{"gene":"TNIK","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":1999,"finding":"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.","method":"Cloning and characterization; transfection overexpression/kinase-mutant rescue; in vitro kinase assay (Gelsolin phosphorylation); co-immunoprecipitation with TRAF2 and Nck","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay plus mutant rescue plus binding experiments in original discovery paper with multiple orthogonal methods","pmids":["10521462"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Proteomics (TCF4 interactor screen); ChIP; in vitro binding and kinase assays; siRNA depletion followed by expression array analysis; kinase-mutant overexpression","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro kinase/binding assay plus ChIP plus siRNA/mutant rescue, multiple orthogonal methods in a highly cited study","pmids":["19816403"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Neuronal overexpression of wild-type and truncated mutants; AMPA receptor surface expression assays; dendritic arborization quantification; Rap2 activity manipulation","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — clean loss-of-function/gain-of-function with specific cellular phenotypes and domain-mapping mutants, replicated across MINK/TNIK comparisons","pmids":["21048137"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Co-immunoprecipitation; synaptic fractionation; functional assays of postsynaptic density protein levels","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal interaction validated with functional consequence on PSD protein levels, single lab","pmids":["20838393"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Knockout mouse; co-immunoprecipitation (AKAP9/NMDAR); AMPA receptor expression; behavioral testing (touchscreen); pharmacological rescue with GSK3β inhibitors","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — comprehensive knockout study with multiple phenotypes, binding partners identified, pharmacological rescue, replicated by subsequent papers","pmids":["23035106"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Functional proteomics; RNAi knockdown; Co-IP; domain-mapping experiments; NF-κB and JNK reporter assays; B-cell proliferation/survival assays","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 — functional proteomics plus RNAi plus co-IP plus domain mapping, multiple orthogonal methods, strong evidence for pathway bifurcation","pmids":["22904686"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Xenopus embryo overexpression; proteolytic cleavage characterization; canonical/non-canonical Wnt reporter assays; domain-deletion mutants","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — domain mapping with functional Wnt assays in an ortholog model organism, single lab","pmids":["22984420"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Co-immunoprecipitation (Rap2-LRP6); siRNA knockdown; proteasome/lysosome inhibitors; Wnt reporter assays; epistasis in Xenopus neural crest induction","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP plus epistasis plus reporter assay, single lab","pmids":["23743195"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Immunoprecipitation with phosphomotif antibody followed by mass spectrometry; selective small-molecule TNIK inhibitor; shRNA knockdown; activation-loop mutagenesis; cell-based phosphorylation assays","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"High","confidence_rationale":"Tier 1 — substrate identification by phosphoproteomic MS plus mutagenesis of activation loop plus inhibitor validation, multiple orthogonal methods","pmids":["26645429"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Spinal nerve ligation model; TNIK knockdown (siRNA); Co-IP (TNIK-GluR1); phosphorylation assays; GluR1 trafficking/subcellular fractionation; pharmacological rescue with Fbxo3 inhibitor","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — co-IP, in vivo knockdown with specific behavioral phenotype, ubiquitination pathway mapping, multiple orthogonal methods","pmids":["26674878"],"is_preprint":false},{"year":2015,"finding":"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.","method":"High-resolution light and electron microscopic immunocytochemistry; subcellular fractionation","journal":"The Journal of comparative neurology","confidence":"Medium","confidence_rationale":"Tier 2 — direct ultrastructural localization experiment with clear subcellular specificity, single lab","pmids":["25753355"],"is_preprint":false},{"year":2016,"finding":"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.","method":"X-ray crystallography (TNIK/inhibitor co-crystal); Tnik knockout mouse (AOM carcinogenesis model, Apcmin/+ cross); sphere- and tumor-forming assays; NCB-0846 pharmacological inhibition","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus in vivo genetic models plus cancer stem cell functional assays, replicated across multiple models","pmids":["27562646"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Trophic factor withdrawal model in mouse DRG neurons; siRNA/pharmacological inhibition of MAP4Ks; DLK phosphorylation/stabilization assays; retrograde JNK translocation assays; neuroprotection assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — genetic and pharmacological epistasis in neurons, DLK phosphorylation and retrograde transport mechanistically characterized, replicated with multiple kinase perturbations","pmids":["28993483"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Genetic epistasis in C. elegans (mig-15 mutants, constitutively active/inactive rap-2 mutants, plx-1 mutants); overexpression of mig-15; synaptic tiling assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — clean genetic epistasis with multiple alleles in vivo, well-controlled C. elegans ortholog study","pmids":["30063210"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Splicing assays; iPSC neuronal differentiation; neuroblastoma cells; co-IP (RNA-dependent TDP-43/NOVA-1 interaction); functional assays (cell spreading, neuritogenesis)","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 — RNA-dependent co-IP plus functional isoform characterization, single lab but multiple cell