ITK (IL-2-inducible T cell kinase, also EMT/TSK) is a Tec-family non-receptor protein tyrosine kinase expressed mainly in T cells, NK cells and mast cells. It has an N-terminal pleckstrin homology (PH) domain, a Tec homology region with a proline-rich motif, SH3 and SH2 domains and a C-terminal kinase domain. On T cell receptor (TCR) engagement, PI3K-generated PIP3 recruits ITK to the plasma membrane through its PH domain, and its SH2 domain docks on the ZAP70-phosphorylated N-terminal tyrosines of the adaptor SLP-76 (LCP2) within the LAT-SLP-76 signalosome. LCK then phosphorylates the activation-loop tyrosine (Tyr512 in human, Tyr511 in mouse), followed by autophosphorylation of Tyr180 in the SH3 domain. Active ITK phosphorylates phospholipase C gamma 1 (PLCG1) on Tyr783 and Tyr775, switching on PIP2 hydrolysis to IP3 and diacylglycerol and thus calcium/NFAT and DAG-dependent signaling; it also phosphorylates LAT and SLP-76 (Tyr173). Independently of its kinase activity, ITK helps localize VAV1 for TCR-induced actin polarization. ITK signaling tunes T helper differentiation (Th2/Th17 versus regulatory T cells) and is required for invariant NKT cell development. Biallelic loss-of-function ITK variants in humans cause a primary immunodeficiency with absent invariant NKT cells, CD4+ T cell lymphopenia and susceptibility to fatal EBV-driven lymphoproliferation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001819 positive regulation of cytokine production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from mouse Itk (Q03526): Itk-deficient T cells produce less IL-2 and Th2 cytokines. Reason: Cytokine output is a downstream consequence of ITK-dependent TCR signaling (PLCG1/Ca2+/NFAT). The knockout data record necessity rather than a direct step performed by ITK in cytokine production, so this is kept as non-core. Supporting Evidence: PMID:18443296 T cells from ITK-deficient mice show decreases in IL-2 production and proliferation and defects in T H 2 cytokine production PMID:39042726 in the absence of ITK activity, naΓ―ve murine CD4+ T cells cultured under TH17-inducing conditions expressed the Treg transcription factor Foxp3 and did not develop into TH17 cells |
| GO:0001865 NK T cell differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA for NK T cell differentiation, grounded in mouse Itk knockout data (absence of iNKT cells). Reason: Itk-deficient mice and ITK-deficient patients lack NKT cells, so ITK signaling is required for iNKT development. This is a requirement downstream of its TCR-signaling kinase activity rather than a step that ITK executes; kept as non-core per the project rule that knockout phenotypes record necessity. Supporting Evidence: PMID:19425169 Characteristics of ITK deficiency in mouse models, such as absence of NKT cells and high levels of eomesodermin in CD8+ cells, were seen in either one or both of the girls. PMID:25061172 illustrating that the absence of iNKT-cells is a primary phenotype of ITK deficiency |
| GO:0002250 adaptive immune response | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA for adaptive immune response at the Tec-family node. Reason: Correct but very broad; ITK acts in adaptive immunity through TCR signaling, which is captured more precisely by T cell receptor signaling pathway (GO:0050852). Kept as non-core, matching the LCK review. Supporting Evidence: PMID:18443296 is important for TCR-mediated activation of T cells, where it participates in regulation of PLCΞ³-1, Ca 2+ mobilization, and downstream activation of transcription factors |
| GO:0002250 adaptive immune response | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Itk for adaptive immune response. Reason: Same as the IBA row: correct but broad; the specific process is TCR signaling. Supporting Evidence: PMID:18443296 T cells from ITK-deficient mice show decreases in IL-2 production and proliferation and defects in T H 2 cytokine production |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based protein kinase activity. Reason: Correct but general parent of the tyrosine kinase activity (GO:0004715) established experimentally; acceptable as an IEA. Supporting Evidence: PMID:17420479 ITK efficiently phosphorylated Y(783) and Y(775) of PLC-gamma1, two phosphorylation sites that are critical for its activation, whereas ZAP-70 did not |
