{"gene":"TAOK2","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":1999,"finding":"TAO2 is a serine/threonine kinase that selectively activates MAP kinase kinases MEK3, MEK4, and MEK6 of stress-responsive MAPK pathways in vitro. TAO2 copurified with endogenous MEK3 in Sf9 cells. The MEK-binding domain was localized to an ~135-residue sequence just C-terminal to the catalytic domain; this domain binds MEK3 and MEK6 (but not MEKs 1, 2, or 4) via the MEK N-terminus. Catalytic activity of full-length TAO2 enhanced MEK binding.","method":"Recombinant protein kinase assay, copurification from Sf9 cells, MEK-binding domain mapping with chimeric MEK proteins","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with domain mapping and chimeric protein experiments, single lab but multiple orthogonal methods","pmids":["10497253"],"is_preprint":false},{"year":2000,"finding":"PSK (TAOK2) is a STE20-family serine/threonine kinase that activates MKK4 and MKK7 and thereby activates the JNK MAPK pathway when transfected into cells. Immunoprecipitated PSK phosphorylates myelin basic protein. Microinjection of PSK causes its localization to a vesicular compartment and a marked reduction in actin stress fibers; this requires the C-terminus (residues 1–1235 but not 1–349) and kinase activity (K57A mutant fails to reduce stress fibers).","method":"Immunoprecipitation kinase assay, transfection reporter assay, microinjection with live-cell imaging, kinase-dead and truncation mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay, cell-based pathway activation, domain/mutant analysis; single lab with multiple orthogonal methods","pmids":["10660600"],"is_preprint":false},{"year":2001,"finding":"TAO2 overexpression in cells activates endogenous JNK/SAPK and p38 but not ERK1/2. Cotransfection experiments showed selective activation of MEK3 and MEK6 but not MEKs 1, 4, or 7. Co-immunoprecipitation demonstrated that endogenous TAO2 specifically associates with MEK3 and MEK6. Sorbitol, NaCl, Taxol, and nocodazole increase TAO2 activity toward itself and kinase-dead MEK3/6. Endogenous TAO2 activity is also induced during C2C12 myoblast differentiation in parallel with p38 activation.","method":"Overexpression in cells with reporter/western assays, co-immunoprecipitation, in vitro kinase assay with osmo/chemical stresses, cell differentiation model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus multiple cell-based pathway assays, single lab with orthogonal methods","pmids":["11279118"],"is_preprint":false},{"year":2003,"finding":"PSK (TAOK2) colocalizes with microtubules in cells; this colocalization is disrupted by nocodazole. PSK association with microtubules produces stabilized, perinuclear, nocodazole-resistant microtubule cables enriched in acetylated alpha-tubulin. Kinase-dead PSK (K57A) or the isolated C-terminus (residues 745–1235) lacking the kinase domain are sufficient for microtubule binding and stabilization. The N-terminus (1–940) alone cannot bind or stabilize microtubules. PSK binds and phosphorylates alpha- and beta-tubulin in vitro.","method":"Immunofluorescence colocalization, nocodazole treatment, kinase-dead and domain truncation mutants, in vitro binding/phosphorylation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro binding/phosphorylation plus cell imaging with domain mutants; single lab, multiple orthogonal methods","pmids":["12639963"],"is_preprint":false},{"year":2004,"finding":"Crystal structure of the TAO2 kinase domain (residues 1–320) solved in its phosphorylated active conformation. Structure-based mutagenesis revealed that positively charged residues in the substrate-binding groove mediate the first phosphorylation step of MEK6 (on threonine in the motif DS*VAKT*I). Comparison with low-activity PAK1 reveals how Ste20p-family kinases are activated by phosphorylation. Active TAO2 displays unusual ATP interactions involving a subgroup-specific C-terminal extension.","method":"X-ray crystallography, structure-based mutagenesis, in vitro kinase assay","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at active conformation with mutagenic functional validation; rigorous single study","pmids":["15458637"],"is_preprint":false},{"year":2006,"finding":"TAO2 associates with TAK1 (MAP3K) and inhibits TAK1-mediated NF-κB activation but not TAK1-mediated JNK activation during osmotic stress. TAO2 interferes with the interaction between TAK1 and IKK, providing a mechanism for pathway-selective TAK1 signaling. TAO2 was identified as a TAK1-binding protein in a binding screen.","method":"Binding screen, co-immunoprecipitation, cell-based NF-κB and JNK reporter assays, osmotic stress treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus pathway-selective reporter assays; single lab with multiple orthogonal methods","pmids":["16893890"],"is_preprint":false},{"year":2006,"finding":"Crystal structure of the TAO2 kinase domain bound to staurosporine reveals that the inhibitor occupies the ATP adenosine-binding site. Staurosporine induces limited conformational changes around the binding pocket. The structure provides atomic detail for TAO2 inhibitor interactions.","method":"X-ray crystallography with staurosporine co-crystal","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure in single study; limited functional validation beyond structural description","pmids":["16761096"],"is_preprint":false},{"year":2012,"finding":"TAOK2 is essential for basal dendrite formation in cortical pyramidal neurons in vivo; knockdown impairs basal (but not apical) dendrites and axonal projections. TAOK2 interacts physically with Neuropilin-1 (Nrp1). TAOK2 overexpression rescues basal dendrite deficits in Nrp1(Sema-) neurons that cannot bind Sema3A, and rescues Nrp1-knockdown phenotypes in vivo. Sema3A and TAOK2 regulate basal dendrite formation through JNK activation, placing TAOK2 downstream of Sema3A/Nrp1 and upstream of JNK.","method":"In vivo knockdown/overexpression in cortical neurons, co-immunoprecipitation (TAOK2-Nrp1), epistasis rescue experiments, JNK pathway readouts","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vivo KD/OE with specific phenotypic readouts, genetic epistasis across multiple models; replicated in multiple systems","pmids":["22683681"],"is_preprint":false},{"year":2012,"finding":"Conditional nervous-system-specific ablation of Taok2 in mice produces strain-specific alterations in ethanol-dependent behaviors (locomotor stimulation response to ethanol), functionally conserving the role of its Drosophila ortholog dtao.","method":"Conditional knockout (nervous system-specific Cre), behavioral assays for ethanol responses","journal":"Genes, brain, and behavior","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean conditional KO with specific behavioral phenotype; single lab, single method category","pmids":["22883308"],"is_preprint":false},{"year":2017,"finding":"TAOK2 kinase activity is required for dendritic spine maturation. Using chemical genetics and mass spectrometry, TAOK2 was shown to directly phosphorylate Septin7 at an evolutionarily conserved residue. This phosphorylation induces Septin7 translocation to the spine, where Septin7 associates with and stabilizes PSD95, promoting spine maturation and compartmentalization of NMDA receptor-mediated calcium influx. TAOK2 depletion causes unstable dendritic protrusions, mislocalized shaft-synapses, and loss of calcium compartmentalization.","method":"Chemical genetics (analog-sensitive kinase), mass spectrometry phosphoproteomics, in vitro kinase assay, live-cell imaging of calcium, shRNA knockdown with spine morphology analysis","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct phosphorylation identified by chemical genetics + MS + in vitro