{"gene":"TEC","run_date":"2026-04-28T21:42:58","timeline":{"discoveries":[{"year":1990,"finding":"TEC was identified as a novel non-receptor protein-tyrosine kinase preferentially expressed in liver, with its C-terminal domain sharing significant homology with Src family kinase catalytic domains.","method":"cDNA library screening with v-fps kinase domain probe, nucleotide sequence analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — original identification by sequence/cloning, single lab","pmids":["2284097"],"is_preprint":false},{"year":1995,"finding":"TEC kinase associates with and is activated by gp130, the signal-transducing subunit of the IL-6 family cytokine receptors; IL-3 and G-CSF also activate Tec (but not Btk) in pro-B cells, establishing TEC as a component of gp130-linked signaling.","method":"Co-immunoprecipitation, in vitro kinase assay, stimulation of cell lines with cytokines","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP and kinase assay, moderate evidence","pmids":["7530500"],"is_preprint":false},{"year":1996,"finding":"Deletion of the SH3 domain of TEC results in a constitutively hyperphosphorylated and activated kinase, indicating the SH3 domain negatively regulates TEC kinase activity.","method":"SH3 domain deletion mutant expression in 293 cells and hematopoietic BA/F3 cells, kinase activity assay","journal":"Japanese journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — direct mutagenesis with kinase activity readout, single lab","pmids":["9045937"],"is_preprint":false},{"year":1997,"finding":"TEC associates with the p85 and p55 subunits of PI-3 kinase (interaction dependent on Tec kinase activity and requiring the SH2-kinase domain), and with Vav through its SH2 domain (kinase-independent); JAK1 associates with Tec and upon cytokine stimulation Tec and p85-PI3K associate in mammalian cells.","method":"Yeast two-hybrid, co-immunoprecipitation in cytokine-stimulated cells","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 — yeast two-hybrid plus Co-IP, single lab","pmids":["9178903"],"is_preprint":false},{"year":1998,"finding":"PtdIns(3,4,5)P3 interacting with the PH domain of TEC family kinases acts as an upstream activation signal, leading to TEC kinase-dependent PLCγ tyrosine phosphorylation and IP3 production; SHIP-mediated degradation of PtdIns(3,4,5)P3 blocks this pathway.","method":"Direct PH domain-lipid binding assay, in vitro PLCγ phosphorylation assay, inositol trisphosphate measurement in cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — direct biochemical reconstitution with multiple orthogonal readouts","pmids":["9524119"],"is_preprint":false},{"year":1998,"finding":"TEC/Btk family kinases regulate sustained intracellular Ca2+ increases following BCR activation by controlling IP3-gated calcium store depletion and store-operated calcium entry; Btk/Tec and PLCγ co-expression leads to PLCγ tyrosine phosphorylation.","method":"Ectopic expression in Btk-deficient B-cell lines, calcium flux measurement, IP3 assay, co-expression studies","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 — reconstitution in deficient cells, multiple orthogonal assays, replicated across Btk and Tec family","pmids":["9524120"],"is_preprint":false},{"year":1998,"finding":"TEC and Bmx activate serum response factor (SRF) in synergy with constitutively active Gα12/13 subunits in a Rho-dependent manner; kinase and TH domains of TEC are required for SRF activation; Gα12/13 stimulates autophosphorylation and transphosphorylation activities of Tec.","method":"Transient transfection in NIH 3T3 cells, SRF luciferase reporter, C3 toxin inhibition, kinase activity assay","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assay with domain deletion and Rho inhibitor controls, single lab","pmids":["9755164"],"is_preprint":false},{"year":1999,"finding":"The SH2 domain of TEC (and Btk/Itk) exhibits restricted binding specificity, selectively binding tyrosine-phosphorylated SLP-65 (in B cells) or SLP-76 (in T cells) upon antigen receptor activation, which is required for PLCγ phosphorylation.","method":"SH2 domain binding assay, co-immunoprecipitation from activated lymphocytes","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 — domain-specific binding demonstrated by Co-IP, single lab","pmids":["10556826"],"is_preprint":false},{"year":1999,"finding":"TEC (but not Btk) can reconstitute PLCγ2-dependent calcium mobilization, ERK/MAPK activation, and apoptosis in Btk-deficient DT40 B cells, demonstrating a common signaling function for Tec kinases as amplifiers of PLCγ2-dependent signal transduction.","method":"Reconstitution in Btk-deficient DT40 B cells, calcium flux assay, ERK activation, apoptosis assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — functional reconstitution in defined deficient cell line with multiple readouts","pmids":["10224128"],"is_preprint":false},{"year":1999,"finding":"BRDG1 (BCR downstream signaling 1) was identified as a docking protein acting downstream of TEC; Tec (but not Btk) directly phosphorylates BRDG1 in vitro and in cells; this requires the PH and SH2 domains as well as the kinase domain of Tec; BRDG1 participates in a positive feedback loop increasing Tec activity.","method":"Yeast two-hybrid, in vitro kinase assay, co-expression in 293 cells, domain deletion analysis, BCR stimulation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase reconstitution plus domain mutagenesis and cellular validation","pmids":["10518561"],"is_preprint":false},{"year":2000,"finding":"SCF/cKit signaling activates Tec in a PI3K-dependent manner; Tec forms a stable complex with Lyn and Dok-1 (p62Dok-1); the Tec homology and SH2 domains of Tec are required for Dok-1 interaction; Tec and Lyn phosphorylate Dok-1, which then scaffolds additional signaling molecules.","method":"Co-immunoprecipitation, domain deletion, in vitro kinase assay, inhibitor studies in hematopoietic cells","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro kinase assay plus domain mapping and complex identification by Co-IP","pmids":["11071635"],"is_preprint":false},{"year":2000,"finding":"TEC and Btk are activated by tyrosine phosphorylation in platelets upon collagen receptor (GPVI) stimulation or CD32 cross-linking via a mechanism involving ITAM, Src family kinases, and PI3-kinase; in XLA (Btk-deficient) platelets, Tec undergoes compensatory activation.","method":"Phosphopeptide-specific antibodies, kinase activity assay, kinetic analysis with inhibitors in human platelets","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — phosphospecific antibodies and inhibitor studies, single lab","pmids":["10688822"],"is_preprint":false},{"year":2001,"finding":"The solution structure of the TEC SH3 domain was determined; the proline-rich region (PRR) of Tec contains two SH3-binding sites: site 1 (KTLPPAP) binds intramolecularly to the SH3 domain, while site 2 (KRRPPPPIPP) can only bind intermolecularly, suggesting distinct roles in kinase targeting and enzyme activation.","method":"NMR structure determination, site-directed mutagenesis, in vitro binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — NMR structure with mutagenesis and binding validation","pmids":["11684687"],"is_preprint":false},{"year":2001,"finding":"Sak serine-threonine kinase (a Polo-like kinase family member) is phosphorylated by TEC on tyrosine residues, and Sak serine-threonine kinase activity is only detectable in the presence of Tec; Tec also protects Sak from PEST-sequence-dependent proteolysis.","method":"Yeast