systems","pmids":["31382054"],"is_preprint":false},{"year":2020,"finding":"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.","method":"TNIK-deficient T cell transfer; LCMV infection model; β-catenin nuclear translocation assay; symmetric/asymmetric division analysis; serial re-transplantation experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — in vivo knockout model with mechanistic readouts (β-catenin translocation, division mode), multiple phenotypic assays","pmids":["32242021"],"is_preprint":false},{"year":2021,"finding":"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.","method":"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","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 1 — substrate identification by mass spectrometry plus in vitro kinase assay plus genetic/pharmacological loss-of-function in PDX models","pmids":["33495197"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Mass spectrometry phosphosite mapping; in vitro kinase assay; site-directed mutagenesis (S67A, T278A); subcellular localization assays; capsid formation assays","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay plus site-directed mutagenesis plus functional consequence on Arc localization and capsid assembly","pmids":["34077555"],"is_preprint":false},{"year":2021,"finding":"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.","method":"TNIK inhibition (NCB-0846) and RNAi; transcriptome analysis; metabolome analysis; in vitro and in vivo OS models; PPARγ pathway analysis","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 — transcriptome + metabolome + in vivo models, single lab","pmids":["33400690"],"is_preprint":false},{"year":2022,"finding":"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.","method":"X-ray crystallography; in vitro enzymatic assays; KD measurement (SPR/affinity); cell-based TNIK inhibition assays in HCT116 cells","journal":"Journal of the American Chemical Society","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional in vitro assay validation, substrate-competitive mechanism defined","pmids":["36282922"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Drosophila misshapen knockout (metabolite profiling); Tnik knockout mouse (high-fat diet model); glucose uptake assays; metabolomics","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 — ortholog genetic loss-of-function in two model organisms with multiple metabolic readouts","pmids":["37556547"],"is_preprint":false},{"year":2023,"finding":"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.","method":"CRISPR-Cas9 LKB1 knockout; RNA-seq; western blot; TNIK shRNA knockdown; Co-IP (TNIK-ARHGAP29); actin cytoskeleton assays; in vivo metastasis model","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis (LKB1→TNIK) plus TNIK-ARHGAP29 co-IP plus actin cytoskeleton functional assay, single lab","pmids":["37449799"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Microarray gene expression; ChIP (AR/H3K27me3 at TNIK promoter); TNIK silencing; EGFR phosphorylation assays in C4-2 cells","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP for epigenetic mechanism plus EGFR phosphorylation functional assay, single lab","pmids":["38226156"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay plus redox mechanism (Cys202 mutagenesis implied by disulfide detection) plus in vivo model, multiple orthogonal methods","pmids":["39705357"],"is_preprint":false},{"year":2024,"finding":"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.","method":"hiPSC-derived excitatory neurons; TNIK kinase-dead and null mutations; phosphoproteomics; interactome analysis; neuronal activity measurements","journal":"Frontiers in molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — human iPSC model with phosphoproteomic readout, kinase-dead mutant mechanistic characterization, single lab","pmids":["38638602"],"is_preprint":false},{"year":2024,"finding":"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.","method":"siRNA depletion in two hRPTEC cell lines; bulk RNA-sequencing; pathway analysis; apoptosis assays (annexin V, PARP-1 cleavage, flow cytometry)","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA knockdown with transcriptomic readout and multiple apoptosis assays, single lab","pmids":["38482555"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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","journal":"Frontiers in cardiovascular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis with MEK5 mutants plus TNIK phosphorylation mutants defining kinase-independent role, single lab","pmids":["40672381"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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","journal":"Blood advances","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific knockout with distinct phenotypes in two contexts, co-IP binding partners identified, pathway epistasis established, multiple orthogonal methods","pmids":["41512175"],"is_preprint":false},{"year":2025,"finding":"TNIK regulates focal adhesion turnover and mitosis in lung adenocarcinoma cells via the RHO/ROCK2/LIMK1 signaling pathway, controlling F-actin and microtubule organization.","method":"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)","journal":"Frontiers in bioscience (Landmark edition)","confidence":"Medium","confidence_rationale":"Tier 2 — clean knockdown with pathway identification by RNA-seq and protein assays, in vivo validation, single lab","pmids":["40464520"],"is_preprint":false}],"current_model":"TNIK is a germinal center kinase family serine/threonine kinase that functions as a critical signaling hub in multiple contexts: it directly phosphorylates TCF4 to activate Wnt/β-catenin target gene transcription as part of the TCF4/β-catenin complex; it phosphorylates substrates including Gelsolin, Merlin/NF2, ERM proteins, Arc, GluR1, and delta-catenin family members to regulate cytoskeletal dynamics, focal adhesion kinase activation, endothelial barrier function, and synaptic AMPA receptor trafficking; it activates the JNK pathway via its GCK homology domain and regulates DLK/JNK stress signaling in neurons as a MAP4K; it organizes postsynaptic density protein complexes at glutamatergic synapses (binding NMDA receptor via AKAP9 and interacting with DISC1); it mediates NF-κB and JNK signaling in B cells downstream of TRAF6/TAK1 at the LMP1/CD40 signalosome; and its kinase activity is redox-regulated by H2O2-mediated oxidation of Cys202, forming inhibitory disulfide bonds."