assay, functional validation by multiple imaging and morphological readouts; single lab but multiple highly orthogonal methods","pmids":["28065648"],"is_preprint":false},{"year":2018,"finding":"Loss of Taok2 activity in mice causes reduction in RhoA activation, and pharmacological enhancement of RhoA activity rescues synaptic phenotypes caused by Taok2 loss. De novo ASD mutations in TAOK2 impair protein stability and differentially affect kinase activity, dendrite growth, and spine/synapse development. Taok2 KO mice show dosage-dependent defects in brain size, neural connectivity, cortical layering, dendrite/synapse formation, and excitatory neurotransmission.","method":"Taok2 knockout/heterozygous mice, RhoA activation assay, pharmacological rescue, human cell functional analysis of patient mutations, behavioral assays","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with specific cellular phenotypes, RhoA pathway assay with pharmacological rescue, multiple orthogonal readouts across labs/models","pmids":["29467497"],"is_preprint":false},{"year":2021,"finding":"TAOK2 localizes to distinct ER subdomains via transmembrane helices and an adjacent amphipathic region, and directly binds microtubules through its C-terminal tail, functioning as an ER-MT tether. In TAOK2 knockout cells, ER membrane dynamics increase but movement of ER along growing MT plus ends is disrupted. ER-MT tethering is regulated by TAOK2 kinase activity; perturbation of catalytic activity causes defects in ER morphology, ER-MT association, and cell division.","method":"Subcellular fractionation, live-cell imaging (ER dynamics), TAOK2 KO cells, domain mapping (transmembrane/amphipathic/C-terminal), in vitro MT binding, kinase-dead mutant analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct MT binding in vitro, live imaging of ER dynamics in KO cells, domain mapping with mutants; single lab but multiple orthogonal methods","pmids":["34879262"],"is_preprint":false},{"year":2022,"finding":"TAOK2α isoform (but not TAOK2β) colocalizes with microtubules. Loss of Taok2 causes unstable microtubules with reduced acetylated tubulin and reduced phospho-JNK1. Taok2 KO and acute knockdown delay migration of upper-layer cortical neurons; expression of constitutively active JNK1 rescues these migration defects, placing TAOK2 upstream of JNK1 in neuronal migration. TAOK2α introduction into 16p11.2 heterozygous deletion mice (which have reduced p-JNK1) rescues neuronal migration deficits.","method":"Taok2 KO mice, in utero electroporation for acute knockdown/overexpression, immunostaining for cortical layering, phospho-JNK1 western blot, constitutively active JNK1 rescue, 16p11.2 del mouse model","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mice + acute KD with specific migration phenotype, genetic epistasis with CA-JNK1 rescue, replicated across multiple models","pmids":["36123424"],"is_preprint":false},{"year":2022,"finding":"A nuclear pool of TAO2 localizes to nuclear speckles and interacts with nuclear speckle factors SRSF1 and Aly/Ref (involved in RNA splicing and nuclear export). Depletion or kinase inhibition of TAO2 disrupts nuclear speckle structure, decreases levels of SC35 and SON (speckle assembly/splicing proteins), and impairs pre-mRNA splicing and nuclear export of influenza M mRNA, reducing viral replication.","method":"Immunofluorescence localization, co-immunoprecipitation (TAO2 with SRSF1/Aly-Ref), siRNA depletion, kinase inhibitor treatment, western blot for SC35/SON, mRNA splicing/export assays, viral replication assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP with speckle factors, KD plus kinase inhibition with specific functional readouts (splicing, export, viral replication); single lab with multiple orthogonal methods","pmids":["35704758"],"is_preprint":false},{"year":2022,"finding":"Taok2 is required for vacuolar escape of Listeria monocytogenes in epithelial cells; siRNA knockdown of Taok2 reduces vacuolar rupture and cytoplasmic access of Listeria. Pharmacological inhibition of Taok2 kinase activity validated this role. Taok2 recruitment to Listeria vacuoles requires the pore-forming toxin listeriolysin O.","method":"High-content siRNA microscopy screen, pharmacological kinase inhibition, immunofluorescence imaging of Listeria vacuolar rupture","journal":"The Journal of infectious diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA screen validated by pharmacological inhibition and imaging; single study with two orthogonal loss-of-function methods","pmids":["32582947"],"is_preprint":false},{"year":2024,"finding":"TAOK2 associates with the translational machinery and directly phosphorylates eukaryotic elongation factor 2 (eEF2) at the same regulatory site (Thr56) as eEF2K, functioning as a translational brake. This pathway operates independently of eEF2K. Loss of TAOK2 (in 16p11.2 deletion models) leads to increased translation. This identifies an eEF2K-independent mechanism of translation elongation control.","method":"Proteomics (co-IP mass spectrometry for translational machinery association), in vitro kinase assay (direct eEF2 phosphorylation), translation assays in cultured cells and mouse brain, genetic models (16p11.2 deletion mice and cells)","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro phosphorylation of eEF2 demonstrated, proteomics for complex, functional translation assays in cells and in vivo; single lab but multiple orthogonal methods","pmids":["38608030"],"is_preprint":false},{"year":2016,"finding":"Three small-molecule compounds identified by high-throughput screening (200,000 compounds) inhibit TAOK2 kinase activity and also inhibit autophagy, providing early evidence that TAOK2 kinase activity is required for autophagy in NSCLC cells.","method":"High-throughput kinase inhibitor screen, SAR analysis, autophagy assay","journal":"Bioorganic & medicinal chemistry letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — compound screen with limited mechanistic follow-up; single study, indirect link between kinase inhibition and autophagy","pmids":["27426302"],"is_preprint":false}],"current_model":"TAOK2 is a multifunctional STE20-family serine/threonine MAP3K that activates p38 and JNK pathways by directly phosphorylating MEK3/6 (and MEK4), associates with and inhibits TAK1-IKK signaling during osmotic stress, phosphorylates cytoskeletal substrates including tubulin and Septin7 (inducing Septin7 translocation to stabilize PSD95 at dendritic spines), tethers ER membranes to microtubules via its C-terminal tail and transmembrane domain, functions as a translational brake by directly phosphorylating eEF2 independently of eEF2K, localizes to nuclear speckles where its kinase activity maintains speckle integrity and pre-mRNA splicing/export, and acts upstream of RhoA and JNK1 to regulate neuronal migration and basal dendrite formation downstream of Sema3A/Nrp1 signaling."