{"gene":"TEC","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":1990,"finding":"Tec was identified as a novel non-receptor protein-tyrosine kinase preferentially expressed in liver, with C-terminal domain homology to Src family members, representing the founding member of what became the Tec kinase family.","method":"cDNA library screening with v-fps kinase domain probe; Northern blot analysis; sequence analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — original cloning and characterization with sequence analysis and expression studies; single lab, foundational identification paper","pmids":["2284097"],"is_preprint":false},{"year":1994,"finding":"Tec physically associates with c-kit through a proline-rich motif N-terminal to the SH3 domain; following stem cell factor (SCF) binding, Tec is tyrosine phosphorylated and its in vitro kinase activity is increased. This activation is SCF-specific and not induced by CSF-1, GM-CSF, or IL-3.","method":"Co-immunoprecipitation; in vitro kinase assay; tyrosine phosphorylation assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, in vitro kinase assay, and specificity controls across multiple cytokines; single lab but multiple orthogonal methods","pmids":["7526158"],"is_preprint":false},{"year":1994,"finding":"Tec directly associates with Lyn protein-tyrosine kinase through the N-terminal unique domain (NTec2 region) of Tec; Lyn binds via its SH3 domain; the p56 form of Lyn is inducibly tyrosine-phosphorylated in response to IL-3 within this complex.","method":"GST-fusion pull-down; in vivo co-immunoprecipitation; in vitro binding assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro GST pull-down plus in vivo co-IP; domain mapping; single lab with multiple orthogonal methods","pmids":["7936643"],"is_preprint":false},{"year":1994,"finding":"The Tec homology (TH) domain adjacent to the PH domain contains a conserved ~27 amino acid Btk motif and a proline-rich region, defining it as a distinct structural element within Tec family kinases likely involved in protein-protein interactions.","method":"Sequence analysis; domain structure characterization","journal":"FEBS letters","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational/sequence-based domain identification only, no functional validation experiment described","pmids":["8070576"],"is_preprint":false},{"year":1995,"finding":"Tec kinase associates with Vav upon erythropoietin and IL-3 stimulation; this interaction occurs through the Tec homology domain of Tec. Tec kinase is transiently activated by these cytokines, and Grb2 constitutively associates with Vav.","method":"Co-immunoprecipitation; in vitro binding assay; kinase activity assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro and in vivo binding assays with domain mapping; kinase activity measurement; single lab with multiple orthogonal methods","pmids":["7651724"],"is_preprint":false},{"year":1995,"finding":"Tec and Btk associate with gp130 (the shared signal transducer of IL-6 family cytokines) without ligand stimulation; IL-6 stimulation activates both Btk and Tec, while IL-3 and G-CSF activate Tec but not Btk in a pro-B cell line.","method":"Co-immunoprecipitation; kinase activation assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP demonstrating constitutive association plus ligand-induced activation assays distinguishing Tec from Btk; single lab with multiple receptor systems tested","pmids":["7530500"],"is_preprint":false},{"year":1995,"finding":"Tec is tyrosine phosphorylated and its kinase activity is activated following IL-3 stimulation in myeloid and pro-B cell lines; Tec constitutively associates with the Shc adapter protein in vivo.","method":"Anti-Tec immunoprecipitation; in vitro kinase assay; co-immunoprecipitation","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase activity assay and co-IP; single lab, two orthogonal methods","pmids":["7811991"],"is_preprint":false},{"year":1996,"finding":"Lyn kinase directly phosphorylates tyrosine residues of Tec and thereby activates Tec, while Tec co-expression has little effect on Lyn phosphotyrosine content, establishing that Tec acts downstream of Lyn. Demonstrated both in vitro and in a yeast system.","method":"In vitro kinase assay; yeast two-hybrid system; co-expression in 3T3 fibroblasts","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro phosphorylation assay plus yeast system validation; unidirectional regulation clearly established with multiple approaches","pmids":["8621063"],"is_preprint":false},{"year":1996,"finding":"Tec is tyrosine phosphorylated and activated by G-CSF stimulation in both cell growth and differentiation contexts; Vav associates with Tec and is tyrosine phosphorylated in response to G-CSF.","method":"Immunoprecipitation; kinase activity assay; co-immunoprecipitation","journal":"Cell growth & differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and kinase activity assay; single lab, two orthogonal methods","pmids":["8877094"],"is_preprint":false},{"year":1997,"finding":"SOCS-1/JAB/SSI-1 (identified as TIP3) associates with Tec in 293 cells and suppresses its kinase activity, while also down-regulating Jak2 but not Lyn activity, identifying SOCS-1 as a negative regulator of Tec.","method":"Yeast two-hybrid screening; co-immunoprecipitation in 293 cells; kinase activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid identification followed by co-IP in mammalian cells and kinase suppression assay; single lab with multiple orthogonal methods","pmids":["9341160"],"is_preprint":false},{"year":1997,"finding":"JAK1 (but not JAK2) associates with Tec and Btk; JAK1 induces tyrosine phosphorylation of Btk but not Tec. Tec interacts with p85 and p55PIK subunits of PI-3 kinase (dependent on Tec kinase activity) and with Vav (via SH2 domain, independent of kinase activity). IL-6 and IL-3 induce Tec-p85 PI3K association in mammalian cells.","method":"Co-immunoprecipitation; yeast two-hybrid; overexpression in mammalian cells","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid plus in vivo co-IP; domain dependency established; single lab with multiple orthogonal methods","pmids":["9178903"],"is_preprint":false},{"year":1998,"finding":"PtdIns-3,4,5-P3 interacting with the Tec PH domain acts as an upstream activation signal for Tec kinases, resulting in Tec kinase-dependent PLCγ tyrosine phosphorylation and IP3 production. The SHIP inositol phosphatase blocks this pathway by degrading PtdIns-3,4,5-P3.","method":"Cell-based signaling assays; phospholipid binding; PLCγ phosphorylation assay; IP3 production measurement","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct demonstration of PH domain-PIP3 interaction coupled with downstream PLCγ phosphorylation and IP3 production; SHIP inhibition mechanistically linked; replicated across Tec family members","pmids":["9524119"],"is_preprint":false},{"year":1998,"finding":"Tec and Bmx activate serum response factor (SRF) in synergy with constitutively active Gα12/13 subunits; this SRF activation is Rho-dependent (blocked by C3 transferase). The kinase and Tec homology domains are required. Gα12 and Gα13 stimulate Tec autophosphorylation and transphosphorylation activities.","method":"Transient transfection; SRF reporter assay; C3 transferase inhibition; kinase activity assay; domain deletion analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reporter assays with domain mutants, pharmacological inhibition of Rho, and direct kinase activity assays; single lab with multiple orthogonal methods","pmids":["9755164"],"is_preprint":false},{"year":1998,"finding":"Tec is rapidly tyrosine phosphorylated in human platelets in response to G protein-coupled receptor agonists (thromboxane A2 analog, thrombin, TRAP) and integrin engagement (adhesion to fibrinogen or collagen). Tec translocates to the cytoskeleton upon TRAP stimulation in a manner dependent on platelet aggregation, indicating a role in integrin-mediated signaling.","method":"Immunoprecipitation; tyrosine phosphorylation assay; subcellular fractionation; platelet activation assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation and subcellular fractionation with pharmacological controls; single lab, two orthogonal methods","pmids":["9652744"],"is_preprint":false},{"year":1998,"finding":"Tec is expressed throughout human B cell differentiation and can be activated by BCR cross-linking (inducing tyrosine phosphorylation and increased kinase activity) and CD19 or CD38 ligation; Tec responds to CD38 stimulation whereas Btk does not, indicating differential regulation.","method":"Immunoprecipitation; in vitro kinase assay; anti-receptor antibody stimulation","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase activity assay plus differential receptor stimulation comparison; single lab with multiple receptor systems","pmids":["9446655"],"is_preprint":false},{"year":1999,"finding":"Tec is activated following TCR/CD3 or CD28 ligation in T cells. Tec interacts with CD28 in an activation-dependent manner via the Tec SH3 domain binding to proline-rich motifs in CD28. Tec phosphorylates p62dok, a CD28-specific substrate (unlike Itk). Overexpression of Tec (but not Itk) enhances IL-2 promoter activity following TCR/CD3 or CD28 stimulation.","method":"Co-immunoprecipitation; in vitro kinase assay; luciferase reporter assay; dominant-negative overexpression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP with domain specificity, substrate phosphorylation in vitro, and reporter assays with gain- and loss-of-function; single lab with multiple orthogonal methods establishing distinct Tec vs Itk functions","pmids":["9872994"],"is_preprint":false},{"year":1999,"finding":"Tec kinase is involved in IL-2 and IL-4 transcriptional regulation downstream of CD28; CD28-mediated Tec activation requires Src family PTK activity (Lck), as kinase-dead Lck blocks Tec activation and Tec-induced cytokine expression.","method":"Reporter assay (IL-2 and IL-4 promoter-luciferase); co-expression of kinase-dead mutants","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reporter assays with gain/loss of function; single lab, but consistent with other work on Tec in CD28 signaling","pmids":["10382746"],"is_preprint":false},{"year":1999,"finding":"BRDG1 (BCR downstream signaling 1) was identified as a downstream docking protein of Tec. Tec (but not Btk, Bmx, Lyn, Syk, or c-Abl) phosphorylates BRDG1 on tyrosine in cells and directly in vitro. Efficient phosphorylation requires PH and SH2 domains plus the kinase domain of Tec. BRDG1 participates in a positive feedback loop increasing Tec activity, and undergoes tyrosine phosphorylation in response to BCR stimulation.","method":"Yeast two-hybrid; in vitro kinase assay; in vivo phosphorylation in 293 cells; BCR stimulation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro direct phosphorylation assay plus in vivo confirmation; substrate specificity established with multiple kinase comparisons; single lab with multiple orthogonal methods","pmids":["10518561"],"is_preprint":false},{"year":2000,"finding":"SCF/cKit signaling leads to PI3K-dependent activation and phosphorylation of Tec and Dok-1, which form a stable complex with Lyn and two unidentified phosphoproteins. The Tec homology domain and SH2 domain of Tec are required for interaction with Dok-1. Tec and Lyn phosphorylate Dok-1, which then binds SH2 domains of Abl, CrkL, SHIP, and PLCγ-1.","method":"Co-immunoprecipitation; in vitro kinase assay; PI3K inhibitor studies; domain deletion analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — complex formation by co-IP, domain requirements mapped, in vitro phosphorylation of Dok-1 by Tec, downstream SH2 binding confirmed; single lab with multiple orthogonal methods","pmids":["11071635"],"is_preprint":false},{"year":2000,"finding":"Tec/Btk double-deficient mice exhibit a block at the B220+CD43+ stage of B cell development and severe reduction of peripheral B cells (particularly IgMloIgDhi), demonstrating that Tec and Btk together have an essential non-redundant role in B cell development that neither alone is required for.","method":"Genetic knockout; B cell developmental analysis by flow cytometry; immunological phenotyping","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — double-KO genetic epistasis with detailed developmental staging; definitive loss-of-function phenotype","pmids":["11104803"],"is_preprint":false},{"year":2000,"finding":"Both Btk and Tec undergo rapid tyrosine phosphorylation in platelets following stimulation of the GPVI collagen receptor or CD32 cross-linking, with coordinate recruitment through ITAM, Src family kinases, and PI3K. In XLA platelets lacking Btk, Tec phosphorylation is preserved along with downstream signaling molecules.","method":"Immunoprecipitation; phosphopeptide-specific antibodies; kinase inhibitor studies; platelet stimulation assays","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation kinetics and inhibitor studies; mechanistic pathway proposed with supporting biochemical evidence; single lab","pmids":["10688822"],"is_preprint":false},{"year":2001,"finding":"The solution NMR structure of the Tec SH3 domain was determined; the Tec proline-rich region (PRR) can bind intramolecularly to the SH3 domain (site 1: 155KTLPPAP161 binds intramolecularly; site 2: 165KRRPPPPIPP174 binds intermolecularly/dimerization). The affinity for dimerization via reciprocal PRR-SH3 is higher than for the intramolecular interaction.","method":"NMR solution structure determination; site-directed mutagenesis; binding affinity measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure with mutagenesis validation of two distinct binding sites; functional significance of intramolecular vs intermolecular interactions defined","pmids":["11684687"],"is_preprint":false},{"year":2001,"finding":"Sak serine-threonine kinase (a Polo-family member) is phosphorylated on tyrosine by Tec in 293 cells and directly in vitro; Tec activates the serine-threonine kinase activity of Sak and protects it from PEST sequence-dependent proteolysis, establishing Sak as an effector molecule of Tec.","method":"Yeast two-hybrid; in vitro kinase assay; co-expression in 293 cells; proteolysis assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro phosphorylation confirmed in cells; Sak kinase activity dependent on Tec; stability regulated by Tec; single lab with multiple orthogonal methods","pmids":["11489907"],"is_preprint":false},{"year":2003,"finding":"Tec plays a role in platelet activation by GPVI in the absence of Btk. Btk/Tec double-deficient platelets fail to undergo Ca2+ increase, aggregation, secretion, and spreading in response to collagen or CRP, whereas Tec-/- alone shows only minor reduction. PLCγ2 tyrosine phosphorylation is further reduced in Btk/Tec double-deficient compared to Btk-/- platelets.","method":"Genetic knockout (single and double KO); platelet aggregation assay; calcium measurement; PLCγ2 phosphorylation assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — double-KO epistasis with multiple functional readouts; PLCγ2 phosphorylation biochemical endpoint; single lab with multiple orthogonal methods","pmids":["12842985"],"is_preprint":false},{"year":2003,"finding":"TGF-β inhibits Tec kinase (Itk) phosphorylation and activation in stimulated CD4+ T cells, leading to reduced Ca2+ influx, impaired NFATc translocation, and reduced ERK activation, thereby blocking T cell differentiation at a proximal signaling step.","method":"Kinase phosphorylation assay; calcium influx measurement; NFATc translocation assay; ERK activation assay","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple downstream readouts of Tec inhibition by TGF-β; single lab with orthogonal methods; note this paper focuses primarily on Itk but demonstrates Tec-family regulation","pmids":["12810687"],"is_preprint":false},{"year":2004,"finding":"Tec overexpression in lymphocyte cell lines induces PLCγ phosphorylation and NFAT activation, whereas overexpression of Btk, Itk, or Bmx does not induce NFAT activation. Tec-induced NFAT activation requires PLCγ but not the adapters LAT, SLP-76, and BLNK (which are required for Btk and Itk). Tec has a unique subcellular localization correlating with this distinct effector function.","method":"Overexpression in cell lines; NFAT reporter assay; PLCγ phosphorylation; subcellular localization","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reporter assays with comparison across family members; adapter independence established; subcellular localization difference observed; single lab with multiple orthogonal methods","pmids":["14993283"],"is_preprint":false},{"year":2004,"finding":"PKCθ constitutively associates with Tec (interaction requires the Tec PH domain). Wild-type Tec (but not Itk or Rlk) potently activates AP-1 downstream of PKCθ, and dominant-negative Tec blocks PKCθ-induced AP-1 (but not NF-κB) activation. Tec thus mediates a PKCθ→Tec→PLCγ1→Ca2+ positive feedback loop regulating AP-1 in restimulated T cells.","method":"Co-immunoprecipitation; reporter assay (AP-1, NF-κB); dominant-negative overexpression; calcium measurement","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain requirement plus reporter and functional assays; single lab with multiple orthogonal methods","pmids":["15214048"],"is_preprint":false},{"year":2004,"finding":"SHIP1 and SHIP2 interact preferentially with Tec (via its SH3 domain) compared to other Tec family members, and function as negative regulators: they inhibit Tec activity, and SHIP1 inhibits Tec membrane localization. Inactivation of the Tec SH3 domain generates a hyperactive Tec. Constitutive membrane targeting of Tec relieves SHIP1-mediated inhibition.","method":"Co-immunoprecipitation; kinase activity assay; subcellular fractionation; constitutively membrane-targeted mutant; SH3 domain mutant analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple lines of evidence (interaction, inhibition, domain mutant, membrane targeting rescue); single lab with multiple orthogonal methods","pmids":["15492005"],"is_preprint":false},{"year":2004,"finding":"Dok-1 and Dok-2 are major tyrosine-phosphorylated proteins associated with Tec in T cells and act as negative feedback regulators of Tec, downregulating its tyrosine phosphorylation and downstream Ras pathway signaling.","method":"Co-immunoprecipitation; tyrosine phosphorylation assay; Ras pathway reporter assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and functional assays in T cells; single lab, two orthogonal methods","pmids":["14647425"],"is_preprint":false},{"year":2004,"finding":"Tec PH domain is required for Tec-mediated IL-2 gene induction and TCR-mediated Tec tyrosine phosphorylation in T cells. Tec colocalizes with the TCR after cross-linking (both PH and SH2 domains involved). Wortmannin (PI3K inhibitor) abolishes Tec phosphorylation and IL-2 induction, establishing PI3K-PH domain signaling axis upstream of Tec.","method":"PH domain mutant overexpression; IL-2 reporter assay; tyrosine phosphorylation assay; confocal microscopy; wortmannin inhibition","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple domain mutants, reporter assays, and localization; single lab with multiple orthogonal methods","pmids":["11123316"],"is_preprint":false},{"year":2007,"finding":"The short linker region between the SH2 and kinase domains of Tec family kinases (studied via Itk as model) positively regulates catalytic activity. Precise conserved residues in this linker allosterically regulate activity, a mechanism conserved among Tec kinases but distinct from Src kinase regulation.","method":"Quantitative in vitro kinase assay; linker deletion/mutation analysis","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative in vitro kinase assay with defined mutations; conserved mechanism identified across Tec family; single lab","pmids":["17425330"],"is_preprint":false},{"year":2008,"finding":"Btk and Tec together regulate osteoclast differentiation downstream of RANK and ITAM signals. Mice lacking both Btk and Tec show severe osteopetrosis. RANK and ITAM signaling forms a Btk(Tec)/BLNK(SLP-76)-containing complex leading to PLCγ-mediated calcium signaling required for NFATc1 activation and osteoclastogenesis.","method":"Double-KO mouse model; osteoclast differentiation assay; co-immunoprecipitation of signaling complex; calcium measurement; Tec kinase inhibitor in disease models","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic double-KO epistasis, biochemical complex formation by co-IP, functional calcium/NFATc1 readouts, and pharmacological inhibition in disease models; rigorous multi-approach study","pmids":["18329366"],"is_preprint":false},{"year":2008,"finding":"Btk and Tec are activated throughout FcγR-induced phagocytosis in macrophages, accumulating at the base of phagocytic cups. Their inhibition (by LFM-A13 or siRNA) significantly inhibits FcγR-induced phagocytosis. Btk and Tec regulate FcγR-induced Mac-1 activation required for optimal phagocytosis. A late/prolonged PLCγ2 activation (after initial Syk-dependent phase) is dependent on Btk and Tec. Activated Btk (but not Tec) co-localizes with phagosomal diacylglycerol.","method":"siRNA knockdown; pharmacological inhibition; live-cell imaging; subcellular fractionation; PLCγ2 phosphorylation assay; Mac-1 activation assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA and pharmacological inhibition with live imaging and biochemical readouts; distinct roles of Btk vs Tec at different phagocytic stages established; single lab with multiple orthogonal methods","pmids":["18566394"],"is_preprint":false},{"year":2010,"finding":"The extended regulatory spine within Tec kinases (identified via Itk/Btk) includes a conserved methionine in the C-helix and a conserved tryptophan in the SH2-kinase linker, forming an allosteric conduit from regulatory domains to the catalytic domain. Mutation of the gatekeeper residue stabilizes the regulatory spine, rendering a constitutively active kinase in which activation loop phosphorylation is unnecessary.","method":"In vitro kinase assay; mutagenesis; structural analysis of regulatory spine residues","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase activity measurements with defined point mutations; mechanistic model of regulatory spine validated functionally; single lab","pmids":["20826165"],"is_preprint":false},{"year":2013,"finding":"Btk and Itk (Tec family members) have distinct catalytic efficiencies due to differences in activation loop dynamics. Substitution of 6 residues in the activation segment of Itk with corresponding Btk residues (and vice versa) completely swaps their kinase activities. NMR and HDX-MS revealed distinct dynamics in the activation loop explaining the catalytic efficiency differences.","method":"In vitro kinase assay; mutagenesis (activation segment substitutions); NMR; hydrogen-deuterium exchange mass spectrometry; T cell TCR signaling assays","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution/mutagenesis with NMR and HDX-MS structural validation; activity swap confirmed functionally in cells; single rigorous study with multiple orthogonal methods","pmids":["23982207"],"is_preprint":false},{"year":2014,"finding":"Tec kinase is required for activation and assembly of the noncanonical caspase-8 inflammasome (but not the caspase-1 inflammasome) in macrophages during Candida albicans infection. Dectin-1 is the pathogen recognition receptor required for Syk-dependent Tec activation. Tec genetic ablation or small-molecule inhibition protects mice from fungal sepsis.","method":"Genetic knockout; small-molecule inhibition; in vivo fungal infection model; inflammasome assembly assay; IL-1β production assay","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mice plus pharmacological inhibition with specific pathway readout (caspase-8 vs caspase-1 specificity), in vivo disease model; single lab with multiple orthogonal methods","pmids":["25474208"],"is_preprint":false},{"year":2016,"finding":"Tec kinase directly phosphorylates FGF2 on tyrosine to stimulate FGF2 membrane pore formation during unconventional secretion. Small molecules that inhibit FGF2-Tec interaction also inhibit FGF2 tyrosine phosphorylation in vitro and in cells, and block unconventional FGF2 secretion. Inhibitors are specific for FGF2 as a Tec substrate (tyrosine phosphorylation of a different Tec substrate is unaffected).","method":"In vitro kinase assay; co-immunoprecipitation; small-molecule inhibitor; unconventional secretion assay in cells; substrate specificity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro direct phosphorylation assay plus cellular validation; substrate specificity confirmed; inhibitor mechanism established; single lab with multiple orthogonal methods","pmids":["27382052"],"is_preprint":false},{"year":2016,"finding":"A conserved tryptophan in the SH2-kinase linker of Tec family kinases mediates allosteric activation of Btk; mutation to alanine abolishes activity. Specific tryptophan side chain rotamer promotes coordinated motions across the kinase domain. This dynamic allostery is conserved across the Tec family.","method":"HDX mass spectrometry; molecular dynamics simulations; principal component analysis; mutagenesis; kinase activity assay","journal":"PLoS computational biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — HDX-MS plus MD simulations; mutagenesis confirms functional importance; study focused on Btk but mechanism is generalized to Tec family including TEC; single lab","pmids":["27010561"],"is_preprint":false}],"current_model":"TEC is a non-receptor tyrosine kinase (founding member of the Tec family) that is activated downstream of multiple cell-surface receptors — including cytokine receptors (via JAK1/Lyn), antigen receptors (BCR, TCR), receptor tyrosine kinases (c-Kit), G protein-coupled receptors, and integrins — through a PI3K-PtdIns(3,4,5)P3/PH domain membrane-recruitment mechanism; once membrane-localized, TEC is phosphorylated and activated by Lyn (and Src family kinases downstream of CD28 via Lck), then phosphorylates PLCγ to drive IP3 production and Ca2+ mobilization, and also phosphorylates substrates including FGF2, BRDG1, Sak, and Dok proteins; its activity is negatively regulated by SOCS-1 (direct binding and suppression), SHIP1/2 (via SH3 domain interaction that depletes local PtdIns(3,4,5)P3), and Dok-1/2 (negative feedback); structurally, TEC kinase activity is allosterically controlled by an extended regulatory spine (including a conserved tryptophan in the SH2-kinase linker and a methionine in the C-helix) and by intramolecular SH3-PRR interactions that maintain autoinhibition; in B cells TEC cooperates with Btk for B cell development and BCR/GPVI signaling; in T cells TEC activates AP-1/NFAT through a PKCθ-dependent pathway unique from Itk; TEC also assembles the RANK/ITAM/BLNK(SLP-76) complex for PLCγ-Ca2+-NFATc1-driven osteoclastogenesis, controls caspase-8 inflammasome assembly during fungal infection downstream of Dectin-1/Syk, and participates in FcγR-mediated phagocytosis and platelet activation by GPVI."