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| Figure 2: Schematic illustration of TNIK protein domains. |
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Description | The serine/threonine kinase Traf2- and Nck interacting kinase (TNIK), is a member of the germinal center kinase (GCK) family, that it was isolated by yeast two-hybrid screening for proteins that interact with TRAF2 and NCK (Fu CA et al.,1999). It was demonstrated that TNIK regulates Jun N-terminal kinase pathway (JNK), the actin cytoskeleton, it is an important activator of Wnt signaling and it is involved in in the survival of many human cancer cells (Lee Y. et al., 2017). The gene TNIK encodes a 1360 aa protein with several spliced isoforms. This protein has an N-terminal kinase domain, an intermediate domain and an C-terminal germinal center kinase homology (GCKH) region, later called Citron homology (CNH) domain (Fu CA et al.,1999; Taira K. et al., 2004) It was observed that it shared about 90% amino acid identity with other two previously cloned GCK family member, NIK and MAPK4, in both its kinase and CNH domains. However, this homology goes down to about 50% in the intermediate region suggesting potentially different signaling role for these GCK proteins (Su YC. et al.,1997; Taira K. et al., 2004). |
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| Figure 3: Representative images of: A) TNIK FISH on gastric cancer cells sample; B) TNIK immunostaining on CRC epithelium sample; C) TNIK Immunofluorescent staining of human cell line U-2 OS (Yu DH et al., 2014; Takahashi H et al.,2015; https://www.proteinatlas.org/) |
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Expression | TNIK is ubiquitously expressed in human. It is expressed with high level in brain, small intestine, duodenum, testis, heart, normal and cancer epithelia colon tissues. Its expression it also observed in endometrium, lung, lymph node, kidney, spleen, thyroid, urinary bladder, gall bladder, prostate, endometrium, adrenal, bone marrow (https://www.ncbi.nlm.nih.gov/) |
Localisation | TNIK is mainly localized in the nucleoplasm and cytosol (https://www.uniprot.org/) |
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| Figure 4: Schematic illustration of Wnt signaling activation. Binding of Wnt proteins to FZD leads to activation of CTNNB1 (β-catenin) in the cytoplasm. Subsequently, TNIK binds to active β-catenin and this complex is recruited to the nucleus, where TNIK directly phosphorylates TCF4 inducing the transcription of Wnt target genes. |
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Function | TNIK was discovered by Fu CA et al. in 1999, with a yeast-two-hybrid screen for interaction partners of the adapter proteins TRAF2 and NCK. Like several other GCK family members, TNIK regulates activation of JNK pathway which is induced through the CNH domain by a yet undefined mechanism (Fu CA et al., 1999). TNIK overexpression also modulates the actin cytoskeleton; through its kinase domain, inducing disruption of F-actin structure and inhibiting cell spreading (Taira K et al., 2004). TNIK protein is known to be implicated in Wnt pathway activation. Mahmoudi T. et al. in 2009, have identified TNIK as a co-activator protein that interact both TCF4/β-catenin complex in the proliferative cripts of mouse small intestine. Through in vitro assays they showed that TNIK directly bind both TCF4 and β-catenin and phosphorylates TCF4 leading to transcriptional activation of Wnt target genes. This protein is also involved in the dendrite development. NEDD4, the TNIK, and RAP2A form a complex that controls NEDD4-mediated ubiquitination of RAP2A. Ubiquitination by NEDD4 inhibits RAP2A function, which reduces the activity of Rap2 effector kinases of the TNIK family and promotes dendrite growth (Kawabe H. et al., 2010). |
Homology | TNIK is conserved in human, mouse, chicken, C. Elegans |
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Entity | Mental retardation, autosomal recessive 54; MRT54 |
Note | Mental retardation autosomal recessive 54 (MRT54) is a disorder characterized by significantly below average general intellectual functioning. MRT54 is caused by homozygous mutation in the TNIK gene. Anazi S. et al. in 2016 identified a homozygous c.538C-T transition (c.538C-T, NM_001161563) in the TNIK gene, resulting in an arg180-to-ter (R180X) substitution. This mutation causes the formation of a truncated protein resulting in a null allele. |