| GO:0004713 protein tyrosine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Protein tyrosine kinase activity from combined automated methods (RHEA:10596). Reason: ITK is a catalytically active tyrosine kinase that phosphorylates PLCG1, LAT and SLP-76; the parent term is correct. Supporting Evidence: PMID:17420479 ITK efficiently phosphorylated Y(783) and Y(775) of PLC-gamma1, two phosphorylation sites that are critical for its activation, whereas ZAP-70 did not |
| GO:0004715 non-membrane spanning protein tyrosine kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for non-membrane spanning protein tyrosine kinase activity at the Tec-family node (BTK, BMX, TEC, ITK). Reason: ITK is a cytoplasmic Tec-family tyrosine kinase; the node placement is sound and ITK itself contributes experimental grounding. This is the core MF, consistent with LCK and ZAP70. Supporting Evidence: PMID:17420479 ITK efficiently phosphorylated Y(783) and Y(775) of PLC-gamma1, two phosphorylation sites that are critical for its activation, whereas ZAP-70 did not PMID:12186560 the Syk-family kinase ZAP-70 and the Tec-family kinase Itk favor phosphorylation of carboxy-terminal tyrosines in LAT PMID:23219468 Itk catalyzes phosphorylation on tyrosine residues within a number of its natural substrates, including the well-characterized Y783 of PLCΞ³1. |
| GO:0004715 non-membrane spanning protein tyrosine kinase activity | IDA PMID:12186560 Phosphorylation of the linker for activation of T-cells by I... | ACCEPT | Summary: Itk phosphorylates C-terminal tyrosines of LAT; kinase-dead Itk reduces LAT phosphorylation and VAV recruitment in T cells. Reason: Direct kinase assay data on LAT; consistent with the PLCG1 Y783/Y775 and SLP-76 Y173 phosphorylation shown in other papers. Core MF. Supporting Evidence: PMID:12186560 the Syk-family kinase ZAP-70 and the Tec-family kinase Itk favor phosphorylation of carboxy-terminal tyrosines in LAT PMID:12186560 overexpression of a kinase-deficient mutant of Itk in T-cells reduced both the tyrosine phosphorylation of endogenous LAT and the recruitment of Vav to LAT complexes |
| GO:0004715 non-membrane spanning protein tyrosine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA for non-membrane spanning PTK activity (InterPro ITK_PTKc, EC:2.7.10.2). Reason: Consistent with experimental evidence; ITK has no transmembrane segment and is recruited to the membrane via its PH domain. Supporting Evidence: PMID:17420479 ITK efficiently phosphorylated Y(783) and Y(775) of PLC-gamma1, two phosphorylation sites that are critical for its activation, whereas ZAP-70 did not |
| GO:0004715 non-membrane spanning protein tyrosine kinase activity | TAS PMID:8364206 Identification, cloning, and characterization of a novel hum... | ACCEPT | Summary: Cloning paper describing EMT/ITK as a T-cell-specific intracellular tyrosine kinase. Reason: The original cloning paper identifies ITK as an intracellular SH2/SH3-containing tyrosine kinase; the activity is confirmed experimentally elsewhere. Supporting Evidence: PMID:8364206 We have cloned the complete cDNA for a unique human tyrosine kinase that is expressed mainly in T lymphocytes (EMT) and natural killer (NK) cells. |
| GO:0005515 protein binding | IPI PMID:12186560 Phosphorylation of the linker for activation of T-cells by I... | REMOVE | Summary: IPI with LAT (O43561); LAT is an ITK substrate in this paper. Reason: Generic protein binding is uninformative (CLAUDE.md). This is an enzyme-substrate relationship that is already captured by the IDA tyrosine kinase activity row from the same paper. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:12186560 the Syk-family kinase ZAP-70 and the Tec-family kinase Itk favor phosphorylation of carboxy-terminal tyrosines in LAT |
| GO:0005515 protein binding | IPI PMID:16273093 A quantitative protein interaction network for the ErbB rece... | REMOVE | Summary: ITK SH2 domain binding an ERBB2 phosphopeptide on a protein microarray. Reason: Generic protein binding is uninformative (CLAUDE.md). This is a proteome-scale in vitro SH2-domain array against ErbB receptor phosphopeptides; ITK is not expressed with ERBB2 in its physiological context and no function follows from the hit. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:16273093 we use protein microarrays comprising virtually every Src homology 2 (SH2) and phosphotyrosine binding (PTB) domain encoded in the human genome |
