Affinage

TNIK

TRAF2 and NCK-interacting protein kinase · UniProt Q9UKE5

Length
1360 aa
Mass
154.9 kDa
Annotated
2026-06-10
81 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNIK is a germinal center kinase (GCK) family serine/threonine kinase that couples upstream signals to cytoskeletal remodeling, Wnt-dependent transcription, and synaptic function (PMID:10521462, PMID:19816403). It was first defined as a TRAF2- and NCK-interacting kinase that, when active, disrupts F-actin and inhibits cell spreading while activating the JNK pathway through its GCK homology region (PMID:10521462). A central, well-defined role is as an essential component of the TCF4/β-catenin transcriptional complex: TNIK binds TCF4 and β-catenin, is recruited to Wnt target promoters, directly phosphorylates TCF4, and its kinase activity is required for TCF-LEF transcription (PMID:19816403); genetically, Tnik loss confers resistance to intestinal and colon tumorigenesis, and inhibitors that trap TNIK in an inactive conformation block Wnt output (PMID:27562646). TNIK phosphorylates a broad substrate set whose engagement depends on activation-loop autophosphorylation at T181/T187, including delta-catenin family proteins (p120-catenin, δ-catenin, ARVCF) (PMID:26645429), the tumor suppressor Merlin/NF2 to drive FAK activation (PMID:33495197), the synaptic protein Arc to control its capsid self-assembly and distribution (PMID:34077555), and ERM proteins at the plasma membrane, where this activity is reversibly inactivated by H2O2-mediated oxidation of cysteine 202 (PMID:39705357). In the nervous system TNIK is concentrated in dendritic spines (PMID:25753355), is positioned downstream of Rap2 and within NMDA-receptor-associated complexes to support AMPA receptor expression, dendritic arborization, and learning, with its loss elevating GSK3β activity (PMID:21048137, PMID:23035106), and acts redundantly with MAP4K4/MINK1 upstream of DLK/JNK signaling in stressed neurons (PMID:28993483). Beyond these roles, TNIK scaffolds TRAF6–TAK1–IKKβ complexes for NF-κB/JNK activation downstream of CD40 and LMP1 (PMID:22904686), regulates glucose and lipid homeostasis in flies and mice (PMID:37556547), and acts as a molecular switch in platelets through distinct JIP1/MLK3/JNK and PKCε/NOX2/ERK5 complexes under normal versus hyperlipidemic conditions (PMID:41512175).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1999 High

    Established TNIK as a novel GCK-family kinase physically linking TRAF2/NCK signaling to cytoskeletal control and JNK activation, defining its founding biochemical identity.

    Evidence Yeast two-hybrid/co-IP, kinase-dead overexpression, in vitro kinase assay, and F-actin imaging across multiple cell lines

    PMID:10521462

    Open questions at the time
    • Physiological substrates beyond Gelsolin not identified
    • Mechanism by which the GCK homology region activates JNK independent of the kinase domain unresolved
  2. 2009 High

    Defined TNIK as a kinase-active core component of the TCF4/β-catenin complex required for Wnt target gene transcription, answering how a kinase is integrated into nuclear Wnt output.

    Evidence Proteomics, in vitro binding and kinase assays, ChIP, and siRNA + TCF-LEF reporter in intestinal crypt systems

    PMID:19816403

    Open questions at the time
    • Functional consequence of TCF4 phosphorylation on complex assembly not fully resolved
    • Upstream signals controlling promoter recruitment unclear
  3. 2010 Medium

    Positioned TNIK at the postsynaptic density downstream of Rap2 and bound to DISC1, establishing roles in dendritic morphology, AMPA receptor surface expression, and synaptic protein stability.

    Evidence Neuronal overexpression/knockdown, surface AMPA receptor staining, dominant-negative Rap2, and synaptic co-IP

    PMID:20838393 PMID:21048137

    Open questions at the time
    • Direct synaptic substrates not identified at this stage
    • Distinct mechanisms separating TNIK from MINK downstream of Rap2 undefined
  4. 2012 High

    In vivo knockout established TNIK's requirement for synaptic function, neurogenesis, and learning, and linked its loss to elevated GSK3β and altered nuclear Wnt signaling, connecting molecular and behavioral roles.