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Entity | Glioma |
Note | Glioma is the most common primary cancers of the central nervous system. NEDD4 is reported to bind rather than ubiquitinate TNIK in regulating the ubiquitination of GTP-RAP2A in neuron development. Wang L.et al in 2017, showed that NEDD4 plays a pivotal role in promoting the migration and invasion of glioma cell lines U251 and U87 by the inhibition of the RAP2A/TNIK complex activity. |
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Entity | Colorectal cancer |
Note | TNIK protein is essential for the Wnt signaling activation and it was demonstrated that colorectal cancer cells were highly dependent on TNIK for their growth (Shitashige M. et al., 2010). Masuda M et al. in 2016, showed that NCB-0846 small molecule, with high inhibitory activity against TNIK, blocked Wnt signaling and presented anti tumor and anti-CSC effect on CRC cells. |
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Entity | Gastric cancer |
Note | Microarray analysis in Chinese gastric cancer patients reported that TNIK gene is amplified in 7% of samples analyzed. Moreover, it was showed that both silencing and TNIK inhibitor increased cell death and reduced cell growth in TNIK amplified gastric cancer cell line, but not in TNIK not amplified cell line. Difference of CRC, in gastric cancer the role of TNIK protein is independent of Wnt pathway. (Yu DH et. al., 2014) |
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Entity | Pancreatic cancer |
Note | In pancreatic cancer patients has been shown the clinical and prognostic value of TNIK. It was observed that mRNA and protein levels of TNIK in pancreatic cancer were both significantly higher than those in corresponding paratumor tissues. In addition, they revealed that patients with high expression of TNIK had a shorter overall survival (OS) and disease-free survival (DFS) than those with low expression (Zhang Y. et al., 2016). |
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Entity | Prostate cancer |
Note | Prostate cancer is the fifth leading cause of cancer-related deaths in men worldwide. It was demonstrated a nuclear expression of TNIK in prostate cancer primary cells and its correlation with ERG expression. Interestingly, inhibition of expression and activity of TNIK in ERG positive prostate cancer cells reduced colony formation and cell viability suggesting TNIK as a novel therapeutic target to the treatment of ERG positive prostate cancer. (Lee RS et al., 2019) |
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Entity | Lung adenocarcinoma |
Note | It is known that TINK regulates both the Wnt and Smad pathways, which are both important for epithelial-to-mesenchymal transition (EMT) on cancer cells (Mahmoudi T. et al., 2009; Kaneko S. et al., 2011). Jiyeon Kim J. et al. in 2014, showed that KY-05009 molecule, a potent inhibitor of TNIK activity reduces TGFB1 (TGF-β1=-Mediated Epithelial-to-Mesenchymal Transition in Human Lung Adenocarcinoma A549 cell line. They observed that KY-05009 inhibitor had a double effects on A549 cells: it is able to inhibits TGF-β1- mediated Wnt signaling through inhibition of the kinase activity of TNIK, which phosphorylates TCF4 and it inhibits TGF-β1-induced phosphorylation and nuclear translocation of SMAD2 and the expression of SNAI2 (Snail) and TWIST1 cofactors involved in the TGF-β1-induced EMT. |
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Entity | Breast cancer |
Note | Breast cancer is the most common cancer in the woman malignant with a high percentage of chemoresistance. It was observed that RNA interference assays on breast cancer cell lines led to inhibition of cell growth (Jiao X et al., 2013). Li Z. et al. in 2018 through RNA-seq data showed that TNIK is positive regulated by transcriptional coactivator WBP2 in triple negative breast cancer cells (TNBC). They demonstrated that WBP2 primes cells to response to Wnt ligands by up-regulation of TNIK and GPS1 in triple negative TNBC cells. WBP2 integrates JNK with Wnt signaling improving the growth of TNBC cells. |
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Entity | Multiple Myeloma |