| GO:0005515 protein binding | IPI PMID:17420479 SLP-76 mediates and maintains activation of the Tec family k... | MODIFY | Summary: TCR-induced association of ITK with SLP-76 (LCP2), required to activate and maintain ITK catalytic activity. Reason: Generic protein binding is uninformative (CLAUDE.md). The ITK SH2 domain binds the phosphorylated N-terminal tyrosines of SLP-76, and this binding is what recruits and activates ITK. Phosphotyrosine residue binding (GO:0001784) is the informative MF, matching how SH2 docking was captured for ZAP70 and PLCG1. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:17420479 We propose that SLP-76 is required for ITK activation; furthermore, an ongoing physical interaction between SLP-76 and ITK is required to maintain ITK in an active conformation PMID:21725281 Catalytic activation of Itk depends on the inducible interaction of its SH2 domain with the N-terminal tyrosines of SLP-76 |
| GO:0005515 protein binding | IPI PMID:18443296 Selective targeting of ITK blocks multiple steps of HIV repl... | REMOVE | Summary: PLCG1 (P10686) used as substrate in ITK in vitro kinase assays in an HIV replication study. Reason: Generic protein binding is uninformative (CLAUDE.md). The paper uses a GST-PLC-gamma construct as a kinase substrate; this is an enzyme-substrate relationship, already captured by the tyrosine kinase activity rows. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:18443296 in vitro kinase assays performed by using a GST-PLC-Ξ³ construct as a synthetic substrate |
| GO:0005515 protein binding | IPI PMID:19807924 Identification of SH3 domain interaction partners of human F... | REMOVE | Summary: Isolated ITK SH3 domain found once in a phage-display screen for FasL proline-rich region binders and confirmed by GST-SH3 pulldown. Reason: Generic protein binding is uninformative (CLAUDE.md). Only the isolated SH3 domain was tested and the authors leave open whether full-length ITK binds FasL; no functional consequence was shown. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:19807924 FasL was precipitated with Itk SH3 domains from lysates of stably FasL expressing KFL9 cells |
| GO:0005515 protein binding | IPI PMID:21725281 Sequential phosphorylation of SLP-76 at tyrosine 173 is requ... | MODIFY | Summary: ITK binds phospho-SLP-76 N-terminal tyrosines through its SH2 domain and in turn phosphorylates SLP-76 Y173. Reason: Generic protein binding is uninformative (CLAUDE.md). The paper describes the SH2-phosphotyrosine docking of ITK on SLP-76 that activates ITK; replace with phosphotyrosine residue binding (GO:0001784). The ITK-to-SLP-76 Y173 phosphorylation is captured by the kinase activity rows. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:21725281 Catalytic activation of Itk depends on the inducible interaction of its SH2 domain with the N-terminal tyrosines of SLP-76 PMID:21725281 Itk, a kinase that selectively phosphorylated Y173 in vitro |
| GO:0005515 protein binding | IPI PMID:22939624 Quantitative analysis of HSP90-client interactions reveals p... | REMOVE | Summary: HSP90AB1 chaperone-client interaction from a systematic HSP90 client survey. Reason: Generic protein binding is uninformative (CLAUDE.md). This is a proteome-scale screen hit (chaperone/14-3-3 client capture or bulk AP-MS/XL-MS) with no follow-up on ITK function; HSP90 and 14-3-3 bind many kinases as clients. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:22939624 We systematically and quantitatively surveyed most human kinases, transcription factors, and E3 ligases for interaction with HSP90 and its cochaperone CDC37. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: HSP90AB1 co-purification in the BioPlex 2.0 AP-MS network. Reason: Generic protein binding is uninformative (CLAUDE.md). This is a proteome-scale screen hit (chaperone/14-3-3 client capture or bulk AP-MS/XL-MS) with no follow-up on ITK function; HSP90 and 14-3-3 bind many kinases as clients. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:28514442 Here we present BioPlex 2.0 (Biophysical Interactions of ORFeome-derived complexes), which uses robust affinity purification-mass spectrometry methodology |
| GO:0005515 protein binding | IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma... | REMOVE | Summary: AHNAK crosslink from nuclear crosslinking mass spectrometry. Reason: Generic protein binding is uninformative (CLAUDE.md). This is a proteome-scale screen hit (chaperone/14-3-3 client capture or bulk AP-MS/XL-MS) with no follow-up on ITK function; HSP90 and 14-3-3 bind many kinases as clients. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:30021884 Here we use crosslinking mass spectrometry (XL-MS) to chart the protein-protein interactions in intact human nuclei. |