},"narrative":{"teleology":[{"year":1999,"claim":"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","pmids":["10521462"],"confidence":"High","gaps":["Endogenous substrates beyond Gelsolin unknown","Physiological context of TRAF2/Nck interactions unresolved","In vivo function not addressed"]},{"year":2009,"claim":"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","pmids":["19816403"],"confidence":"High","gaps":["TCF4 phosphorylation sites and their individual functional contributions undefined","Relationship to other Wnt kinases not clarified","In vivo cancer relevance not yet tested"]},{"year":2010,"claim":"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","pmids":["21048137","20838393"],"confidence":"High","gaps":["Direct TNIK substrates at the PSD not identified","Whether DISC1 regulates TNIK kinase activity unknown","Behavioral consequences of TNIK synaptic loss not yet shown"]},{"year":2012,"claim":"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","pmids":["23035106"],"confidence":"High","gaps":["Mechanism by which TNIK restrains GSK3β not molecularly defined","Contribution of kinase versus scaffold function in vivo not separated","Human relevance not yet demonstrated"]},{"year":2012,"claim":"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","pmids":["22904686"],"confidence":"High","gaps":["Whether TNIK kinase directly phosphorylates IKKβ or acts through an intermediary unclear","Relevance to non-EBV B cell activation not tested"]},{"year":2015,"claim":"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","pmids":["26645429","26674878"],"confidence":"High","gaps":["Whether delta-catenin phosphorylation mediates specific adhesion phenotypes in vivo not shown","Precise phosphorylation sites on GluR1 by TNIK not mapped"]},{"year":2016,"claim":"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","pmids":["27562646"],"confidence":"High","gaps":["Whether TNIK kinase activity alone or scaffold function drives stem cell maintenance unclear","Patient-stratification biomarkers not defined"]},{"year":2017,"claim":"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","pmids":["28993483"],"confidence":"High","gaps":["Individual contribution of TNIK versus MAP4K4 versus MINK1 in vivo not genetically separated","Whether TNIK directly phosphorylates DLK not biochemically shown"]},{"year":2020,"claim":"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","pmids":["32242021"],"confidence":"High","gaps":["Direct TNIK substrates in T cells not identified","Whether kinase activity or scaffold function mediates division symmetry switch unknown"]},{"year":2021,"claim":"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","pmids":["33495197","34077555"],"confidence":"High","gaps":["Functional consequence of Merlin phosphorylation sites not individually mapped","In vivo relevance of Arc phosphorylation by TNIK not tested"]},{"year":2023,"claim":"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","pmids":["37556547"],"confidence":"High","gaps":["Direct TNIK substrates in metabolic tissues not identified","Whether Wnt or JNK pathway mediates the metabolic phenotype unclear"]},{"year":2024,"claim":"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","pmids":["39705357"],"confidence":"High","gaps":["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"]},{"year":2025,"claim":"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","pmids":["41512175"],"confidence":"High","gaps":["Whether TNIK directly phosphorylates JIP1 or PKCε not shown","Mechanism triggering partner switch from JIP1 to PKCε under hyperlipidemia undefined"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length TNIK structure available","Kinase-dead knockin mouse not reported","Causal human disease mutations not validated by family/rescue studies"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,8,9,16,17,23]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,12,15,26,27]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,14,28]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[23]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,5,7,12,15,22,27]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[11,16,22]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[2,4,9,10,13]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[20]}],"complexes":["TCF4/β-catenin transcription complex","TRAF6/TAK1/TAB2/IKKβ signalosome","Postsynaptic density complex"],"partners":["TCF4","CTNNB1","TRAF6","TRAF2","DISC1","AKAP9","RAP2A","JIP1"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"Q9UKE5","full_name":"TRAF2 and NCK-interacting protein kinase","aliases":[],"length_aa":1360,"mass_kda":154.9,"function":"Serine/threonine kinase that acts as an essential activator of the Wnt signaling pathway. Recruited to promoters of Wnt target genes and required to activate their expression. May act by phosphorylating TCF4/TCF7L2. Appears to act upstream of the JUN N-terminal pathway. May play a role in the response to environmental stress. Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development. More generally, it may play a role in cytoskeletal rearrangements and regulate cell spreading. Phosphorylates SMAD1 on Thr-322. Activator of the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. MAP4Ks act in parallel to and are partially redundant with STK3/MST2 and STK4/MST2 in the phosphorylation and activation of LATS1/2, and establish MAP4Ks as components of the expanded Hippo pathway (PubMed:26437443)","subcellular_location":"Nucleus; Cytoplasm; Recycling endosome; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q9UKE5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TNIK","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TNIK","total_profiled":1310},"omim":[{"mim_id":"617028","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 54; MRT54","url":"https://www.omim.org/entry/617028"},{"mim_id":"610005","title":"TRAF2- AND NCK-INTERACTING KINASE; TNIK","url":"https://www.omim.org/entry/610005"},{"mim_id":"602278","title":"NEURAL PRECURSOR CELL EXPRESSED, DEVELOPMENTALLY DOWNREGULATED 4; NEDD4","url":"https://www.omim.org/entry/602278"},{"mim_id":"601949","title":"CALCIUM CHANNEL, VOLTAGE-DEPENDENT, BETA-4 