    Evidence Tnik knockout mice with co-IP, electrophysiology, touchscreen behavior, and GSK3β inhibitor rescue

    PMID:23035106

    Open questions at the time
    • How TNIK loss raises GSK3β activity mechanistically unclear
    • Direct nuclear complex composition not defined
  5. 2012 High

    Revealed a scaffolding function: TNIK assembles a TRAF6–TAK1–IKKβ signalosome downstream of CD40/LMP1, with separable kinase-domain (NF-κB) and C-terminal (JNK) requirements.

    Evidence Functional proteomics of the LMP1 signalosome, RNAi + NF-κB/JNK reporters, co-IP, and domain mapping in B cells

    PMID:22904686

    Open questions at the time
    • Whether kinase activity is required for IKKβ activation versus scaffolding alone not fully separated
    • Direct IKKβ phosphorylation not demonstrated
  6. 2013 Medium

    Placed TNIK within Rap2 control of Wnt receptor stability, showing it acts downstream of Rap2 to maintain LRP6 levels and Wnt-dependent transcription.

    Evidence Xenopus knockdown/rescue, co-IP, and proteasome/lysosome inhibition with Wnt reporters

    PMID:23743195

    Open questions at the time
    • Whether TNIK directly phosphorylates LRP6 or a regulator unknown
    • Mechanism of LRP6 degradation control not defined
  7. 2015 High

    Identified endogenous TNIK substrates (p120-catenin, δ-catenin, ARVCF) and demonstrated dependence on activation-loop autophosphorylation at T181/T187, defining its catalytic requirements and direct targets.

    Evidence Selective inhibitor, phosphomotif IP-MS, activation-loop mutants, and shRNA cell-based phosphorylation assays

    PMID:26645429

    Open questions at the time
    • Functional output of delta-catenin family phosphorylation not established
    • Full substrate repertoire incomplete
  8. 2016 High

    Provided structural and in vivo genetic proof that TNIK kinase function drives Wnt-dependent tumorigenesis and that inactive-conformation inhibitor binding is required for Wnt inhibition.

    Evidence TNIK/NCB-0846 co-crystal structure plus Tnik knockout tumor-resistance models

    PMID:27562646

    Open questions at the time
    • Whether Wnt-independent activities contribute to tumor suppression by Tnik loss not separated
  9. 2017 High

    Established TNIK as a redundant upstream activator of the DLK/JNK axis in neurons under trophic stress, clarifying a degeneration-relevant pathway.

    Evidence DRG neuron trophic withdrawal with MAP4K4/MINK1/TNIK triple knockdown and MAP4K inhibitors

    PMID:28993483

    Open questions at the time
    • Direct DLK phosphorylation by TNIK not shown
    • Relative TNIK contribution within the redundant trio unresolved
  10. 2018 High

    Genetic epistasis in C. elegans positioned TNIK (mig-15) downstream of Plexin and Rap2 to restrict presynaptic assembly and establish synaptic tiling, conserving the Rap2–TNIK module across species.

    Evidence C. elegans mutant epistasis with GDP/GTP-locked Rap2 and synaptic marker imaging

    PMID:30063210

    Open questions at the time
    • Synaptic substrates mediating tiling not identified
    • Mammalian relevance of tiling role untested here
  11. 2021 High

    Expanded the substrate map to Merlin/NF2 and Arc, linking TNIK to FAK activation in cancer and to Arc capsid assembly, and embedded it in a GPCR–EPAC–RAP2c–LATS–YAP/TAZ cascade.

    Evidence In vitro kinase assays, phosphosite mutagenesis, FAK/YAP readouts, and sequential siRNA epistasis

    PMID:33495197 PMID:34046891 PMID:34077555

    Open questions at the time
    • How Merlin phosphorylation activates FAK mechanistically unclear
    • Whether YAP/TAZ regulation is via direct LATS phosphorylation by TNIK not shown
  12. 2022 High

    Structural studies defined two distinct druggable modes—ATP-competitive inactive-conformation binding and a unique substrate-competitive site—and revealed TNIK governs systemic lipid and glucose homeostasis.

