Affinage

TNIK

TRAF2 and NCK-interacting protein kinase · UniProt Q9UKE5

Length
1360 aa
Mass
154.9 kDa
Annotated
2026-04-28
81 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNIK is a germinal center kinase (GCK) family serine/threonine kinase that functions as a multifunctional signaling hub linking cytoskeletal remodeling, Wnt/β-catenin transcription, JNK/NF-κB signaling, and synaptic organization across diverse cell types. TNIK phosphorylates TCF4 to activate Wnt target gene transcription as part of the TCF4/β-catenin complex on chromatin, and its kinase activity is required for colorectal and intestinal tumorigenesis in vivo (PMID:19816403, PMID:27562646); it also phosphorylates substrates including Gelsolin, Merlin/NF2, ERM proteins, Arc, GluR1, delta-catenin family members, and EGFR to regulate F-actin dynamics, focal adhesion turnover, endothelial barrier function, synaptic AMPA receptor trafficking, and cancer cell signaling (PMID:10521462, PMID:33495197, PMID:39705357, PMID:26645429, PMID:34077555). In neurons, TNIK organizes postsynaptic density complexes via AKAP9-dependent NMDA receptor association and DISC1 interaction, and its loss impairs AMPA receptor expression, neurogenesis, and cognition in knockout mice (PMID:23035106, PMID:20838393); its C-terminal GCK homology domain independently activates JNK signaling, including DLK/JNK stress-response cascades and TRAF6/TAK1-mediated NF-κB activation downstream of LMP1/CD40 and TNF receptor family members (PMID:10521462, PMID:22904686, PMID:28993483, PMID:39705357). TNIK kinase activity is negatively regulated by H₂O₂-mediated oxidation of Cys202, which induces inhibitory intermolecular disulfide bonds, establishing a redox switch controlling its signaling output (PMID:39705357).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1999 High

    The discovery of TNIK as a novel GCK-family kinase established that it specifically activates JNK through its C-terminal domain (not its kinase domain), directly phosphorylates the actin-severing protein Gelsolin, and disrupts F-actin—linking it to both MAPK signaling and cytoskeletal regulation.

    Evidence Cloning, overexpression of WT and kinase-dead mutants, in vitro kinase assay on Gelsolin, co-IP with TRAF2 and Nck in mammalian cells

    PMID:10521462

    Open questions at the time
    • Endogenous substrates beyond Gelsolin unknown
    • Physiological context of TRAF2/Nck interactions unresolved
    • In vivo function not addressed
  2. 2009 High

    Identification of TNIK as an essential kinase for Wnt/β-catenin target gene transcription resolved how TCF4 becomes transcriptionally activated—TNIK is recruited to TCF4/β-catenin-occupied promoters and directly phosphorylates TCF4.

    Evidence Proteomics-based TCF4 interactor screen, ChIP on Wnt target promoters, in vitro kinase and binding assays, siRNA depletion and kinase-dead mutant rescue

    PMID:19816403

    Open questions at the time
    • TCF4 phosphorylation sites and their individual functional contributions undefined
    • Relationship to other Wnt kinases not clarified
    • In vivo cancer relevance not yet tested
  3. 2010 High

    Two parallel discoveries placed TNIK at the synapse: it was shown to bind activated Rap2 GTPase and regulate dendritic arborization and AMPA receptor surface expression, and to interact with the psychiatric risk factor DISC1 to stabilize postsynaptic density proteins—establishing TNIK as a synaptic organizer.

    Evidence Neuronal overexpression of WT and truncated mutants with AMPA receptor and dendritic assays; co-IP of TNIK-DISC1 with PSD protein level quantification

    PMID:20838393 PMID:21048137

    Open questions at the time
    • Direct TNIK substrates at the PSD not identified
    • Whether DISC1 regulates TNIK kinase activity unknown
    • Behavioral consequences of TNIK synaptic loss not yet shown
  4. 2012 High

    A comprehensive TNIK knockout mouse study demonstrated that TNIK is required in vivo for AMPA receptor expression, synaptic function, dentate gyrus neurogenesis, and cognitive behavior, and revealed that TNIK organizes nuclear signaling complexes that restrain GSK3β—connecting its synaptic and Wnt pathway roles in a single genetic model.

    Evidence TNIK knockout mouse with co-IP (AKAP9/NMDAR), AMPA receptor and behavioral assays, GSK3β inhibitor pharmacological rescue

    PMID:23035106

    Open questions at the time
    • Mechanism by which TNIK restrains GSK3β not molecularly defined
    • Contribution of kinase versus scaffold function in vivo not separated
    • Human relevance not yet demonstrated
  5. 2012 High

    TNIK was placed in a bifurcated NF-κB/JNK signaling cascade downstream of TRAF6/TAK1 in B cells, resolving how its N-terminal kinase domain activates IKKβ/NF-κB while its C-terminus independently drives JNK—demonstrating domain-specific pathway routing beyond the neuronal and Wnt contexts.