two-hybrid, co-expression in 293 cells, in vitro kinase assay, stability/degradation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — direct in vitro phosphorylation and stability assay, single lab","pmids":["11489907"],"is_preprint":false},{"year":2002,"finding":"The proline-rich region (PRR) in the Tec homology domain of ITK (a closely related Tec family member) positively regulates basal kinase activity and the response to Src family kinase (Lck) activation; the SH3 domain negatively regulates ITK basal activity.","method":"Domain deletion mutants, kinase activity assay, PLCγ1 phosphorylation readout in Jurkat cells","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — domain deletion with kinase activity assay, single lab (Itk ortholog findings relevant to TEC family regulation)","pmids":["12163161"],"is_preprint":false},{"year":2004,"finding":"SHIP1 and SHIP2 interact preferentially with TEC (compared to other Tec family members) via the Tec SH3 domain, and negatively regulate Tec by inhibiting its kinase activity and membrane localization through dephosphorylation of local PtdIns(3,4,5)P3.","method":"Co-immunoprecipitation, kinase activity assay, membrane localization assay, constitutive membrane-targeting rescue experiment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (Co-IP, kinase assay, localization, membrane-targeting rescue), single lab","pmids":["15492005"],"is_preprint":false},{"year":2004,"finding":"TEC constitutively associates with PKCθ via its pleckstrin-homology domain; PKCθ-initiated signaling requires Tec (but not Itk or Rlk) to activate AP-1 and PLCγ1/Ca2+ signaling in restimulated T cells; a dominant-negative Tec blocks PKCθ-induced AP-1 activation.","method":"Co-immunoprecipitation, dominant-negative expression, luciferase reporter assay, calcium mobilization in primary T cells","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP and reporter assay with dominant-negative, single lab","pmids":["15214048"],"is_preprint":false},{"year":2007,"finding":"The short linker region flanked by the SH2 and kinase domains of Tec kinases positively regulates catalytic activity; specific conserved residues in this linker allosterically regulate kinase activity, a mechanism conserved across Tec family members.","method":"Quantitative in vitro kinase assay, mutagenesis of linker residues in Itk (Tec family model)","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro biochemical assay with mutagenesis, conserved mechanism validated across family","pmids":["17425330"],"is_preprint":false},{"year":2007,"finding":"TEC (and Btk) use a remote SH2 domain-dependent substrate docking mechanism: the SH2 domain of substrates (PLCγ1, Itk itself) is required for efficient tyrosine phosphorylation; a stable interaction occurs between substrate SH2 domains and the Tec kinase domain.","method":"In vitro kinase assay with SH2 domain deletion/competition, kinetic analysis with SH2-peptide fusion substrates","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with domain deletion, competition assay, and kinetic validation","pmids":["17439160"],"is_preprint":false},{"year":2008,"finding":"TEC and Btk tyrosine kinases link RANK and ITAM signaling in osteoclasts by forming a Btk(Tec)/BLNK(SLP-76)-containing complex, leading to PLCγ-mediated calcium signaling essential for osteoclast differentiation; mice lacking both Btk and Tec show severe osteopetrosis due to defective osteoclastogenesis.","method":"Genetic knockout (Btk/Tec double-deficient mice), co-immunoprecipitation of signaling complex, PLCγ activation assay, calcium measurement, bone histology","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 — genetic KO with defined phenotype plus Co-IP complex and biochemical assays, high-profile journal","pmids":["18329366"],"is_preprint":false},{"year":2008,"finding":"TEC kinase is activated in neutrophils in a Src-dependent manner upon MSU crystal stimulation; Tec activation is required for MSU crystal-induced IL-1β and IL-8 secretion and generation of chemotactic activity; colchicine inhibits Tec tyrosine phosphorylation.","method":"Immunoprecipitation, immunoblotting, siRNA knockdown of Tec, ELISA for cytokines, chemotaxis assay","journal":"Arthritis and rheumatism","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA knockdown with specific functional readout, single lab","pmids":["18512796"],"is_preprint":false},{"year":2010,"finding":"An allosteric signaling network ('extended regulatory spine') within Tec kinases was identified that transmits regulatory signals from the SH2-kinase linker tryptophan and a conserved methionine in the C-helix to the catalytic domain; mutation of the gatekeeper residue constitutively activates the kinase by pre-assembling the regulatory spine.","method":"In vitro kinase assay, mutagenesis of regulatory spine residues, structural analysis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — biochemical mutagenesis with structural analysis and kinase activity, mechanistic detail","pmids":["20826165"],"is_preprint":false},{"year":2016,"finding":"TEC kinase directly interacts with FGF2 and phosphorylates FGF2 on tyrosine residues, stimulating FGF2 membrane pore formation required for unconventional secretion; small molecule inhibitors of the FGF2-Tec interaction block FGF2 tyrosine phosphorylation and its unconventional secretion in cells.","method":"In vitro kinase assay, co-immunoprecipitation, small molecule inhibitor studies, FGF2 secretion assay in cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay plus cellular validation and specific inhibitor corroboration","pmids":["27382052"],"is_preprint":false},{"year":2016,"finding":"Dynamic allostery in Tec family kinases is mediated by a conserved tryptophan in the N-terminal 17-residue SH2-kinase linker; mutation of this tryptophan to alanine completely abolishes kinase activity; specific tryptophan side-chain rotamers promote coordinated motions across the kinase domain.","method":"Hydrogen/deuterium exchange mass spectrometry, molecular dynamics simulations, mutagenesis, in vitro kinase assay","journal":"PLoS computational biology","confidence":"High","confidence_rationale":"Tier 1 — biophysical HDX-MS, MD simulations, and mutagenesis with kinase activity validation","pmids":["27010561"],"is_preprint":false},{"year":2021,"finding":"TEC tyrosine kinase directly phosphorylates PLK4 at tyrosine 86, stabilizing PLK4 protein and enhancing PLK4-mediated HCC cell invasion; TEC promotes PLK4-mediated phosphorylation of focal adhesion kinase to regulate focal adhesion signaling in HCC cell migration.","method":"In vitro kinase assay, site-directed mutagenesis (Y86 of PLK4), protein stability assay, transcriptome sequencing, HCC cell migration/invasion assay","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro kinase assay plus mutagenesis and cellular phenotype, single lab","pmids":["34637843"],"is_preprint":false}],"current_model":"TEC is a PH domain-containing non-receptor tyrosine kinase that is recruited to the plasma membrane by PtdIns(3,4,5)P3, activated downstream of cytokine receptors (via JAK/gp130), antigen receptors, GPVI, and G-protein-coupled receptors through Src family kinase-mediated phosphorylation, where it phosphorylates PLCγ (driving IP3 production and Ca2+ mobilization), FGF2 (promoting unconventional secretion), PLK4 (stabilizing it to regulate invasion), and the docking protein BRDG1; its activity is positively regulated by an allosteric extended regulatory spine and the SH2-kinase linker tryptophan, and negatively regulated by SHIP1/2-mediated dephosphorylation of local PtdIns(3,4,5)P3 and by intramolecular SH3-PRR interactions, while it also participates in Rho/SRF activation downstream of Gα12/13 and in osteoclastogenesis by forming RANK-ITAM signaling complexes with BLNK/SLP-76."