},"narrative":{"mechanistic_narrative":"TEC is the founding member of the Tec family of non-receptor protein-tyrosine kinases, originally identified as a Src-homologous kinase preferentially expressed in liver [PMID:2284097], that couples diverse cell-surface receptors to phospholipase Cγ-driven calcium signaling [PMID:9524119]. TEC is recruited to the membrane when its PH domain binds PtdIns(3,4,5)P3 generated by PI3K, where it phosphorylates PLCγ to drive IP3 production and Ca2+ mobilization; the SHIP inositol phosphatase opposes this by degrading PtdIns(3,4,5)P3 [PMID:9524119, PMID:15492005]. Activation occurs downstream of cytokine receptors, the receptor tyrosine kinase c-Kit, the IL-6-family transducer gp130, antigen and costimulatory receptors, GPCRs, and integrins, with TEC being phosphorylated and activated directly by Lyn [PMID:7526158, PMID:7530500, PMID:8621063, PMID:9652744]; in T cells CD28-mediated activation requires Src-family (Lck) activity [PMID:9872994, PMID:10382746]. TEC propagates signaling by phosphorylating docking and effector substrates including BRDG1, Dok-1, the Polo-family kinase Sak, and FGF2, the last during unconventional FGF2 secretion [PMID:10518561, PMID:11071635, PMID:11489907, PMID:27382052]. In T cells TEC has a unique adapter-independent route to PLCγ/NFAT activation distinct from Itk, acting through a PKCθ→TEC→PLCγ1→Ca2+ feedback loop to drive AP-1 and IL-2 expression [PMID:14993283, PMID:15214048, PMID:9872994]. Genetically, TEC acts redundantly with Btk: Btk/Tec double-deficient mice fail at an early stage of B cell development, lose GPVI-dependent platelet activation, and develop severe osteopetrosis through a RANK/ITAM/BLNK(SLP-76)→PLCγ→NFATc1 osteoclastogenic complex [PMID:11104803, PMID:12842985, PMID:18329366]. TEC also drives Fcγ-receptor phagocytosis and assembly of the noncanonical caspase-8 inflammasome downstream of Dectin-1/Syk during fungal infection [PMID:18566394, PMID:25474208]. TEC activity is held in check by intramolecular SH3–proline-rich interactions and an extended regulatory spine relaying allosteric signals from the SH2-kinase linker to the catalytic domain [PMID:11684687, PMID:17425330, PMID:20826165], and is negatively regulated by SOCS-1, SHIP1/2, and Dok-1/2 [PMID:9341160, PMID:15492005, PMID:14647425].","teleology":[{"year":1990,"claim":"Establishing that a distinct non-receptor tyrosine kinase existed defined the founding member of a new kinase family and set the stage for its functional dissection.","evidence":"cDNA cloning with a v-fps kinase probe and Northern expression analysis in liver","pmids":["2284097"],"confidence":"Medium","gaps":["No catalytic substrate or signaling pathway identified","Function beyond sequence homology unknown"]},{"year":1994,"claim":"Linking TEC to specific receptor systems showed it is an inducibly activated kinase, answering which upstream signals engage it.","evidence":"Co-IP and in vitro kinase assays with c-Kit/SCF, Lyn, and Vav associations with domain mapping","pmids":["7526158","7936643","7651724"],"confidence":"High","gaps":["Order of kinase activation not yet resolved","Downstream substrates not defined"]},{"year":1996,"claim":"Resolving the directionality of the TEC–Lyn relationship placed TEC downstream of a Src-family kinase, clarifying activation hierarchy.","evidence":"In vitro phosphorylation, yeast two-hybrid, and fibroblast co-expression showing Lyn phosphorylates and activates TEC unidirectionally","pmids":["8621063"],"confidence":"High","gaps":["Physiological receptor context of Lyn-TEC activation not fully defined"]},{"year":1998,"claim":"Identifying the PI3K-PtdIns(3,4,5)P3/PH-domain axis and PLCγ output defined the core membrane-recruitment and effector mechanism of TEC.","evidence":"Phospholipid binding, PLCγ phosphorylation, IP3 measurement, and SHIP inhibition in cell-based assays","pmids":["9524119"],"confidence":"High","gaps":["Precise activation-loop phosphorylation events not mapped here","Receptor-specific contributions of PI3K not dissected"]},{"year":1999,"claim":"Distinguishing TEC from Itk in T cells answered whether Tec-family members have non-redundant effector functions, revealing a CD28-specific signaling role.","evidence":"Co-IP with SH3-domain specificity, in vitro phosphorylation of p62dok, and IL-2 reporter gain/loss-of-function in T cells","pmids":["9872994","10382746"],"confidence":"High","gaps":["In vivo T-cell phenotype of TEC alone not established","Endogenous CD28-TEC stoichiometry unknown"]},{"year":1999,"claim":"Identifying BRDG1 as a TEC-selective substrate revealed a positive feedback docking protein that amplifies TEC activity in BCR signaling.","evidence":"Yeast two-hybrid, in vitro and in-cell phosphorylation with kinase-specificity comparison, and BCR stimulation","pmids":["10518561"],"confidence":"High","gaps":["Structural basis of feedback amplification not resolved","In vivo requirement of BRDG1 not tested"]},{"year":2000,"claim":"Genetic and biochemical work defined TEC substrates and an essential Btk-redundant role, answering whether TEC matters at the organismal level.","evidence":"Btk/Tec double-knockout B cell developmental analysis plus Dok-1 complex/phosphorylation studies downstream of c-Kit","pmids":["11104803","11071635"],"confidence":"High","gaps":["Mechanism of TEC/Btk functional overlap at molecular level not detailed","Whether unique TEC substrates contribute in vivo unclear"]},{"year":2001,"claim":"NMR structure of the SH3 domain and effector identification clarified autoinhibitory/dimerization control and extended the TEC substrate repertoire.","evidence":"NMR solution structure with mutagenesis defining intramolecular vs dimerization PRR-SH3 sites, plus identification of Sak as a TEC substrate","pmids":["11684687","11489907"],"confidence":"High","gaps":["Cellular relevance of TEC dimerization not established","Physiological Sak-TEC pathway context unknown"]},{"year":2004,"claim":"Defining a unique adapter-independent route to NFAT and the PKCθ feedback loop established how TEC effector function diverges from other Tec-family kinases, while SHIP/Dok work mapped negative regulation.","evidence":"Reporter assays comparing family members, PKCθ co-IP with PH-domain requirement, and SHIP1/2 and Dok-1/2 inhibition assays","pmids":["14993283","15214048","15492005","14647425"],"confidence":"High","gaps":["Identity of TEC's unique subcellular compartment not molecularly defined","Quantitative balance of positive vs negative regulators in vivo unclear"]},{"year":2010,"claim":"Defining the extended regulatory spine and SH2-kinase linker allostery explained how regulatory domains control catalysis, answering the structural logic of TEC activation.","evidence":"In vitro kinase assays with linker and spine mutations, gatekeeper mutation analysis, HDX-MS, and MD simulations (studied across Tec family)","pmids":["17425330","20826165","23982207","27010561"],"confidence":"High","gaps":["Several mechanistic studies use Itk/Btk as model and generalize to TEC","Full-length autoinhibited TEC structure not solved"]},{"year":2008,"claim":"Genetic and biochemical work in osteoclasts, phagocytes, and antifungal immunity expanded TEC's role beyond lymphocytes to innate immunity and bone homeostasis.","evidence":"Btk/Tec double-KO osteopetrosis with RANK/ITAM/BLNK complex co-IP, Fcγ-receptor phagocytosis siRNA/inhibitor imaging, and Dectin-1/Syk-dependent caspase-8 inflammasome in fungal infection models","pmids":["18329366","18566394","25474208"],"confidence":"High","gaps":["TEC-specific (vs Btk) contributions in some innate settings not separated","Direct TEC substrates in the caspase-8 inflammasome not identified"]},{"year":2016,"claim":"Identifying FGF2 as a direct TEC substrate during unconventional secretion revealed a function outside classical receptor-signaling pathways.","evidence":"In vitro kinase assay, co-IP, substrate-specific small-molecule inhibitors, and unconventional secretion assays","pmids":["27382052"],"confidence":"High","gaps":["Physiological/in vivo significance of TEC in FGF2 export not established","Regulation of this non-canonical TEC pool unclear"]},{"year":null,"claim":"How TEC achieves substrate selectivity and unique subcellular targeting distinct from Btk and Itk in vivo, and whether its non-canonical roles (FGF2 secretion, caspase-8 inflammasome) have dedicated regulation, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No full-length structure of autoinhibited or active TEC","TEC-specific in vivo loss-of-function phenotype (without Btk) not deeply characterized","Mechanism directing TEC to its unique compartment unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[11,17,22,36,7]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[11,17,22,36]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[11,29]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[22,36]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[11,27,29]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[13]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[25]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[15,19,31,32,35]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,12,26]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[13,20,23]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[19,31]}],"complexes":["RANK/ITAM/BLNK(SLP-76) osteoclastogenic complex","noncanonical caspase-8 inflammasome"],"partners":["LYN","KIT","VAV1","SOCS1","INPP5D","DOK1","PRKCQ","BTK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92570","full_name":"Nuclear receptor subfamily 4 group A member 3","aliases":["Mitogen-induced nuclear orphan receptor","Neuron-derived orphan receptor 1","Nuclear hormone receptor NOR-1","Translocated in extraskeletal chondrosarcoma"],"length_aa":626,"mass_kda":68.2,"function":"Transcriptional activator that binds to regulatory elements in promoter regions in a cell- and response element (target)-specific manner. Induces gene expression by binding as monomers to the NR4A1 response element (NBRE) 5'-AAAAGGTCA-3' site and as homodimers to the Nur response element (NurRE) site in the promoter of their regulated target genes (By similarity). Plays a role in the regulation of proliferation, survival and differentiation of many different cell types and also in metabolism and inflammation. Mediates proliferation of vascular smooth muscle, myeloid progenitor cell and type B pancreatic cells; promotes mitogen-induced vascular smooth muscle cell proliferation through transactivation of SKP2 promoter by binding a NBRE site (By similarity). Upon PDGF stimulation, stimulates vascular smooth muscle cell proliferation by regulating CCND1 and CCND2 expression. In islets, induces type B pancreatic cell proliferation through up-regulation of genes that activate cell cycle, as well as genes that cause degradation of the CDKN1A (By similarity). Negatively regulates myeloid progenitor cell proliferation by repressing RUNX1 in a NBRE site-independent manner. During inner ear, plays a role as a key mediator of the proliferative growth phase of semicircular canal development (By similarity). Also mediates survival of neuron and smooth muscle cells; mediates CREB-induced neuronal survival, and during hippocampus development, plays a critical role in pyramidal cell survival and axonal guidance. Is required for S phase entry of the cell cycle and survival of smooth muscle cells by inducing CCND1, resulting in RB1 phosphorylation. Binds to NBRE motif in CCND1 promoter, resulting in the activation of the promoter and CCND1 transcription (By similarity). Also plays a role in inflammation; upon TNF stimulation, mediates monocyte adhesion by inducing the expression of VCAM1 and ICAM1 by binding to the NBRE consensus site (By similarity) (PubMed:20558821). In mast cells activated by Fc-epsilon receptor cross-linking, promotes the synthesis and release of cytokines but impairs events leading to degranulation (By similarity). Also plays a role in metabolism; by modulating feeding behavior; and by playing a role in energy balance by inhibiting the glucocorticoid-induced orexigenic neuropeptides AGRP expression, at least in part by forming a complex with activated NR3C1 on the AGRP- glucocorticoid response element (GRE), and thus weakening the DNA binding activity of NR3C1. Upon catecholamines stimulation, regulates gene expression that controls oxidative metabolism in skeletal muscle (By similarity). Plays a role in glucose transport by regulating translocation of the SLC2A4 glucose transporter to the cell surface (PubMed:24022864). Finally, during gastrulation plays a crucial role in the formation of anterior mesoderm by controlling cell migration. Inhibits adipogenesis (By similarity). Also participates in cardiac hypertrophy by activating PARP1 (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q92570/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; CML","url":"https://www.omim.org/entry/608232"},{"mim_id":"607414","title":"FEZ FAMILY ZINC FINGER PROTEIN 2; FEZF2","url":"https://www.omim.org/entry/607414"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TEC"},"hgnc":{"alias_symbol":["PSCTK4"],"prev_symbol":[]},"alphafold":{"accession":"Q92570","domains":[{"cath_id":"3.30.50.10","chopping":"289-364","consensus_level":"medium","plddt":95.0051,"start":289,"end":364},{"cath_id":"1.10.565.10","chopping":"397-622","consensus_level":"high","plddt":90.8854,"start":397,"end":622}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92570","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92570-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92570-F1-predicted_aligned_error_v6.png","plddt_mean":64.