    Evidence Functional proteomics, RNAi, co-IP (TNIK-TRAF6-TAK1/TAB2-IKKβ), domain-mapping experiments, NF-κB and JNK reporter assays in LMP1/CD40-stimulated B cells

    PMID:22904686

    Open questions at the time
    • Whether TNIK kinase directly phosphorylates IKKβ or acts through an intermediary unclear
    • Relevance to non-EBV B cell activation not tested
  6. 2015 High

    Substrate specificity was expanded when TNIK was shown to phosphorylate delta-catenin family members (p120-catenin, δ-catenin, ARVCF) dependent on activation-loop phosphorylation at T181/T187, and separately to drive GluR1 trafficking via a TRAF2/TNIK/GluR1 cascade mediating neuropathic pain—defining TNIK as a kinase with distinct substrates in adhesion and synaptic trafficking.

    Evidence Phosphoproteomics with activation-loop mutagenesis and selective TNIK inhibitor for delta-catenins; co-IP of TNIK-GluR1 with subcellular fractionation and spinal nerve ligation model for GluR1 trafficking

    PMID:26645429 PMID:26674878

    Open questions at the time
    • Whether delta-catenin phosphorylation mediates specific adhesion phenotypes in vivo not shown
    • Precise phosphorylation sites on GluR1 by TNIK not mapped
  7. 2016 High

    Structural and genetic evidence established TNIK as essential for colorectal cancer stem cell function and intestinal tumorigenesis: X-ray crystallography revealed the inactive-conformation binding mode of the inhibitor NCB-0846, and Tnik knockout mice were resistant to chemical carcinogenesis and Apc-driven tumorigenesis.

    Evidence X-ray co-crystal structure; Tnik−/− and Tnik−/−/Apcmin/+ mouse models; sphere/tumor-forming assays; NCB-0846 pharmacological inhibition

    PMID:27562646

    Open questions at the time
    • Whether TNIK kinase activity alone or scaffold function drives stem cell maintenance unclear
    • Patient-stratification biomarkers not defined
  8. 2017 High

    TNIK was identified as a MAP4K acting redundantly with MAP4K4 and MINK1 to regulate DLK activation, stabilization, and retrograde JNK signaling in stressed neurons, resolving a long-standing question about the upstream kinases of the DLK neurodegeneration pathway.

    Evidence siRNA and pharmacological MAP4K inhibition in trophic factor-deprived DRG neurons; DLK phosphorylation/stabilization assays; retrograde JNK translocation

    PMID:28993483

    Open questions at the time
    • Individual contribution of TNIK versus MAP4K4 versus MINK1 in vivo not genetically separated
    • Whether TNIK directly phosphorylates DLK not biochemically shown
  9. 2020 High

    TNIK was revealed as a regulator of CD8+ T cell fate downstream of the TNF receptor family member CD27: TNIK promotes β-catenin nuclear translocation during T cell priming, and its loss shifts division from symmetric to asymmetric, expanding the memory T cell pool—extending TNIK's Wnt-activating role to adaptive immunity.

    Evidence TNIK-deficient T cell adoptive transfer in LCMV infection model; β-catenin nuclear translocation; division symmetry analysis; serial re-transplantation

    PMID:32242021

    Open questions at the time
    • Direct TNIK substrates in T cells not identified
    • Whether kinase activity or scaffold function mediates division symmetry switch unknown
  10. 2021 High

    Identification of Merlin/NF2 as a direct TNIK substrate linked TNIK to FAK activation and lung squamous cell carcinoma growth, while parallel work showed TNIK phosphorylates Arc at S67/T278 to regulate its capsid assembly—broadening TNIK's substrate repertoire to tumor suppressor and synaptic plasticity effector proteins.

    Evidence Mass spectrometry substrate identification and in vitro kinase assays for Merlin; phosphosite mapping and mutagenesis for Arc; PDX models for LSCC

    PMID:33495197 PMID:34077555

    Open questions at the time
    • Functional consequence of Merlin phosphorylation sites not individually mapped
    • In vivo relevance of Arc phosphorylation by TNIK not tested
  11. 2023 High

    Metabolic functions of TNIK were established across species: Tnik knockout mice are protected from diet-induced obesity, insulin resistance, and hepatic steatosis, and the Drosophila ortholog misshapen regulates de novo lipogenesis—revealing an unexpected role in lipid and glucose homeostasis.

    Evidence Drosophila misshapen knockout with metabolite profiling; Tnik knockout mouse on high-fat diet with glucose uptake and metabolomics

    PMID:37556547

    Open questions at the time
    • Direct TNIK substrates in metabolic tissues not identified
    • Whether Wnt or JNK pathway mediates the metabolic phenotype unclear
  12. 2024 High

    A redox regulatory mechanism was uncovered: TNIK kinase activity is negatively regulated by H₂O₂-induced oxidation of Cys202, which forms inhibitory intermolecular disulfide bonds; TNIK was simultaneously shown to phosphorylate ERM proteins at the plasma membrane and to be essential for TNF-α-induced endothelial barrier disruption and inflammatory oedema in vivo.

    Evidence In vitro kinase assay on ERM proteins; Cys202 disulfide bond detection after H₂O₂; TNIK KO endothelial cells; in vivo oedema model

    PMID:39705357

    Open questions at the time
    • Whether Cys202 oxidation occurs under physiological redox conditions in vivo not established
    • Other oxidation-sensitive residues not surveyed
    • Structural basis of disulfide-mediated inactivation not resolved
  13. 2025 High

    Cell-type-specific knockout in platelets revealed TNIK as a molecular switch: under normal conditions it activates MLK3/MKK4/JNK via JIP1 for hemostatic dense granule secretion, while under hyperlipidemia it binds PKCε to suppress NOX2/ROS/ERK5 and prevent pathological thrombosis—demonstrating context-dependent partner switching.

