TNIK (TRAF2 and NCK interacting kinase)

Alias (NCBI)	TRAF2 and NCK-Interacting Protein Kinase 3 4
	EC 2.7.11.1 4 52
	EC 2.7.11 52
	KIAA0551 4
	MRT54 3
HGNC (Hugo)	TNIK
HGNC Alias symb	KIAA0551
LocusID (NCBI)	23043
Atlas_Id	43532
Location	3q26.2-q26.31  [Link to chromosome band 3q26]
Location_base_pair	Starts at 171058414 and ends at 171460405 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping TNIK.png]
Local_order	Starts at 171058414 and ends at 171460408 bp from pter
	Figure 1: Location of TNIK gene on chr3.

	Figure 2: Schematic illustration of TNIK protein domains.
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).
	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/)
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/)
	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.
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

	Figure 5: Overview of the major types of mutations occurring in TNIK
Germinal	Recently, Anazi S. et al. in 2016 have identified in 2 unrelated consanguineous Saudi families affected with autosomal recessive mental retardation-54 (MRT54) the same homozygous truncating mutation in the TNIK gene that results in complete loss of the protein, indicating that the mutation resulted in a null allele.
Somatic	Some somatic mutations have been identified and described by COSMIC (Catalogue of Somatic Mutation In Cancer) and they are listed mostly as substitution; their role in disease has not yet been fully elucidated.

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