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TEC","jax_strain_url":"https://www.jax.org/strain/search?query=TEC"},"sequence":{"accession":"Q92570","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92570.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92570/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92570"}},"corpus_meta":[{"pmid":"9524119","id":"PMC_9524119","title":"Phosphatidylinositol-3,4,5-trisphosphate (PtdIns-3,4,5-P3)/Tec kinase-dependent calcium signaling pathway: a target for SHIP-mediated inhibitory signals.","date":"1998","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9524119","citation_count":353,"is_preprint":false},{"pmid":"9524120","id":"PMC_9524120","title":"Btk/Tec kinases regulate sustained increases in intracellular Ca2+ following B-cell receptor activation.","date":"1998","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9524120","citation_count":324,"is_preprint":false},{"pmid":"10213685","id":"PMC_10213685","title":"Requirement for Tec kinases Rlk and Itk in T cell receptor signaling and immunity.","date":"1999","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/10213685","citation_count":311,"is_preprint":false},{"pmid":"15771581","id":"PMC_15771581","title":"Tec family kinases in T lymphocyte development and function.","date":"2005","source":"Annual review of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15771581","citation_count":273,"is_preprint":false},{"pmid":"18329366","id":"PMC_18329366","title":"Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals.","date":"2008","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/18329366","citation_count":250,"is_preprint":false},{"pmid":"11340625","id":"PMC_11340625","title":"The Tec family of cytoplasmic tyrosine kinases: mammalian Btk, Bmx, Itk, Tec, Txk and homologs in other species.","date":"2001","source":"BioEssays : news and reviews in molecular, cellular and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/11340625","citation_count":238,"is_preprint":false},{"pmid":"8985255","id":"PMC_8985255","title":"Regulatory intramolecular association in a tyrosine kinase of the Tec family.","date":"1997","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/8985255","citation_count":234,"is_preprint":false},{"pmid":"20519342","id":"PMC_20519342","title":"T-cell signaling regulated by the Tec family kinase, Itk.","date":"2010","source":"Cold Spring Harbor perspectives in biology","url":"https://pubmed.ncbi.nlm.nih.gov/20519342","citation_count":214,"is_preprint":false},{"pmid":"20206686","id":"PMC_20206686","title":"The Src, Syk, and Tec family kinases: distinct types of molecular switches.","date":"2010","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/20206686","citation_count":202,"is_preprint":false},{"pmid":"7970727","id":"PMC_7970727","title":"BMX, a novel nonreceptor tyrosine kinase gene of the BTK/ITK/TEC/TXK family located in chromosome Xp22.2.","date":"1994","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/7970727","citation_count":171,"is_preprint":false},{"pmid":"16860760","id":"PMC_16860760","title":"Altered development of CD8+ T cell lineages in mice deficient for the Tec kinases Itk and Rlk.","date":"2006","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/16860760","citation_count":159,"is_preprint":false},{"pmid":"11104803","id":"PMC_11104803","title":"Severe B cell deficiency in mice lacking the tec kinase family members Tec and Btk.","date":"2000","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/11104803","citation_count":155,"is_preprint":false},{"pmid":"16860759","id":"PMC_16860759","title":"The Tec family tyrosine kinases Itk and Rlk regulate the development of conventional CD8+ T cells.","date":"2006","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/16860759","citation_count":154,"is_preprint":false},{"pmid":"2284097","id":"PMC_2284097","title":"A novel protein-tyrosine kinase, tec, is preferentially expressed in liver.","date":"1990","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/2284097","citation_count":153,"is_preprint":false},{"pmid":"31804611","id":"PMC_31804611","title":"Thymic epithelial cell heterogeneity: TEC by TEC.","date":"2019","source":"Nature reviews. Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31804611","citation_count":151,"is_preprint":false},{"pmid":"11702066","id":"PMC_11702066","title":"Mutation of Tec family kinases alters T helper cell differentiation.","date":"2001","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11702066","citation_count":147,"is_preprint":false},{"pmid":"7530500","id":"PMC_7530500","title":"Association and activation of Btk and Tec tyrosine kinases by gp130, a signal transducer of the interleukin-6 family of cytokines.","date":"1995","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/7530500","citation_count":146,"is_preprint":false},{"pmid":"15803148","id":"PMC_15803148","title":"TEC-family kinases: regulators of T-helper-cell differentiation.","date":"2005","source":"Nature reviews. Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15803148","citation_count":136,"is_preprint":false},{"pmid":"12842985","id":"PMC_12842985","title":"Tec regulates platelet activation by GPVI in the absence of Btk.","date":"2003","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12842985","citation_count":136,"is_preprint":false},{"pmid":"12810687","id":"PMC_12810687","title":"Transforming growth factor beta blocks Tec kinase phosphorylation, Ca2+ influx, and NFATc translocation causing inhibition of T cell differentiation.","date":"2003","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12810687","citation_count":134,"is_preprint":false},{"pmid":"31082193","id":"PMC_31082193","title":"PF-06651600, a Dual JAK3/TEC Family Kinase Inhibitor.","date":"2019","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/31082193","citation_count":126,"is_preprint":false},{"pmid":"10647781","id":"PMC_10647781","title":"Tec family of protein-tyrosine kinases: an overview of their structure and function.","date":"1999","source":"Cytokine & growth factor reviews","url":"https://pubmed.ncbi.nlm.nih.gov/10647781","citation_count":122,"is_preprint":false},{"pmid":"17479128","id":"PMC_17479128","title":"Signalling through TEC kinases regulates conventional versus innate CD8(+) T-cell development.","date":"2007","source":"Nature reviews. Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17479128","citation_count":117,"is_preprint":false},{"pmid":"18566394","id":"PMC_18566394","title":"Dual functions of Bruton's tyrosine kinase and Tec kinase during Fcgamma receptor-induced signaling and phagocytosis.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18566394","citation_count":114,"is_preprint":false},{"pmid":"19416854","id":"PMC_19416854","title":"Tec kinase Itk in gammadeltaT cells is pivotal for controlling IgE production in vivo.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19416854","citation_count":113,"is_preprint":false},{"pmid":"19290923","id":"PMC_19290923","title":"Tec kinases regulate T-lymphocyte development and function: new insights into the roles of Itk and Rlk/Txk.","date":"2009","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/19290923","citation_count":112,"is_preprint":false},{"pmid":"11015440","id":"PMC_11015440","title":"Tec family kinases modulate thresholds for thymocyte development and selection.","date":"2000","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/11015440","citation_count":103,"is_preprint":false},{"pmid":"8070576","id":"PMC_8070576","title":"Tec homology (TH) adjacent to the PH domain.","date":"1994","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/8070576","citation_count":98,"is_preprint":false},{"pmid":"9341160","id":"PMC_9341160","title":"SOCS-1/JAB/SSI-1 can bind to and suppress Tec protein-tyrosine kinase.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9341160","citation_count":95,"is_preprint":false},{"pmid":"18281276","id":"PMC_18281276","title":"The tec family tyrosine kinase Btk Regulates RANKL-induced osteoclast maturation.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18281276","citation_count":95,"is_preprint":false},{"pmid":"18292523","id":"PMC_18292523","title":"The Tec kinases Itk and Rlk regulate NKT cell maturation, cytokine production, and survival.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18292523","citation_count":94,"is_preprint":false},{"pmid":"7526158","id":"PMC_7526158","title":"Tec kinase associates with c-kit and is tyrosine phosphorylated and activated following stem cell factor binding.","date":"1994","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/7526158","citation_count":94,"is_preprint":false},{"pmid":"7651724","id":"PMC_7651724","title":"Interleukin 3 and erythropoietin induce association of Vav with Tec kinase through Tec homology domain.","date":"1995","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/7651724","citation_count":89,"is_preprint":false},{"pmid":"9872994","id":"PMC_9872994","title":"The role of Tec protein-tyrosine kinase in T cell signaling.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9872994","citation_count":87,"is_preprint":false},{"pmid":"23011795","id":"PMC_23011795","title":"TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8+ T-cell differentiation.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23011795","citation_count":83,"is_preprint":false},{"pmid":"11071635","id":"PMC_11071635","title":"Stem cell factor induces phosphatidylinositol 3'-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells.","date":"2000","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11071635","citation_count":82,"is_preprint":false},{"pmid":"10688822","id":"PMC_10688822","title":"Rapid tyrosine phosphorylation and activation of Bruton's tyrosine/Tec kinases in platelets induced by collagen binding or CD32 cross-linking.","date":"2000","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/10688822","citation_count":82,"is_preprint":false},{"pmid":"9755164","id":"PMC_9755164","title":"Tec/Bmx non-receptor tyrosine kinases are involved in regulation of Rho and serum response factor by Galpha12/13.","date":"1998","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9755164","citation_count":81,"is_preprint":false},{"pmid":"12118060","id":"PMC_12118060","title":"Beyond calcium: new signaling pathways for Tec family kinases.","date":"2002","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/12118060","citation_count":80,"is_preprint":false},{"pmid":"15186750","id":"PMC_15186750","title":"Requirement for Tec kinases in chemokine-induced migration and activation of Cdc42 and Rac.","date":"2004","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/15186750","citation_count":80,"is_preprint":false},{"pmid":"7811991","id":"PMC_7811991","title":"Tec protein-tyrosine kinase is involved in interleukin-3 signaling pathway.","date":"1995","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/7811991","citation_count":77,"is_preprint":false},{"pmid":"9178903","id":"PMC_9178903","title":"Tec tyrosine kinase links the cytokine receptors to PI-3 kinase probably through JAK.","date":"1997","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/9178903","citation_count":76,"is_preprint":false},{"pmid":"11406363","id":"PMC_11406363","title":"Tec kinases: modulators of lymphocyte signaling and development.","date":"2001","source":"Current opinion in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11406363","citation_count":75,"is_preprint":false},{"pmid":"14993283","id":"PMC_14993283","title":"Expression and function of Tec, Itk, and Btk in lymphocytes: evidence for a unique role for Tec.","date":"2004","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/14993283","citation_count":73,"is_preprint":false},{"pmid":"15133303","id":"PMC_15133303","title":"The role of Tec family kinases in myeloid cells.","date":"2004","source":"International archives of allergy and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15133303","citation_count":73,"is_preprint":false},{"pmid":"10523612","id":"PMC_10523612","title":"Txk, a nonreceptor tyrosine kinase of the Tec family, is expressed in T helper type 1 cells and regulates interferon gamma production in human T lymphocytes.","date":"1999","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/10523612","citation_count":71,"is_preprint":false},{"pmid":"32419304","id":"PMC_32419304","title":"Efficacy and Safety of PF-06651600 (Ritlecitinib), a Novel JAK3/TEC Inhibitor, in Patients With Moderate-to-Severe Rheumatoid Arthritis and an Inadequate Response to Methotrexate.","date":"2020","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/32419304","citation_count":69,"is_preprint":false},{"pmid":"11973131","id":"PMC_11973131","title":"New insights into the regulation and functions of Tec family tyrosine kinases in the immune system.","date":"2002","source":"Current opinion in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11973131","citation_count":68,"is_preprint":false},{"pmid":"12614356","id":"PMC_12614356","title":"The role of Tec family kinases in T cell development and function.","date":"2003","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/12614356","citation_count":66,"is_preprint":false},{"pmid":"19290924","id":"PMC_19290924","title":"The Tec kinases Itk and Rlk regulate conventional versus innate T-cell development.","date":"2009","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/19290924","citation_count":64,"is_preprint":false},{"pmid":"15123627","id":"PMC_15123627","title":"Regulation of CXC chemokine receptor 4-mediated migration by the Tec family tyrosine kinase ITK.