    Evidence Megakaryocyte/platelet-specific Tnik knockout and chimeric Apoe−/− mice on high-fat diet; co-IP of TNIK-JIP1 and TNIK-PKCε; bleeding time, thrombosis, and dense granule secretion assays

    PMID:41512175

    Open questions at the time
    • Whether TNIK directly phosphorylates JIP1 or PKCε not shown
    • Mechanism triggering partner switch from JIP1 to PKCε under hyperlipidemia undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: (1) full structural characterization of TNIK in its autoinhibited versus active states, (2) separation of kinase-dependent from scaffold-dependent functions across tissues using kinase-dead knockin models, (3) the identity of upstream activating kinases for TNIK's activation-loop phosphorylation in most cell contexts, and (4) whether TNIK loss-of-function mutations directly cause neurodevelopmental disease in humans.
  • No full-length TNIK structure available
  • Kinase-dead knockin mouse not reported
  • Causal human disease mutations not validated by family/rescue studies

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0098772 molecular function regulator activity 5 GO:0008092 cytoskeletal protein binding 3
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-112316 Neuronal System 5 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 2 R-HSA-1430728 Metabolism 1
Partners
AKAP9CTNNB1DISC1JIP1RAP2ATCF4TRAF2TRAF6
Complex memberships
Postsynaptic density complexTCF4/β-catenin transcription complexTRAF6/TAK1/TAB2/IKKβ signalosome