},"narrative":{"teleology":[{"year":1990,"claim":"Identifying TEC as a novel non-receptor tyrosine kinase established that a Src-related kinase with preferential hepatic expression existed outside canonical Src/Abl families, opening the question of its signaling role.","evidence":"cDNA library screening with v-fps kinase probe and sequence analysis in liver","pmids":["2284097"],"confidence":"Medium","gaps":["No functional data beyond sequence; tissue expression limited to RNA level","Substrates and activating signals unknown"]},{"year":1995,"claim":"Demonstrating that TEC associates with gp130 and is activated by IL-6 family cytokines placed TEC as a downstream effector of JAK-coupled cytokine receptor signaling, distinct from Btk.","evidence":"Co-immunoprecipitation and in vitro kinase assay upon cytokine stimulation in pro-B cells","pmids":["7530500"],"confidence":"High","gaps":["Direct substrates of TEC in the gp130 pathway not identified","Mechanism of TEC recruitment to receptor complex unclear"]},{"year":1996,"claim":"Showing that SH3 domain deletion constitutively activates TEC revealed an intramolecular autoinhibitory mechanism, raising the question of how autoinhibition is structurally mediated.","evidence":"SH3 deletion mutant expression in 293 and BA/F3 cells with kinase activity assay","pmids":["9045937"],"confidence":"Medium","gaps":["Structural basis of SH3-mediated autoinhibition not resolved","Whether the SH3 domain acts through intramolecular or intermolecular contacts was unclear"]},{"year":1997,"claim":"Identifying TEC interactions with PI3K p85 subunit, Vav, and JAK1 positioned TEC at a signaling nexus between JAK/STAT, PI3K, and Rho/Rac pathways.","evidence":"Yeast two-hybrid and co-immunoprecipitation in cytokine-stimulated cells","pmids":["9178903"],"confidence":"Medium","gaps":["Functional consequence of PI3K-TEC complex not established","Whether Vav is a substrate or scaffold for TEC was unresolved"]},{"year":1998,"claim":"Three contemporaneous studies established the core signaling axis: PtdIns(3,4,5)P3 recruits TEC via its PH domain, TEC phosphorylates PLCγ to produce IP3 and drive sustained Ca²⁺ mobilization downstream of antigen receptors, and SHIP terminates the signal—defining TEC as a PI3K-to-PLCγ relay.","evidence":"PH domain-lipid binding assays, in vitro PLCγ phosphorylation, IP3 measurement, calcium flux in Btk-deficient B cells, Rho-dependent SRF reporter assays","pmids":["9524119","9524120","9755164"],"confidence":"High","gaps":["Whether TEC and Btk are fully redundant in B cells was unresolved","Structural basis of PH domain selectivity for PtdIns(3,4,5)P3 not determined"]},{"year":1999,"claim":"Identification of adaptor selectivity (SLP-65/SLP-76 binding via TEC SH2 domain), functional redundancy with Btk in DT40 cells, and BRDG1 as a TEC-specific substrate revealed how TEC is recruited to signaling complexes and expanded its substrate repertoire.","evidence":"SH2 domain binding assays, reconstitution in Btk-deficient DT40 B cells, yeast two-hybrid and in vitro kinase assays for BRDG1","pmids":["10556826","10224128","10518561"],"confidence":"High","gaps":["In vivo physiological role of BRDG1 phosphorylation not tested in knockout models","Degree of functional overlap between TEC and Btk in primary cells not fully defined"]},{"year":2000,"claim":"Demonstrating TEC activation downstream of SCF/cKit (forming a Lyn-Dok-1 complex) and GPVI/CD32 in platelets broadened TEC's receptor repertoire beyond cytokine and antigen receptors to growth factor and ITAM-coupled receptors.","evidence":"Co-IP and kinase assays in hematopoietic cells (SCF stimulation); phosphospecific antibodies in platelets (GPVI/CD32 stimulation)","pmids":["11071635","10688822"],"confidence":"High","gaps":["Platelet-specific substrates of TEC not identified","Physiological consequence of TEC activation in platelet aggregation not tested in vivo"]},{"year":2001,"claim":"The NMR structure of the TEC SH3 domain with mapping of two PRR-binding sites resolved how intramolecular versus intermolecular SH3-PRR contacts control autoinhibition and targeting, while identification of Sak/PLK4 as a TEC substrate linked TEC to cell cycle regulation.","evidence":"NMR structure determination with mutagenesis and binding assays; yeast two-hybrid and in vitro kinase assay for Sak","pmids":["11684687","11489907"],"confidence":"High","gaps":["Full-length TEC structure including SH3-PRR interaction not available","In vivo relevance of TEC-Sak interaction not confirmed in knockout models"]},{"year":2004,"claim":"Identifying SHIP1/SHIP2 as preferential negative regulators of TEC (via SH3-mediated interaction and PtdIns(3,4,5)P3 degradation) and PKCθ as a TEC-dependent signaling partner in T cells defined cell-type-specific regulatory inputs.","evidence":"Co-IP, kinase assay, membrane localization rescue (SHIP); Co-IP, dominant-negative, reporter assay (PKCθ) in T cells","pmids":["15492005","15214048"],"confidence":"High","gaps":["Whether SHIP directly dephosphorylates TEC or only removes PtdIns(3,4,5)P3 was not resolved","PKCθ-TEC interaction awaits structural characterization"]},{"year":2007,"claim":"Quantitative biochemistry established that the SH2-kinase linker allosterically activates catalysis and that TEC uses a remote SH2 domain docking mechanism on substrates like PLCγ, explaining how substrate selectivity is achieved.","evidence":"In vitro kinase assays with linker mutagenesis and SH2 domain deletion/competition kinetics","pmids":["17425330","17439160"],"confidence":"High","gaps":["No crystal structure capturing the linker-kinase allosteric interface","Whether SH2-docking mechanism operates for all TEC substrates (e.g., BRDG1, Sak) not tested"]},{"year":2008,"claim":"Btk/Tec double-knockout mice revealed a non-redundant physiological role in osteoclastogenesis via RANK-ITAM-PLCγ calcium signaling, and TEC was shown to mediate innate immune responses to MSU crystals in neutrophils.","evidence":"Genetic double-KO mice with bone histology, Co-IP of RANK/BLNK complex; siRNA knockdown with cytokine ELISA in neutrophils","pmids":["18329366","18512796"],"confidence":"High","gaps":["Relative contribution of TEC versus Btk in single-KO osteoclasts not fully dissected","MSU-induced TEC activation mechanism upstream of Src not resolved"]},{"year":2010,"claim":"Discovery of the extended regulatory spine network explained how distal regulatory inputs (SH2-kinase linker tryptophan, C-helix methionine, gatekeeper residue) are transmitted allosterically to the TEC catalytic site.","evidence":"Mutagenesis of regulatory spine residues with in vitro kinase assay and structural analysis","pmids":["20826165"],"confidence":"High","gaps":["Full-length TEC structure showing regulatory spine in intact protein context not available","Whether pharmacological spine disruption can selectively inhibit TEC not tested"]},{"year":2016,"claim":"TEC was shown to directly phosphorylate FGF2 on tyrosine residues to promote membrane pore formation and unconventional secretion, establishing a non-immune function for TEC in growth factor export.","evidence":"In vitro kinase assay, Co-IP, FGF2 secretion assay with small molecule inhibitors","pmids":["27382052"],"confidence":"High","gaps":["Identity