},"narrative":{"mechanistic_narrative":"TAOK2 (TAO2/PSK) is a STE20-family serine/threonine MAP3K that couples stress and cytoskeletal cues to MAPK signaling and that organizes microtubule, ER, and neuronal architecture [PMID:10497253, PMID:11279118]. As a MAP3K it selectively activates the stress-responsive p38 and JNK pathways by binding and phosphorylating MEK3 and MEK6 (and MKK4/MKK7), while sparing ERK; its kinase domain has been crystallized in an active, autophosphorylated conformation that phosphorylates MEK6 within a defined motif [PMID:10497253, PMID:11279118, PMID:15458637]. Beyond canonical MAPK signaling, TAOK2 binds TAK1 and selectively interferes with the TAK1–IKK interaction to restrain NF-κB activation during osmotic stress [PMID:16893890]. TAOK2 is also a cytoskeletal organizer: its kinase-independent C-terminal tail binds and stabilizes microtubules into acetylated, nocodazole-resistant cables, and the same tail together with transmembrane and amphipathic regions tethers ER subdomains to growing microtubule plus ends [PMID:12639963, PMID:34879262]. In neurons, TAOK2 acts downstream of Sema3A/Neuropilin-1 and upstream of JNK1 and RhoA to drive basal dendrite formation, cortical neuronal migration, and spine maturation, the last via direct phosphorylation of Septin7 that recruits it to spines to stabilize PSD95 [PMID:22683681, PMID:28065648, PMID:29467497, PMID:36123424]. A nuclear pool localizes to nuclear speckles where its kinase activity maintains speckle integrity and supports pre-mRNA splicing and mRNA export [PMID:35704758], and TAOK2 additionally acts as an eEF2K-independent translational brake by directly phosphorylating eEF2 at Thr56 [PMID:38608030]. De novo TAOK2 mutations and 16p11.2 deletion link the gene to autism-spectrum neurodevelopmental phenotypes through impaired protein stability, kinase activity, dendrite growth, and synapse development [PMID:29467497, PMID:36123424].","teleology":[{"year":1999,"claim":"Established TAOK2 as a MAP3K by showing it selectively activates and binds stress-pathway MAP kinase kinases, defining its position upstream of p38/JNK signaling.","evidence":"Recombinant kinase assays, copurification with MEK3 from Sf9 cells, and MEK-binding domain mapping with chimeric MEKs","pmids":["10497253"],"confidence":"High","gaps":["Did not establish which physiological stimuli engage this kinase in cells","In vitro substrate selectivity not yet validated for endogenous complexes"]},{"year":2000,"claim":"Showed TAOK2 activates the JNK pathway and that its C-terminus and kinase activity drive vesicular localization and actin stress fiber loss, linking the kinase to cytoskeletal remodeling.","evidence":"Immunoprecipitation kinase assay, transfection reporter assays, microinjection with live imaging, and truncation/kinase-dead mutants","pmids":["10660600"],"confidence":"High","gaps":["Direct cytoskeletal substrate not identified","Mechanism connecting kinase activity to actin disassembly unresolved"]},{"year":2001,"claim":"Demonstrated endogenous TAOK2 selectively activates p38 and JNK (not ERK) via MEK3/6 and is induced by osmotic/microtubule stress and myoblast differentiation, framing it as a stress- and cytoskeleton-responsive kinase.","evidence":"Cell overexpression with reporter/western readouts, reciprocal co-IP, and in vitro kinase assays under sorbitol/NaCl/Taxol/nocodazole","pmids":["11279118"],"confidence":"High","gaps":["Upstream sensor that activates TAOK2 under stress not defined","Link between microtubule perturbation and kinase activation mechanistic only by correlation"]},{"year":2004,"claim":"Resolved how TAOK2 is catalytically activated and recognizes substrate, providing the structural basis for STE20-family activation by phosphorylation.","evidence":"X-ray crystallography of the active kinase domain with structure-based mutagenesis and in vitro kinase assays","pmids":["15458637"],"confidence":"High","gaps":["Structure limited to isolated kinase domain","Full-length regulatory architecture not visualized"]},{"year":2003,"claim":"Identified a kinase-independent microtubule-binding and -stabilizing function in the C-terminus and tubulin as a direct substrate, distinguishing TAOK2's scaffolding role from its catalytic role.","evidence":"Immunofluorescence colocalization with nocodazole challenge, domain/kinase-dead mutants, and in vitro tubulin binding/phosphorylation","pmids":["12639963"],"confidence":"High","gaps":["Functional consequence of tubulin phosphorylation undefined","Relationship between MT stabilization and MAPK signaling unresolved"]},{"year":2006,"claim":"Defined a pathway-selective brake on innate signaling: TAOK2 binds TAK1 and blocks the TAK1–IKK interaction to suppress NF-κB without affecting TAK1-driven JNK.","evidence":"Binding screen, reciprocal co-IP, and NF-κB/JNK reporter assays under osmotic stress","pmids":["16893890"],"confidence":"High","gaps":["Whether inhibition requires TAOK2 kinase activity not established","Physiological setting of TAK1 antagonism in vivo unknown"]},{"year":2006,"claim":"Provided atomic detail of inhibitor binding to the TAOK2 ATP pocket, enabling structure-guided inhibitor design.","evidence":"X-ray crystallography of the kinase domain co-crystallized with staurosporine","pmids":["16761096"],"confidence":"Medium","gaps":["Limited functional validation beyond structural description","Selectivity over related kinases not addressed"]},{"year":2012,"claim":"Placed TAOK2 in a neurodevelopmental signaling axis, acting downstream of Sema3A/Nrp1 and upstream of JNK to direct basal dendrite and axon formation in vivo.","evidence":"In vivo cortical knockdown/overexpression, TAOK2-Nrp1 co-IP, and epistasis rescue with JNK readouts","pmids":["22683681"],"confidence":"High","gaps":["Direct phosphorylation substrate in the dendrite pathway not identified","How Nrp1 engagement activates TAOK2 kinase activity unknown"]},{"year":2012,"claim":"Demonstrated functional conservation of TAOK2 in nervous-system behavior using a conditional knockout, linking the kinase to ethanol-response phenotypes.","evidence":"Nervous-system-specific conditional knockout mice with ethanol behavioral assays","pmids":["22883308"],"confidence":"Medium","gaps":["Molecular mechanism underlying behavioral phenotype undefined","Strain-specific effects complicate interpretation"]},{"year":2017,"claim":"Identified Septin7 as a direct TAOK2 substrate whose phosphorylation drives spine localization and PSD95 stabilization, providing a molecular mechanism for spine maturation and calcium compartmentalization.","evidence":"Analog-sensitive kinase chemical genetics, MS phosphoproteomics, in vitro kinase assay, and calcium/spine imaging with knockdown","pmids":["28065648"],"confidence":"High","gaps":["How Septin7 phosphorylation triggers its translocation mechanistically unresolved","Whether other spine substrates exist not addressed"]},{"year":2018,"claim":"Tied TAOK2 to RhoA activation and to autism-associated dysfunction, showing patient mutations and gene dosage perturb kinase activity, dendrite/synapse development, and cortical structure.","evidence":"Taok2 KO/het mice, RhoA activation assay with pharmacological rescue, and functional analysis of de novo ASD mutations","pmids":["29467497"],"confidence":"High","gaps":["Direct effector linking TAOK2 to RhoA activation not identified","How distinct mutations differentially affect activity not fully mapped"]},{"year":2021,"claim":"Established TAOK2 as an ER–microtubule tether through its transmembrane/amphipathic and C-terminal MT-binding regions, with kinase activity governing ER morphology, ER-MT coupling, and cell division.","evidence":"Fractionation, live ER-dynamics imaging in KO cells, domain mapping, in vitro MT binding, and kinase-dead mutants","pmids":["34879262"],"confidence":"High","gaps":["Substrate phosphorylated to regulate ER-MT tethering unidentified","Connection between ER tethering and MAPK/neuronal roles unexplored"]},{"year":2022,"claim":"Resolved a TAOK2α-specific role in cortical neuron migration upstream of JNK1, with constitutively active JNK1 rescuing migration defects in KO and 16p11.2 deletion models.","evidence":"Taok2 KO mice, in utero electroporation knockdown/overexpression, phospho-JNK1 westerns, and CA-JNK1 genetic rescue","pmids":["36123424"],"confidence":"High","gaps":["Isoform-specific determinant of MT colocalization not pinned to a sequence element","Direct kinase substrate driving migration not defined"]},{"year":2022,"claim":"Uncovered a nuclear function: a speckle-localized TAOK2 pool whose kinase activity maintains speckle integrity