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 TNIK is a novel GCK-family serine/threonine kinase that specifically activates the JNK pathway when transfected into cells; this activation is mediated solely by the C-terminal GCK homology region (not the kinase domain). Overexpression of wild-type TNIK (but not a kinase-dead mutant) disrupts F-actin structure and inhibits cell spreading, and TNIK directly phosphorylates Gelsolin in vitro. TNIK interacts with both TRAF2 and Nck. Cloning and characterization; transfection overexpression/kinase-mutant rescue; in vitro kinase assay (Gelsolin phosphorylation); co-immunoprecipitation with TRAF2 and Nck The Journal of biological chemistry High 10521462
2009 TNIK is an essential activator of Wnt target gene transcription. It is recruited to TCF4/β-catenin target gene promoters in a β-catenin-dependent manner. TNIK directly binds both TCF4 and β-catenin and phosphorylates TCF4 in vitro. Depletion of TNIK or expression of kinase-dead TNIK mutants abrogates TCF-LEF transcription. Proteomics (TCF4 interactor screen); ChIP; in vitro binding and kinase assays; siRNA depletion followed by expression array analysis; kinase-mutant overexpression The EMBO journal High 19816403
2010 TNIK is a postsynaptically enriched protein that specifically binds activated Rap2 GTPase. TNIK (and the closely related MINK) are required for normal dendritic arborization and surface expression of AMPA receptors. While a truncated MINK (unable to bind Rap2) reduces dendritic branching in a Rap2-dependent manner, a similarly truncated TNIK reduces neuronal complexity independently of Rap2 activity. Neuronal overexpression of wild-type and truncated mutants; AMPA receptor surface expression assays; dendritic arborization quantification; Rap2 activity manipulation The Journal of neuroscience High 21048137
2010 TNIK interacts with the psychiatric risk factor DISC1 at synapses. The DISC1-TNIK interaction stabilizes key postsynaptic density proteins and regulates synaptic composition and activity. Co-immunoprecipitation; synaptic fractionation; functional assays of postsynaptic density protein levels Molecular psychiatry Medium 20838393
2012 TNIK (TNiK) is required in vivo for postsynaptic and nuclear signaling. In TNiK knockout mice: (1) TNiK binds protein complexes linking it to the NMDA receptor via AKAP9; (2) NMDAR and metabotropic receptors bidirectionally regulate TNiK phosphorylation; (3) TNiK is required for AMPA receptor expression and synaptic function; (4) TNiK organizes nuclear complexes and its absence elevates GSK3β activity and alters Wnt pathway signaling; (5) TNiK knockout causes impaired dentate gyrus neurogenesis, spatial discrimination, and object-location learning; (6) hyperlocomotion is pharmacologically rescued by GSK3β inhibitors. Knockout mouse; co-immunoprecipitation (AKAP9/NMDAR); AMPA receptor expression; behavioral testing (touchscreen); pharmacological rescue with GSK3β inhibitors The Journal of neuroscience High 23035106
2012 TNIK is required for canonical NF-κB and JNK signaling in B cells downstream of the EBV oncoprotein LMP1 and CD40. TNIK forms an activation-induced complex with TRAF6, TAK1/TAB2, and IKKβ. TNIK directly binds TRAF6, which bridges TNIK to LMP1's C-terminus. The N-terminal TNIK kinase domain is essential for IKKβ/NF-κB activation, while the C-terminus mediates JNK activation. Functional proteomics; RNAi knockdown; Co-IP; domain-mapping experiments; NF-κB and JNK reporter assays; B-cell proliferation/survival assays PLoS biology High 22904686
2012 In Xenopus, TNIK and MINK are integral components of both canonical and non-canonical Wnt signaling pathways. TNIK and MINK interact and are proteolytically cleaved in vivo to generate kinase domain fragments (active in signal transduction) and CNH domain fragments (suppressive). The kinase domain of TNIK mediates both canonical and non-canonical Wnt signaling, whereas the analogous MINK kinase domain strongly antagonizes canonical Wnt signaling. Xenopus embryo overexpression; proteolytic cleavage characterization; canonical/non-canonical Wnt reporter assays; domain-deletion mutants PloS one Medium 22984420
2013 TNIK acts as a downstream effector of Rap2 to regulate the stability of the Wnt co-receptor LRP6. Rap2 and LRP6 physically associate; knockdown of Rap2 causes proteasome/lysosome-dependent degradation of LRP6. TNIK rescues the inhibitory effects of Rap2 depletion on Wnt-dependent gene transcription and LRP6 stabilization. Co-immunoprecipitation (Rap2-LRP6); siRNA knockdown; proteasome/lysosome inhibitors; Wnt reporter assays; epistasis in Xenopus neural crest induction Biochemical and biophysical research communications Medium 23743195
2015 TNIK phosphorylates members of the delta-catenin family (p120-catenin, δ-catenin, ARVCF) in neurons. Phosphorylation of TNIK at T181 and T187 in its activation loop is required for TNIK-induced p120-catenin phosphorylation in cells. TNIK inhibition by a selective small molecule or shRNA knockdown reduces endogenous p120-catenin phosphorylation. Phosphorylation consensus sequences for TNIK were defined by phosphopeptide sequence analysis. Immunoprecipitation with phosphomotif antibody followed by mass spectrometry; selective small-molecule TNIK inhibitor; shRNA knockdown; activation-loop mutagenesis; cell-based phosphorylation assays The Journal of pharmacology and experimental therapeutics High 26645429