    Evidence Multiple TNIK/inhibitor co-crystal structures with kinase assays; Drosophila and mouse metabolic knockout phenotyping

    PMID:36282922 PMID:36361804 PMID:37556547

    Open questions at the time
    • Substrates mediating metabolic phenotypes not identified
    • Tissue-specific contributions to glucose/lipid control unresolved
  13. 2024 High

    Identified ERM proteins as direct plasma-membrane substrates driving inflammatory endothelial stiffening and oedema, and uncovered redox control of TNIK via reversible C202 oxidation, defining a sensor-coupled activity switch.

    Evidence In vitro kinase assay, C202 mutagenesis, H2O2/ROS-inhibitor treatment, and in vivo oedema model

    PMID:39705357

    Open questions at the time
    • Physiological sources of C202-oxidizing ROS in vivo not defined
    • Reversal kinetics of the disulfide switch in cells unresolved
  14. 2025 High

    Defined TNIK as a context-dependent platelet switch operating through distinct JIP1/MLK3/JNK and PKCε/NOX2/ERK5 complexes, controlling hemostasis under normal versus hyperlipidemic conditions.

    Evidence Platelet-specific Tnik knockout mice, co-IP of JIP1 and PKCε, bleeding/thrombosis models, and ROS measurement

    PMID:41512175

    Open questions at the time
    • Whether kinase activity versus scaffolding drives each complex unresolved
    • Molecular trigger selecting between the two complexes undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how TNIK partitions between kinase-dependent and scaffolding/kinase-independent functions across its many contexts, and which upstream signals select among its diverse substrate and complex repertoires.
  • No unifying model distinguishing catalytic from scaffolding outputs
  • Tissue- and stimulus-specific substrate selection mechanisms unknown
  • Structural basis for partner-dependent complex assembly undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016740 transferase activity 5 GO:0060090 molecular adaptor activity 2 GO:0140110 transcription regulator activity 2 GO:0140299 molecular sensor activity 1
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-112316 Neuronal System 5 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-168256 Immune System 2 R-HSA-109582 Hemostasis 1 R-HSA-1430728 Metabolism 1
Partners
CTNNB1DISC1JIP1NCKNF2TCF4TRAF2TRAF6
Complex memberships
TCF4/β-catenin transcriptional complexTRAF6–TAK1/TAB2–IKKβ LMP1 signalosomepostsynaptic density