SUBUNIT; CACNB4","url":"https://www.omim.org/entry/601949"},{"mim_id":"179540","title":"RAS-RELATED PROTEIN 2A; RAP2A","url":"https://www.omim.org/entry/179540"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TNIK"},"hgnc":{"alias_symbol":["MAP4K7","KIAA0551"],"prev_symbol":[]},"alphafold":{"accession":"Q9UKE5","domains":[{"cath_id":"3.30.200.20","chopping":"12-108","consensus_level":"medium","plddt":84.3861,"start":12,"end":108},{"cath_id":"1.10.510.10","chopping":"109-293","consensus_level":"medium","plddt":85.6075,"start":109,"end":293},{"cath_id":"2.130.10.10","chopping":"1144-1275","consensus_level":"medium","plddt":90.1287,"start":1144,"end":1275},{"cath_id":"1.20.5","chopping":"389-465","consensus_level":"medium","plddt":82.171,"start":389,"end":465}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKE5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKE5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKE5-F1-predicted_aligned_error_v6.png","plddt_mean":63.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TNIK","jax_strain_url":"https://www.jax.org/strain/search?query=TNIK"},"sequence":{"accession":"Q9UKE5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UKE5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UKE5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKE5"}},"corpus_meta":[{"pmid":"19816403","id":"PMC_19816403","title":"The 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Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/21048137","citation_count":65,"is_preprint":false},{"pmid":"33495197","id":"PMC_33495197","title":"TNIK Is a Therapeutic Target in Lung Squamous Cell Carcinoma and Regulates FAK Activation through Merlin.","date":"2021","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/33495197","citation_count":51,"is_preprint":false},{"pmid":"31302315","id":"PMC_31302315","title":"Jatrorrhizine inhibits mammary carcinoma cells by targeting TNIK mediated Wnt/β-catenin signalling and epithelial-mesenchymal transition (EMT).","date":"2019","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31302315","citation_count":48,"is_preprint":false},{"pmid":"36282922","id":"PMC_36282922","title":"De Novo Discovery of Thiopeptide Pseudo-natural Products Acting as Potent and Selective TNIK Kinase Inhibitors.","date":"2022","source":"Journal of the American Chemical 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therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/26645429","citation_count":30,"is_preprint":false},{"pmid":"27106596","id":"PMC_27106596","title":"A null mutation in TNIK defines a novel locus for intellectual disability.","date":"2016","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27106596","citation_count":30,"is_preprint":false},{"pmid":"37556547","id":"PMC_37556547","title":"TNIK is a conserved regulator of glucose and lipid metabolism in obesity.","date":"2023","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/37556547","citation_count":29,"is_preprint":false},{"pmid":"36302395","id":"PMC_36302395","title":"Inhibition of Wnt Signaling in Colon Cancer Cells via an Oral Drug that Facilitates TNIK Degradation.","date":"2023","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/36302395","citation_count":25,"is_preprint":false},{"pmid":"30901730","id":"PMC_30901730","title":"Characterization of the ERG-regulated Kinome in Prostate Cancer Identifies TNIK as a Potential Therapeutic Target.","date":"2019","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/30901730","citation_count":24,"is_preprint":false},{"pmid":"23232060","id":"PMC_23232060","title":"Discovery of 4-phenyl-2-phenylaminopyridine based TNIK inhibitors.","date":"2012","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/23232060","citation_count":24,"is_preprint":false},{"pmid":"30063210","id":"PMC_30063210","title":"Rap2 and TNIK control Plexin-dependent tiled synaptic innervation in C. elegans.","date":"2018","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/30063210","citation_count":24,"is_preprint":false},{"pmid":"32242021","id":"PMC_32242021","title":"TNIK signaling imprints CD8+ T cell memory formation early after priming.","date":"2020","source":"Nature 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Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/38482555","citation_count":8,"is_preprint":false},{"pmid":"32828291","id":"PMC_32828291","title":"Effect of TNIK upregulation on JQ1-resistant human colorectal cancer HCT116 cells.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/32828291","citation_count":8,"is_preprint":false},{"pmid":"39965245","id":"PMC_39965245","title":"AI-Driven Robotics Laboratory Identifies Pharmacological TNIK Inhibition as a Potent Senomorphic Agent.","date":"2025","source":"Aging and disease","url":"https://pubmed.ncbi.nlm.nih.gov/39965245","citation_count":8,"is_preprint":false},{"pmid":"34350475","id":"PMC_34350475","title":"TNIK influence the effects of antipsychotics on Wnt/β-catenin signaling pathway.","date":"2021","source":"Psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34350475","citation_count":7,"is_preprint":false},{"pmid":"32831519","id":"PMC_32831519","title":"Molecular Docking analysis of the TNIK Receptor protein with a potential Inhibitor from the NPACT databas.","date":"2020","source":"Bioinformation","url":"https://pubmed.ncbi.nlm.nih.gov/32831519","citation_count":7,"is_preprint":false},{"pmid":"38670554","id":"PMC_38670554","title":"TNIK Inhibition Sensitizes TNIK-Overexpressing Lung Squamous Cell Carcinoma to Radiotherapy.","date":"2024","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/38670554","citation_count":6,"is_preprint":false},{"pmid":"38853204","id":"PMC_38853204","title":"TNIK in disease: from molecular insights to therapeutic prospects.","date":"2024","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/38853204","citation_count":6,"is_preprint":false},{"pmid":"36287174","id":"PMC_36287174","title":"Computational study on new natural compound inhibitors of Traf2 and Nck-interacting kinase (TNIK).","date":"2022","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/36287174","citation_count":6,"is_preprint":false},{"pmid":"38422698","id":"PMC_38422698","title":"Fragment growth-based discovery of novel TNIK inhibitors for the treatment of colorectal