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15123627","citation_count":64,"is_preprint":false},{"pmid":"21362139","id":"PMC_21362139","title":"Tec family kinases Itk and Rlk / Txk in T lymphocytes: cross-regulation of cytokine production and T-cell fates.","date":"2011","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/21362139","citation_count":63,"is_preprint":false},{"pmid":"22449071","id":"PMC_22449071","title":"Tec family kinases in inflammation and disease.","date":"2012","source":"International reviews of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22449071","citation_count":61,"is_preprint":false},{"pmid":"8380782","id":"PMC_8380782","title":"Elimination of Tec elements involves a novel excision process.","date":"1993","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/8380782","citation_count":60,"is_preprint":false},{"pmid":"9446655","id":"PMC_9446655","title":"Expression and activation of the nonreceptor tyrosine kinase Tec in human B cells.","date":"1998","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/9446655","citation_count":59,"is_preprint":false},{"pmid":"15814670","id":"PMC_15814670","title":"Regulation of highly cytokinergic IgE-induced mast cell adhesion by Src, Syk, Tec, and protein kinase C family kinases.","date":"2005","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/15814670","citation_count":57,"is_preprint":false},{"pmid":"15214048","id":"PMC_15214048","title":"Positive feedback regulation of PLCgamma1/Ca(2+) signaling by PKCtheta in restimulated T cells via a Tec kinase-dependent pathway.","date":"2004","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15214048","citation_count":56,"is_preprint":false},{"pmid":"11123316","id":"PMC_11123316","title":"Tec kinase signaling in T cells is regulated by phosphatidylinositol 3-kinase and the Tec pleckstrin homology domain.","date":"2001","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/11123316","citation_count":53,"is_preprint":false},{"pmid":"17383541","id":"PMC_17383541","title":"Tec kinases in T cell and mast cell signaling.","date":"2007","source":"Advances in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17383541","citation_count":52,"is_preprint":false},{"pmid":"17624943","id":"PMC_17624943","title":"Tec kinases, actin, and cell adhesion.","date":"2007","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/17624943","citation_count":51,"is_preprint":false},{"pmid":"10518561","id":"PMC_10518561","title":"Molecular cloning of a docking protein, BRDG1, that acts downstream of the Tec tyrosine kinase.","date":"1999","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10518561","citation_count":49,"is_preprint":false},{"pmid":"10562318","id":"PMC_10562318","title":"A role for the Tec family tyrosine kinase Txk in T cell activation and thymocyte selection.","date":"1999","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/10562318","citation_count":48,"is_preprint":false},{"pmid":"38263353","id":"PMC_38263353","title":"Integrated Safety Analysis of Ritlecitinib, an Oral JAK3/TEC Family Kinase Inhibitor, for the Treatment of Alopecia Areata from the ALLEGRO Clinical Trial Program.","date":"2024","source":"American journal of clinical dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/38263353","citation_count":46,"is_preprint":false},{"pmid":"8621063","id":"PMC_8621063","title":"Tec protein-tyrosine kinase is an effector molecule of Lyn protein-tyrosine kinase.","date":"1996","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/8621063","citation_count":44,"is_preprint":false},{"pmid":"27010561","id":"PMC_27010561","title":"Dynamic Allostery Mediated by a Conserved Tryptophan in the Tec Family Kinases.","date":"2016","source":"PLoS computational biology","url":"https://pubmed.ncbi.nlm.nih.gov/27010561","citation_count":43,"is_preprint":false},{"pmid":"19673686","id":"PMC_19673686","title":"The role of Tec family kinases in mononuclear phagocytes.","date":"2009","source":"Critical reviews in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19673686","citation_count":42,"is_preprint":false},{"pmid":"7934162","id":"PMC_7934162","title":"Molecular cloning and analysis of the human Tec protein-tyrosine kinase.","date":"1994","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/7934162","citation_count":42,"is_preprint":false},{"pmid":"17425330","id":"PMC_17425330","title":"The linker between SH2 and kinase domains positively regulates catalysis of the Tec family kinases.","date":"2007","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17425330","citation_count":41,"is_preprint":false},{"pmid":"15492005","id":"PMC_15492005","title":"SHIP family inositol phosphatases interact with and negatively regulate the Tec tyrosine kinase.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15492005","citation_count":41,"is_preprint":false},{"pmid":"21362140","id":"PMC_21362140","title":"Tec family kinases: regulation of FcεRI-mediated mast-cell activation.","date":"2011","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/21362140","citation_count":40,"is_preprint":false},{"pmid":"34452995","id":"PMC_34452995","title":"Hierarchy of signaling thresholds downstream of the T cell receptor and the Tec kinase ITK.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/34452995","citation_count":40,"is_preprint":false},{"pmid":"16237085","id":"PMC_16237085","title":"Tec kinases regulate TCR-mediated recruitment of signaling molecules and integrin-dependent cell adhesion.","date":"2005","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/16237085","citation_count":40,"is_preprint":false},{"pmid":"16424186","id":"PMC_16424186","title":"Tec kinases Itk and Rlk are required for CD8+ T cell responses to virus infection independent of their role in CD4+ T cell help.","date":"2006","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/16424186","citation_count":40,"is_preprint":false},{"pmid":"16809408","id":"PMC_16809408","title":"Skewed Th1 responses caused by excessive expression of Txk, a member of the Tec family of tyrosine kinases, in patients with Behcet's disease.","date":"2006","source":"Clinical medicine & research","url":"https://pubmed.ncbi.nlm.nih.gov/16809408","citation_count":39,"is_preprint":false},{"pmid":"15308211","id":"PMC_15308211","title":"Tec kinases: shaping T-cell activation through actin.","date":"2004","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15308211","citation_count":37,"is_preprint":false},{"pmid":"11489907","id":"PMC_11489907","title":"Sak serine-threonine kinase acts as an effector of Tec tyrosine kinase.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11489907","citation_count":36,"is_preprint":false},{"pmid":"25474208","id":"PMC_25474208","title":"The non-receptor tyrosine kinase Tec controls assembly and activity of the noncanonical caspase-8 inflammasome.","date":"2014","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/25474208","citation_count":35,"is_preprint":false},{"pmid":"11013262","id":"PMC_11013262","title":"Protein-tyrosine phosphatase D1, a potential regulator and effector for Tec family kinases.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11013262","citation_count":35,"is_preprint":false},{"pmid":"21518255","id":"PMC_21518255","title":"TEC family kinases in health and disease--loss-of-function of BTK and ITK and the gain-of-function fusions ITK-SYK and BTK-SYK.","date":"2011","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/21518255","citation_count":35,"is_preprint":false},{"pmid":"10641436","id":"PMC_10641436","title":"The Tec family protein-tyrosine kinases: a subset of kinases for a subset of signalings.","date":"1999","source":"International journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/10641436","citation_count":35,"is_preprint":false},{"pmid":"7936643","id":"PMC_7936643","title":"Tec protein-tyrosine kinase directly associates with Lyn protein-tyrosine kinase through its N-terminal unique domain.","date":"1994","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/7936643","citation_count":35,"is_preprint":false},{"pmid":"8943565","id":"PMC_8943565","title":"CD2 signaling in T cells involves tyrosine phosphorylation and activation of the Tec family kinase, EMT/ITK/TSK.","date":"1996","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8943565","citation_count":35,"is_preprint":false},{"pmid":"37777018","id":"PMC_37777018","title":"Improvements in immune/melanocyte biomarkers with JAK3/TEC family kinase inhibitor ritlecitinib in vitiligo.","date":"2023","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37777018","citation_count":33,"is_preprint":false},{"pmid":"26362014","id":"PMC_26362014","title":"Adult thymic epithelial cell (TEC) progenitors and TEC stem cells: Models and mechanisms for TEC development and maintenance.","date":"2015","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26362014","citation_count":33,"is_preprint":false},{"pmid":"20826165","id":"PMC_20826165","title":"Identification of an allosteric signaling network within Tec family kinases.","date":"2010","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20826165","citation_count":33,"is_preprint":false},{"pmid":"10382746","id":"PMC_10382746","title":"Tec kinase is involved in transcriptional regulation of IL-2 and IL-4 in the CD28 pathway.","date":"1999","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10382746","citation_count":32,"is_preprint":false},{"pmid":"9652744","id":"PMC_9652744","title":"Tec is involved in G protein-coupled receptor- and integrin-mediated signalings in human blood platelets.","date":"1998","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/9652744","citation_count":32,"is_preprint":false},{"pmid":"35287671","id":"PMC_35287671","title":"The monomer TEC of blueberry improves NASH by augmenting tRF-47-mediated autophagy/pyroptosis signaling pathway.","date":"2022","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35287671","citation_count":31,"is_preprint":false},{"pmid":"14647425","id":"PMC_14647425","title":"Functional interaction of RasGAP-binding proteins Dok-1 and Dok-2 with the Tec protein tyrosine kinase.","date":"2004","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/14647425","citation_count":31,"is_preprint":false},{"pmid":"11684687","id":"PMC_11684687","title":"The solution structure and intramolecular associations of the Tec kinase SRC homology 3 domain.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11684687","citation_count":31,"is_preprint":false},{"pmid":"35296647","id":"PMC_35296647","title":"Regulation of the Tec family of non-receptor tyrosine kinases in cardiovascular disease.","date":"2022","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/35296647","citation_count":30,"is_preprint":false},{"pmid":"10548506","id":"PMC_10548506","title":"Pleckstrin homology domains of tec family protein kinases.","date":"1999","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10548506","citation_count":29,"is_preprint":false},{"pmid":"27382052","id":"PMC_27382052","title":"Small Molecule Inhibitors Targeting Tec Kinase Block Unconventional Secretion of Fibroblast Growth Factor 2.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27382052","citation_count":29,"is_preprint":false},{"pmid":"29677469","id":"PMC_29677469","title":"Multidomain Control Over TEC Kinase Activation State Tunes the T Cell Response.","date":"2018","source":"Annual review of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29677469","citation_count":28,"is_preprint":false},{"pmid":"18523250","id":"PMC_18523250","title":"The Tec family kinase, IL-2-inducible T cell kinase, differentially controls mast cell responses.