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 TNIK was cloned as a novel GCK family kinase that interacts with both TRAF2 and NCK. Overexpression of wild-type TNIK (but not a kinase-dead mutant) disrupts F-actin structure and inhibits cell spreading in Phoenix-A, NIH-3T3, and HeLa cells. TNIK activates the JNK pathway, with this activation mediated solely by the GCK homology region rather than the kinase domain. TNIK can phosphorylate Gelsolin in vitro. Yeast two-hybrid/co-IP (TRAF2/NCK interaction), transient overexpression with kinase mutant, in vitro kinase assay (Gelsolin phosphorylation), F-actin immunofluorescence The Journal of biological chemistry High 10521462
2009 TNIK is a direct binding partner of TCF4 and β-catenin (identified by proteomics, confirmed by in vitro binding assays), is recruited to Wnt target gene promoters in a β-catenin-dependent manner, and phosphorylates TCF4 in vitro. Depletion of TNIK or expression of TNIK kinase-dead mutants abrogates TCF-LEF transcription, establishing TNIK kinase activity as essential for Wnt target gene activation. Proteomics pull-down (TCF4 interactome in mouse intestinal crypts), in vitro binding assay, in vitro kinase assay (TCF4 phosphorylation), ChIP, siRNA depletion + TCF-LEF reporter assay, expression array The EMBO journal High 19816403
2010 TNIK and MINK are postsynaptically enriched proteins whose dendritic clustering is bidirectionally regulated by the activation state of Rap2. TNIK expression in neurons is required for normal dendritic arborization and surface expression of AMPA receptors. Unlike MINK, TNIK-mediated reduction of neuronal complexity does not require Rap2 activity, and TNIK does not mediate Rap2-driven removal of surface AMPA receptors, indicating TNIK and MINK employ distinct mechanisms downstream of Rap2. Neuronal overexpression/knockdown, immunostaining for surface AMPA receptors, dendritic morphology analysis, dominant-negative Rap2 constructs The Journal of neuroscience Medium 21048137
2010 TNIK interacts with DISC1 at synapses; the DISC1-TNIK interaction stabilizes levels of key postsynaptic density proteins and regulates synaptic composition and activity. Co-immunoprecipitation (synaptic fractions), synaptic protein quantification after DISC1/TNIK manipulation Molecular psychiatry Medium 20838393
2012 In vivo (Tnik knockout mice), TNiK binds protein complexes linking it to the NMDA receptor via AKAP9. NMDA and metabotropic receptors bidirectionally regulate TNiK phosphorylation. TNiK is required for AMPA receptor expression and synaptic function. In the nucleus, TNiK organizes complexes; its absence leads to elevated GSK3β activity and altered Wnt signaling. TNiK knockout mice show impaired dentate gyrus neurogenesis, deficits in spatial discrimination and paired-associate learning, and hyperlocomotion reversible by GSK3β inhibitors. Knockout mouse model, co-immunoprecipitation, western blot (phosphorylation), electrophysiology, behavioral testing (touchscreen), pharmacological rescue (GSK3β inhibitor) The Journal of neuroscience High 23035106
2012 TNIK is required for canonical NF-κB and JNK signaling in B cells stimulated by EBV oncoprotein LMP1 and the CD40 receptor. TNIK forms an activation-induced complex with TRAF6, TAK1/TAB2, and IKKβ at the LMP1 signalosome. TNIK directly binds TRAF6, which bridges TNIK's interaction with LMP1's C-terminus. The N-terminal TNIK kinase domain is essential for IKKβ/NF-κB activation, while the C-terminus is required for JNK activation. Functional proteomics (LMP1 signalosome pull-down), RNAi knockdown + NF-κB/JNK reporter assays, co-immunoprecipitation, domain-deletion mapping PLoS biology High 22904686
2012 In Xenopus, TNIK (xTNIK) and MINK are integral components of both canonical and non-canonical Wnt pathways. xTNIK and xMINK interact and are proteolytically cleaved in vivo to generate kinase domain fragments (active in signaling) and CNH domain fragments (suppressive). The kinase domain of xTNIK mediates both canonical and non-canonical Wnt signaling, whereas the analogous xMINK kinase domain fragment antagonizes canonical Wnt signaling. Xenopus embryo overexpression, domain truncation constructs, co-immunoprecipitation, in vivo proteolytic cleavage analysis, Wnt reporter assays PloS one Medium 22984420