cancer.","date":"2024","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38422698","citation_count":6,"is_preprint":false},{"pmid":"39705357","id":"PMC_39705357","title":"TNIK: A redox sensor in endothelial cell permeability.","date":"2024","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/39705357","citation_count":5,"is_preprint":false},{"pmid":"37318197","id":"PMC_37318197","title":"MiR-5590-3p inhibits the proliferation and invasion of ovarian cancer cells through mediating the Wnt/β-catenin signaling pathway by targeting TNIK.","date":"2023","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/37318197","citation_count":5,"is_preprint":false},{"pmid":"38264262","id":"PMC_38264262","title":"TNIK regulation of interferon signaling and endothelial cell response to virus infection.","date":"2024","source":"Frontiers in cardiovascular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38264262","citation_count":4,"is_preprint":false},{"pmid":"38226156","id":"PMC_38226156","title":"TNIK drives castration-resistant prostate cancer via phosphorylating EGFR.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/38226156","citation_count":4,"is_preprint":false},{"pmid":"38763968","id":"PMC_38763968","title":"Therapeutic targeting of TNIK in papillary thyroid carcinoma: a novel approach for tumor growth suppression.","date":"2024","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/38763968","citation_count":3,"is_preprint":false},{"pmid":"39284759","id":"PMC_39284759","title":"miR-151a-3p regulates the TNIK/PI3K/Akt axis and influences the progression of polycystic ovary syndrome.","date":"2024","source":"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","url":"https://pubmed.ncbi.nlm.nih.gov/39284759","citation_count":3,"is_preprint":false},{"pmid":"40999821","id":"PMC_40999821","title":"Integrated Machine Learning and Structure-Based Virtual Screening Identify Osimertinib as a TNIK Inhibitor for Idiopathic Pulmonary Fibrosis.","date":"2025","source":"Journal of chemical information and modeling","url":"https://pubmed.ncbi.nlm.nih.gov/40999821","citation_count":3,"is_preprint":false},{"pmid":"37215541","id":"PMC_37215541","title":"Deficiency of germinal center kinase TRAF2 and NCK-interacting kinase (TNIK) in B cells does not affect atherosclerosis.","date":"2023","source":"Frontiers in cardiovascular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37215541","citation_count":3,"is_preprint":false},{"pmid":"37332335","id":"PMC_37332335","title":"Expression analysis of TRAF2‑ and NCK‑interacting protein kinase (TNIK) and phosphorylated TNIK in papillary thyroid carcinoma.","date":"2023","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/37332335","citation_count":3,"is_preprint":false},{"pmid":"39873147","id":"PMC_39873147","title":"Identification of a TNIK-CDK9 Axis as a Targetable Strategy for Platinum-Resistant Ovarian Cancer.","date":"2025","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/39873147","citation_count":2,"is_preprint":false},{"pmid":"35698907","id":"PMC_35698907","title":"The influence of TNIK gene polymorphisms on risperidone response in a Chinese Han population.","date":"2022","source":"Pharmacogenomics","url":"https://pubmed.ncbi.nlm.nih.gov/35698907","citation_count":2,"is_preprint":false},{"pmid":"23355318","id":"PMC_23355318","title":"Dynamic change of TNIK in response to tumor necrosis factor alpha in a TRAF2-dependent manner.","date":"2013","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/23355318","citation_count":2,"is_preprint":false},{"pmid":"40706539","id":"PMC_40706539","title":"Therapeutic applications and molecular mechanisms of TNIK inhibitors: A comprehensive review of current advances.","date":"2025","source":"Bioorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40706539","citation_count":1,"is_preprint":false},{"pmid":"40332594","id":"PMC_40332594","title":"Rap2a promotes cardiac fibrosis and exacerbates myocardial infarction through the TNIK/Merlin/YAP axis.","date":"2025","source":"Cell biology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/40332594","citation_count":1,"is_preprint":false},{"pmid":"39268461","id":"PMC_39268461","title":"Transcriptome analysis to explore the mechanism of downregulated TNIK influencing the effect of risperidone.","date":"2024","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39268461","citation_count":1,"is_preprint":false},{"pmid":"40176540","id":"PMC_40176540","title":"Pleiotropic Role of TNIK in Sepsis-Induced Cardiomyopathy.","date":"2025","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/40176540","citation_count":0,"is_preprint":false},{"pmid":"40464520","id":"PMC_40464520","title":"TNIK Regulates Cytoskeletal Organization to Promote Focal Adhesion Turnover and Mitosis in Lung Adenocarcinoma.","date":"2025","source":"Frontiers in bioscience (Landmark edition)","url":"https://pubmed.ncbi.nlm.nih.gov/40464520","citation_count":0,"is_preprint":false},{"pmid":"41341599","id":"PMC_41341599","title":"Mendelian randomization integrated with multi-omics analysis identifies TNIK as a key gene in gut microbiota-induced IBD development.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41341599","citation_count":0,"is_preprint":false},{"pmid":"41909809","id":"PMC_41909809","title":"A system-wide investigation into the phosphoregulatory network of TNIK and its cellular implications.","date":"2026","source":"Frontiers in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/41909809","citation_count":0,"is_preprint":false},{"pmid":"41512175","id":"PMC_41512175","title":"TNIK as a molecular switch regulating platelet function in hemostasis and hyperlipidemia-associated thrombosis.","date":"2026","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/41512175","citation_count":0,"is_preprint":false},{"pmid":"41838988","id":"PMC_41838988","title":"TNIK overexpression is sufficient for chemoradiation resistance in limited-stage small cell lung cancer.","date":"2026","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/41838988","citation_count":0,"is_preprint":false},{"pmid":"40672381","id":"PMC_40672381","title":"TNIK-driven regulation of ERK5 transcriptional activity in endothelial cells.","date":"2025","source":"Frontiers in cardiovascular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40672381","citation_count":0,"is_preprint":false},{"pmid":"41818865","id":"PMC_41818865","title":"Discovery