and supports pre-mRNA splicing and nuclear export.","evidence":"Immunofluorescence, co-IP with SRSF1/Aly-Ref, siRNA and kinase inhibition with splicing/export and viral-replication readouts","pmids":["35704758"],"confidence":"High","gaps":["Direct splicing/speckle substrate of TAOK2 not identified","How TAOK2 partitions between cytoplasmic and nuclear pools unknown"]},{"year":2022,"claim":"Listeria exploitation revealed TAOK2 kinase activity is required for pathogen vacuolar escape, with recruitment depending on listeriolysin O.","evidence":"High-content siRNA screen, pharmacological kinase inhibition, and imaging of vacuolar rupture","pmids":["32582947"],"confidence":"Medium","gaps":["Host substrate mediating vacuolar rupture not identified","Mechanism of TAOK2 recruitment to vacuoles undefined"]},{"year":2024,"claim":"Defined an eEF2K-independent translational brake: TAOK2 directly phosphorylates eEF2 at Thr56 to repress elongation, linking the kinase to translational control disrupted in 16p11.2 deletion.","evidence":"Co-IP MS for translational machinery, in vitro kinase assay on eEF2, and translation assays in cells and mouse brain","pmids":["38608030"],"confidence":"High","gaps":["Signals that engage TAOK2-dependent eEF2 phosphorylation not mapped","Crosstalk with eEF2K regulation unresolved"]},{"year":2016,"claim":"Provided early pharmacological evidence linking TAOK2 kinase activity to autophagy in cancer cells.","evidence":"High-throughput inhibitor screen with SAR and autophagy assays","pmids":["27426302"],"confidence":"Low","gaps":["Indirect link between kinase inhibition and autophagy not mechanistically established","Compound selectivity for TAOK2 not validated","No autophagy substrate identified"]},{"year":null,"claim":"How TAOK2's distinct subcellular pools (cytoplasmic MAPK signaling, microtubule/ER tethering, nuclear speckles, translational machinery) are coordinated and which upstream signals partition the kinase among them remains unknown.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking the kinase-dependent and kinase-independent functions","Direct substrates for several functions (ER tethering, splicing, migration) not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,9,15]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,4,9,15]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[3,11]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[4,6]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[3,11,12]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[11]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[13]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,5,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,10,12]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[13]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10]}],"complexes":[],"partners":["MAP2K3","MAP2K6","MAP3K7","NRP1","SEPTIN7","SRSF1","ALYREF","EEF2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UL54","full_name":"Serine/threonine-protein kinase TAO2","aliases":["Kinase from chicken homolog C","hKFC-C","Prostate-derived sterile 20-like kinase 1","PSK-1","PSK1","Prostate-derived STE20-like kinase 1","Thousand and one amino acid protein kinase 2"],"length_aa":1235,"mass_kda":138.3,"function":"Serine/threonine-protein kinase involved in different processes such as membrane blebbing and apoptotic bodies formation DNA damage response and MAPK14/p38 MAPK stress-activated MAPK cascade. Phosphorylates itself, MBP, activated MAPK8, MAP2K3, MAP2K6 and tubulins. Activates the MAPK14/p38 MAPK signaling pathway through the specific activation and phosphorylation of the upstream MAP2K3 and MAP2K6 kinases. In response to DNA damage, involved in the G2/M transition DNA damage checkpoint by activating the p38/MAPK14 stress-activated MAPK cascade, probably by mediating phosphorylation of upstream MAP2K3 and MAP2K6 kinases. Isoform 1, but not isoform 2, plays a role in apoptotic morphological changes, including cell contraction, membrane blebbing and apoptotic bodies formation. This function, which requires the activation of MAPK8/JNK and nuclear localization of C-terminally truncated isoform 1, may be linked to the mitochondrial CASP9-associated death pathway. Isoform 1 binds to microtubules and affects their organization and stability independently of its kinase activity. Prevents MAP3K7-mediated activation of CHUK, and thus NF-kappa-B activation, but not that of MAPK8/JNK. May play a role in the osmotic stress-MAPK8 pathway. Isoform 2, but not isoform 1, is required for PCDH8 endocytosis. Following homophilic interactions between PCDH8 extracellular domains, isoform 2 phosphorylates and activates MAPK14/p38 MAPK which in turn phosphorylates isoform 2. This process leads to PCDH8 endocytosis and CDH2 cointernalization. Both isoforms are involved in MAPK14 phosphorylation","subcellular_location":"Cell projection, dendrite","url":"https://www.uniprot.org/uniprotkb/Q9UL54/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TAOK2","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000149930","cell_line_id":"CID001288","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"vesicles","grade":2}],"interactors":[{"gene":"MAPRE1","stoichiometry":0.2},{"gene":"HIST1H2AJ;HIST1H2AH;HIST1H2AD;HIST1H2AG;H2AFJ","stoichiometry":0.2},{"gene":"S100A7","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001288","total_profiled":1310},"omim":[{"mim_id":"616711","title":"TAO KINASE 3; TAOK3","url":"https://www.omim.org/entry/616711"},{"mim_id":"613199","title":"TAO 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sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31690047","citation_count":13,"is_preprint":false},{"pmid":"3204014","id":"PMC_3204014","title":"Morphological and biochemical alterations of macrophages produced by a glycan, PSK.","date":"1988","source":"Immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/3204014","citation_count":13,"is_preprint":false},{"pmid":"8196915","id":"PMC_8196915","title":"Immunochemotherapy in B-16-melanoma-cell-transplanted mice with combinations of interleukin-2, cyclophosphamide, and PSK.","date":"1994","source":"Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/8196915","citation_count":13,"is_preprint":false},{"pmid":"10374675","id":"PMC_10374675","title":"Differential effect of protein-bound polysaccharide (PSK) on survival of experimental murine tumors.","date":"1999","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/10374675","citation_count":13,"is_preprint":false},{"pmid":"19243246","id":"PMC_19243246","title":"Efficacy of postoperative UFT (Tegafur/Uracil) plus PSK therapies in elderly patients with resected colorectal cancer.","date":"2009","source":"Cancer biotherapy & radiopharmaceuticals","url":"https://pubmed.ncbi.nlm.nih.gov/19243246","citation_count":13,"is_preprint":false},{"pmid":"16761096","id":"PMC_16761096","title":"Crystal structure of the MAP3K TAO2 kinase domain bound by an inhibitor staurosporine.","date":"2006","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/16761096","citation_count":12,"is_preprint":false},{"pmid":"23685781","id":"PMC_23685781","title":"Gamma delta T cells are activated by polysaccharide K (PSK) and contribute to the anti-tumor effect of PSK.","date":"2013","source":"Cancer immunology, immunotherapy : CII","url":"https://pubmed.ncbi.nlm.nih.gov/23685781","citation_count":12,"is_preprint":false},{"pmid":"7762991","id":"PMC_7762991","title":"Polysaccharide preparation PSK augments the proliferation and cytotoxicity of tumor-infiltrating lymphocytes in vitro.","date":"1995","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/7762991","citation_count":12,"is_preprint":false},{"pmid":"3128500","id":"PMC_3128500","title":"Effects of PSK on interleukin-2 production by peripheral lymphocytes of patients with advanced ovarian carcinoma during chemotherapy.","date":"1988","source":"Japanese journal of cancer research : Gann","url":"https://pubmed.ncbi.nlm.nih.gov/3128500","citation_count":12,"is_preprint":false},{"pmid":"2369086","id":"PMC_2369086","title":"Stimulation of human peripheral blood polymorphonuclear cell iodination by PSK subfractions.","date":"1990","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/2369086","citation_count":12,"is_preprint":false},{"pmid":"7812358","id":"PMC_7812358","title":"Suppression of cancer cell growth in vitro by the protein-bound polysaccharide of Coriolus versicolor QUEL (PS-K) with SOD mimicking activity.","date":"1994","source":"Cancer biotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/7812358","citation_count":12,"is_preprint":false},{"pmid":"35704758","id":"PMC_35704758","title":"Nuclear speckle integrity and function require TAO2 kinase.