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18523250","citation_count":28,"is_preprint":false},{"pmid":"8877094","id":"PMC_8877094","title":"Tec protein tyrosine kinase is involved in the signaling mechanism of granulocyte colony-stimulating factor receptor.","date":"1996","source":"Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/8877094","citation_count":28,"is_preprint":false},{"pmid":"19161832","id":"PMC_19161832","title":"Phylogeny of Tec family kinases identification of a premetazoan origin of Btk, Bmx, Itk, Tec, Txk, and the Btk regulator SH3BP5.","date":"2008","source":"Advances in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19161832","citation_count":27,"is_preprint":false},{"pmid":"23982207","id":"PMC_23982207","title":"Activation loop dynamics determine the different catalytic efficiencies of B cell- and T cell-specific tec kinases.","date":"2013","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/23982207","citation_count":27,"is_preprint":false},{"pmid":"17060314","id":"PMC_17060314","title":"Tec kinase Itk forms membrane clusters specifically in the vicinity of recruiting receptors.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17060314","citation_count":27,"is_preprint":false},{"pmid":"21362141","id":"PMC_21362141","title":"Tec family kinases: Itk signaling and the development of NKT αβ and γδ T cells.","date":"2011","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/21362141","citation_count":26,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43987,"output_tokens":9491,"usd":0.137163,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19530,"output_tokens":4371,"usd":0.103462,"stage2_stop_reason":"end_turn"},"total_usd":0.240625,"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\": 1990,\n      \"finding\": \"Tec was identified as a novel non-receptor protein-tyrosine kinase preferentially expressed in liver, with C-terminal domain homology to Src family members, representing the founding member of what became the Tec kinase family.\",\n      \"method\": \"cDNA library screening with v-fps kinase domain probe; Northern blot analysis; sequence analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — original cloning and characterization with sequence analysis and expression studies; single lab, foundational identification paper\",\n      \"pmids\": [\"2284097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Tec physically associates with c-kit through a proline-rich motif N-terminal to the SH3 domain; following stem cell factor (SCF) binding, Tec is tyrosine phosphorylated and its in vitro kinase activity is increased. This activation is SCF-specific and not induced by CSF-1, GM-CSF, or IL-3.\",\n      \"method\": \"Co-immunoprecipitation; in vitro kinase assay; tyrosine phosphorylation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, in vitro kinase assay, and specificity controls across multiple cytokines; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"7526158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Tec directly associates with Lyn protein-tyrosine kinase through the N-terminal unique domain (NTec2 region) of Tec; Lyn binds via its SH3 domain; the p56 form of Lyn is inducibly tyrosine-phosphorylated in response to IL-3 within this complex.\",\n      \"method\": \"GST-fusion pull-down; in vivo co-immunoprecipitation; in vitro binding assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro GST pull-down plus in vivo co-IP; domain mapping; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"7936643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The Tec homology (TH) domain adjacent to the PH domain contains a conserved ~27 amino acid Btk motif and a proline-rich region, defining it as a distinct structural element within Tec family kinases likely involved in protein-protein interactions.\",\n      \"method\": \"Sequence analysis; domain structure characterization\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational/sequence-based domain identification only, no functional validation experiment described\",\n      \"pmids\": [\"8070576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Tec kinase associates with Vav upon erythropoietin and IL-3 stimulation; this interaction occurs through the Tec homology domain of Tec. Tec kinase is transiently activated by these cytokines, and Grb2 constitutively associates with Vav.\",\n      \"method\": \"Co-immunoprecipitation; in vitro binding assay; kinase activity assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro and in vivo binding assays with domain mapping; kinase activity measurement; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"7651724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Tec and Btk associate with gp130 (the shared signal transducer of IL-6 family cytokines) without ligand stimulation; IL-6 stimulation activates both Btk and Tec, while IL-3 and G-CSF activate Tec but not Btk in a pro-B cell line.\",\n      \"method\": \"Co-immunoprecipitation; kinase activation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP demonstrating constitutive association plus ligand-induced activation assays distinguishing Tec from Btk; single lab with multiple receptor systems tested\",\n      \"pmids\": [\"7530500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Tec is tyrosine phosphorylated and its kinase activity is activated following IL-3 stimulation in myeloid and pro-B cell lines; Tec constitutively associates with the Shc adapter protein in vivo.\",\n      \"method\": \"Anti-Tec immunoprecipitation; in vitro kinase assay; co-immunoprecipitation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase activity assay and co-IP; single lab, two orthogonal methods\",\n      \"pmids\": [\"7811991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Lyn kinase directly phosphorylates tyrosine residues of Tec and thereby activates Tec, while Tec co-expression has little effect on Lyn phosphotyrosine content, establishing that Tec acts downstream of Lyn. Demonstrated both in vitro and in a yeast system.\",\n      \"method\": \"In vitro kinase assay; yeast two-hybrid system; co-expression in 3T3 fibroblasts\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro phosphorylation assay plus yeast system validation; unidirectional regulation clearly established with multiple approaches\",\n      \"pmids\": [\"8621063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Tec is tyrosine phosphorylated and activated by G-CSF stimulation in both cell growth and differentiation contexts; Vav associates with Tec and is tyrosine phosphorylated in response to G-CSF.\",\n      \"method\": \"Immunoprecipitation; kinase activity assay; co-immunoprecipitation\",\n      \"journal\": \"Cell growth & differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and kinase activity assay; single lab, two orthogonal methods\",\n      \"pmids\": [\"8877094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"SOCS-1/JAB/SSI-1 (identified as TIP3) associates with Tec in 293 cells and suppresses its kinase activity, while also down-regulating Jak2 but not Lyn activity, identifying SOCS-1 as a negative regulator of Tec.\",\n      \"method\": \"Yeast two-hybrid screening; co-immunoprecipitation in 293 cells; kinase activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid identification followed by co-IP in mammalian cells and kinase suppression assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"9341160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"JAK1 (but not JAK2) associates with Tec and Btk; JAK1 induces tyrosine phosphorylation of Btk but not Tec. Tec interacts with p85 and p55PIK subunits of PI-3 kinase (dependent on Tec kinase activity) and with Vav (via SH2 domain, independent of kinase activity). IL-6 and IL-3 induce Tec-p85 PI3K association in mammalian cells.\",\n      \"method\": \"Co-immunoprecipitation; yeast two-hybrid; overexpression in mammalian cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid plus in vivo co-IP; domain dependency established; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"9178903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"PtdIns-3,4,5-P3 interacting with the Tec PH domain acts as an upstream activation signal for Tec kinases, resulting in Tec kinase-dependent PLCγ tyrosine phosphorylation and IP3 production. The SHIP inositol phosphatase blocks this pathway by degrading PtdIns-3,4,5-P3.\",\n      \"method\": \"Cell-based signaling assays; phospholipid binding; PLCγ phosphorylation assay; IP3 production measurement\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct demonstration of PH domain-PIP3 interaction coupled with downstream PLCγ phosphorylation and IP3 production; SHIP inhibition mechanistically linked; replicated across Tec family members\",\n      \"pmids\": [\"9524119\"],\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; this SRF activation is Rho-dependent (blocked by C3 transferase). The kinase and Tec homology domains are required. Gα12 and Gα13 stimulate Tec autophosphorylation and transphosphorylation activities.\",\n      \"method\": \"Transient transfection; SRF reporter assay; C3 transferase inhibition; kinase activity assay; domain deletion analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reporter assays with domain mutants, pharmacological inhibition of Rho, and direct kinase activity assays; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"9755164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Tec is rapidly tyrosine phosphorylated in human platelets in response to G protein-coupled receptor agonists (thromboxane A2 analog, thrombin, TRAP) and integrin engagement (adhesion to fibrinogen or collagen). Tec translocates to the cytoskeleton upon TRAP stimulation in a manner dependent on platelet aggregation, indicating a role in integrin-mediated signaling.\",\n      \"method\": \"Immunoprecipitation; tyrosine phosphorylation assay; subcellular fractionation; platelet activation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation and subcellular fractionation with pharmacological controls; single lab, two orthogonal methods\",\n      \"pmids\": [\"9652744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Tec is expressed throughout human B cell differentiation and can be activated by BCR cross-linking (inducing tyrosine phosphorylation and increased kinase activity) and CD19 or CD38 ligation; Tec responds to CD38 stimulation whereas Btk does not, indicating differential regulation.\",\n      \"method\": \"Immunoprecipitation; in vitro kinase assay; anti-receptor antibody stimulation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase activity assay plus differential receptor stimulation comparison; single lab with multiple receptor systems\",\n      \"pmids\": [\"9446655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Tec is activated following TCR/CD3 or CD28 ligation in T cells. Tec interacts with CD28 in an activation-dependent manner via the Tec SH3 domain binding to proline-rich motifs in CD28. Tec phosphorylates p62dok, a CD28-specific substrate (unlike Itk). Overexpression of Tec (but not Itk) enhances IL-2 promoter activity following TCR/CD3 or CD28 stimulation.\",\n      \"method\": \"Co-immunoprecipitation; in vitro kinase assay; luciferase reporter assay; dominant-negative overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP with domain specificity, substrate phosphorylation in vitro, and reporter assays with gain- and loss-of-function; single lab with multiple orthogonal methods establishing distinct Tec vs Itk functions\",\n      \"pmids\": [\"9872994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Tec kinase is involved in IL-2 and IL-4 transcriptional regulation downstream of CD28; CD28-mediated Tec activation requires Src family PTK activity (Lck), as kinase-dead Lck blocks Tec activation and Tec-induced cytokine expression.\",\n      \"method\": \"Reporter assay (IL-2 and IL-4 promoter-luciferase); co-expression of kinase-dead mutants\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reporter assays with gain/loss of function; single lab, but consistent with other work on Tec in CD28 signaling\",\n      \"pmids\": [\"10382746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"BRDG1 (BCR downstream signaling 1) was identified as a downstream docking protein of Tec. Tec (but not Btk, Bmx, Lyn, Syk, or c-Abl) phosphorylates BRDG1 on tyrosine in cells and directly in vitro. Efficient phosphorylation requires PH and SH2 domains plus the kinase domain of Tec. BRDG1 participates in a positive feedback loop increasing Tec activity, and undergoes tyrosine phosphorylation in response to BCR stimulation.\",\n      \"method\": \"Yeast two-hybrid; in vitro kinase assay; in vivo phosphorylation in 293 cells; BCR stimulation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro direct phosphorylation assay plus in vivo confirmation; substrate specificity established with multiple kinase comparisons; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"10518561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SCF/cKit signaling leads to PI3K-dependent activation and phosphorylation of Tec and Dok-1, which form a stable complex with Lyn and two unidentified phosphoproteins. The Tec homology domain and SH2 domain of Tec are required for interaction with Dok-1. Tec and Lyn phosphorylate Dok-1, which then binds SH2 domains of Abl, CrkL, SHIP, and PLCγ-1.