of potent TNIK inhibitors containing a 1H-pyrrolo[2,3-b]pyridine scaffold as promising therapeutics for colorectal cancer.","date":"2026","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41818865","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.26.661826","title":"Interactome Analysis of the CC2D1A Scaffold Reveals Novel Neuronal Interactions and a Postsynaptic Role","date":"2025-06-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.26.661826","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.06.12.598725","title":"PTBP1 mediates Sertoli cell actin cytoskeleton organization by regulating alternative splicing of actin regulators","date":"2024-06-12","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.12.598725","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.31.646367","title":"Human-chimpanzee tetraploid system defines mechanisms of species-specific neural gene regulation","date":"2025-03-31","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.31.646367","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":41186,"output_tokens":7799,"usd":0.120272},"stage2":{"model":"claude-opus-4-6","input_tokens":11558,"output_tokens":4190,"usd":0.24381},"total_usd":0.364082,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Cloning and characterization; transfection overexpression/kinase-mutant rescue; in vitro kinase assay (Gelsolin phosphorylation); co-immunoprecipitation with TRAF2 and Nck\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay plus mutant rescue plus binding experiments in original discovery paper with multiple orthogonal methods\",\n      \"pmids\": [\"10521462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Proteomics (TCF4 interactor screen); ChIP; in vitro binding and kinase assays; siRNA depletion followed by expression array analysis; kinase-mutant overexpression\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro kinase/binding assay plus ChIP plus siRNA/mutant rescue, multiple orthogonal methods in a highly cited study\",\n      \"pmids\": [\"19816403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Neuronal overexpression of wild-type and truncated mutants; AMPA receptor surface expression assays; dendritic arborization quantification; Rap2 activity manipulation\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function/gain-of-function with specific cellular phenotypes and domain-mapping mutants, replicated across MINK/TNIK comparisons\",\n      \"pmids\": [\"21048137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; synaptic fractionation; functional assays of postsynaptic density protein levels\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction validated with functional consequence on PSD protein levels, single lab\",\n      \"pmids\": [\"20838393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Knockout mouse; co-immunoprecipitation (AKAP9/NMDAR); AMPA receptor expression; behavioral testing (touchscreen); pharmacological rescue with GSK3β inhibitors\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — comprehensive knockout study with multiple phenotypes, binding partners identified, pharmacological rescue, replicated by subsequent papers\",\n      \"pmids\": [\"23035106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Functional proteomics; RNAi knockdown; Co-IP; domain-mapping experiments; NF-κB and JNK reporter assays; B-cell proliferation/survival assays\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional proteomics plus RNAi plus co-IP plus domain mapping, multiple orthogonal methods, strong evidence for pathway bifurcation\",\n      \"pmids\": [\"22904686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Xenopus embryo overexpression; proteolytic cleavage characterization; canonical/non-canonical Wnt reporter assays; domain-deletion mutants\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping with functional Wnt assays in an ortholog model organism, single lab\",\n      \"pmids\": [\"22984420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (Rap2-LRP6); siRNA knockdown; proteasome/lysosome inhibitors; Wnt reporter assays; epistasis in Xenopus neural crest induction\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus epistasis plus reporter assay, single lab\",\n      \"pmids\": [\"23743195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Immunoprecipitation with phosphomotif antibody followed by mass spectrometry; selective small-molecule TNIK inhibitor; shRNA knockdown; activation-loop mutagenesis; cell-based phosphorylation assays\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — substrate identification by phosphoproteomic MS plus mutagenesis of activation loop plus inhibitor validation, multiple orthogonal methods\",\n      \"pmids\": [\"26645429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Spinal nerve ligation model; TNIK knockdown (siRNA); Co-IP (TNIK-GluR1); phosphorylation assays; GluR1 trafficking/subcellular fractionation; pharmacological rescue with Fbxo3 inhibitor\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP, in vivo knockdown with specific behavioral phenotype, ubiquitination pathway mapping, multiple orthogonal methods\",\n      \"pmids\": [\"26674878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"High-resolution light and electron microscopic immunocytochemistry; subcellular fractionation\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct ultrastructural localization experiment with clear subcellular specificity, single lab\",\n      \"pmids\": [\"25753355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography (TNIK/inhibitor co-crystal); Tnik knockout mouse (AOM carcinogenesis model, Apcmin/+ cross); sphere- and tumor-forming assays; NCB-0846 pharmacological inhibition\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus in vivo genetic models plus cancer stem cell functional assays, replicated across multiple models\",\n      \"pmids\": [\"27562646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Trophic factor withdrawal model in mouse DRG neurons; siRNA/pharmacological inhibition of MAP4Ks; DLK phosphorylation/stabilization assays; retrograde JNK translocation assays; neuroprotection assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological epistasis in neurons, DLK