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/35704758","citation_count":11,"is_preprint":false},{"pmid":"6094413","id":"PMC_6094413","title":"Construction of plasmid vectors from Streptomyces kasugaensis plasmids, pSK1 and pSK2.","date":"1984","source":"The Journal of antibiotics","url":"https://pubmed.ncbi.nlm.nih.gov/6094413","citation_count":11,"is_preprint":false},{"pmid":"18848763","id":"PMC_18848763","title":"Protein-bound polysaccharide-K (PSK) directly enhanced IgM production in the human B cell line BALL-1.","date":"2008","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/18848763","citation_count":11,"is_preprint":false},{"pmid":"38608030","id":"PMC_38608030","title":"The autism susceptibility kinase, TAOK2, phosphorylates eEF2 and modulates translation.","date":"2024","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/38608030","citation_count":10,"is_preprint":false},{"pmid":"11803050","id":"PMC_11803050","title":"SH2D1A expression reflects activation of T and NK cells in cord blood lymphocytes infected with EBV and treated with the immunomodulator PSK.","date":"2002","source":"Immunology letters","url":"https://pubmed.ncbi.nlm.nih.gov/11803050","citation_count":10,"is_preprint":false},{"pmid":"3141579","id":"PMC_3141579","title":"PSK, a polysaccharide from Coriolus vesicolor, enhances oxygen metabolism of murine peritoneal macrophages and the host resistance to listerial infection.","date":"1988","source":"Journal of general microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/3141579","citation_count":10,"is_preprint":false},{"pmid":"17764620","id":"PMC_17764620","title":"Enhancement of antitumor effect of tegafur/uracil (UFT) plus leucovorin by combined treatment with protein-bound polysaccharide, PSK, in mouse models.","date":"2007","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17764620","citation_count":10,"is_preprint":false},{"pmid":"37687322","id":"PMC_37687322","title":"The Research Process of PSK Biosynthesis, Signaling Transduction, and Potential Applications in Brassica napus.","date":"2023","source":"Plants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37687322","citation_count":9,"is_preprint":false},{"pmid":"28385331","id":"PMC_28385331","title":"RETRACTED: Generalized verrucosis and abnormal T cell activation due to homozygous TAOK2 mutation.","date":"2017","source":"Journal of dermatological science","url":"https://pubmed.ncbi.nlm.nih.gov/28385331","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47996,"output_tokens":4940,"usd":0.109044,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13122,"output_tokens":5345,"usd":0.099617,"stage2_stop_reason":"end_turn"},"total_usd":0.208661,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"TAO2 is a serine/threonine kinase that selectively activates MAP kinase kinases MEK3, MEK4, and MEK6 of stress-responsive MAPK pathways in vitro. TAO2 copurified with endogenous MEK3 in Sf9 cells. The MEK-binding domain was localized to an ~135-residue sequence just C-terminal to the catalytic domain; this domain binds MEK3 and MEK6 (but not MEKs 1, 2, or 4) via the MEK N-terminus. Catalytic activity of full-length TAO2 enhanced MEK binding.\",\n      \"method\": \"Recombinant protein kinase assay, copurification from Sf9 cells, MEK-binding domain mapping with chimeric MEK proteins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with domain mapping and chimeric protein experiments, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"10497253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PSK (TAOK2) is a STE20-family serine/threonine kinase that activates MKK4 and MKK7 and thereby activates the JNK MAPK pathway when transfected into cells. Immunoprecipitated PSK phosphorylates myelin basic protein. Microinjection of PSK causes its localization to a vesicular compartment and a marked reduction in actin stress fibers; this requires the C-terminus (residues 1–1235 but not 1–349) and kinase activity (K57A mutant fails to reduce stress fibers).\",\n      \"method\": \"Immunoprecipitation kinase assay, transfection reporter assay, microinjection with live-cell imaging, kinase-dead and truncation mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay, cell-based pathway activation, domain/mutant analysis; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"10660600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"TAO2 overexpression in cells activates endogenous JNK/SAPK and p38 but not ERK1/2. Cotransfection experiments showed selective activation of MEK3 and MEK6 but not MEKs 1, 4, or 7. Co-immunoprecipitation demonstrated that endogenous TAO2 specifically associates with MEK3 and MEK6. Sorbitol, NaCl, Taxol, and nocodazole increase TAO2 activity toward itself and kinase-dead MEK3/6. Endogenous TAO2 activity is also induced during C2C12 myoblast differentiation in parallel with p38 activation.\",\n      \"method\": \"Overexpression in cells with reporter/western assays, co-immunoprecipitation, in vitro kinase assay with osmo/chemical stresses, cell differentiation model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus multiple cell-based pathway assays, single lab with orthogonal methods\",\n      \"pmids\": [\"11279118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PSK (TAOK2) colocalizes with microtubules in cells; this colocalization is disrupted by nocodazole. PSK association with microtubules produces stabilized, perinuclear, nocodazole-resistant microtubule cables enriched in acetylated alpha-tubulin. Kinase-dead PSK (K57A) or the isolated C-terminus (residues 745–1235) lacking the kinase domain are sufficient for microtubule binding and stabilization. The N-terminus (1–940) alone cannot bind or stabilize microtubules. PSK binds and phosphorylates alpha- and beta-tubulin in vitro.\",\n      \"method\": \"Immunofluorescence colocalization, nocodazole treatment, kinase-dead and domain truncation mutants, in vitro binding/phosphorylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro binding/phosphorylation plus cell imaging with domain mutants; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"12639963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Crystal structure of the TAO2 kinase domain (residues 1–320) solved in its phosphorylated active conformation. Structure-based mutagenesis revealed that positively charged residues in the substrate-binding groove mediate the first phosphorylation step of MEK6 (on threonine in the motif DS*VAKT*I). Comparison with low-activity PAK1 reveals how Ste20p-family kinases are activated by phosphorylation. Active TAO2 displays unusual ATP interactions involving a subgroup-specific C-terminal extension.