| GO:0005515 protein binding | IPI PMID:31585087 Oncogenic Mutations Rewire Signaling Pathways by Switching P... | REMOVE | Summary: Phosphotyrosine-peptide pulldown proteomics in lung tissue (PLCG1, P10686). Reason: Generic protein binding is uninformative (CLAUDE.md). This is a proteome-scale screen hit (chaperone/14-3-3 client capture or bulk AP-MS/XL-MS) with no follow-up on ITK function; HSP90 and 14-3-3 bind many kinases as clients. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:31585087 we determined their recruited protein signaling complexes in lung tissue by interaction proteomics |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | REMOVE | Summary: HSP90AB1 from a kinase interaction network AP-MS study. Reason: Generic protein binding is uninformative (CLAUDE.md). This is a proteome-scale screen hit (chaperone/14-3-3 client capture or bulk AP-MS/XL-MS) with no follow-up on ITK function; HSP90 and 14-3-3 bind many kinases as clients. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:32707033 we present a comprehensive mass-spectrometry-based analysis of a human kinase interaction network covering more than 300 kinases |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | REMOVE | Summary: 14-3-3 sigma (SFN) from a kinase interaction network AP-MS study. Reason: Generic protein binding is uninformative (CLAUDE.md). This is a proteome-scale screen hit (chaperone/14-3-3 client capture or bulk AP-MS/XL-MS) with no follow-up on ITK function; HSP90 and 14-3-3 bind many kinases as clients. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:32707033 we present a comprehensive mass-spectrometry-based analysis of a human kinase interaction network covering more than 300 kinases |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ domain of UniProtKB:Q07157 binding a peptide carrying the ITK C-terminal PDZ-binding motif in a holdup affinity screen. Reason: Generic protein binding is uninformative (CLAUDE.md). This is a quantitative fragmentomics screen of PDZ domains against C-terminal peptides; no PDZ partner of ITK has been shown to act in ITK signaling. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ domain of UniProtKB:Q09666 binding a peptide carrying the ITK C-terminal PDZ-binding motif in a holdup affinity screen. Reason: Generic protein binding is uninformative (CLAUDE.md). This is a quantitative fragmentomics screen of PDZ domains against C-terminal peptides; no PDZ partner of ITK has been shown to act in ITK signaling. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ domain of UniProtKB:Q12959 binding a peptide carrying the ITK C-terminal PDZ-binding motif in a holdup affinity screen. Reason: Generic protein binding is uninformative (CLAUDE.md). This is a quantitative fragmentomics screen of PDZ domains against C-terminal peptides; no PDZ partner of ITK has been shown to act in ITK signaling. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ domain of UniProtKB:Q5T2W1 binding a peptide carrying the ITK C-terminal PDZ-binding motif in a holdup affinity screen. Reason: Generic protein binding is uninformative (CLAUDE.md). This is a quantitative fragmentomics screen of PDZ domains against C-terminal peptides; no PDZ partner of ITK has been shown to act in ITK signaling. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ domain of UniProtKB:Q68DX3 binding a peptide carrying the ITK C-terminal PDZ-binding motif in a holdup affinity screen. Reason: Generic protein binding is uninformative (CLAUDE.md). This is a quantitative fragmentomics screen of PDZ domains against C-terminal peptides; no PDZ partner of ITK has been shown to act in ITK signaling. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ domain of UniProtKB:Q86UL8 binding a peptide carrying the ITK C-terminal PDZ-binding motif in a holdup affinity screen. Reason: Generic protein binding is uninformative (CLAUDE.md). This is a quantitative fragmentomics screen of PDZ domains against C-terminal peptides; no PDZ partner of ITK has been shown to act in ITK signaling. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ domain of UniProtKB:Q8N448 binding a peptide carrying the ITK C-terminal PDZ-binding motif in a holdup affinity screen. Reason: Generic protein binding is uninformative (CLAUDE.md). This is a quantitative fragmentomics screen of PDZ domains against C-terminal peptides; no PDZ partner of ITK has been shown to act in ITK signaling. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ domain of UniProtKB:Q8NI35 binding a peptide carrying the ITK C-terminal PDZ-binding motif in a holdup affinity screen. Reason: Generic protein binding is uninformative (CLAUDE.md). This is a quantitative fragmentomics screen of PDZ domains against C-terminal peptides; no PDZ partner of ITK has been shown to act in ITK signaling. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ domain of UniProtKB:Q9P202 binding a peptide carrying the ITK C-terminal PDZ-binding motif in a holdup affinity screen. Reason: Generic protein binding is uninformative (CLAUDE.md). This is a quantitative fragmentomics screen of PDZ domains against C-terminal peptides; no PDZ partner of ITK has been shown to act in ITK signaling. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZ domain of UniProtKB:Q9Y3R0 binding a peptide carrying the ITK C-terminal PDZ-binding motif in a holdup affinity screen. Reason: Generic protein binding is uninformative (CLAUDE.md). This is a quantitative fragmentomics screen of PDZ domains against C-terminal peptides; no PDZ partner of ITK has been shown to act in ITK signaling. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | REMOVE | Summary: 14-3-3 sigma (SFN) client from a 14-3-3 interactome survey. Reason: Generic protein binding is uninformative (CLAUDE.md). This is a proteome-scale screen hit (chaperone/14-3-3 client capture or bulk AP-MS/XL-MS) with no follow-up on ITK function; HSP90 and 14-3-3 bind many kinases as clients. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:36931259 we map the interactomes of all human 14-3-3 paralogs |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | REMOVE | Summary: 14-3-3 epsilon (YWHAE) client from a 14-3-3 interactome survey. Reason: Generic protein binding is uninformative (CLAUDE.md). This is a proteome-scale screen hit (chaperone/14-3-3 client capture or bulk AP-MS/XL-MS) with no follow-up on ITK function; HSP90 and 14-3-3 bind many kinases as clients. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:36931259 we map the interactomes of all human 14-3-3 paralogs |
| GO:0005515 protein binding | IPI PMID:8892607 Evidence that the Wiskott-Aldrich syndrome protein may be in... | REMOVE | Summary: WASP binding to the isolated SH3 domain of ITK (and of BTK, TEC, GRB2 and PLCG1). Reason: Generic protein binding is uninformative (CLAUDE.md). The abstract reports binding of WASP to isolated SH3 domains of several proteins, and the functional relevance for ITK was not tested. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:8892607 we show binding of WASP to the Src homology 3 domains of Btk, Itk, Tec, Grb2, and phospholipase C-gamma |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding from the kinase domain. Reason: Required for its kinase activity; correct. Supporting Evidence: PMID:17420479 ITK efficiently phosphorylated Y(783) and Y(775) of PLC-gamma1, two phosphorylation sites that are critical for its activation, whereas ZAP-70 did not |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Nucleus from UniProt subcellular location (by similarity to mouse Itk). Reason: Nuclear localization is asserted by similarity to mouse Itk; ITK acts mainly at the plasma membrane and in the cytosol during TCR signaling, so a nuclear pool is at most a minor, non-core location. Supporting Evidence: PMID:17060314 Itk is activated by receptors via a phosphatidylinositol 3-kinase-mediated pathway, which results in recruitment of Itk to the plasma membrane via its pleckstrin homology domain. |
| GO:0005634 nucleus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Nucleus by ISS from mouse Itk (Q03526). Reason: As for the IEA row: plausible minor pool, not where ITK performs its core function. Supporting Evidence: PMID:17060314 Itk is activated by receptors via a phosphatidylinositol 3-kinase-mediated pathway, which results in recruitment of Itk to the plasma membrane via its pleckstrin homology domain. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasm from UniProt subcellular location. Reason: ITK is a cytoplasmic kinase recruited to the membrane on receptor stimulation. Supporting Evidence: PMID:17060314 Itk is activated by receptors via a phosphatidylinositol 3-kinase-mediated pathway, which results in recruitment of Itk to the plasma membrane via its pleckstrin homology domain. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Cytosol from Human Protein Atlas immunofluorescence. Reason: Consistent with a soluble cytoplasmic kinase in resting cells. Supporting Evidence: PMID:17060314 Itk is activated by receptors via a phosphatidylinositol 3-kinase-mediated pathway, which results in recruitment of Itk to the plasma membrane via its pleckstrin homology domain. |