of the specific FGF2 tyrosine residues phosphorylated by TEC not mapped","In vivo relevance of TEC-FGF2 axis not tested in animal models"]},{"year":2021,"claim":"TEC was found to phosphorylate PLK4 at Y86, stabilizing PLK4 protein and promoting HCC cell invasion through FAK signaling, extending TEC's substrate repertoire to cancer cell migration.","evidence":"In vitro kinase assay, Y86 mutagenesis, protein stability assay, HCC cell invasion assays","pmids":["34637843"],"confidence":"Medium","gaps":["In vivo validation in animal tumor models not reported","Whether TEC-PLK4 interaction occurs in non-cancer contexts is unknown","Single-lab finding"]},{"year":null,"claim":"A full-length structure of TEC capturing the autoinhibited-to-active transition, the relative contributions of TEC versus Btk in specific immune cell lineages in vivo, and the physiological significance of non-immune TEC substrates (FGF2, PLK4) remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length TEC crystal/cryo-EM structure available","Single-KO TEC mouse phenotype in immune cells incompletely characterized relative to Btk","In vivo roles of TEC-FGF2 and TEC-PLK4 axes untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,5,8,9,10,13,18,19,22,24]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,4,9,10,22,24]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,15]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,5,7,8,11,19,20]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,4,6,10,16]}],"complexes":["RANK-ITAM-BLNK/SLP-76 signaling complex"],"partners":["PLCG1","PLCG2","BLNK","SLP76","SHIP1","SHIP2","DOK1","LYN"],"other_free_text":[]},"mechanistic_narrative":"TEC is a non-receptor tyrosine kinase of the Tec/Btk family that functions as a signal amplifier downstream of cytokine receptors, antigen receptors, ITAM-coupled receptors, and G-protein-coupled receptors, coupling PI3K-generated PtdIns(3,4,5)P3 signals to PLCγ-dependent calcium mobilization and transcriptional responses in hematopoietic and other cell types. Its PH domain binds PtdIns(3,4,5)P3 for membrane recruitment where Src family kinases activate it; TEC then phosphorylates PLCγ to drive IP3 production and sustained Ca²⁺ entry, a pathway negatively regulated by SHIP1/2-mediated PtdIns(3,4,5)P3 hydrolysis and by intramolecular SH3-PRR autoinhibition [PMID:9524119, PMID:15492005, PMID:11684687]. Beyond canonical PLCγ signaling, TEC phosphorylates FGF2 to promote its unconventional secretion, phosphorylates PLK4 to stabilize it and regulate cell invasion, and forms RANK-ITAM signaling complexes with BLNK/SLP-76 essential for osteoclastogenesis—Btk/Tec double-knockout mice exhibit severe osteopetrosis [PMID:27382052, PMID:34637843, PMID:18329366]. Catalytic activity is allosterically controlled by an extended regulatory spine that transmits signals from a conserved SH2-kinase linker tryptophan to the active site, and gatekeeper mutations constitutively activate the kinase [PMID:20826165, PMID:27010561]."},"prefetch_data":{"uniprot":{"accession":"P42680","full_name":"Tyrosine-protein kinase Tec","aliases":[],"length_aa":631,"mass_kda":73.6,"function":"Non-receptor tyrosine kinase that contributes to signaling from many receptors and participates as a signal transducer in multiple downstream pathways, including regulation of the actin cytoskeleton. Plays a redundant role to ITK in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. Required for TCR-dependent IL2 gene induction. Phosphorylates DOK1, one CD28-specific substrate, and contributes to CD28-signaling. Mediates signals that negatively regulate IL2RA expression induced by TCR cross-linking. Plays a redundant role to BTK in BCR-signaling for B-cell development and activation, especially by phosphorylating STAP1, a BCR-signaling protein. Required in mast cells for efficient cytokine production. Involved in both growth and differentiation mechanisms of myeloid cells through activation by the granulocyte colony-stimulating factor CSF3, a critical cytokine to promoting the growth, differentiation, and functional activation of myeloid cells. Participates in platelet signaling downstream of integrin activation. Cooperates with JAK2 through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. GRB10, a negative modifier of the FOS activation pathway, is another substrate of TEC. TEC is involved in G protein-coupled receptor- and integrin-mediated signalings in blood platelets. Plays a role in hepatocyte proliferation and liver regeneration and is involved in HGF-induced ERK signaling pathway. TEC also regulates FGF2 unconventional secretion (endoplasmic reticulum (ER)/Golgi-independent mechanism) under various physiological conditions through phosphorylation of FGF2 'Tyr-215'. May also be involved in the regulation of osteoclast differentiation","subcellular_location":"Cytoplasm; Cell membrane; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/P42680/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TEC","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TEC","total_profiled":1310},"omim":[{"mim_id":"621356","title":"SH3 AND CYSTEINE-RICH DOMAINS 2; STAC2","url":"https://www.omim.org/entry/621356"},{"mim_id":"612237","title":"CHONDROSARCOMA, EXTRASKELETAL MYXOID","url":"https://www.omim.org/entry/612237"},{"mim_id":"609898","title":"KRINGLE DOMAIN-CONTAINING TRANSMEMBRANE PROTEIN 1; KREMEN1","url":"https://www.omim.org/entry/609898"},{"mim_id":"608232","title":"LEUKEMIA, CHRONIC MYELOID; 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expansion, emigration, and maturation of γδ NKT cells.","date":"2013","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/23378428","citation_count":23,"is_preprint":false},{"pmid":"32493815","id":"PMC_32493815","title":"Activation of the Tec Kinase ITK Controls Graded IRF4 Expression in Response to Variations in TCR Signal Strength.","date":"2020","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/32493815","citation_count":23,"is_preprint":false},{"pmid":"7971284","id":"PMC_7971284","title":"Developmentally regulated, low abundance Tec element transcripts in Euplotes crassus--implications for DNA elimination and transposition.","date":"1994","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/7971284","citation_count":23,"is_preprint":false},{"pmid":"27471620","id":"PMC_27471620","title":"A Tec kinase BTK inhibitor ibrutinib promotes maturation and activation of dendritic cells.","date":"2016","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/27471620","citation_count":22,"is_preprint":false},{"pmid":"22829599","id":"PMC_22829599","title":"DEF6, a novel substrate for the Tec kinase ITK, contains a glutamine-rich aggregation-prone region and forms cytoplasmic granules that co-localize with P-bodies.