2013 Rap2 acts via TNIK to regulate stability of the Wnt receptor LRP6. Knockdown of Rap2 causes proteasome/lysosome-dependent degradation of LRP6; TNIK acts downstream of Rap2 to rescue LRP6 stability. Rap2 and LRP6 physically associate, and TNIK rescues the inhibitory effects of Rap2 depletion on Wnt-dependent gene transcription and neural crest induction. Xenopus embryo knockdown/rescue, co-immunoprecipitation, proteasome/lysosome inhibitor treatment, Wnt reporter assay Biochemical and biophysical research communications Medium 23743195
2013 TNIK protein levels dynamically change in response to TNFα stimulation in a TRAF2-dependent manner. TRAF2 negatively modulates TNIK protein levels by regulating ubiquitin conjugation to TNIK. TNFα stimulation time course, siRNA knockdown of TRAF2, ubiquitination assay Human cell Low 23355318
2015 TNIK directly phosphorylates TCF4 and regulates Wnt signaling. Using a selective TNIK inhibitor and phosphomotif antibody immunoprecipitation followed by mass spectrometry, endogenous neuronal TNIK substrates were identified, including p120-catenin, δ-catenin, and ARVCF (delta-catenin family). TNIK-induced p120-catenin phosphorylation requires intact kinase activity and phosphorylation of TNIK at T181 and T187 in the activation loop. TNIK inhibitor or shRNA knockdown reduces endogenous p120-catenin phosphorylation in cells. Selective TNIK inhibitor, phosphomotif antibody immunoprecipitation + mass spectrometry, site-directed mutagenesis (T181A, T187A activation-loop mutants), shRNA knockdown, cell-based phosphorylation assay The Journal of pharmacology and experimental therapeutics High 26645429
2015 TNIK is concentrated in dendritic spines of neurons throughout the adult mouse brain, with particularly high enrichment near the lateral edge of the synapse (a microdomain critical for glutamatergic signaling), established by high-resolution light and electron microscopic immunocytochemistry. High-resolution light microscopy and electron microscopic immunocytochemistry The Journal of comparative neurology Medium 25753355
2015 TNIK mediates neuropathic allodynia through a TRAF2/TNIK/GluR1 cascade. TNIK couples with GluR1, and TNIK-mediated phosphorylation drives GluR1 trafficking to the plasma membrane in dorsal horn neurons after spinal nerve ligation. TRAF2, regulated by Fbxo3-dependent Fbxl2 ubiquitination, contributes to allodynia by modifying TNIK/GluR1 phosphorylation. TNF-α upregulates this cascade via Fbxo3/Fbxl2-dependent modification. Spinal nerve ligation model, intrathecal siRNA knockdown, immunoprecipitation (TNIK-GluR1 coupling), subcellular fractionation (GluR1 trafficking), behavioral allodynia testing, Fbxo3 inhibitor treatment The Journal of neuroscience Medium 26674878
2016 TNIK is an essential regulatory component of the TCF4/β-catenin transcriptional complex. Tnik-deficient mice are resistant to azoxymethane-induced colon tumorigenesis and develop fewer intestinal tumors in the Apc(min/+) background. X-ray co-crystal structure of TNIK with NCB-0846 reveals the inhibitor binds TNIK in an inactive conformation; this inactive-conformation binding mode is essential for Wnt inhibition. Tnik knockout mouse (tumor resistance), X-ray crystallography (TNIK/NCB-0846 co-crystal), in vivo tumorigenesis models, sphere-forming and tumor-forming assays Nature communications High 27562646
2017 TNIK (MAP4K7), together with MAP4K4 and MINK1 (MAP4K6), acts redundantly as an upstream regulator of DLK activation and downstream JNK-dependent c-Jun phosphorylation in neurons under trophic factor withdrawal stress. Pharmacological inhibition of MAP4Ks blocks DLK stabilization/phosphorylation within axons and prevents retrograde translocation of the JNK signaling complex to the nucleus. Embryonic mouse DRG neurons, trophic factor withdrawal, siRNA triple knockdown (MAP4K4/MINK1/TNIK), pharmacological MAP4K inhibitors, immunofluorescence (axonal DLK), c-Jun phosphorylation western blot, neuronal survival assay The Journal of neuroscience High 28993483
2018 In C. elegans, TNIK (mig-15) acts genetically downstream of Plexin (plx-1) and Rap2 (rap-2) to restrict presynaptic assembly and form tiled synaptic innervation. Overexpression of mig-15 strongly inhibits synapse formation, while mig-15 mutants display excessive ectopic synapse formation. PLX-1 suppresses local RAP-2 activity, and cycling of the RAP-2 nucleotide state is critical for synapse inhibition. C. elegans genetic epistasis (plx-1, rap-2, mig-15 mutants), constitutively active/GDP-locked Rap2 mutants, mig-15 overexpression, synaptic marker imaging eLife High 30063210