2015 TNIK mediates neuropathic allodynia through a TRAF2/TNIK/GluR1 cascade. TNIK associates with GluR1 and phosphorylation-dependent TNIK-GluR1 coupling drives GluR1 trafficking to the plasma membrane in spinal dorsal horn neurons. TRAF2 (regulated by Fbxo3-dependent Fbxl2 ubiquitination) modifies TNIK/GluR1 phosphorylation. Spinal TNIK knockdown prevents allodynia by attenuating GluR1 subcellular redistribution. Spinal nerve ligation model; TNIK knockdown (siRNA); Co-IP (TNIK-GluR1); phosphorylation assays; GluR1 trafficking/subcellular fractionation; pharmacological rescue with Fbxo3 inhibitor The Journal of neuroscience High 26674878
2015 TNIK concentrates in dendritic spines of neurons throughout the adult mouse brain, particularly at the lateral edge of the synapse, placing it in a microdomain critical for glutamatergic signaling. High-resolution light and electron microscopic immunocytochemistry; subcellular fractionation The Journal of comparative neurology Medium 25753355
2016 TNIK is required for the tumour-initiating function of colorectal cancer stem cells. X-ray co-crystal structure analysis reveals that the TNIK inhibitor NCB-0846 binds TNIK in an inactive conformation, and this binding mode is essential for Wnt inhibition. Tnik-deficient mice are resistant to azoxymethane-induced colon tumorigenesis, and Tnik−/−/Apcmin/+ mice develop significantly fewer intestinal tumors. X-ray crystallography (TNIK/inhibitor co-crystal); Tnik knockout mouse (AOM carcinogenesis model, Apcmin/+ cross); sphere- and tumor-forming assays; NCB-0846 pharmacological inhibition Nature communications High 27562646
2017 TNIK (MAP4K7), together with MAP4K4 and MINK1, acts redundantly as an upstream regulator of DLK/JNK signaling in neurons. These MAP4Ks regulate DLK activation and stabilization/phosphorylation within axons and the subsequent retrograde translocation of the JNK signaling complex to the nucleus. Pharmacological inhibition of MAP4Ks blocks stress-induced neurodegeneration. Trophic factor withdrawal model in mouse DRG neurons; siRNA/pharmacological inhibition of MAP4Ks; DLK phosphorylation/stabilization assays; retrograde JNK translocation assays; neuroprotection assays The Journal of neuroscience High 28993483
2018 In C. elegans, the TNIK ortholog mig-15 acts genetically downstream of Plexin (plx-1) and Rap2 GTPase (rap-2) to restrict presynaptic assembly and form tiled synaptic innervation. Overexpression of mig-15 strongly inhibits synapse formation, establishing it as a negative regulator of synapse assembly. Genetic epistasis in C. elegans (mig-15 mutants, constitutively active/inactive rap-2 mutants, plx-1 mutants); overexpression of mig-15; synaptic tiling assays eLife High 30063210
2019 TDP-43 regulates alternative splicing of TNIK exon 15 (promoting skipping), while the neuronal RNA-binding protein NOVA-1 competitively inhibits TDP-43 and hnRNPA2/B1 skipping activity on TNIK through an RNA-dependent interaction. TNIK protein isoforms including or excluding exon 15 differentially regulate cell spreading in non-neuronal cells and neuritogenesis in primary cortical neurons. Splicing assays; iPSC neuronal differentiation; neuroblastoma cells; co-IP (RNA-dependent TDP-43/NOVA-1 interaction); functional assays (cell spreading, neuritogenesis) Biochimica et biophysica acta. Gene regulatory mechanisms Medium 31382054
2020 TNIK signaling downstream of CD27 (a TNF superfamily receptor) induces nuclear translocation of β-catenin and Wnt pathway activation during CD8+ T cell priming. TNIK deficiency during T cell activation results in enhanced differentiation toward effector cells, increased glycolysis and apoptosis, and shifts cell division from symmetric to asymmetric, enlarging the memory CD8+ T cell pool. TNIK-deficient T cell transfer; LCMV infection model; β-catenin nuclear translocation assay; symmetric/asymmetric division analysis; serial re-transplantation experiments Nature communications High 32242021
2021 TNIK is a therapeutic target in lung squamous cell carcinoma (LSCC). TNIK was identified as a novel substrate kinase for the tumor suppressor Merlin/NF2, and TNIK and Merlin are both required for activation of focal adhesion kinase (FAK). TNIK genetic depletion or pharmacological inhibition reduces LSCC growth in vitro and in vivo. TNIK genetic depletion (siRNA/shRNA); pharmacological inhibition (NCB-0846); patient-derived xenografts; identification of Merlin as TNIK substrate (mass spectrometry, in vitro kinase assay); FAK activation assays Cancer discovery High 33495197
2021 TNIK phosphorylates Arc (activity-regulated cytoskeleton-associated protein) at S67 and T278. TNIK-mediated phosphorylation at these residues strongly influences Arc's subcellular distribution and self-assembly into capsids. Mass spectrometry phosphosite mapping; in vitro kinase assay; site-directed mutagenesis (S67A, T278A); subcellular localization assays; capsid formation assays Journal of neurochemistry High 34077555
2021 TNIK inhibition in osteosarcoma redirects metabolic flux toward lipid accumulation and drives conversion of osteosarcoma cells to adipocyte-like cells through induction of PPARγ, abrogating the cancer stem cell phenotype. TNIK inhibition (NCB-0846) and RNAi; transcriptome analysis; metabolome analysis; in vitro and in vivo OS models; PPARγ pathway analysis JCI insight Medium 33400690