\",\n      \"method\": \"X-ray crystallography, structure-based mutagenesis, in vitro kinase assay\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at active conformation with mutagenic functional validation; rigorous single study\",\n      \"pmids\": [\"15458637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TAO2 associates with TAK1 (MAP3K) and inhibits TAK1-mediated NF-κB activation but not TAK1-mediated JNK activation during osmotic stress. TAO2 interferes with the interaction between TAK1 and IKK, providing a mechanism for pathway-selective TAK1 signaling. TAO2 was identified as a TAK1-binding protein in a binding screen.\",\n      \"method\": \"Binding screen, co-immunoprecipitation, cell-based NF-κB and JNK reporter assays, osmotic stress treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus pathway-selective reporter assays; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"16893890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structure of the TAO2 kinase domain bound to staurosporine reveals that the inhibitor occupies the ATP adenosine-binding site. Staurosporine induces limited conformational changes around the binding pocket. The structure provides atomic detail for TAO2 inhibitor interactions.\",\n      \"method\": \"X-ray crystallography with staurosporine co-crystal\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure in single study; limited functional validation beyond structural description\",\n      \"pmids\": [\"16761096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TAOK2 is essential for basal dendrite formation in cortical pyramidal neurons in vivo; knockdown impairs basal (but not apical) dendrites and axonal projections. TAOK2 interacts physically with Neuropilin-1 (Nrp1). TAOK2 overexpression rescues basal dendrite deficits in Nrp1(Sema-) neurons that cannot bind Sema3A, and rescues Nrp1-knockdown phenotypes in vivo. Sema3A and TAOK2 regulate basal dendrite formation through JNK activation, placing TAOK2 downstream of Sema3A/Nrp1 and upstream of JNK.\",\n      \"method\": \"In vivo knockdown/overexpression in cortical neurons, co-immunoprecipitation (TAOK2-Nrp1), epistasis rescue experiments, JNK pathway readouts\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vivo KD/OE with specific phenotypic readouts, genetic epistasis across multiple models; replicated in multiple systems\",\n      \"pmids\": [\"22683681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Conditional nervous-system-specific ablation of Taok2 in mice produces strain-specific alterations in ethanol-dependent behaviors (locomotor stimulation response to ethanol), functionally conserving the role of its Drosophila ortholog dtao.\",\n      \"method\": \"Conditional knockout (nervous system-specific Cre), behavioral assays for ethanol responses\",\n      \"journal\": \"Genes, brain, and behavior\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean conditional KO with specific behavioral phenotype; single lab, single method category\",\n      \"pmids\": [\"22883308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TAOK2 kinase activity is required for dendritic spine maturation. Using chemical genetics and mass spectrometry, TAOK2 was shown to directly phosphorylate Septin7 at an evolutionarily conserved residue. This phosphorylation induces Septin7 translocation to the spine, where Septin7 associates with and stabilizes PSD95, promoting spine maturation and compartmentalization of NMDA receptor-mediated calcium influx. TAOK2 depletion causes unstable dendritic protrusions, mislocalized shaft-synapses, and loss of calcium compartmentalization.\",\n      \"method\": \"Chemical genetics (analog-sensitive kinase), mass spectrometry phosphoproteomics, in vitro kinase assay, live-cell imaging of calcium, shRNA knockdown with spine morphology analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct phosphorylation identified by chemical genetics + MS + in vitro assay, functional validation by multiple imaging and morphological readouts; single lab but multiple highly orthogonal methods\",\n      \"pmids\": [\"28065648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of Taok2 activity in mice causes reduction in RhoA activation, and pharmacological enhancement of RhoA activity rescues synaptic phenotypes caused by Taok2 loss. De novo ASD mutations in TAOK2 impair protein stability and differentially affect kinase activity, dendrite growth, and spine/synapse development. Taok2 KO mice show dosage-dependent defects in brain size, neural connectivity, cortical layering, dendrite/synapse formation, and excitatory neurotransmission.\",\n      \"method\": \"Taok2 knockout/heterozygous mice, RhoA activation assay, pharmacological rescue, human cell functional analysis of patient mutations, behavioral assays\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with specific cellular phenotypes, RhoA pathway assay with pharmacological rescue, multiple orthogonal readouts across labs/models\",\n      \"pmids\": [\"29467497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TAOK2 localizes to distinct ER subdomains via transmembrane helices and an adjacent amphipathic region, and directly binds microtubules through its C-terminal tail, functioning as an ER-MT tether. In TAOK2 knockout cells, ER membrane dynamics increase but movement of ER along growing MT plus ends is disrupted. ER-MT tethering is regulated by TAOK2 kinase activity; perturbation of catalytic activity causes defects in ER morphology, ER-MT association, and cell division.\",\n      \"method\": \"Subcellular fractionation, live-cell imaging (ER dynamics), TAOK2 KO cells, domain mapping (transmembrane/amphipathic/C-terminal), in vitro MT binding, kinase-dead mutant analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct MT binding in vitro, live imaging of ER dynamics in KO cells, domain mapping with mutants; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"34879262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TAOK2α isoform (but not TAOK2β) colocalizes with microtubules. Loss of Taok2 causes unstable microtubules with reduced acetylated tubulin and reduced phospho-JNK1. Taok2 KO and acute knockdown delay migration of upper-layer cortical neurons; expression of constitutively active JNK1 rescues these migration defects, placing TAOK2 upstream of JNK1 in neuronal migration. TAOK2α introduction into 16p11.2 heterozygous deletion mice (which have reduced p-JNK1) rescues neuronal migration deficits.\",\n      \"method\": \"Taok2 KO mice, in utero electroporation for acute knockdown/overexpression, immunostaining for cortical layering, phospho-JNK1 western blot, constitutively active JNK1 rescue, 16p11.2 del mouse model\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mice + acute KD with specific migration phenotype, genetic epistasis with CA-JNK1 rescue, replicated across multiple models\",\n      \"pmids\": [\"36123424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A nuclear pool of TAO2 localizes to nuclear speckles and interacts with nuclear speckle factors SRSF1 and Aly/Ref (involved in RNA splicing and nuclear export). Depletion or kinase inhibition of TAO2 disrupts nuclear speckle structure, decreases levels of SC35 and SON (speckle assembly/splicing proteins), and impairs pre-mRNA splicing and nuclear export of influenza M mRNA, reducing viral replication.\",\n      \"method\": \"Immunofluorescence localization, co-immunoprecipitation (TAO2 with SRSF1/Aly-Ref), siRNA depletion, kinase inhibitor treatment, western blot for SC35/SON, mRNA splicing/export assays, viral replication assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with speckle factors, KD plus kinase inhibition with specific functional readouts (splicing, export, viral replication); single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35704758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Taok2 is required for vacuolar escape of Listeria monocytogenes in epithelial cells; siRNA knockdown of Taok2 reduces vacuolar rupture and cytoplasmic access of Listeria. Pharmacological inhibition of Taok2 kinase activity validated this role. Taok2 recruitment to Listeria vacuoles requires the pore-forming toxin listeriolysin O.