Note | Multiple myeloma (MM) is a plasma cell malignancy characterized by an accumulation of monoclonal plasma cells in the bone marrow. It was demonstrated that silencing and pharmacological inhibition of endogenous TNIK protein suppressed the proliferation of MM cells and induced caspase-dependent apoptosis (Chon HJ. Et al., 2016). Moreover, inhibition of Wnt signaling by TNIK inhibitors can suppress the IL6 -induced proliferation of MM cells suggesting TNIK protein as a target to develop new therapeutic strategies against MM (Lee Y. et al., 2017). |
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Entity | Chronic myelogenous leukemia |
Note | Schürch C. et al. in 2012, identified CD27 signal transduction as a new link between the immune system and Wnt signaling/leukemia development in CML. It was demonstrated that the TNF receptor family member CD27 is present on leukemia stem cells and its bond with CD70 ligand increased expression of Wnt target genes in LSCs by enhancing nuclear localization of active β-catenin and TRAF2-and NCK-interacting kinase (TNIK). As a consequence of this, they revealed an increased proliferation and differentiation of LCS. Moreover, blocking CD70 by monoclonal antibody (mAb) treatment reduced disease progression and prolonged survival of CML mice. |
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Entity | Polycystic ovarian syndrome (PCOS) |
Note | Polycystic ovary syndrome (PCOS) is the most common endocrinopathy, affecting about 10% of the reproductive-age female population. Wang XX et al. in 2014, saw that PCOS ovarian tissues showed a specific methylation and expression pattern of the TNIK gene. They also reported that the TNIK transcript was up-regulated in PCOS ovarian tissues, compared with normal ovarian tissues, and that methylation of cg10180092 site play a key role in the regulation of TNIK transcription (Li D. et al., 2015). It is necessary other studies to better understood the epigenetic mechanism involved in the initiation and progression of TNIK-related PCOS. |
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A null mutation in TNIK defines a novel locus for intellectual disability |
Anazi S, Shamseldin HE, AlNaqeb D, Abouelhoda M, Monies D, Salih MA, Al-Rubeaan K, Alkuraya FS |
Hum Genet 2016 Jul;135(7):773-8 |
PMID 27106596 |
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Traf2- and Nck-interacting kinase (TNIK) is involved in the anti-cancer mechanism of dovitinib in human multiple myeloma IM-9 cells |
Chon HJ, Lee Y, Bae KJ, Byun BJ, Kim SA, Kim J |
Amino Acids 2016 Jul;48(7):1591-9 |
PMID 26995282 |
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TNIK, a novel member of the germinal center kinase family that activates the c-Jun N-terminal kinase pathway and regulates the cytoskeleton |
Fu CA, Shen M, Huang BC, Lasaga J, Payan DG, Luo Y |
J Biol Chem 1999 Oct 22;274(43):30729-37 |
PMID 10521462 |
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Gene rearrangements in hormone receptor negative breast cancers revealed by mate pair sequencing |
Jiao X, Hooper SD, Djureinovic T, Larsson C, Wärnberg F, Tellgren-Roth C, Botling J, Sjöblom T |
BMC Genomics 2013 Mar 12;14:165 |
PMID 23496902 |
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Smad inhibition by the Ste20 kinase Misshapen |
Kaneko S, Chen X, Lu P, Yao X, Wright TG, Rajurkar M, Kariya K, Mao J, Ip YT, Xu L |
Proc Natl Acad Sci U S A 2011 Jul 5;108(27):11127-32 |
PMID 21690388 |
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Regulation of Rap2A by the ubiquitin ligase Nedd4-1 controls neurite development |
Kawabe H, Neeb A, Dimova K, Young SM Jr, Takeda M, Katsurabayashi S, Mitkovski M, Malakhova OA, Zhang DE, Umikawa M, Kariya K, Goebbels S, Nave KA, Rosenmund C, Jahn O, Rhee J, Brose N |
Neuron 2010 Feb 11;65(3):358-72 |
PMID 20159449 |
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A novel aminothiazole KY-05009 with potential to inhibit Traf2- and Nck-interacting kinase (TNIK) attenuates TGF-β1-mediated epithelial-to-mesenchymal transition in human lung adenocarcinoma A549 cells |
Kim J, Moon SH, Kim BT, Chae CH, Lee JY, Kim SH |
PLoS One 2014 Oct 22;9(10):e110180 |
PMID 25337707 |
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Characterization of the ERG-regulated Kinome in Prostate Cancer Identifies TNIK as a Potential Therapeutic Target |