phosphorylation and retrograde transport mechanistically characterized, replicated with multiple kinase perturbations\",\n      \"pmids\": [\"28993483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic epistasis in C. elegans (mig-15 mutants, constitutively active/inactive rap-2 mutants, plx-1 mutants); overexpression of mig-15; synaptic tiling assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic epistasis with multiple alleles in vivo, well-controlled C. elegans ortholog study\",\n      \"pmids\": [\"30063210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Splicing assays; iPSC neuronal differentiation; neuroblastoma cells; co-IP (RNA-dependent TDP-43/NOVA-1 interaction); functional assays (cell spreading, neuritogenesis)\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNA-dependent co-IP plus functional isoform characterization, single lab but multiple cell systems\",\n      \"pmids\": [\"31382054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"TNIK-deficient T cell transfer; LCMV infection model; β-catenin nuclear translocation assay; symmetric/asymmetric division analysis; serial re-transplantation experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo knockout model with mechanistic readouts (β-catenin translocation, division mode), multiple phenotypic assays\",\n      \"pmids\": [\"32242021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — substrate identification by mass spectrometry plus in vitro kinase assay plus genetic/pharmacological loss-of-function in PDX models\",\n      \"pmids\": [\"33495197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry phosphosite mapping; in vitro kinase assay; site-directed mutagenesis (S67A, T278A); subcellular localization assays; capsid formation assays\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay plus site-directed mutagenesis plus functional consequence on Arc localization and capsid assembly\",\n      \"pmids\": [\"34077555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"TNIK inhibition (NCB-0846) and RNAi; transcriptome analysis; metabolome analysis; in vitro and in vivo OS models; PPARγ pathway analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcriptome + metabolome + in vivo models, single lab\",\n      \"pmids\": [\"33400690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography; in vitro enzymatic assays; KD measurement (SPR/affinity); cell-based TNIK inhibition assays in HCT116 cells\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional in vitro assay validation, substrate-competitive mechanism defined\",\n      \"pmids\": [\"36282922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Drosophila misshapen knockout (metabolite profiling); Tnik knockout mouse (high-fat diet model); glucose uptake assays; metabolomics\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ortholog genetic loss-of-function in two model organisms with multiple metabolic readouts\",\n      \"pmids\": [\"37556547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR-Cas9 LKB1 knockout; RNA-seq; western blot; TNIK shRNA knockdown; Co-IP (TNIK-ARHGAP29); actin cytoskeleton assays; in vivo metastasis model\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis (LKB1→TNIK) plus TNIK-ARHGAP29 co-IP plus actin cytoskeleton functional assay, single lab\",\n      \"pmids\": [\"37449799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Microarray gene expression; ChIP (AR/H3K27me3 at TNIK promoter); TNIK silencing; EGFR phosphorylation assays in C4-2 cells\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP for epigenetic mechanism plus EGFR phosphorylation functional assay, single lab\",\n      \"pmids\": [\"38226156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay plus redox mechanism (Cys202 mutagenesis implied by disulfide detection) plus in vivo model, multiple orthogonal methods\",\n      \"pmids\": [\"39705357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"hiPSC-derived excitatory neurons; TNIK kinase-dead and null mutations; phosphoproteomics; interactome analysis; neuronal activity measurements\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — human iPSC model with phosphoproteomic readout, kinase-dead mutant mechanistic characterization, single lab\",\n      \"pmids\": [\"38638602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA depletion in two hRPTEC cell lines; bulk RNA-sequencing; pathway analysis; apoptosis assays (annexin V, PARP-1 cleavage, flow cytometry)\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA knockdown with transcriptomic readout and multiple apoptosis assays, single lab\",\n      \"pmids\": [\"38482555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Frontiers in cardiovascular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis with MEK5 mutants plus TNIK phosphorylation mutants defining kinase-independent role, single lab\",\n      \"pmids\": [\"40672381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific knockout with distinct phenotypes in two contexts, co-IP binding partners identified, pathway epistasis established, multiple orthogonal methods\",\n      \"pmids\": [\"41512175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TNIK regulates focal adhesion turnover and mitosis in lung adenocarcinoma cells via the RHO/ROCK2/LIMK1 signaling pathway, controlling F-actin and microtubule organization.\",\n      \"method\": \"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)\",\n      \"journal\": \"Frontiers in bioscience (Landmark edition)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean knockdown with pathway identification by RNA-seq and protein assays, in vivo validation, single lab\",\n      \"pmids\": [\"40464520\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TNIK is a germinal center kinase family serine/threonine kinase that functions as a critical signaling hub in multiple contexts: it directly phosphorylates TCF4 to activate Wnt/β-catenin target gene transcription as part of the TCF4/β-catenin complex; it phosphorylates substrates including Gelsolin, Merlin/NF2, ERM proteins, Arc, GluR1, and delta-catenin family members to regulate cytoskeletal dynamics, focal adhesion kinase activation, endothelial barrier function, and synaptic AMPA receptor trafficking; it activates the JNK pathway via its GCK homology domain and regulates DLK/JNK stress signaling in neurons as a MAP4K; it organizes postsynaptic density protein complexes at glutamatergic synapses (binding NMDA receptor via AKAP9 and interacting with DISC1); it mediates NF-κB and JNK signaling in B cells downstream of TRAF6/TAK1 at the LMP1/CD40 signalosome; and its kinase activity is redox-regulated by H2O2-mediated oxidation of Cys202, forming inhibitory disulfide bonds.