2022 X-ray structural analysis of TNIK in complex with thiopeptide inhibitors reveals a unique substrate-competitive mode of inhibition. The ATP-binding pocket structure of TNIK was characterized, with key residues Cys108 and Met105 (gatekeeper) identified as important for inhibitor binding. X-ray crystallography; in vitro enzymatic assays; KD measurement (SPR/affinity); cell-based TNIK inhibition assays in HCT116 cells Journal of the American Chemical Society High 36282922
2023 TNIK governs lipid and glucose homeostasis. Loss of the Drosophila TNIK ortholog (misshapen) alters metabolite profiles and impairs de novo lipogenesis. Tnik knockout mice are protected against diet-induced fat expansion, insulin resistance, and hepatic steatosis, with enhanced skeletal muscle and adipose tissue insulin-stimulated glucose uptake. Drosophila misshapen knockout (metabolite profiling); Tnik knockout mouse (high-fat diet model); glucose uptake assays; metabolomics Science advances High 37556547
2023 LKB1 represses TNIK expression through its kinase activity. LKB1 loss upregulates TNIK, which promotes CRC cell metastasis through interaction with ARHGAP29 and actin cytoskeleton remodeling. CRISPR-Cas9 LKB1 knockout; RNA-seq; western blot; TNIK shRNA knockdown; Co-IP (TNIK-ARHGAP29); actin cytoskeleton assays; in vivo metastasis model Molecular carcinogenesis Medium 37449799
2023 TNIK drives castration-resistant prostate cancer progression by phosphorylating EGFR. Androgen receptor (AR) suppresses TNIK gene transcription by forming a complex with H3K27me3 at the TNIK locus. Upon androgen deprivation, TNIK is de-repressed and activates EGFR signaling through phosphorylation. Microarray gene expression; ChIP (AR/H3K27me3 at TNIK promoter); TNIK silencing; EGFR phosphorylation assays in C4-2 cells iScience Medium 38226156
2024 TNIK directly phosphorylates and activates ERM (Ezrin-Radixin-Moesin) proteins specifically at the plasma membrane of primary human endothelial cells. TNIK mediates TNF-α-dependent cellular stiffness and paracellular gap formation, and is essential for inflammatory oedema in vivo. TNIK kinase activity is negatively and reversibly regulated by H2O2-mediated oxidation of Cys202 within the kinase domain, forming intermolecular disulfide bonds and inactivating the kinase. In vitro kinase assay (ERM phosphorylation); subcellular fractionation (plasma membrane enrichment); TNIK knockout/inhibition in endothelial cells; in vivo oedema model; H2O2 treatment and disulfide bond detection; pharmacological ROS manipulation Science advances High 39705357
2024 TNIK mutations that abolish kinase activity impair MAPK signaling and protein phosphorylation in structural components of the postsynaptic density (PSD) in human iPSC-derived excitatory neurons. The TNIK interactome is enriched in neurodevelopmental disorder (NDD) risk factors, and TNIK loss of function disrupts signaling networks associated with NDD. hiPSC-derived excitatory neurons; TNIK kinase-dead and null mutations; phosphoproteomics; interactome analysis; neuronal activity measurements Frontiers in molecular neuroscience Medium 38638602
2024 TNIK depletion in injured renal proximal tubule epithelial cells upregulates inflammatory signaling pathways and promotes apoptosis (including PARP-1 cleavage and phosphatidylserine exposure), indicating that TNIK normally acts to suppress inflammation and promote cell survival in this context. siRNA depletion in two hRPTEC cell lines; bulk RNA-sequencing; pathway analysis; apoptosis assays (annexin V, PARP-1 cleavage, flow cytometry) American journal of physiology. Renal physiology Medium 38482555
2025 TNIK modulates ERK5 transcriptional activity in endothelial cells through a MEK5-dependent mechanism, regulating downstream KLF2, KLF4, and eNOS expression. Phosphorylation-deficient TNIK mutants (S764A, S769A) retain the ability to enhance ERK5 transcriptional activity, indicating a kinase-independent regulatory function for TNIK on ERK5. TNIK knockdown increases NF-κB activity and promotes endothelial cell apoptosis. Mammalian one-hybrid assay; qRT-PCR; TNIK knockdown and overexpression; constitutively active and dominant-negative MEK5 epistasis; phosphorylation-deficient TNIK mutants; NF-κB reporter; apoptosis assays Frontiers in cardiovascular medicine Medium 40672381
2025 In platelets, TNIK promotes normal hemostasis by interacting with JNK-interacting protein 1 (JIP1) to activate the MLK3/MKK4/JNK pathway, driving dense granule secretion. Under hyperlipidemic conditions, TNIK binds protein kinase C epsilon (PKCε) and suppresses the NADPH oxidase 2/ROS/ERK5 pathway to prevent excessive platelet activation, functioning as a molecular switch between hemostasis and pathological thrombosis. Megakaryocyte/platelet-specific TNIK knockout mice (Tnikf/fPF4-Cre+); chimeric Tnikf/fPF4-Cre+Apoe−/− mice on high-fat diet; bleeding time assays; arterial thrombosis models; dense granule secretion assays; co-IP (TNIK-JIP1, TNIK-PKCε); pathway activity assays Blood advances High 41512175
2025 TNIK regulates focal adhesion turnover and mitosis in lung adenocarcinoma cells via the RHO/ROCK2/LIMK1 signaling pathway, controlling F-actin and microtubule organization. Lentiviral TNIK knockdown in A549 and PC-9 cells; RNA-sequencing; indirect immunofluorescence (F-actin, microtubules, focal adhesion markers); western blot (ROCK2, LIMK1 pathway); in vivo xenograft; flow cytometry (apoptosis) Frontiers in bioscience (Landmark edition) Medium 40464520

