancer patients47.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

TNIK inhibition abrogates colorectal cancer stemness

Masuda¹,

Uno²,

Ohbayashi³

et al. 2016

Nat Commun

132

158

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Canonical Wnt/β-catenin signalling is essential for maintaining intestinal stem cells, and its constitutive activation has been implicated in colorectal carcinogenesis. We and others have previously identified Traf2- and Nck-interacting kinase (TNIK) as an essential regulatory component of the T-cell factor-4 and β-catenin transcriptional complex. Consistent with this, Tnik-deficient mice are resistant to azoxymethane-induced colon tumorigenesis, and Tnik−/−/Apcmin/+ mutant mice develop significantly fewer intestinal tumours. Here we report the first orally available small-molecule TNIK inhibitor, NCB-0846, having anti-Wnt activity. X-ray co-crystal structure analysis reveals that NCB-0846 binds to TNIK in an inactive conformation, and this binding mode seems to be essential for Wnt inhibition. NCB-0846 suppresses Wnt-driven intestinal tumorigenesis in Apcmin/+ mice and the sphere- and tumour-forming activities of colorectal cancer cells. TNIK is required for the tumour-initiating function of colorectal cancer stem cells. Its inhibition is a promising therapeutic approach.

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Section: Discussionmentioning

confidence: 99%

“…Here we report the development of a novel small-molecule TNIK inhibitor having anti-Wnt and anti-cancer stem cell activities. TNIK has various functions other than regulation of Wnt signalling1920. We therefore initiated this study by developing Tnik -deficient mice to confirm the safety and feasibility of TNIK targeting.…”

mentioning

confidence: 99%

TNIK inhibition abrogates colorectal cancer stemness

Masuda¹,

Uno²,

Ohbayashi³

et al. 2016

Nat Commun

132

158

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“…Conversely, several studies have demonstrated the reciprocal regulation between TNIK and the JNK/c-Jun signaling pathway (51)(52)(53), where TNIK is essential for activation of the JNK pathway via JNK1 and JNK2. We therefore hypothesized the existence of a positive feedback loop where the WBP2-induced TNIK expression leads to the reciprocal activation of JNK and c-Jun, which in turn further up-regulate its own expression.…”

Section: Wbp2 Primes Wnt Response In Tnbc Wbp2 May Trigger a Positivementioning

confidence: 99%

The transcriptional coactivator WBP2 primes triple-negative breast cancer cells for responses to Wnt signaling via the JNK/Jun kinase pathway

Lim

et al. 2018

Journal of Biological Chemistry

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The transcriptional coactivator WW domain-binding protein 2 (WBP2) is an emerging oncogene and serves as a node between the signaling protein Wnt and other signaling molecules and pathways, including epidermal growth factor receptor, estrogen receptor/progesterone receptor, and the Hippo pathway. The upstream regulation of WBP2 is well-studied, but its downstream activity remains unclear. Here, we elucidated WBP2's role in triple-negative breast cancer (TNBC), in which Wnt signaling is predominantly activated. Using RNAi coupled with RNA-Seq and MS analyses to identify Wnt/WBP2-and WBP2-dependent targets in MDA-MB-231 TNBC cells, we found that WBP2 is required for the expression of a core set of genes in Wnt signaling. These included AXIN2, which was essential for Wnt/WBP2-mediated breast cancer growth and migration. WBP2 also regulated a much larger set of genes and proteins independently of Wnt, revealing that WBP2 primes cells to Wnt activity by up-regulating G protein pathway suppressor 1 (GPS1) and TRAF2-and NCK-interacting kinase (TNIK). GPS1 activated the c-Jun N-terminal kinase (JNK)/Jun pathway, resulting in a positive feedback loop with TNIK that mediated Wnt-induced AXIN2 expression. WBP2 promoted TNBC growth by integrating JNK with Wnt signaling, and its expression profoundly influenced the sensitivity of TNBC to JNK/TNIK inhibitors. In conclusion, WBP2 links JNK to Wnt signaling in TNBC. GPS1 and TNIK are constituents of a WBP2initiated cascade that primes responses to Wnt ligands and are also important for TNBC biology. We propose that WBP2 is a potential drug target for JNK/TNIK-based precision medicine for managing TNBC.

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“…TNIK is a multifunctional protein with serine-threonine kinase and scaffold domains [55] and is considered to be involved in cellular functions other than Wnt signaling [56]. TNIK was originally identified as a new member of the Germinal Center Kinase (GCK) family by Fu et al [57].…”

Section: Other Functions Of Tnikmentioning

confidence: 99%

“…Aminothiazole-based TNIK inhibitors have been shown to exhibit strong anti-tumor activities. Considering the diverse functions of TNIK [56], the targeted activities may not be limited to Wnt signaling, or indeed to colorectal cancer.…”

Section: Expert Opinionmentioning

confidence: 99%

Targeting the Wnt signaling pathway in colorectal cancer

Sawa¹,

Masuda²,

Yamada³

2015

Expert Opinion on Therapeutic Targets

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APC is a tumor suppressor, and therefore only downstream signal transducers of the APC protein can be considered as targets for pharmaceutical intervention. TRAF2 and NCK-interacting protein kinase (TNIK) was identified as the most downstream regulator of Wnt signaling by two independent research groups, and several classes of small-molecule inhibitors targeting this protein kinase have been developed. TNIK is a multifunctional protein with actions that extend beyond Wnt signaling regulation. Such TNIK inhibitors are expected to have a large variety of clinical applications.

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The enormous influence of TNIK knockdown on intracellular signals and cell survival

Cited by 20 publications

References 22 publications

TNIK inhibition abrogates colorectal cancer stemness

TNIK inhibition abrogates colorectal cancer stemness

The transcriptional coactivator WBP2 primes triple-negative breast cancer cells for responses to Wnt signaling via the JNK/Jun kinase pathway

Targeting the Wnt signaling pathway in colorectal cancer

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