Lee RS, Zhang L, Berger A, Lawrence MG, Song J, Niranjan B, Davies RG, Lister NL, Sandhu SK, Rubin MA, Risbridger GP, Taylor RA, Rickman DS, Horvath LG, Daly RJ |
Neoplasia 2019 Apr;21(4):389-400 |
PMID 30901730 |
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Synergistic inhibition effect of TNIK inhibitor KY-05009 and receptor tyrosine kinase inhibitor dovitinib on IL-6-induced proliferation and Wnt signaling pathway in human multiple myeloma cells |
Lee Y, Jung JI, Park KY, Kim SA, Kim J |
Oncotarget 2017 Jun 20;8(25):41091-41101 |
PMID 28467797 |
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Epigenetic regulation of traf2- and Nck-interacting kinase (TNIK) in polycystic ovary syndrome |
Li D, Jiao J, Zhou YM, Wang XX |
Am J Transl Res 2015 Jun 15;7(6):1152-60 |
PMID 26279758 |
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The transcriptional coactivator WBP2 primes triple-negative breast cancer cells for responses to Wnt signaling via the JNK/Jun kinase pathway |
Li Z, Lim SK, Liang X, Lim YP |
J Biol Chem 2018 Dec 28;293(52):20014-20028 |
PMID 30442712 |
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The kinase TNIK is an essential activator of Wnt target genes |
Mahmoudi T, Li VS, Ng SS, Taouatas N, Vries RG, Mohammed S, Heck AJ, Clevers H |
EMBO J 2009 Nov 4;28(21):3329-40 |
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TNIK inhibition abrogates colorectal cancer stemness |
Masuda M, Uno Y, Ohbayashi N, Ohata H, Mimata A, Kukimoto-Niino M, Moriyama H, Kashimoto S, Inoue T, Goto N, Okamoto K, Shirouzu M, Sawa M, Yamada T |
Nat Commun 2016 Aug 26;7:12586 |
PMID 27562646 |
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CD27 signaling on chronic myelogenous leukemia stem cells activates Wnt target genes and promotes disease progression |
Schürch C, Riether C, Matter MS, Tzankov A, Ochsenbein AF |
J Clin Invest 2012 Feb;122(2):624-38 |
PMID 22232214 |
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Traf2- and Nck-interacting kinase is essential for Wnt signaling and colorectal cancer growth |
Shitashige M, Satow R, Jigami T, Aoki K, Honda K, Shibata T, Ono M, Hirohashi S, Yamada T |
Cancer Res 2010 Jun 15;70(12):5024-33 |
PMID 20530691 |
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NIK is a new Ste20-related kinase that binds NCK and MEKK1 and activates the SAPK/JNK cascade via a conserved regulatory domain |
Su YC, Han J, Xu S, Cobb M, Skolnik EY |
EMBO J 1997 Mar 17;16(6):1279-90 |
PMID 9135144 |
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The Traf2- and Nck-interacting kinase as a putative effector of Rap2 to regulate actin cytoskeleton |
Taira K, Umikawa M, Takei K, Myagmar BE, Shinzato M, Machida N, Uezato H, Nonaka S, Kariya K |
J Biol Chem 2004 Nov 19;279(47):49488-96 |
PMID 15342639 |
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Prognostic significance of Traf2- and Nck- interacting kinase (TNIK) in colorectal cancer |
Takahashi H, Ishikawa T, Ishiguro M, Okazaki S, Mogushi K, Kobayashi H, Iida S, Mizushima H, Tanaka H, Uetake H, Sugihara K |
BMC Cancer 2015 Oct 24;15:794 |
PMID 26499327 |
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Regulation of glioma migration and invasion via modification of Rap2a activity by the ubiquitin ligase Nedd4-1 |
Wang L, Zhu B, Wang S, Wu Y, Zhan W, Xie S, Shi H, Yu R |
Oncol Rep 2017 May;37(5):2565-2574 |
PMID 28405688 |
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Genome-wide DNA methylation and gene expression patterns provide insight into polycystic ovary syndrome development |
Wang XX, Wei JZ, Jiao J, Jiang SY, Yu DH, Li D |
Oncotarget 2014 Aug 30;5(16):6603-10 |
PMID 25051372 |
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The essential role of TNIK gene amplification in gastric cancer growth |
Yu DH, Zhang X, Wang H, Zhang L, Chen H, Hu M, Dong Z, Zhu G, Qian Z, Fan J, Su X, Xu Y, Zheng L, Dong H, Yin X, Ji Q, Ji J |
Oncogenesis 2014 Mar 17;3:e93 |
PMID 24637493 |
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TNIK serves as a novel biomarker associated with poor prognosis in patients with pancreatic cancer |
Zhang Y, Jiang H, Qin M, Su X, Cao Z, Wang J |
Tumour Biol 2016 Jan;37(1):1035-40 |
PMID 26269113 |
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