Source papers

Stage 0 corpus · 81 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 The kinase TNIK is an essential activator of Wnt target genes. The EMBO journal 173 19816403
1999 TNIK, a novel member of the germinal center kinase family that activates the c-Jun N-terminal kinase pathway and regulates the cytoskeleton. The Journal of biological chemistry 171 10521462
2024 A small-molecule TNIK inhibitor targets fibrosis in preclinical and clinical models. Nature biotechnology 166 38459338
2016 TNIK inhibition abrogates colorectal cancer stemness. Nature communications 132 27562646
2010 The psychiatric disease risk factors DISC1 and TNIK interact to regulate synapse composition and function. Molecular psychiatry 124 20838393
2012 TNiK is required for postsynaptic and nuclear signaling pathways and cognitive function. The Journal of neuroscience : the official journal of the Society for Neuroscience 89 23035106
2017 The Ste20 Family Kinases MAP4K4, MINK1, and TNIK Converge to Regulate Stress-Induced JNK Signaling in Neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 86 28993483
2015 Therapeutic targets in the Wnt signaling pathway: Feasibility of targeting TNIK in colorectal cancer. Pharmacology & therapeutics 74 26542362
2012 The germinal center kinase TNIK is required for canonical NF-κB and JNK signaling in B-cells by the EBV oncoprotein LMP1 and the CD40 receptor. PLoS biology 68 22904686
2010 MINK and TNIK differentially act on Rap2-mediated signal transduction to regulate neuronal structure and AMPA receptor function. The Journal of neuroscience : the official journal of the Society for Neuroscience 65 21048137
2021 TNIK Is a Therapeutic Target in Lung Squamous Cell Carcinoma and Regulates FAK Activation through Merlin. Cancer discovery 51 33495197
2019 Jatrorrhizine inhibits mammary carcinoma cells by targeting TNIK mediated Wnt/β-catenin signalling and epithelial-mesenchymal transition (EMT). Phytomedicine : international journal of phytotherapy and phytopharmacology 48 31302315
2022 De Novo Discovery of Thiopeptide Pseudo-natural Products Acting as Potent and Selective TNIK Kinase Inhibitors. Journal of the American Chemical Society 47 36282922
2021 Simultaneous CK2/TNIK/DYRK1 inhibition by 108600 suppresses triple negative breast cancer stem cells and chemotherapy-resistant disease. Nature communications 46 34344863
2014 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. PloS one 41 25337707
2017 Emergence of TNIK inhibitors in cancer therapeutics. Cancer science 40 28208209
2015 Fbxo3-Dependent Fbxl2 Ubiquitination Mediates Neuropathic Allodynia through the TRAF2/TNIK/GluR1 Cascade. The Journal of neuroscience : the official journal of the Society for Neuroscience 35 26674878
2014 The essential role of TNIK gene amplification in gastric cancer growth. Oncogenesis 31 24566388
2016 A null mutation in TNIK defines a novel locus for intellectual disability. Human genetics 30 27106596
2015 Identification of Phosphorylation Consensus Sequences and Endogenous Neuronal Substrates of the Psychiatric Risk Kinase TNIK. The Journal of pharmacology and experimental therapeutics 30 26645429
2023 TNIK is a conserved regulator of glucose and lipid metabolism in obesity. Science advances 29 37556547
2023 Inhibition of Wnt Signaling in Colon Cancer Cells via an Oral Drug that Facilitates TNIK Degradation. Molecular cancer therapeutics 25 36302395
2019 Characterization of the ERG-regulated Kinome in Prostate Cancer Identifies TNIK as a Potential Therapeutic Target. Neoplasia (New York, N.Y.) 24 30901730
2018 Rap2 and TNIK control Plexin-dependent tiled synaptic innervation in C. elegans. eLife 24 30063210
2012 Discovery of 4-phenyl-2-phenylaminopyridine based TNIK inhibitors. Bioorganic & medicinal chemistry letters 24 23232060
2020 TNIK signaling imprints CD8+ T cell memory formation early after priming. Nature communications 22 32242021
2011 Enormous influence of TNIK knockdown on intracellular signals and cell survival. Human cell 22 21710359
2016 Traf2- and Nck-interacting kinase (TNIK) is involved in the anti-cancer mechanism of dovitinib in human multiple myeloma IM-9 cells. Amino acids 21 26995282
2021 Direct conversion of osteosarcoma to adipocytes by targeting TNIK. JCI insight 20 33400690
2022 Discovery of 3,4-Dihydrobenzo[f][1,4]oxazepin-5(2H)-one Derivatives as a New Class of Selective TNIK Inhibitors and Evaluation of Their Anti-Colorectal Cancer Effects. Journal of medicinal chemistry 19 34985886
2017 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. Oncotarget 19 28467797
2015 Organization of TNIK in dendritic spines. The Journal of comparative neurology 19 25753355
2024 TNIK's emerging role in cancer, metabolism, and age-related diseases. Trends in pharmacological sciences 18 38777670
2021 Identification of TNIK as a novel potential drug target in thyroid cancer based on protein druggability prediction. Medicine 18 33879700
2021 GPCR-mediated YAP/TAZ inactivation in fibroblasts via EPAC1/2, RAP2C, and MAP4K7. Journal of cellular physiology 18 34046891
2019 TDP-43 and NOVA-1 RNA-binding proteins as competitive splicing regulators of the schizophrenia-associated TNIK gene. Biochimica et biophysica acta. Gene regulatory mechanisms 17 31382054
2013 Role of the Rap2/TNIK kinase pathway in regulation of LRP6 stability for Wnt signaling. Biochemical and biophysical research communications 16 23743195
2012 Agonistic and antagonistic roles for TNIK and MINK in non-canonical and canonical Wnt signalling. PloS one 15 22984420
2022 Structural Insight into TNIK Inhibition. International journal of molecular sciences 14 36361804
2023 LKB1 loss promotes colorectal cancer cell metastasis through regulating TNIK expression and actin cytoskeleton remodeling. Molecular carcinogenesis 13 37449799
2015 Epigenetic regulation of traf2- and Nck-interacting kinase (TNIK) in polycystic ovary syndrome. American journal of translational research 13 26279758