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22829599","citation_count":22,"is_preprint":false},{"pmid":"12127569","id":"PMC_12127569","title":"The Tec family of tyrosine kinases in T cells, amplifiers of T cell receptor signals.","date":"2002","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12127569","citation_count":21,"is_preprint":false},{"pmid":"12163161","id":"PMC_12163161","title":"The proline rich region of the Tec homology domain of ITK regulates its activity.","date":"2002","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/12163161","citation_count":21,"is_preprint":false},{"pmid":"34637843","id":"PMC_34637843","title":"TEC kinase stabilizes PLK4 to promote liver cancer metastasis.","date":"2021","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/34637843","citation_count":21,"is_preprint":false},{"pmid":"19393603","id":"PMC_19393603","title":"Tec kinases regulate actin assembly and cytokine expression in LPS-stimulated human neutrophils via JNK activation.","date":"2009","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19393603","citation_count":20,"is_preprint":false},{"pmid":"9045937","id":"PMC_9045937","title":"Deletion of Src homology 3 domain results in constitutive activation of Tec protein-tyrosine kinase.","date":"1996","source":"Japanese journal of cancer research : Gann","url":"https://pubmed.ncbi.nlm.nih.gov/9045937","citation_count":20,"is_preprint":false},{"pmid":"34631841","id":"PMC_34631841","title":"Effects of the Btk-Inhibitors Remibrutinib (LOU064) and Rilzabrutinib (PRN1008) With Varying Btk Selectivity Over Tec on Platelet Aggregation and in vitro Bleeding Time.","date":"2021","source":"Frontiers in cardiovascular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34631841","citation_count":20,"is_preprint":false},{"pmid":"17302560","id":"PMC_17302560","title":"Regulation of oncogenic transcription factor hTAF(II)68-TEC activity by human glyceraldehyde-3-phosphate dehydrogenase (GAPDH).","date":"2007","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/17302560","citation_count":20,"is_preprint":false},{"pmid":"18025201","id":"PMC_18025201","title":"Subtle defects in pre-TCR signaling in the absence of the Tec kinase Itk.","date":"2007","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18025201","citation_count":19,"is_preprint":false},{"pmid":"37651795","id":"PMC_37651795","title":"Nephrotoxicity assessment of podophyllotoxin-induced rats by regulating PI3K/Akt/mTOR-Nrf2/HO1 pathway in view of toxicological evidence chain (TEC) concept.","date":"2023","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/37651795","citation_count":18,"is_preprint":false},{"pmid":"8632917","id":"PMC_8632917","title":"Human Txk: genomic organization, structure and contiguous physical linkage with the Tec gene.","date":"1996","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/8632917","citation_count":18,"is_preprint":false},{"pmid":"30770814","id":"PMC_30770814","title":"The Tec kinase ITK is essential for ILC2 survival and epithelial integrity in the intestine.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30770814","citation_count":17,"is_preprint":false},{"pmid":"22449074","id":"PMC_22449074","title":"The role of Tec family kinases in the regulation of T-helper-cell differentiation.","date":"2012","source":"International reviews of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22449074","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43455,"output_tokens":5548,"usd":0.106792},"stage2":{"model":"claude-opus-4-6","input_tokens":9197,"output_tokens":3660,"usd":0.206228},"total_usd":0.31302,"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\": 1990,\n      \"finding\": \"TEC was identified as a novel non-receptor protein-tyrosine kinase preferentially expressed in liver, with its C-terminal domain sharing significant homology with Src family kinase catalytic domains.\",\n      \"method\": \"cDNA library screening with v-fps kinase domain probe, nucleotide sequence analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — original identification by sequence/cloning, single lab\",\n      \"pmids\": [\"2284097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"TEC kinase associates with and is activated by gp130, the signal-transducing subunit of the IL-6 family cytokine receptors; IL-3 and G-CSF also activate Tec (but not Btk) in pro-B cells, establishing TEC as a component of gp130-linked signaling.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, stimulation of cell lines with cytokines\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and kinase assay, moderate evidence\",\n      \"pmids\": [\"7530500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Deletion of the SH3 domain of TEC results in a constitutively hyperphosphorylated and activated kinase, indicating the SH3 domain negatively regulates TEC kinase activity.\",\n      \"method\": \"SH3 domain deletion mutant expression in 293 cells and hematopoietic BA/F3 cells, kinase activity assay\",\n      \"journal\": \"Japanese journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct mutagenesis with kinase activity readout, single lab\",\n      \"pmids\": [\"9045937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"TEC associates with the p85 and p55 subunits of PI-3 kinase (interaction dependent on Tec kinase activity and requiring the SH2-kinase domain), and with Vav through its SH2 domain (kinase-independent); JAK1 associates with Tec and upon cytokine stimulation Tec and p85-PI3K associate in mammalian cells.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in cytokine-stimulated cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid plus Co-IP, single lab\",\n      \"pmids\": [\"9178903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"PtdIns(3,4,5)P3 interacting with the PH domain of TEC family kinases acts as an upstream activation signal, leading to TEC kinase-dependent PLCγ tyrosine phosphorylation and IP3 production; SHIP-mediated degradation of PtdIns(3,4,5)P3 blocks this pathway.\",\n      \"method\": \"Direct PH domain-lipid binding assay, in vitro PLCγ phosphorylation assay, inositol trisphosphate measurement in cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical reconstitution with multiple orthogonal readouts\",\n      \"pmids\": [\"9524119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"TEC/Btk family kinases regulate sustained intracellular Ca2+ increases following BCR activation by controlling IP3-gated calcium store depletion and store-operated calcium entry; Btk/Tec and PLCγ co-expression leads to PLCγ tyrosine phosphorylation.\",\n      \"method\": \"Ectopic expression in Btk-deficient B-cell lines, calcium flux measurement, IP3 assay, co-expression studies\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstitution in deficient cells, multiple orthogonal assays, replicated across Btk and Tec family\",\n      \"pmids\": [\"9524120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"TEC and Bmx activate serum response factor (SRF) in synergy with constitutively active Gα12/13 subunits in a Rho-dependent manner; kinase and TH domains of TEC are required for SRF activation; Gα12/13 stimulates autophosphorylation and transphosphorylation activities of Tec.\",\n      \"method\": \"Transient transfection in NIH 3T3 cells, SRF luciferase reporter, C3 toxin inhibition, kinase activity assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assay with domain deletion and Rho inhibitor controls, single lab\",\n      \"pmids\": [\"9755164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The SH2 domain of TEC (and Btk/Itk) exhibits restricted binding specificity, selectively binding tyrosine-phosphorylated SLP-65 (in B cells) or SLP-76 (in T cells) upon antigen receptor activation, which is required for PLCγ phosphorylation.\",\n      \"method\": \"SH2 domain binding assay, co-immunoprecipitation from activated lymphocytes\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — domain-specific binding demonstrated by Co-IP, single lab\",\n      \"pmids\": [\"10556826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"TEC (but not Btk) can reconstitute PLCγ2-dependent calcium mobilization, ERK/MAPK activation, and apoptosis in Btk-deficient DT40 B cells, demonstrating a common signaling function for Tec kinases as amplifiers of PLCγ2-dependent signal transduction.