2019 TNIK alternative splicing is competitively regulated by TDP-43 (promotes exon 15 skipping) and NOVA-1 (promotes exon 15 inclusion) via an RNA-dependent interaction. TNIK protein isoforms including/excluding exon 15 differently regulate cell spreading in non-neuronal cells and neuritogenesis in primary cortical neurons. iPSC neuronal differentiation, RT-PCR splicing assay, TDP-43/NOVA-1 overexpression/knockdown, RNA immunoprecipitation, neurite outgrowth assay, cell spreading assay 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 in CD8+ T cells during priming. TNIK deficiency during T cell activation results in enhanced effector differentiation, increased glycolysis and apoptosis, and promotes symmetric over asymmetric cell division, thereby enlarging the memory CD8+ T cell pool. TNIK-deficient T cell adoptive transfer, LCMV infection model, β-catenin nuclear translocation imaging, metabolic (glycolysis) assay, cell division symmetry analysis, serial re-transplantation Nature communications Medium 32242021
2021 TNIK phosphorylates the tumor suppressor Merlin/NF2, and both TNIK and Merlin are required for activation of focal adhesion kinase (FAK) in lung squamous cell carcinoma cells. This was established by identifying Merlin as a novel TNIK substrate and showing that TNIK and Merlin are required for FAK activation. In vitro kinase assay (TNIK phosphorylates Merlin), co-immunoprecipitation, TNIK genetic depletion/pharmacologic inhibition, FAK activation western blot, in vitro and in vivo LSCC growth assays Cancer discovery High 33495197
2021 TNIK phosphorylates Arc at serine 67 (S67) and threonine 278 (T278). TNIK-mediated phosphorylation at these residues strongly influences Arc's subcellular distribution and self-assembly into virus-like capsids, as demonstrated by site-directed mutagenesis of S67 and T278. Mass spectrometry phosphosite mapping, site-directed mutagenesis (S67A, T278A), immunofluorescence (Arc subcellular distribution), capsid assembly assay Journal of neurochemistry Medium 34077555
2021 TNIK (MAP4K7) is an essential element in a GPCR-EPAC1/2-RAP2c-MAP4K7-LATS1/2 signaling cascade that mediates YAP/TAZ phosphorylation and nuclear exclusion in human lung fibroblasts. Disruption of this cascade abolishes the effects of dopamine D1 receptor agonism on reducing fibroblast proliferation, contraction, and extracellular matrix production. siRNA knockdown of EPAC1/2, RAP2c, MAP4K7 (TNIK); YAP/TAZ nuclear localization imaging; LATS1/2 phosphorylation western blot; fibroblast functional assays (proliferation, contraction, ECM) Journal of cellular physiology Medium 34046891
2022 X-ray structural analysis of TNIK bound to thiopeptide inhibitors reveals a unique substrate-competitive (non-ATP-competitive) mode of inhibition. The thiopeptide inhibitors access a site distinct from the ATP-binding pocket, establishing the structural basis for substrate-competitive TNIK inhibition. X-ray crystallography (TNIK/thiopeptide co-crystals), in vitro kinase inhibition assay (Ki = 3 nM), mRNA display combinatorial library selection Journal of the American Chemical Society High 36282922
2022 Structural insights into TNIK inhibition show that inhibitors (including NCB-0846) bind the ATP-binding site of TNIK in an inactive conformation, and that different chemical scaffolds of nanomolar inhibitors alter the structure and function of TNIK distinctly. X-ray crystallography (multiple TNIK/inhibitor co-crystal structures), kinase activity assays International journal of molecular sciences High 36361804
2023 TNIK governs lipid and glucose homeostasis in Drosophila and mice. Loss of the Drosophila TNIK ortholog (misshapen) impairs de novo lipogenesis in high-sugar-fed larvae. 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, lipogenesis assay), Tnik knockout mouse (high-fat diet, metabolic phenotyping, insulin tolerance test, glucose uptake assay) Science advances High 37556547