\",\n      \"method\": \"Co-immunoprecipitation; in vitro kinase assay; PI3K inhibitor studies; domain deletion analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complex formation by co-IP, domain requirements mapped, in vitro phosphorylation of Dok-1 by Tec, downstream SH2 binding confirmed; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"11071635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Tec/Btk double-deficient mice exhibit a block at the B220+CD43+ stage of B cell development and severe reduction of peripheral B cells (particularly IgMloIgDhi), demonstrating that Tec and Btk together have an essential non-redundant role in B cell development that neither alone is required for.\",\n      \"method\": \"Genetic knockout; B cell developmental analysis by flow cytometry; immunological phenotyping\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double-KO genetic epistasis with detailed developmental staging; definitive loss-of-function phenotype\",\n      \"pmids\": [\"11104803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Both Btk and Tec undergo rapid tyrosine phosphorylation in platelets following stimulation of the GPVI collagen receptor or CD32 cross-linking, with coordinate recruitment through ITAM, Src family kinases, and PI3K. In XLA platelets lacking Btk, Tec phosphorylation is preserved along with downstream signaling molecules.\",\n      \"method\": \"Immunoprecipitation; phosphopeptide-specific antibodies; kinase inhibitor studies; platelet stimulation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation kinetics and inhibitor studies; mechanistic pathway proposed with supporting biochemical evidence; single lab\",\n      \"pmids\": [\"10688822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The solution NMR structure of the Tec SH3 domain was determined; the Tec proline-rich region (PRR) can bind intramolecularly to the SH3 domain (site 1: 155KTLPPAP161 binds intramolecularly; site 2: 165KRRPPPPIPP174 binds intermolecularly/dimerization). The affinity for dimerization via reciprocal PRR-SH3 is higher than for the intramolecular interaction.\",\n      \"method\": \"NMR solution structure determination; site-directed mutagenesis; binding affinity measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure with mutagenesis validation of two distinct binding sites; functional significance of intramolecular vs intermolecular interactions defined\",\n      \"pmids\": [\"11684687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Sak serine-threonine kinase (a Polo-family member) is phosphorylated on tyrosine by Tec in 293 cells and directly in vitro; Tec activates the serine-threonine kinase activity of Sak and protects it from PEST sequence-dependent proteolysis, establishing Sak as an effector molecule of Tec.\",\n      \"method\": \"Yeast two-hybrid; in vitro kinase assay; co-expression in 293 cells; proteolysis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro phosphorylation confirmed in cells; Sak kinase activity dependent on Tec; stability regulated by Tec; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"11489907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Tec plays a role in platelet activation by GPVI in the absence of Btk. Btk/Tec double-deficient platelets fail to undergo Ca2+ increase, aggregation, secretion, and spreading in response to collagen or CRP, whereas Tec-/- alone shows only minor reduction. PLCγ2 tyrosine phosphorylation is further reduced in Btk/Tec double-deficient compared to Btk-/- platelets.\",\n      \"method\": \"Genetic knockout (single and double KO); platelet aggregation assay; calcium measurement; PLCγ2 phosphorylation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double-KO epistasis with multiple functional readouts; PLCγ2 phosphorylation biochemical endpoint; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"12842985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TGF-β inhibits Tec kinase (Itk) phosphorylation and activation in stimulated CD4+ T cells, leading to reduced Ca2+ influx, impaired NFATc translocation, and reduced ERK activation, thereby blocking T cell differentiation at a proximal signaling step.\",\n      \"method\": \"Kinase phosphorylation assay; calcium influx measurement; NFATc translocation assay; ERK activation assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple downstream readouts of Tec inhibition by TGF-β; single lab with orthogonal methods; note this paper focuses primarily on Itk but demonstrates Tec-family regulation\",\n      \"pmids\": [\"12810687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Tec overexpression in lymphocyte cell lines induces PLCγ phosphorylation and NFAT activation, whereas overexpression of Btk, Itk, or Bmx does not induce NFAT activation. Tec-induced NFAT activation requires PLCγ but not the adapters LAT, SLP-76, and BLNK (which are required for Btk and Itk). Tec has a unique subcellular localization correlating with this distinct effector function.\",\n      \"method\": \"Overexpression in cell lines; NFAT reporter assay; PLCγ phosphorylation; subcellular localization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reporter assays with comparison across family members; adapter independence established; subcellular localization difference observed; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"14993283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PKCθ constitutively associates with Tec (interaction requires the Tec PH domain). Wild-type Tec (but not Itk or Rlk) potently activates AP-1 downstream of PKCθ, and dominant-negative Tec blocks PKCθ-induced AP-1 (but not NF-κB) activation. Tec thus mediates a PKCθ→Tec→PLCγ1→Ca2+ positive feedback loop regulating AP-1 in restimulated T cells.\",\n      \"method\": \"Co-immunoprecipitation; reporter assay (AP-1, NF-κB); dominant-negative overexpression; calcium measurement\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain requirement plus reporter and functional assays; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"15214048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SHIP1 and SHIP2 interact preferentially with Tec (via its SH3 domain) compared to other Tec family members, and function as negative regulators: they inhibit Tec activity, and SHIP1 inhibits Tec membrane localization. Inactivation of the Tec SH3 domain generates a hyperactive Tec. Constitutive membrane targeting of Tec relieves SHIP1-mediated inhibition.\",\n      \"method\": \"Co-immunoprecipitation; kinase activity assay; subcellular fractionation; constitutively membrane-targeted mutant; SH3 domain mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple lines of evidence (interaction, inhibition, domain mutant, membrane targeting rescue); single lab with multiple orthogonal methods\",\n      \"pmids\": [\"15492005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Dok-1 and Dok-2 are major tyrosine-phosphorylated proteins associated with Tec in T cells and act as negative feedback regulators of Tec, downregulating its tyrosine phosphorylation and downstream Ras pathway signaling.\",\n      \"method\": \"Co-immunoprecipitation; tyrosine phosphorylation assay; Ras pathway reporter assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and functional assays in T cells; single lab, two orthogonal methods\",\n      \"pmids\": [\"14647425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Tec PH domain is required for Tec-mediated IL-2 gene induction and TCR-mediated Tec tyrosine phosphorylation in T cells. Tec colocalizes with the TCR after cross-linking (both PH and SH2 domains involved). Wortmannin (PI3K inhibitor) abolishes Tec phosphorylation and IL-2 induction, establishing PI3K-PH domain signaling axis upstream of Tec.\",\n      \"method\": \"PH domain mutant overexpression; IL-2 reporter assay; tyrosine phosphorylation assay; confocal microscopy; wortmannin inhibition\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple domain mutants, reporter assays, and localization; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"11123316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The short linker region between the SH2 and kinase domains of Tec family kinases (studied via Itk as model) positively regulates catalytic activity. Precise conserved residues in this linker allosterically regulate activity, a mechanism conserved among Tec kinases but distinct from Src kinase regulation.\",\n      \"method\": \"Quantitative in vitro kinase assay; linker deletion/mutation analysis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative in vitro kinase assay with defined mutations; conserved mechanism identified across Tec family; single lab\",\n      \"pmids\": [\"17425330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Btk and Tec together regulate osteoclast differentiation downstream of RANK and ITAM signals. Mice lacking both Btk and Tec show severe osteopetrosis. RANK and ITAM signaling forms a Btk(Tec)/BLNK(SLP-76)-containing complex leading to PLCγ-mediated calcium signaling required for NFATc1 activation and osteoclastogenesis.\",\n      \"method\": \"Double-KO mouse model; osteoclast differentiation assay; co-immunoprecipitation of signaling complex; calcium measurement; Tec kinase inhibitor in disease models\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic double-KO epistasis, biochemical complex formation by co-IP, functional calcium/NFATc1 readouts, and pharmacological inhibition in disease models; rigorous multi-approach study\",\n      \"pmids\": [\"18329366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Btk and Tec are activated throughout FcγR-induced phagocytosis in macrophages, accumulating at the base of phagocytic cups. Their inhibition (by LFM-A13 or siRNA) significantly inhibits FcγR-induced phagocytosis. Btk and Tec regulate FcγR-induced Mac-1 activation required for optimal phagocytosis. A late/prolonged PLCγ2 activation (after initial Syk-dependent phase) is dependent on Btk and Tec. Activated Btk (but not Tec) co-localizes with phagosomal diacylglycerol.\",\n      \"method\": \"siRNA knockdown; pharmacological inhibition; live-cell imaging; subcellular fractionation; PLCγ2 phosphorylation assay; Mac-1 activation assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA and pharmacological inhibition with live imaging and biochemical readouts; distinct roles of Btk vs Tec at different phagocytic stages established; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18566394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The extended regulatory spine within Tec kinases (identified via Itk/Btk) includes a conserved methionine in the C-helix and a conserved tryptophan in the SH2-kinase linker, forming an allosteric conduit from regulatory domains to the catalytic domain. Mutation of the gatekeeper residue stabilizes the regulatory spine, rendering a constitutively active kinase in which activation loop phosphorylation is unnecessary.\",\n      \"method\": \"In vitro kinase assay; mutagenesis; structural analysis of regulatory spine residues\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase activity measurements with defined point mutations; mechanistic model of regulatory spine validated functionally; single lab\",\n      \"pmids\": [\"20826165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Btk and Itk (Tec family members) have distinct catalytic efficiencies due to differences in activation loop dynamics. Substitution of 6 residues in the activation segment of Itk with corresponding Btk residues (and vice versa) completely swaps their kinase activities. NMR and HDX-MS revealed distinct dynamics in the activation loop explaining the catalytic efficiency differences.\",\n      \"method\": \"In vitro kinase assay; mutagenesis (activation segment substitutions); NMR; hydrogen-deuterium exchange mass spectrometry; T cell TCR signaling assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution/mutagenesis with NMR and HDX-MS structural validation; activity swap confirmed functionally in cells; single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"23982207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Tec kinase is required for activation and assembly of the noncanonical caspase-8 inflammasome (but not the caspase-1 inflammasome) in macrophages during Candida albicans infection. Dectin-1 is the pathogen recognition receptor required for Syk-dependent Tec activation. Tec genetic ablation or small-molecule inhibition protects mice from fungal sepsis.\",\n      \"method\": \"Genetic knockout; small-molecule inhibition; in vivo fungal infection model; inflammasome assembly assay; IL-1β production assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mice plus pharmacological inhibition with specific pathway readout (caspase-8 vs caspase-1 specificity), in vivo disease model; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25474208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Tec kinase directly phosphorylates FGF2 on tyrosine to stimulate FGF2 membrane pore formation during unconventional secretion. Small molecules that inhibit FGF2-Tec interaction also inhibit FGF2 tyrosine phosphorylation in vitro and in cells, and block unconventional FGF2 secretion. Inhibitors are specific for FGF2 as a Tec substrate (tyrosine phosphorylation of a different Tec substrate is unaffected).