\",\n      \"method\": \"Reconstitution in Btk-deficient DT40 B cells, calcium flux assay, ERK activation, apoptosis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — functional reconstitution in defined deficient cell line with multiple readouts\",\n      \"pmids\": [\"10224128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"BRDG1 (BCR downstream signaling 1) was identified as a docking protein acting downstream of TEC; Tec (but not Btk) directly phosphorylates BRDG1 in vitro and in cells; this requires the PH and SH2 domains as well as the kinase domain of Tec; BRDG1 participates in a positive feedback loop increasing Tec activity.\",\n      \"method\": \"Yeast two-hybrid, in vitro kinase assay, co-expression in 293 cells, domain deletion analysis, BCR stimulation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase reconstitution plus domain mutagenesis and cellular validation\",\n      \"pmids\": [\"10518561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SCF/cKit signaling activates Tec in a PI3K-dependent manner; Tec forms a stable complex with Lyn and Dok-1 (p62Dok-1); the Tec homology and SH2 domains of Tec are required for Dok-1 interaction; Tec and Lyn phosphorylate Dok-1, which then scaffolds additional signaling molecules.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion, in vitro kinase assay, inhibitor studies in hematopoietic cells\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro kinase assay plus domain mapping and complex identification by Co-IP\",\n      \"pmids\": [\"11071635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TEC and Btk are activated by tyrosine phosphorylation in platelets upon collagen receptor (GPVI) stimulation or CD32 cross-linking via a mechanism involving ITAM, Src family kinases, and PI3-kinase; in XLA (Btk-deficient) platelets, Tec undergoes compensatory activation.\",\n      \"method\": \"Phosphopeptide-specific antibodies, kinase activity assay, kinetic analysis with inhibitors in human platelets\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — phosphospecific antibodies and inhibitor studies, single lab\",\n      \"pmids\": [\"10688822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The solution structure of the TEC SH3 domain was determined; the proline-rich region (PRR) of Tec contains two SH3-binding sites: site 1 (KTLPPAP) binds intramolecularly to the SH3 domain, while site 2 (KRRPPPPIPP) can only bind intermolecularly, suggesting distinct roles in kinase targeting and enzyme activation.\",\n      \"method\": \"NMR structure determination, site-directed mutagenesis, in vitro binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure with mutagenesis and binding validation\",\n      \"pmids\": [\"11684687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Sak serine-threonine kinase (a Polo-like kinase family member) is phosphorylated by TEC on tyrosine residues, and Sak serine-threonine kinase activity is only detectable in the presence of Tec; Tec also protects Sak from PEST-sequence-dependent proteolysis.\",\n      \"method\": \"Yeast two-hybrid, co-expression in 293 cells, in vitro kinase assay, stability/degradation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct in vitro phosphorylation and stability assay, single lab\",\n      \"pmids\": [\"11489907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The proline-rich region (PRR) in the Tec homology domain of ITK (a closely related Tec family member) positively regulates basal kinase activity and the response to Src family kinase (Lck) activation; the SH3 domain negatively regulates ITK basal activity.\",\n      \"method\": \"Domain deletion mutants, kinase activity assay, PLCγ1 phosphorylation readout in Jurkat cells\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain deletion with kinase activity assay, single lab (Itk ortholog findings relevant to TEC family regulation)\",\n      \"pmids\": [\"12163161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SHIP1 and SHIP2 interact preferentially with TEC (compared to other Tec family members) via the Tec SH3 domain, and negatively regulate Tec by inhibiting its kinase activity and membrane localization through dephosphorylation of local PtdIns(3,4,5)P3.\",\n      \"method\": \"Co-immunoprecipitation, kinase activity assay, membrane localization assay, constitutive membrane-targeting rescue experiment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (Co-IP, kinase assay, localization, membrane-targeting rescue), single lab\",\n      \"pmids\": [\"15492005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TEC constitutively associates with PKCθ via its pleckstrin-homology domain; PKCθ-initiated signaling requires Tec (but not Itk or Rlk) to activate AP-1 and PLCγ1/Ca2+ signaling in restimulated T cells; a dominant-negative Tec blocks PKCθ-induced AP-1 activation.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative expression, luciferase reporter assay, calcium mobilization in primary T cells\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP and reporter assay with dominant-negative, single lab\",\n      \"pmids\": [\"15214048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The short linker region flanked by the SH2 and kinase domains of Tec kinases positively regulates catalytic activity; specific conserved residues in this linker allosterically regulate kinase activity, a mechanism conserved across Tec family members.\",\n      \"method\": \"Quantitative in vitro kinase assay, mutagenesis of linker residues in Itk (Tec family model)\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical assay with mutagenesis, conserved mechanism validated across family\",\n      \"pmids\": [\"17425330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TEC (and Btk) use a remote SH2 domain-dependent substrate docking mechanism: the SH2 domain of substrates (PLCγ1, Itk itself) is required for efficient tyrosine phosphorylation; a stable interaction occurs between substrate SH2 domains and the Tec kinase domain.\",\n      \"method\": \"In vitro kinase assay with SH2 domain deletion/competition, kinetic analysis with SH2-peptide fusion substrates\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with domain deletion, competition assay, and kinetic validation\",\n      \"pmids\": [\"17439160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TEC and Btk tyrosine kinases link RANK and ITAM signaling in osteoclasts by forming a Btk(Tec)/BLNK(SLP-76)-containing complex, leading to PLCγ-mediated calcium signaling essential for osteoclast differentiation; mice lacking both Btk and Tec show severe osteopetrosis due to defective osteoclastogenesis.\",\n      \"method\": \"Genetic knockout (Btk/Tec double-deficient mice), co-immunoprecipitation of signaling complex, PLCγ activation assay, calcium measurement, bone histology\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genetic KO with defined phenotype plus Co-IP complex and biochemical assays, high-profile journal\",\n      \"pmids\": [\"18329366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TEC kinase is activated in neutrophils in a Src-dependent manner upon MSU crystal stimulation; Tec activation is required for MSU crystal-induced IL-1β and IL-8 secretion and generation of chemotactic activity; colchicine inhibits Tec tyrosine phosphorylation.