2023 TNIK activates EGFR signaling through direct phosphorylation of EGFR in castration-resistant prostate cancer cells. Following androgen deprivation therapy-induced reduction of AR (which normally represses TNIK transcription by forming a complex with H3K27me3), TNIK is upregulated and phosphorylates EGFR to promote CRPC progression. Microarray (TNIK upregulation), ChIP (AR/H3K27me3 at TNIK promoter), in vitro/cell-based kinase assay (TNIK phosphorylates EGFR), TNIK knockdown + EGFR pathway western blot iScience Medium 38226156
2023 LKB1 represses TNIK expression through its kinase activity. LKB1 loss upregulates TNIK, which interacts with ARHGAP29 to promote actin cytoskeleton remodeling and CRC cell metastasis. CRISPR-Cas9 LKB1 KO, RNA-seq + western blot (TNIK expression), co-immunoprecipitation (TNIK-ARHGAP29), shRNA TNIK knockdown + migration/invasion assay, in vivo metastasis model Molecular carcinogenesis Medium 37449799
2024 TNIK directly phosphorylates and activates ERM (Ezrin-Radixin-Moesin) proteins at the plasma membrane of primary human endothelial cells, mediating TNF-α-dependent cellular stiffness and paracellular gap formation in vitro and inflammatory oedema in vivo. TNIK kinase activity is negatively and reversibly regulated by H2O2-mediated oxidation of cysteine 202 (C202) in the kinase domain, leading to intermolecular disulfide bond formation and loss of kinase activity. In vitro kinase assay (TNIK phosphorylates ERM), site-directed mutagenesis (C202), H2O2 treatment + kinase activity assay, ROS inhibitor treatment + ERM phosphorylation, in vivo inflammatory oedema model, TNIK knockdown Science advances High 39705357
2024 TNIK mutations in hiPSC-derived excitatory neurons dysregulate neuronal activity. Loss of TNIK protein kinase activity impairs MAPK signaling and protein phosphorylation in structural components of the postsynaptic density. The TNIK interactome in human neurons is enriched in neurodevelopmental disorder risk factors. hiPSC-derived excitatory neurons with TNIK patient mutations, electrophysiology, phosphoproteomics, TNIK interactome analysis Frontiers in molecular neuroscience Medium 38638602
2025 TNIK in platelets promotes normal hemostasis by interacting with JNK interacting protein 1 (JIP1) to promote MLK3/MKK4/JNK pathway activation. Under hyperlipidemic conditions, TNIK binds protein kinase Cε and suppresses the NADPH oxidase 2/ROS/ERK5 pathway, thereby preventing excessive platelet activation. Megakaryocyte/platelet-specific TNIK knockout mice exhibit prolonged bleeding times, delayed arterial thrombosis, and impaired dense granule secretion under normal conditions, but accelerated thrombosis under hyperlipidemia. Platelet-specific Tnik knockout mice (Tnikf/fPF4-Cre+), co-immunoprecipitation (TNIK-JIP1, TNIK-PKCε), bleeding time assay, arterial thrombosis model, platelet activation assays, ROS measurement Blood advances High 41512175
2025 TNIK knockdown reduces ERK5 transcriptional activity and downregulates KLF2, KLF4, and eNOS in endothelial cells. TNIK overexpression enhances ERK5 transcriptional activity. Constitutively active MEK5 rescues ERK5 transcriptional activity in TNIK-depleted cells (MEK5-dependent mechanism). Phosphorylation-deficient TNIK mutants (S764A and S769A) retain ability to enhance ERK5 transcriptional activity, indicating a kinase-independent regulatory role. TNIK knockdown increases NFκB activity and EC apoptosis. Mammalian one-hybrid assay (ERK5 transcriptional activity), qRT-PCR (KLF2/KLF4/eNOS), siRNA knockdown, constitutively active MEK5 rescue, phosphorylation-deficient TNIK mutants, NFκB reporter Frontiers in cardiovascular medicine Medium 40672381
2024 Pharmacological or siRNA-mediated TNIK inhibition decreases cellular senescence in multiple experimental senescence models, and the TNIK inhibitor INS018_055 reduces SASP (senescence-associated secretory phenotype). Transcriptomics reveal INS018_055 reduces aging signatures and extracellular matrix fibronectin through TGF-β signaling. Automated robotic phenotypic screening, multiple senescence models, siRNA TNIK depletion, SASP measurement (ELISA/proteomics), transcriptomics Aging and disease Medium 39965245
2020 CNK2 scaffold protein directly interacts with TNIK and directs TNIK subcellular localization in neurons. Both CNK2 and TNIK are postsynaptically localized in dendritic spines; CNK2 is required to ensure TNIK is present at correct levels and location in the postsynaptic density. Co-immunoprecipitation (CNK2-TNIK), immunofluorescence (co-localization in dendritic spines), CNK2 knockdown + TNIK localization Scientific reports Medium 32235845

