Alternative titles; symbols
HGNC Approved Gene Symbol: TNIK
Cytogenetic location: 3q26.2-q26.31 Genomic coordinates (GRCh38) : 3:171,058,414-171,460,408 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q26.2-q26.31 | Intellectual developmental disorder, autosomal recessive 54 | 617028 | Autosomal recessive | 3 |
Germinal center kinases (GCKs), such as TNIK, are characterized by an N-terminal kinase domain and a C-terminal GCK domain that serves a regulatory function (Fu et al., 1999).
By sequencing clones obtained from a size-fractionated adult brain cDNA library, Nagase et al. (1998) cloned TNIK, which they designated KIAA0551. The deduced 1,333-amino acid protein has an apparent molecular mass of more than 100 kD and shares 40.9% amino acid identity with mouse Nik (MAP3K14; 604655) over 981 amino acids. RT-PCR analysis detected intermediate expression in brain, weak expression in kidney, testis, and small intestine, and little to no expression in all other tissues examined.
Using TRAF2 (601895) and NCK (600508) as bait in a yeast 2-hybrid screen of brain and T/B-cell cDNA libraries, followed by 5-prime RACE and PCR of brain, heart, and spleen cDNA, Fu et al. (1999) cloned 8 TNIK splice variants. The variants differ in their use of 3 exons encoding the intermediate region between the kinase and GCK domains. The longest deduced protein contains 1,360 amino acids. Northern blot analysis detected ubiquitous TNIK expression, with highest levels in heart, brain, and skeletal muscle. Expression of major 6.5-, 7.5-, and 9.5-kb TNIK transcripts was tissue specific. PCR showed tissue-specific expression of the 8 variants in brain, heart, and spleen. Western blot analysis detected phosphorylated full-length TNIK at an apparent molecular mass of 150 kD.
Coba et al. (2012) found wide expression of the Tnik gene in mouse brain, including the cortex and hippocampus, where strongest expression was observed in dentate gyrus granule cells. The protein was expressed in the postsynaptic density (PSD) and in the nucleus.
Fu et al. (1999) found that TNIK was autophosphorylated in a manner dependent upon lys54 in the ATP-binding pocket of its kinase domain. Immunoprecipitation analysis showed that epitope-tagged TNIK coprecipitated endogenous TRAF2 from human embryonic kidney cells. Mutation analysis revealed that the intermediate domain was sufficient for the interaction, although the GCK domain may contribute. The intermediate domain was also sufficient for interaction with NCK. Cotransfection of TNIK with JNK2 (MAPK9; 602896) enhanced JNK2 kinase activity in a dose-dependent manner, and this effect was mediated by the GCK region of TNIK, but not the kinase domain. TNIK overexpression had no effect on ERK1 (MAPK3; 601795), p38 (MAPK14; 600289), or NF-kappa-B (see 164011). Overexpression of TNIK in several cell lines resulted in cells that rounded up and lost attachment to the culture dish, whereas overexpression of a TNIK mutant lacking the kinase domain had no effect. Cell rounding was associated with enhanced distribution of actin in a detergent-soluble fraction. Wildtype TNIK, but not TNIK lacking the kinase domain, phosphorylated gelsolin (GSN; 137350) in vitro, suggesting that TNIK may be involved in cytoskeleton regulation.
Taira et al. (2004) found that rat Tnik induced disruption of F-actin structures, thereby inhibiting cell spreading. This effect was mediated by interaction of the C-terminal domain of Tnik with Rap2 (RAP2A; 179540). Tnik interaction with Rap2 was dependent on an intact effector region and the GTP-bound configuration of Rap2. When coexpressed in cultured cells, Tnik colocalized with Rap2, and Rap2 potently enhanced the inhibitory function of Tnik against cell spreading. Rap2 did not significantly enhance Tnik-induced Jnk activation, but promoted autophosphorylation and translocation of Tnik to the detergent-insoluble cytoskeletal fraction. Taira et al. (2004) concluded that TNIK is a specific effector of RAP2 to regulate actin cytoskeleton.
By affinity chromatography of rat brain synaptosome extracts, Kawabe et al. (2010) identified Tnik among 15 proteins that interacted with immobilized Nedd4 (602278), an E3 ubiquitin ligase. Rap2a coimmunoprecipitated with Nedd4 and Tnik, but only following protein crosslinking. In vitro ubiquitination experiments revealed that Nedd4 monoubiquitinated Rap2a, but not Tnik or any other Ras (HRAS; 190020)-related small GTPase examined. Tnik was required for Nedd4 ubiquitination of Rap2a, and Rap2a monoubiquitination blocked Rap2a/Tnik signaling. Nedd4 -/- mouse cortical neurons showed underdeveloped dendrite extensions and arborizations, and expression of dominant-negative Rap2a or Tnik mutants rescued dendrite morphology in Nedd4 -/- embryos. Kawabe et al. (2010) concluded that NEDD4 positively regulates dendrite extension by blocking RAP2A/TNIK signaling.