\",\n      \"method\": \"High-content siRNA microscopy screen, pharmacological kinase inhibition, immunofluorescence imaging of Listeria vacuolar rupture\",\n      \"journal\": \"The Journal of infectious diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA screen validated by pharmacological inhibition and imaging; single study with two orthogonal loss-of-function methods\",\n      \"pmids\": [\"32582947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TAOK2 associates with the translational machinery and directly phosphorylates eukaryotic elongation factor 2 (eEF2) at the same regulatory site (Thr56) as eEF2K, functioning as a translational brake. This pathway operates independently of eEF2K. Loss of TAOK2 (in 16p11.2 deletion models) leads to increased translation. This identifies an eEF2K-independent mechanism of translation elongation control.\",\n      \"method\": \"Proteomics (co-IP mass spectrometry for translational machinery association), in vitro kinase assay (direct eEF2 phosphorylation), translation assays in cultured cells and mouse brain, genetic models (16p11.2 deletion mice and cells)\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro phosphorylation of eEF2 demonstrated, proteomics for complex, functional translation assays in cells and in vivo; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"38608030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Three small-molecule compounds identified by high-throughput screening (200,000 compounds) inhibit TAOK2 kinase activity and also inhibit autophagy, providing early evidence that TAOK2 kinase activity is required for autophagy in NSCLC cells.\",\n      \"method\": \"High-throughput kinase inhibitor screen, SAR analysis, autophagy assay\",\n      \"journal\": \"Bioorganic & medicinal chemistry letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — compound screen with limited mechanistic follow-up; single study, indirect link between kinase inhibition and autophagy\",\n      \"pmids\": [\"27426302\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TAOK2 is a multifunctional STE20-family serine/threonine MAP3K that activates p38 and JNK pathways by directly phosphorylating MEK3/6 (and MEK4), associates with and inhibits TAK1-IKK signaling during osmotic stress, phosphorylates cytoskeletal substrates including tubulin and Septin7 (inducing Septin7 translocation to stabilize PSD95 at dendritic spines), tethers ER membranes to microtubules via its C-terminal tail and transmembrane domain, functions as a translational brake by directly phosphorylating eEF2 independently of eEF2K, localizes to nuclear speckles where its kinase activity maintains speckle integrity and pre-mRNA splicing/export, and acts upstream of RhoA and JNK1 to regulate neuronal migration and basal dendrite formation downstream of Sema3A/Nrp1 signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TAOK2 (TAO2/PSK) is a STE20-family serine/threonine MAP3K that couples stress and cytoskeletal cues to MAPK signaling and that organizes microtubule, ER, and neuronal architecture [#0, #2]. As a MAP3K it selectively activates the stress-responsive p38 and JNK pathways by binding and phosphorylating MEK3 and MEK6 (and MKK4/MKK7), while sparing ERK; its kinase domain has been crystallized in an active, autophosphorylated conformation that phosphorylates MEK6 within a defined motif [#0, #2, #4]. Beyond canonical MAPK signaling, TAOK2 binds TAK1 and selectively interferes with the TAK1\\u2013IKK interaction to restrain NF-\\u03baB activation during osmotic stress [#5]. TAOK2 is also a cytoskeletal organizer: its kinase-independent C-terminal tail binds and stabilizes microtubules into acetylated, nocodazole-resistant cables, and the same tail together with transmembrane and amphipathic regions tethers ER subdomains to growing microtubule plus ends [#3, #11]. In neurons, TAOK2 acts downstream of Sema3A/Neuropilin-1 and upstream of JNK1 and RhoA to drive basal dendrite formation, cortical neuronal migration, and spine maturation, the last via direct phosphorylation of Septin7 that recruits it to spines to stabilize PSD95 [#7, #9, #10, #12]. A nuclear pool localizes to nuclear speckles where its kinase activity maintains speckle integrity and supports pre-mRNA splicing and mRNA export [#13], and TAOK2 additionally acts as an eEF2K-independent translational brake by directly phosphorylating eEF2 at Thr56 [#15]. De novo TAOK2 mutations and 16p11.2 deletion link the gene to autism-spectrum neurodevelopmental phenotypes through impaired protein stability, kinase activity, dendrite growth, and synapse development [#10, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established TAOK2 as a MAP3K by showing it selectively activates and binds stress-pathway MAP kinase kinases, defining its position upstream of p38/JNK signaling.\",\n      \"evidence\": \"Recombinant kinase assays, copurification with MEK3 from Sf9 cells, and MEK-binding domain mapping with chimeric MEKs\",\n      \"pmids\": [\"10497253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish which physiological stimuli engage this kinase in cells\", \"In vitro substrate selectivity not yet validated for endogenous complexes\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed TAOK2 activates the JNK pathway and that its C-terminus and kinase activity drive vesicular localization and actin stress fiber loss, linking the kinase to cytoskeletal remodeling.\",\n      \"evidence\": \"Immunoprecipitation kinase assay, transfection reporter assays, microinjection with live imaging, and truncation/kinase-dead mutants\",\n      \"pmids\": [\"10660600\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct cytoskeletal substrate not identified\", \"Mechanism connecting kinase activity to actin disassembly unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrated endogenous TAOK2 selectively activates p38 and JNK (not ERK) via MEK3/6 and is induced by osmotic/microtubule stress and myoblast differentiation, framing it as a stress- and cytoskeleton-responsive kinase.\",\n      \"evidence\": \"Cell overexpression with reporter/western readouts, reciprocal co-IP, and in vitro kinase assays under sorbitol/NaCl/Taxol/nocodazole\",\n      \"pmids\": [\"11279118\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream sensor that activates TAOK2 under stress not defined\", \"Link between microtubule perturbation and kinase activation mechanistic only by correlation\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved how TAOK2 is catalytically activated and recognizes substrate, providing the structural basis for STE20-family activation by phosphorylation.\",\n      \"evidence\": \"X-ray crystallography of the active kinase domain with structure-based mutagenesis and in vitro kinase assays\",\n      \"pmids\": [\"15458637\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure limited to isolated kinase domain\", \"Full-length regulatory architecture not visualized\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified a kinase-independent microtubule-binding and -stabilizing function in the C-terminus and tubulin as a direct substrate, distinguishing TAOK2's scaffolding role from its catalytic role.