Source papers

Stage 0 corpus · 81 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2024 A small-molecule TNIK inhibitor targets fibrosis in preclinical and clinical models. Nature biotechnology 185 38459338
2009 The kinase TNIK is an essential activator of Wnt target genes. The EMBO journal 175 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 172 10521462
2016 TNIK inhibition abrogates colorectal cancer stemness. Nature communications 133 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 87 28993483
2015 Therapeutic targets in the Wnt signaling pathway: Feasibility of targeting TNIK in colorectal cancer. Pharmacology & therapeutics 75 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 70 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 66 21048137
2021 TNIK Is a Therapeutic Target in Lung Squamous Cell Carcinoma and Regulates FAK Activation through Merlin. Cancer discovery 53 33495197
2022 De Novo Discovery of Thiopeptide Pseudo-natural Products Acting as Potent and Selective TNIK Kinase Inhibitors. Journal of the American Chemical Society 50 36282922
2021 Simultaneous CK2/TNIK/DYRK1 inhibition by 108600 suppresses triple negative breast cancer stem cells and chemotherapy-resistant disease. Nature communications 49 34344863
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
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
2023 TNIK is a conserved regulator of glucose and lipid metabolism in obesity. Science advances 31 37556547
2016 A null mutation in TNIK defines a novel locus for intellectual disability. Human genetics 31 27106596
2014 The essential role of TNIK gene amplification in gastric cancer growth. Oncogenesis 31 24566388
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 Inhibition of Wnt Signaling in Colon Cancer Cells via an Oral Drug that Facilitates TNIK Degradation. Molecular cancer therapeutics 26 36302395
2019 Characterization of the ERG-regulated Kinome in Prostate Cancer Identifies TNIK as a Potential Therapeutic Target. Neoplasia (New York, N.Y.) 26 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 23 32242021
2011 Enormous influence of TNIK knockdown on intracellular signals and cell survival. Human cell 22 21710359
2024 TNIK's emerging role in cancer, metabolism, and age-related diseases. Trends in pharmacological sciences 21 38777670
2021 Direct conversion of osteosarcoma to adipocytes by targeting TNIK. JCI insight 21 33400690
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
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
2021 Identification of TNIK as a novel potential drug target in thyroid cancer based on protein druggability prediction. Medicine 19 33879700
2021 GPCR-mediated YAP/TAZ inactivation in fibroblasts via EPAC1/2, RAP2C, and MAP4K7. Journal of cellular physiology 19 34046891
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
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
2022 Structural Insight into TNIK Inhibition. International journal of molecular sciences 15 36361804
2012 Agonistic and antagonistic roles for TNIK and MINK in non-canonical and canonical Wnt signalling. PloS one 15 22984420
2023 LKB1 loss promotes colorectal cancer cell metastasis through regulating TNIK expression and actin cytoskeleton remodeling. Molecular carcinogenesis 14 37449799
2020 Disease-associated synaptic scaffold protein CNK2 modulates PSD size and influences localisation of the regulatory kinase TNIK. Scientific reports 13 32235845
2015 Epigenetic regulation of traf2- and Nck-interacting kinase (TNIK) in polycystic ovary syndrome. American journal of translational research 13 26279758
2024 Mutations in the postsynaptic density signaling hub TNIK disrupt PSD signaling in human models of neurodevelopmental disorders. Frontiers in molecular neuroscience 12 38638602
2024 Discovery of Bis-imidazolecarboxamide Derivatives as Novel, Potent, and Selective TNIK Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis. Journal of medicinal chemistry 12 39422731
2022 TNIK Inhibition Has Dual Synergistic Effects on Tumor and Associated Immune Cells. Advanced biology 11 35675910
2025 AI-Driven Robotics Laboratory Identifies Pharmacological TNIK Inhibition as a Potent Senomorphic Agent. Aging and disease 10 39965245
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
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 Effect of TNIK upregulation on JQ1-resistant human colorectal cancer HCT116 cells. Biochemical and biophysical research communications 9 32828291
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
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
2024 TNIK in disease: from molecular insights to therapeutic prospects. Apoptosis : an international journal on programmed cell death 7 38853204
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 7 37318197
2023 TNIK drives castration-resistant prostate cancer via phosphorylating EGFR. iScience 7 38226156
2022 Computational study on new natural compound inhibitors of Traf2 and Nck-interacting kinase (TNIK). Aging 7 36287174
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: A redox sensor in endothelial cell permeability. Science advances 5 39705357
2025 Identification of a TNIK-CDK9 Axis as a Targetable Strategy for Platinum-Resistant Ovarian Cancer. Molecular cancer therapeutics 4 39873147
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 4 40999821
2024 TNIK regulation of interferon signaling and endothelial cell response to virus infection. Frontiers in cardiovascular medicine 4 38264262
2023 Expression analysis of TRAF2‑ and NCK‑interacting protein kinase (TNIK) and phosphorylated TNIK in papillary thyroid carcinoma. Oncology letters 4 37332335
2025 Rap2a promotes cardiac fibrosis and exacerbates myocardial infarction through the TNIK/Merlin/YAP axis. Cell biology and toxicology 3 40332594
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
2025 TNIK-driven regulation of ERK5 transcriptional activity in endothelial cells. Frontiers in cardiovascular medicine 2 40672381
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 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 Mendelian randomization integrated with multi-omics analysis identifies TNIK as a key gene in gut microbiota-induced IBD development. Frontiers in immunology 0 41341599

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