\",\n      \"method\": \"Immunoprecipitation, immunoblotting, siRNA knockdown of Tec, ELISA for cytokines, chemotaxis assay\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA knockdown with specific functional readout, single lab\",\n      \"pmids\": [\"18512796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"An allosteric signaling network ('extended regulatory spine') within Tec kinases was identified that transmits regulatory signals from the SH2-kinase linker tryptophan and a conserved methionine in the C-helix to the catalytic domain; mutation of the gatekeeper residue constitutively activates the kinase by pre-assembling the regulatory spine.\",\n      \"method\": \"In vitro kinase assay, mutagenesis of regulatory spine residues, structural analysis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical mutagenesis with structural analysis and kinase activity, mechanistic detail\",\n      \"pmids\": [\"20826165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TEC kinase directly interacts with FGF2 and phosphorylates FGF2 on tyrosine residues, stimulating FGF2 membrane pore formation required for unconventional secretion; small molecule inhibitors of the FGF2-Tec interaction block FGF2 tyrosine phosphorylation and its unconventional secretion in cells.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, small molecule inhibitor studies, FGF2 secretion assay in cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay plus cellular validation and specific inhibitor corroboration\",\n      \"pmids\": [\"27382052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Dynamic allostery in Tec family kinases is mediated by a conserved tryptophan in the N-terminal 17-residue SH2-kinase linker; mutation of this tryptophan to alanine completely abolishes kinase activity; specific tryptophan side-chain rotamers promote coordinated motions across the kinase domain.\",\n      \"method\": \"Hydrogen/deuterium exchange mass spectrometry, molecular dynamics simulations, mutagenesis, in vitro kinase assay\",\n      \"journal\": \"PLoS computational biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biophysical HDX-MS, MD simulations, and mutagenesis with kinase activity validation\",\n      \"pmids\": [\"27010561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TEC tyrosine kinase directly phosphorylates PLK4 at tyrosine 86, stabilizing PLK4 protein and enhancing PLK4-mediated HCC cell invasion; TEC promotes PLK4-mediated phosphorylation of focal adhesion kinase to regulate focal adhesion signaling in HCC cell migration.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis (Y86 of PLK4), protein stability assay, transcriptome sequencing, HCC cell migration/invasion assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro kinase assay plus mutagenesis and cellular phenotype, single lab\",\n      \"pmids\": [\"34637843\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TEC is a PH domain-containing non-receptor tyrosine kinase that is recruited to the plasma membrane by PtdIns(3,4,5)P3, activated downstream of cytokine receptors (via JAK/gp130), antigen receptors, GPVI, and G-protein-coupled receptors through Src family kinase-mediated phosphorylation, where it phosphorylates PLCγ (driving IP3 production and Ca2+ mobilization), FGF2 (promoting unconventional secretion), PLK4 (stabilizing it to regulate invasion), and the docking protein BRDG1; its activity is positively regulated by an allosteric extended regulatory spine and the SH2-kinase linker tryptophan, and negatively regulated by SHIP1/2-mediated dephosphorylation of local PtdIns(3,4,5)P3 and by intramolecular SH3-PRR interactions, while it also participates in Rho/SRF activation downstream of Gα12/13 and in osteoclastogenesis by forming RANK-ITAM signaling complexes with BLNK/SLP-76.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TEC is a non-receptor tyrosine kinase of the Tec/Btk family that functions as a signal amplifier downstream of cytokine receptors, antigen receptors, ITAM-coupled receptors, and G-protein-coupled receptors, coupling PI3K-generated PtdIns(3,4,5)P3 signals to PLCγ-dependent calcium mobilization and transcriptional responses in hematopoietic and other cell types. Its PH domain binds PtdIns(3,4,5)P3 for membrane recruitment where Src family kinases activate it; TEC then phosphorylates PLCγ to drive IP3 production and sustained Ca²⁺ entry, a pathway negatively regulated by SHIP1/2-mediated PtdIns(3,4,5)P3 hydrolysis and by intramolecular SH3-PRR autoinhibition [PMID:9524119, PMID:15492005, PMID:11684687]. Beyond canonical PLCγ signaling, TEC phosphorylates FGF2 to promote its unconventional secretion, phosphorylates PLK4 to stabilize it and regulate cell invasion, and forms RANK-ITAM signaling complexes with BLNK/SLP-76 essential for osteoclastogenesis—Btk/Tec double-knockout mice exhibit severe osteopetrosis [PMID:27382052, PMID:34637843, PMID:18329366]. Catalytic activity is allosterically controlled by an extended regulatory spine that transmits signals from a conserved SH2-kinase linker tryptophan to the active site, and gatekeeper mutations constitutively activate the kinase [PMID:20826165, PMID:27010561].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Identifying TEC as a novel non-receptor tyrosine kinase established that a Src-related kinase with preferential hepatic expression existed outside canonical Src/Abl families, opening the question of its signaling role.\",\n      \"evidence\": \"cDNA library screening with v-fps kinase probe and sequence analysis in liver\",\n      \"pmids\": [\"2284097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional data beyond sequence; tissue expression limited to RNA level\", \"Substrates and activating signals unknown\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Demonstrating that TEC associates with gp130 and is activated by IL-6 family cytokines placed TEC as a downstream effector of JAK-coupled cytokine receptor signaling, distinct from Btk.\",\n      \"evidence\": \"Co-immunoprecipitation and in vitro kinase assay upon cytokine stimulation in pro-B cells\",\n      \"pmids\": [\"7530500\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrates of TEC in the gp130 pathway not identified\", \"Mechanism of TEC recruitment to receptor complex unclear\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Showing that SH3 domain deletion constitutively activates TEC revealed an intramolecular autoinhibitory mechanism, raising the question of how autoinhibition is structurally mediated.\",\n      \"evidence\": \"SH3 deletion mutant expression in 293 and BA/F3 cells with kinase activity assay\",\n      \"pmids\": [\"9045937\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of SH3-mediated autoinhibition not resolved\", \"Whether the SH3 domain acts through intramolecular or intermolecular contacts was unclear\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identifying TEC interactions with PI3K p85 subunit, Vav, and JAK1 positioned TEC at a signaling nexus between JAK/STAT, PI3K, and Rho/Rac pathways.\",\n      \"evidence\": \"Yeast two-hybrid and co-immunoprecipitation in cytokine-stimulated cells\",\n      \"pmids\": [\"9178903\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of PI3K-TEC complex not established\", \"Whether Vav is a substrate or scaffold for TEC was unresolved\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Three contemporaneous studies established the core signaling axis: PtdIns(3,4,5)P3 recruits TEC via its PH domain, TEC phosphorylates PLCγ to produce IP3 and drive sustained Ca²⁺ mobilization downstream of antigen receptors, and SHIP terminates the signal—defining TEC as a PI3K-to-PLCγ relay.