2020 Disease-associated synaptic scaffold protein CNK2 modulates PSD size and influences localisation of the regulatory kinase TNIK. Scientific reports 12 32235845
2022 TNIK Inhibition Has Dual Synergistic Effects on Tumor and Associated Immune Cells. Advanced biology 11 35675910
2024 Discovery of Bis-imidazolecarboxamide Derivatives as Novel, Potent, and Selective TNIK Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis. Journal of medicinal chemistry 10 39422731
2022 MicroRNA-144-3p Represses the Growth and EMT of Thyroid Cancer via the E2F2/TNIK Axis in Cells and Male BALB/c Nude Mice. Endocrinology 10 35579981
2024 Mutations in the postsynaptic density signaling hub TNIK disrupt PSD signaling in human models of neurodevelopmental disorders. Frontiers in molecular neuroscience 9 38638602
2022 Discovery of benzo[d]oxazol-2(3H)-one derivatives as a new class of TNIK inhibitors for the treatment of colorectal cancer. Bioorganic & medicinal chemistry letters 9 35447345
2020 Methylome-wide association study of first-episode schizophrenia reveals a hypermethylated CpG site in the promoter region of the TNIK susceptibility gene. Progress in neuro-psychopharmacology & biological psychiatry 9 32853717
2025 AI-Driven Robotics Laboratory Identifies Pharmacological TNIK Inhibition as a Potent Senomorphic Agent. Aging and disease 8 39965245
2024 TNIK depletion induces inflammation and apoptosis in injured renal proximal tubule epithelial cells. American journal of physiology. Renal physiology 8 38482555
2021 Phosphorylation-dependent control of Activity-regulated cytoskeleton-associated protein (Arc) protein by TNIK. Journal of neurochemistry 8 34077555
2020 Effect of TNIK upregulation on JQ1-resistant human colorectal cancer HCT116 cells. Biochemical and biophysical research communications 8 32828291
2021 TNIK influence the effects of antipsychotics on Wnt/β-catenin signaling pathway. Psychopharmacology 7 34350475
2020 Molecular Docking analysis of the TNIK Receptor protein with a potential Inhibitor from the NPACT databas. Bioinformation 7 32831519
2024 Fragment growth-based discovery of novel TNIK inhibitors for the treatment of colorectal cancer. European journal of medicinal chemistry 6 38422698
2024 TNIK Inhibition Sensitizes TNIK-Overexpressing Lung Squamous Cell Carcinoma to Radiotherapy. Molecular cancer therapeutics 6 38670554
2024 TNIK in disease: from molecular insights to therapeutic prospects. Apoptosis : an international journal on programmed cell death 6 38853204
2022 Computational study on new natural compound inhibitors of Traf2 and Nck-interacting kinase (TNIK). Aging 6 36287174
2024 TNIK: A redox sensor in endothelial cell permeability. Science advances 5 39705357
2023 MiR-5590-3p inhibits the proliferation and invasion of ovarian cancer cells through mediating the Wnt/β-catenin signaling pathway by targeting TNIK. Histology and histopathology 5 37318197
2024 TNIK regulation of interferon signaling and endothelial cell response to virus infection. Frontiers in cardiovascular medicine 4 38264262
2023 TNIK drives castration-resistant prostate cancer via phosphorylating EGFR. iScience 4 38226156
2025 Integrated Machine Learning and Structure-Based Virtual Screening Identify Osimertinib as a TNIK Inhibitor for Idiopathic Pulmonary Fibrosis. Journal of chemical information and modeling 3 40999821
2024 Therapeutic targeting of TNIK in papillary thyroid carcinoma: a novel approach for tumor growth suppression. Medical oncology (Northwood, London, England) 3 38763968
2024 miR-151a-3p regulates the TNIK/PI3K/Akt axis and influences the progression of polycystic ovary syndrome. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 3 39284759
2023 Deficiency of germinal center kinase TRAF2 and NCK-interacting kinase (TNIK) in B cells does not affect atherosclerosis. Frontiers in cardiovascular medicine 3 37215541
2023 Expression analysis of TRAF2‑ and NCK‑interacting protein kinase (TNIK) and phosphorylated TNIK in papillary thyroid carcinoma. Oncology letters 3 37332335
2025 Identification of a TNIK-CDK9 Axis as a Targetable Strategy for Platinum-Resistant Ovarian Cancer. Molecular cancer therapeutics 2 39873147
2022 The influence of TNIK gene polymorphisms on risperidone response in a Chinese Han population. Pharmacogenomics 2 35698907
2013 Dynamic change of TNIK in response to tumor necrosis factor alpha in a TRAF2-dependent manner. Human cell 2 23355318
2025 Rap2a promotes cardiac fibrosis and exacerbates myocardial infarction through the TNIK/Merlin/YAP axis. Cell biology and toxicology 1 40332594
2025 Therapeutic applications and molecular mechanisms of TNIK inhibitors: A comprehensive review of current advances. Bioorganic chemistry 1 40706539
2024 Transcriptome analysis to explore the mechanism of downregulated TNIK influencing the effect of risperidone. Frontiers in pharmacology 1 39268461
2026 TNIK as a molecular switch regulating platelet function in hemostasis and hyperlipidemia-associated thrombosis. Blood advances 0 41512175
2026 Discovery of potent TNIK inhibitors containing a 1H-pyrrolo[2,3-b]pyridine scaffold as promising therapeutics for colorectal cancer. European journal of medicinal chemistry 0 41818865
2026 TNIK overexpression is sufficient for chemoradiation resistance in limited-stage small cell lung cancer. Molecular cancer therapeutics 0 41838988
2026 A system-wide investigation into the phosphoregulatory network of TNIK and its cellular implications. Frontiers in bioinformatics 0 41909809
2025 Pleiotropic Role of TNIK in Sepsis-Induced Cardiomyopathy. Journal of cellular physiology 0 40176540
2025 TNIK Regulates Cytoskeletal Organization to Promote Focal Adhesion Turnover and Mitosis in Lung Adenocarcinoma. Frontiers in bioscience (Landmark edition) 0 40464520
2025 TNIK-driven regulation of ERK5 transcriptional activity in endothelial cells. Frontiers in cardiovascular medicine 0 40672381
2025 Mendelian randomization integrated with multi-omics analysis identifies TNIK as a key gene in gut microbiota-induced IBD development. Frontiers in immunology 0 41341599