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cloning, overexpression of WT and kinase-dead mutants, in vitro kinase assay on Gelsolin, co-IP with TRAF2 and Nck in mammalian cells\",\n      \"pmids\": [\"10521462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous substrates beyond Gelsolin unknown\", \"Physiological context of TRAF2/Nck interactions unresolved\", \"In vivo function not addressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"Proteomics-based TCF4 interactor screen, ChIP on Wnt target promoters, in vitro kinase and binding assays, siRNA depletion and kinase-dead mutant rescue\",\n      \"pmids\": [\"19816403\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TCF4 phosphorylation sites and their individual functional contributions undefined\", \"Relationship to other Wnt kinases not clarified\", \"In vivo cancer relevance not yet tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"evidence\": \"Neuronal overexpression of WT and truncated mutants with AMPA receptor and dendritic assays; co-IP of TNIK-DISC1 with PSD protein level quantification\",\n      \"pmids\": [\"21048137\", \"20838393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct TNIK substrates at the PSD not identified\", \"Whether DISC1 regulates TNIK kinase activity unknown\", \"Behavioral consequences of TNIK synaptic loss not yet shown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"TNIK knockout mouse with co-IP (AKAP9/NMDAR), AMPA receptor and behavioral assays, GSK3β inhibitor pharmacological rescue\",\n      \"pmids\": [\"23035106\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which TNIK restrains GSK3β not molecularly defined\", \"Contribution of kinase versus scaffold function in vivo not separated\", \"Human relevance not yet demonstrated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"22904686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TNIK kinase directly phosphorylates IKKβ or acts through an intermediary unclear\", \"Relevance to non-EBV B cell activation not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"26645429\", \"26674878\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether delta-catenin phosphorylation mediates specific adhesion phenotypes in vivo not shown\", \"Precise phosphorylation sites on GluR1 by TNIK not mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"X-ray co-crystal structure; Tnik−/− and Tnik−/−/Apcmin/+ mouse models; sphere/tumor-forming assays; NCB-0846 pharmacological inhibition\",\n      \"pmids\": [\"27562646\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TNIK kinase activity alone or scaffold function drives stem cell maintenance unclear\", \"Patient-stratification biomarkers not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"siRNA and pharmacological MAP4K inhibition in trophic factor-deprived DRG neurons; DLK phosphorylation/stabilization assays; retrograde JNK translocation\",\n      \"pmids\": [\"28993483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual contribution of TNIK versus MAP4K4 versus MINK1 in vivo not genetically separated\", \"Whether TNIK directly phosphorylates DLK not biochemically shown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"TNIK-deficient T cell adoptive transfer in LCMV infection model; β-catenin nuclear translocation; division symmetry analysis; serial re-transplantation\",\n      \"pmids\": [\"32242021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct TNIK substrates in T cells not identified\", \"Whether kinase activity or scaffold function mediates division symmetry switch unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Mass spectrometry substrate identification and in vitro kinase assays for Merlin; phosphosite mapping and mutagenesis for Arc; PDX models for LSCC\",\n      \"pmids\": [\"33495197\", \"34077555\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Merlin phosphorylation sites not individually mapped\", \"In vivo relevance of Arc phosphorylation by TNIK not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Drosophila misshapen knockout with metabolite profiling; Tnik knockout mouse on high-fat diet with glucose uptake and metabolomics\",\n      \"pmids\": [\"37556547\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct TNIK substrates in metabolic tissues not identified\", \"Whether Wnt or JNK pathway mediates the metabolic phenotype unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro kinase assay on ERM proteins; Cys202 disulfide bond detection after H₂O₂; TNIK KO endothelial cells; in vivo oedema model\",\n      \"pmids\": [\"39705357\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"41512175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TNIK directly phosphorylates JIP1 or PKCε not shown\", \"Mechanism triggering partner switch from JIP1 to PKCε under hyperlipidemia undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length TNIK structure available\", \"Kinase-dead knockin mouse not reported\", \"Causal human disease mutations not validated by family/rescue studies\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 8, 9, 16, 17, 23]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 12, 15, 26, 27]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 14, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [23]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 5, 7, 12, 15, 22, 27]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [11, 16, 22]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2, 4, 9, 10, 13]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"complexes\": [\n      \"TCF4/β-catenin transcription complex\",\n      \"TRAF6/TAK1/TAB2/IKKβ signalosome\",\n      \"Postsynaptic density complex\"\n    ],\n    \"partners\": [\n      \"TCF4\",\n      \"CTNNB1\",\n      \"TRAF6\",\n      \"TRAF2\",\n      \"DISC1\",\n      \"AKAP9\",\n      \"RAP2A\",\n      \"JIP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}