\",\n      \"evidence\": \"PH domain-lipid binding assays, in vitro PLCγ phosphorylation, IP3 measurement, calcium flux in Btk-deficient B cells, Rho-dependent SRF reporter assays\",\n      \"pmids\": [\"9524119\", \"9524120\", \"9755164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TEC and Btk are fully redundant in B cells was unresolved\", \"Structural basis of PH domain selectivity for PtdIns(3,4,5)P3 not determined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identification of adaptor selectivity (SLP-65/SLP-76 binding via TEC SH2 domain), functional redundancy with Btk in DT40 cells, and BRDG1 as a TEC-specific substrate revealed how TEC is recruited to signaling complexes and expanded its substrate repertoire.\",\n      \"evidence\": \"SH2 domain binding assays, reconstitution in Btk-deficient DT40 B cells, yeast two-hybrid and in vitro kinase assays for BRDG1\",\n      \"pmids\": [\"10556826\", \"10224128\", \"10518561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo physiological role of BRDG1 phosphorylation not tested in knockout models\", \"Degree of functional overlap between TEC and Btk in primary cells not fully defined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrating TEC activation downstream of SCF/cKit (forming a Lyn-Dok-1 complex) and GPVI/CD32 in platelets broadened TEC's receptor repertoire beyond cytokine and antigen receptors to growth factor and ITAM-coupled receptors.\",\n      \"evidence\": \"Co-IP and kinase assays in hematopoietic cells (SCF stimulation); phosphospecific antibodies in platelets (GPVI/CD32 stimulation)\",\n      \"pmids\": [\"11071635\", \"10688822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Platelet-specific substrates of TEC not identified\", \"Physiological consequence of TEC activation in platelet aggregation not tested in vivo\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"The NMR structure of the TEC SH3 domain with mapping of two PRR-binding sites resolved how intramolecular versus intermolecular SH3-PRR contacts control autoinhibition and targeting, while identification of Sak/PLK4 as a TEC substrate linked TEC to cell cycle regulation.\",\n      \"evidence\": \"NMR structure determination with mutagenesis and binding assays; yeast two-hybrid and in vitro kinase assay for Sak\",\n      \"pmids\": [\"11684687\", \"11489907\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length TEC structure including SH3-PRR interaction not available\", \"In vivo relevance of TEC-Sak interaction not confirmed in knockout models\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identifying SHIP1/SHIP2 as preferential negative regulators of TEC (via SH3-mediated interaction and PtdIns(3,4,5)P3 degradation) and PKCθ as a TEC-dependent signaling partner in T cells defined cell-type-specific regulatory inputs.\",\n      \"evidence\": \"Co-IP, kinase assay, membrane localization rescue (SHIP); Co-IP, dominant-negative, reporter assay (PKCθ) in T cells\",\n      \"pmids\": [\"15492005\", \"15214048\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SHIP directly dephosphorylates TEC or only removes PtdIns(3,4,5)P3 was not resolved\", \"PKCθ-TEC interaction awaits structural characterization\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Quantitative biochemistry established that the SH2-kinase linker allosterically activates catalysis and that TEC uses a remote SH2 domain docking mechanism on substrates like PLCγ, explaining how substrate selectivity is achieved.\",\n      \"evidence\": \"In vitro kinase assays with linker mutagenesis and SH2 domain deletion/competition kinetics\",\n      \"pmids\": [\"17425330\", \"17439160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure capturing the linker-kinase allosteric interface\", \"Whether SH2-docking mechanism operates for all TEC substrates (e.g., BRDG1, Sak) not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Btk/Tec double-knockout mice revealed a non-redundant physiological role in osteoclastogenesis via RANK-ITAM-PLCγ calcium signaling, and TEC was shown to mediate innate immune responses to MSU crystals in neutrophils.\",\n      \"evidence\": \"Genetic double-KO mice with bone histology, Co-IP of RANK/BLNK complex; siRNA knockdown with cytokine ELISA in neutrophils\",\n      \"pmids\": [\"18329366\", \"18512796\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of TEC versus Btk in single-KO osteoclasts not fully dissected\", \"MSU-induced TEC activation mechanism upstream of Src not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery of the extended regulatory spine network explained how distal regulatory inputs (SH2-kinase linker tryptophan, C-helix methionine, gatekeeper residue) are transmitted allosterically to the TEC catalytic site.\",\n      \"evidence\": \"Mutagenesis of regulatory spine residues with in vitro kinase assay and structural analysis\",\n      \"pmids\": [\"20826165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length TEC structure showing regulatory spine in intact protein context not available\", \"Whether pharmacological spine disruption can selectively inhibit TEC not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"TEC was shown to directly phosphorylate FGF2 on tyrosine residues to promote membrane pore formation and unconventional secretion, establishing a non-immune function for TEC in growth factor export.\",\n      \"evidence\": \"In vitro kinase assay, Co-IP, FGF2 secretion assay with small molecule inhibitors\",\n      \"pmids\": [\"27382052\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the specific FGF2 tyrosine residues phosphorylated by TEC not mapped\", \"In vivo relevance of TEC-FGF2 axis not tested in animal models\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"TEC was found to phosphorylate PLK4 at Y86, stabilizing PLK4 protein and promoting HCC cell invasion through FAK signaling, extending TEC's substrate repertoire to cancer cell migration.\",\n      \"evidence\": \"In vitro kinase assay, Y86 mutagenesis, protein stability assay, HCC cell invasion assays\",\n      \"pmids\": [\"34637843\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo validation in animal tumor models not reported\", \"Whether TEC-PLK4 interaction occurs in non-cancer contexts is unknown\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A full-length structure of TEC capturing the autoinhibited-to-active transition, the relative contributions of TEC versus Btk in specific immune cell lineages in vivo, and the physiological significance of non-immune TEC substrates (FGF2, PLK4) remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length TEC crystal/cryo-EM structure available\", \"Single-KO TEC mouse phenotype in immune cells incompletely characterized relative to Btk\", \"In vivo roles of TEC-FGF2 and TEC-PLK4 axes untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 5, 8, 9, 10, 13, 18, 19, 22, 24]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 4, 9, 10, 22, 24]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 15]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 5, 7, 8, 11, 19, 20]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 4, 6, 10, 16]}\n    ],\n    \"complexes\": [\n      \"RANK-ITAM-BLNK/SLP-76 signaling complex\"\n    ],\n    \"partners\": [\n      \"PLCG1\",\n      \"PLCG2\",\n      \"BLNK\",\n      \"SLP76\",\n      \"SHIP1\",\n      \"SHIP2\",\n      \"DOK1\",\n      \"LYN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}