Coba et al. (2012) noted that Tnik binds Disc1 (605210), which binds Gsk3b (605004). By Western blot analysis, they found that all 3 proteins were expressed in nuclear and PSD fractions from mouse hippocampus. Using immunoprecipitations from PSD extracts, the authors coisolated all 3 proteins in NMDA receptor complexes together with Crmp2 (DPYSL2; 602463), a Gsk3b substrate.
By radiation hybrid analysis, Nagase et al. (1998) mapped the TNIK gene to chromosome 3.
In affected patients from 2 unrelated consanguineous families with autosomal recessive intellectual developmental disorder-54 (MRT54; 617028), Anazi et al. (2016) identified the same homozygous truncating mutation in the TNIK gene (R180X; 610005.0001). The mutation, which was found by autozygosity mapping and candidate gene sequencing, segregated with the disorder in the families. Haplotype analysis indicated a founder effect.
Activation of NMDA receptors on the postsynaptic membrane regulates phosphorylation of TNIK, suggesting a signaling function at excitatory synapses. TNIK has also been implicated in controlling dendritic outgrowth. Coba et al. (2012) found that Tnik-null mice showed impaired learning and an increase in locomotor activity that was associated with increased Gsk3b levels and phosphorylation. Examination of mutant mouse brains showed reduced numbers of dentate gyrus granule cells and some evidence of decreased neurotransmitter release from the presynaptic terminals of excitatory synapses. The findings indicated that Tnik plays a key role at the synapse and is essential for cognition, as well as in the nucleus, where it regulates neurogenesis and cell proliferation.
In affected members of 2 unrelated consanguineous Saudi families with autosomal recessive intellectual developmental disorder-54 (MRT54; 617028), Anazi et al. (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. The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder in the families, and was not found in the ExAC database or in 734 control Saudi exomes. Haplotype analysis showed a founder effect. Patient cells did not show evidence of nonsense-mediated mRNA decay, but Western blot analysis showed complete lack of the full-length and predicted truncated protein, indicating that the mutation resulted in a null allele.
Anazi, S., Shamseldin, H. E., AlNaqeb, D., Abouelhoda, M., Monies, D., Salih, M. A., Al-Rubeaan, K., Alkuraya, F. S. A null mutation in TNIK defines a novel locus for intellectual disability. Hum. Genet. 135: 773-778, 2016. [PubMed: 27106596] [Full Text: https://doi.org/10.1007/s00439-016-1671-9]
Coba, M. P., Komiyama, N. H., Nithianantharajah, J., Kopanitsa, M. V., Indersmitten, T., Skene, N. G., Tuck, E. J., Fricker, D. G., Elsegood, K. A., Stanford, L. E., Afinowi, N. O., Saksida, L. M., Bussey, T. J., O'Dell, T. J., Grant, S. G. N. TNiK is required for postsynaptic and nuclear signaling pathways and cognitive function. J. Neurosci. 32: 13987-13999, 2012. [PubMed: 23035106] [Full Text: https://doi.org/10.1523/JNEUROSCI.2433-12.2012]
Fu, C. A., Shen, M., Huang, B. C. B., Lasaga, J., Payan, D. G., Luo, Y. TNIK, a novel member of the germinal center kinase family that activates the c-Jun N-terminal kinase pathway and regulates the cytoskeleton. J. Biol. Chem. 274: 30729-30737, 1999. [PubMed: 10521462] [Full Text: https://doi.org/10.1074/jbc.274.43.30729]
Kawabe, H., Neeb, A., Dimova, K., Young, S. M., Jr., Takeda, M., Katsurabayashi, S., Mitkovski, M., Malakhova, O. A., Zhang, D.-E., Umikawa, M., Kariya, K., Goebbels, S., Nave, K.-A., Rosenmund, C., Jahn, O., Rhee, J., Brose, N. Regulation of Rap2A by the ubiquitin ligase Nedd4-1 controls neurite development. Neuron 65: 358-372, 2010. [PubMed: 20159449] [Full Text: https://doi.org/10.1016/j.neuron.2010.01.007]
Nagase, T., Ishikawa, K., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 5: 31-39, 1998. [PubMed: 9628581] [Full Text: https://doi.org/10.1093/dnares/5.1.31]
Taira, K., Umikawa, M., Takei, K., Myagmar, B.-E., Shinzato, M., Machida, N., Uezato, H., Nonaka, S., Kariya, K. The Traf2- and Nck-interacting kinase as a putative effector of Rap2 to regulate actin cytoskeleton. J. Biol. Chem. 279: 49488-49496, 2004. [PubMed: 15342639] [Full Text: https://doi.org/10.1074/jbc.M406370200]