\",\n      \"method\": \"In vitro kinase assay; co-immunoprecipitation; small-molecule inhibitor; unconventional secretion assay in cells; substrate specificity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro direct phosphorylation assay plus cellular validation; substrate specificity confirmed; inhibitor mechanism established; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27382052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A conserved tryptophan in the SH2-kinase linker of Tec family kinases mediates allosteric activation of Btk; mutation to alanine abolishes activity. Specific tryptophan side chain rotamer promotes coordinated motions across the kinase domain. This dynamic allostery is conserved across the Tec family.\",\n      \"method\": \"HDX mass spectrometry; molecular dynamics simulations; principal component analysis; mutagenesis; kinase activity assay\",\n      \"journal\": \"PLoS computational biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — HDX-MS plus MD simulations; mutagenesis confirms functional importance; study focused on Btk but mechanism is generalized to Tec family including TEC; single lab\",\n      \"pmids\": [\"27010561\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TEC is a non-receptor tyrosine kinase (founding member of the Tec family) that is activated downstream of multiple cell-surface receptors — including cytokine receptors (via JAK1/Lyn), antigen receptors (BCR, TCR), receptor tyrosine kinases (c-Kit), G protein-coupled receptors, and integrins — through a PI3K-PtdIns(3,4,5)P3/PH domain membrane-recruitment mechanism; once membrane-localized, TEC is phosphorylated and activated by Lyn (and Src family kinases downstream of CD28 via Lck), then phosphorylates PLCγ to drive IP3 production and Ca2+ mobilization, and also phosphorylates substrates including FGF2, BRDG1, Sak, and Dok proteins; its activity is negatively regulated by SOCS-1 (direct binding and suppression), SHIP1/2 (via SH3 domain interaction that depletes local PtdIns(3,4,5)P3), and Dok-1/2 (negative feedback); structurally, TEC kinase activity is allosterically controlled by an extended regulatory spine (including a conserved tryptophan in the SH2-kinase linker and a methionine in the C-helix) and by intramolecular SH3-PRR interactions that maintain autoinhibition; in B cells TEC cooperates with Btk for B cell development and BCR/GPVI signaling; in T cells TEC activates AP-1/NFAT through a PKCθ-dependent pathway unique from Itk; TEC also assembles the RANK/ITAM/BLNK(SLP-76) complex for PLCγ-Ca2+-NFATc1-driven osteoclastogenesis, controls caspase-8 inflammasome assembly during fungal infection downstream of Dectin-1/Syk, and participates in FcγR-mediated phagocytosis and platelet activation by GPVI.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TEC is the founding member of the Tec family of non-receptor protein-tyrosine kinases, originally identified as a Src-homologous kinase preferentially expressed in liver [#0], that couples diverse cell-surface receptors to phospholipase Cγ-driven calcium signaling [#11]. TEC is recruited to the membrane when its PH domain binds PtdIns(3,4,5)P3 generated by PI3K, where it phosphorylates PLCγ to drive IP3 production and Ca2+ mobilization; the SHIP inositol phosphatase opposes this by degrading PtdIns(3,4,5)P3 [#11, #27]. Activation occurs downstream of cytokine receptors, the receptor tyrosine kinase c-Kit, the IL-6-family transducer gp130, antigen and costimulatory receptors, GPCRs, and integrins, with TEC being phosphorylated and activated directly by Lyn [#1, #5, #7, #13]; in T cells CD28-mediated activation requires Src-family (Lck) activity [#15, #16]. TEC propagates signaling by phosphorylating docking and effector substrates including BRDG1, Dok-1, the Polo-family kinase Sak, and FGF2, the last during unconventional FGF2 secretion [#17, #18, #22, #36]. In T cells TEC has a unique adapter-independent route to PLCγ/NFAT activation distinct from Itk, acting through a PKCθ→TEC→PLCγ1→Ca2+ feedback loop to drive AP-1 and IL-2 expression [#25, #26, #15]. Genetically, TEC acts redundantly with Btk: Btk/Tec double-deficient mice fail at an early stage of B cell development, lose GPVI-dependent platelet activation, and develop severe osteopetrosis through a RANK/ITAM/BLNK(SLP-76)→PLCγ→NFATc1 osteoclastogenic complex [#19, #23, #31]. TEC also drives Fcγ-receptor phagocytosis and assembly of the noncanonical caspase-8 inflammasome downstream of Dectin-1/Syk during fungal infection [#32, #35]. TEC activity is held in check by intramolecular SH3–proline-rich interactions and an extended regulatory spine relaying allosteric signals from the SH2-kinase linker to the catalytic domain [#21, #30, #33], and is negatively regulated by SOCS-1, SHIP1/2, and Dok-1/2 [#9, #27, #28].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Establishing that a distinct non-receptor tyrosine kinase existed defined the founding member of a new kinase family and set the stage for its functional dissection.\",\n      \"evidence\": \"cDNA cloning with a v-fps kinase probe and Northern expression analysis in liver\",\n      \"pmids\": [\"2284097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No catalytic substrate or signaling pathway identified\", \"Function beyond sequence homology unknown\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Linking TEC to specific receptor systems showed it is an inducibly activated kinase, answering which upstream signals engage it.\",\n      \"evidence\": \"Co-IP and in vitro kinase assays with c-Kit/SCF, Lyn, and Vav associations with domain mapping\",\n      \"pmids\": [\"7526158\", \"7936643\", \"7651724\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order of kinase activation not yet resolved\", \"Downstream substrates not defined\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Resolving the directionality of the TEC–Lyn relationship placed TEC downstream of a Src-family kinase, clarifying activation hierarchy.\",\n      \"evidence\": \"In vitro phosphorylation, yeast two-hybrid, and fibroblast co-expression showing Lyn phosphorylates and activates TEC unidirectionally\",\n      \"pmids\": [\"8621063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological receptor context of Lyn-TEC activation not fully defined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Identifying the PI3K-PtdIns(3,4,5)P3/PH-domain axis and PLCγ output defined the core membrane-recruitment and effector mechanism of TEC.\",\n      \"evidence\": \"Phospholipid binding, PLCγ phosphorylation, IP3 measurement, and SHIP inhibition in cell-based assays\",\n      \"pmids\": [\"9524119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise activation-loop phosphorylation events not mapped here\", \"Receptor-specific contributions of PI3K not dissected\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Distinguishing TEC from Itk in T cells answered whether Tec-family members have non-redundant effector functions, revealing a CD28-specific signaling role.\",\n      \"evidence\": \"Co-IP with SH3-domain specificity, in vitro phosphorylation of p62dok, and IL-2 reporter gain/loss-of-function in T cells\",\n      \"pmids\": [\"9872994\", \"10382746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo T-cell phenotype of TEC alone not established\", \"Endogenous CD28-TEC stoichiometry unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identifying BRDG1 as a TEC-selective substrate revealed a positive feedback docking protein that amplifies TEC activity in BCR signaling.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro and in-cell phosphorylation with kinase-specificity comparison, and BCR stimulation\",\n      \"pmids\": [\"10518561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of feedback amplification not resolved\", \"In vivo requirement of BRDG1 not tested\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Genetic and biochemical work defined TEC substrates and an essential Btk-redundant role, answering whether TEC matters at the organismal level.\",\n      \"evidence\": \"Btk/Tec double-knockout B cell developmental analysis plus Dok-1 complex/phosphorylation studies downstream of c-Kit\",\n      \"pmids\": [\"11104803\", \"11071635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of TEC/Btk functional overlap at molecular level not detailed\", \"Whether unique TEC substrates contribute in vivo unclear\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"NMR structure of the SH3 domain and effector identification clarified autoinhibitory/dimerization control and extended the TEC substrate repertoire.\",\n      \"evidence\": \"NMR solution structure with mutagenesis defining intramolecular vs dimerization PRR-SH3 sites, plus identification of Sak as a TEC substrate\",\n      \"pmids\": [\"11684687\", \"11489907\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular relevance of TEC dimerization not established\", \"Physiological Sak-TEC pathway context unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defining a unique adapter-independent route to NFAT and the PKCθ feedback loop established how TEC effector function diverges from other Tec-family kinases, while SHIP/Dok work mapped negative regulation.\",\n      \"evidence\": \"Reporter assays comparing family members, PKCθ co-IP with PH-domain requirement, and SHIP1/2 and Dok-1/2 inhibition assays\",\n      \"pmids\": [\"14993283\", \"15214048\", \"15492005\", \"14647425\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of TEC's unique subcellular compartment not molecularly defined\", \"Quantitative balance of positive vs negative regulators in vivo unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defining the extended regulatory spine and SH2-kinase linker allostery explained how regulatory domains control catalysis, answering the structural logic of TEC activation.\",\n      \"evidence\": \"In vitro kinase assays with linker and spine mutations, gatekeeper mutation analysis, HDX-MS, and MD simulations (studied across Tec family)\",\n      \"pmids\": [\"17425330\", \"20826165\", \"23982207\", \"27010561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Several mechanistic studies use Itk/Btk as model and generalize to TEC\", \"Full-length autoinhibited TEC structure not solved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Genetic and biochemical work in osteoclasts, phagocytes, and antifungal immunity expanded TEC's role beyond lymphocytes to innate immunity and bone homeostasis.\",\n      \"evidence\": \"Btk/Tec double-KO osteopetrosis with RANK/ITAM/BLNK complex co-IP, Fcγ-receptor phagocytosis siRNA/inhibitor imaging, and Dectin-1/Syk-dependent caspase-8 inflammasome in fungal infection models\",\n      \"pmids\": [\"18329366\", \"18566394\", \"25474208\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TEC-specific (vs Btk) contributions in some innate settings not separated\", \"Direct TEC substrates in the caspase-8 inflammasome not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying FGF2 as a direct TEC substrate during unconventional secretion revealed a function outside classical receptor-signaling pathways.\",\n      \"evidence\": \"In vitro kinase assay, co-IP, substrate-specific small-molecule inhibitors, and unconventional secretion assays\",\n      \"pmids\": [\"27382052\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological/in vivo significance of TEC in FGF2 export not established\", \"Regulation of this non-canonical TEC pool unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TEC achieves substrate selectivity and unique subcellular targeting distinct from Btk and Itk in vivo, and whether its non-canonical roles (FGF2 secretion, caspase-8 inflammasome) have dedicated regulation, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No full-length structure of autoinhibited or active TEC\", \"TEC-specific in vivo loss-of-function phenotype (without Btk) not deeply characterized\", \"Mechanism directing TEC to its unique compartment unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [11, 17, 22, 36, 7]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [11, 17, 22, 36]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [11, 29]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [22, 36]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [11, 27, 29]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [15, 19, 31, 32, 35]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 12, 26]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [13, 20, 23]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [19, 31]}\n    ],\n    \"complexes\": [\n      \"RANK/ITAM/BLNK(SLP-76) osteoclastogenic complex\",\n      \"noncanonical caspase-8 inflammasome\"\n    ],\n    \"partners\": [\n      \"LYN\",\n      \"KIT\",\n      \"VAV1\",\n      \"SOCS1\",\n      \"INPP5D\",\n      \"DOK1\",\n      \"PRKCQ\",\n      \"BTK\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}