\",\n      \"evidence\": \"Immunofluorescence colocalization with nocodazole challenge, domain/kinase-dead mutants, and in vitro tubulin binding/phosphorylation\",\n      \"pmids\": [\"12639963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of tubulin phosphorylation undefined\", \"Relationship between MT stabilization and MAPK signaling unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined a pathway-selective brake on innate signaling: TAOK2 binds TAK1 and blocks the TAK1\\u2013IKK interaction to suppress NF-\\u03baB without affecting TAK1-driven JNK.\",\n      \"evidence\": \"Binding screen, reciprocal co-IP, and NF-\\u03baB/JNK reporter assays under osmotic stress\",\n      \"pmids\": [\"16893890\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether inhibition requires TAOK2 kinase activity not established\", \"Physiological setting of TAK1 antagonism in vivo unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Provided atomic detail of inhibitor binding to the TAOK2 ATP pocket, enabling structure-guided inhibitor design.\",\n      \"evidence\": \"X-ray crystallography of the kinase domain co-crystallized with staurosporine\",\n      \"pmids\": [\"16761096\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited functional validation beyond structural description\", \"Selectivity over related kinases not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed TAOK2 in a neurodevelopmental signaling axis, acting downstream of Sema3A/Nrp1 and upstream of JNK to direct basal dendrite and axon formation in vivo.\",\n      \"evidence\": \"In vivo cortical knockdown/overexpression, TAOK2-Nrp1 co-IP, and epistasis rescue with JNK readouts\",\n      \"pmids\": [\"22683681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct phosphorylation substrate in the dendrite pathway not identified\", \"How Nrp1 engagement activates TAOK2 kinase activity unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated functional conservation of TAOK2 in nervous-system behavior using a conditional knockout, linking the kinase to ethanol-response phenotypes.\",\n      \"evidence\": \"Nervous-system-specific conditional knockout mice with ethanol behavioral assays\",\n      \"pmids\": [\"22883308\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism underlying behavioral phenotype undefined\", \"Strain-specific effects complicate interpretation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified Septin7 as a direct TAOK2 substrate whose phosphorylation drives spine localization and PSD95 stabilization, providing a molecular mechanism for spine maturation and calcium compartmentalization.\",\n      \"evidence\": \"Analog-sensitive kinase chemical genetics, MS phosphoproteomics, in vitro kinase assay, and calcium/spine imaging with knockdown\",\n      \"pmids\": [\"28065648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Septin7 phosphorylation triggers its translocation mechanistically unresolved\", \"Whether other spine substrates exist not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Tied TAOK2 to RhoA activation and to autism-associated dysfunction, showing patient mutations and gene dosage perturb kinase activity, dendrite/synapse development, and cortical structure.\",\n      \"evidence\": \"Taok2 KO/het mice, RhoA activation assay with pharmacological rescue, and functional analysis of de novo ASD mutations\",\n      \"pmids\": [\"29467497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct effector linking TAOK2 to RhoA activation not identified\", \"How distinct mutations differentially affect activity not fully mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established TAOK2 as an ER\\u2013microtubule tether through its transmembrane/amphipathic and C-terminal MT-binding regions, with kinase activity governing ER morphology, ER-MT coupling, and cell division.\",\n      \"evidence\": \"Fractionation, live ER-dynamics imaging in KO cells, domain mapping, in vitro MT binding, and kinase-dead mutants\",\n      \"pmids\": [\"34879262\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate phosphorylated to regulate ER-MT tethering unidentified\", \"Connection between ER tethering and MAPK/neuronal roles unexplored\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved a TAOK2\\u03b1-specific role in cortical neuron migration upstream of JNK1, with constitutively active JNK1 rescuing migration defects in KO and 16p11.2 deletion models.\",\n      \"evidence\": \"Taok2 KO mice, in utero electroporation knockdown/overexpression, phospho-JNK1 westerns, and CA-JNK1 genetic rescue\",\n      \"pmids\": [\"36123424\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Isoform-specific determinant of MT colocalization not pinned to a sequence element\", \"Direct kinase substrate driving migration not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Uncovered a nuclear function: a speckle-localized TAOK2 pool whose kinase activity maintains speckle integrity and supports pre-mRNA splicing and nuclear export.\",\n      \"evidence\": \"Immunofluorescence, co-IP with SRSF1/Aly-Ref, siRNA and kinase inhibition with splicing/export and viral-replication readouts\",\n      \"pmids\": [\"35704758\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct splicing/speckle substrate of TAOK2 not identified\", \"How TAOK2 partitions between cytoplasmic and nuclear pools unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Listeria exploitation revealed TAOK2 kinase activity is required for pathogen vacuolar escape, with recruitment depending on listeriolysin O.\",\n      \"evidence\": \"High-content siRNA screen, pharmacological kinase inhibition, and imaging of vacuolar rupture\",\n      \"pmids\": [\"32582947\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Host substrate mediating vacuolar rupture not identified\", \"Mechanism of TAOK2 recruitment to vacuoles undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined an eEF2K-independent translational brake: TAOK2 directly phosphorylates eEF2 at Thr56 to repress elongation, linking the kinase to translational control disrupted in 16p11.2 deletion.\",\n      \"evidence\": \"Co-IP MS for translational machinery, in vitro kinase assay on eEF2, and translation assays in cells and mouse brain\",\n      \"pmids\": [\"38608030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals that engage TAOK2-dependent eEF2 phosphorylation not mapped\", \"Crosstalk with eEF2K regulation unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided early pharmacological evidence linking TAOK2 kinase activity to autophagy in cancer cells.\",\n      \"evidence\": \"High-throughput inhibitor screen with SAR and autophagy assays\",\n      \"pmids\": [\"27426302\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Indirect link between kinase inhibition and autophagy not mechanistically established\", \"Compound selectivity for TAOK2 not validated\", \"No autophagy substrate identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TAOK2's distinct subcellular pools (cytoplasmic MAPK signaling, microtubule/ER tethering, nuclear speckles, translational machinery) are coordinated and which upstream signals partition the kinase among them remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking the kinase-dependent and kinase-independent functions\", \"Direct substrates for several functions (ER tethering, splicing, migration) not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 9, 15]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 4, 9, 15]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3, 11]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3, 11, 12]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 5, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 10, 12]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MAP2K3\", \"MAP2K6\", \"MAP3K7\", \"NRP1\", \"SEPTIN7\", \"SRSF1\", \"ALYREF\", \"EEF2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}