| GO:0005829 cytosol | IEA GO_REF:0000117 | ACCEPT | Summary: Cytosol by ARBA. Reason: Consistent with the IDA and Reactome rows. Supporting Evidence: PMID:17060314 Itk is activated by receptors via a phosphatidylinositol 3-kinase-mediated pathway, which results in recruitment of Itk to the plasma membrane via its pleckstrin homology domain. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-202248 | ACCEPT | Summary: Reactome places ITK in the cytosol for phosphorylation of PLCG1. Reason: Cytosolic location of the soluble kinase before and during membrane recruitment; acceptable. Supporting Evidence: Reactome:R-HSA-202248 The phosphorylation of the tyrosine residues and the activation of PLC-gamma1 is mediated by both Syk tyrosine kinase ZAP-70 and Tec kinase ITK. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-202375 | ACCEPT | Summary: Reactome places ITK in the cytosol for its recruitment to SLP-76. Reason: Cytosolic location of the soluble kinase before and during membrane recruitment; acceptable. Supporting Evidence: Reactome:R-HSA-202248 The phosphorylation of the tyrosine residues and the activation of PLC-gamma1 is mediated by both Syk tyrosine kinase ZAP-70 and Tec kinase ITK. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730833 | ACCEPT | Summary: Reactome places ITK in the cytosol for activation-loop phosphorylation. Reason: Cytosolic location of the soluble kinase before and during membrane recruitment; acceptable. Supporting Evidence: Reactome:R-HSA-202248 The phosphorylation of the tyrosine residues and the activation of PLC-gamma1 is mediated by both Syk tyrosine kinase ZAP-70 and Tec kinase ITK. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730847 | ACCEPT | Summary: Reactome places ITK in the cytosol in the PIP2 hydrolysis reaction (as part of the PLCG activation context). Reason: Cytosolic location of the soluble kinase before and during membrane recruitment; acceptable. Supporting Evidence: Reactome:R-HSA-202248 The phosphorylation of the tyrosine residues and the activation of PLC-gamma1 is mediated by both Syk tyrosine kinase ZAP-70 and Tec kinase ITK. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730858 | ACCEPT | Summary: Reactome places ITK in the cytosol for autophosphorylation of Y180. Reason: Cytosolic location of the soluble kinase before and during membrane recruitment; acceptable. Supporting Evidence: Reactome:R-HSA-2730858 Y223 (Y180 in ITK and Y206 in TEC) in the SH3 domain of BTK is autophosphorylated |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for plasma membrane (is_active_in) at the non-receptor tyrosine kinase node. Reason: ITK is recruited to the plasma membrane by PIP3 binding of its PH domain and by SLP-76, where it is phosphorylated by LCK and acts on PLCG1. The plasma membrane is where it is active. Supporting Evidence: PMID:17060314 Itk is activated by receptors via a phosphatidylinositol 3-kinase-mediated pathway, which results in recruitment of Itk to the plasma membrane via its pleckstrin homology domain. Reactome:R-HSA-2730833 In the first step they are recruited to the membrane by binding to PIP3 or, alternatively with other binding partners like SLP-76. |
| GO:0006968 cellular defense response | TAS PMID:8364206 Identification, cloning, and characterization of a novel hum... | MARK AS OVER ANNOTATED | Summary: Cellular defense response attributed to the cloning paper. Reason: The cloning paper reports expression in T and NK cells and speculates on receptor signaling, but shows no defense response. ITK contributes to immunity through TCR signaling, which is captured more precisely by GO:0050852; this broad, old-style term adds nothing. Supporting Evidence: PMID:8364206 We have cloned the complete cDNA for a unique human tyrosine kinase that is expressed mainly in T lymphocytes (EMT) and natural killer (NK) cells. |
| GO:0007165 signal transduction | IEA GO_REF:0000117 | ACCEPT | Summary: Signal transduction by ARBA. Reason: Correct but general; the specific process is TCR signaling. Supporting Evidence: PMID:17420479 ITK efficiently phosphorylated Y(783) and Y(775) of PLC-gamma1, two phosphorylation sites that are critical for its activation, whereas ZAP-70 did not |
| GO:0007165 signal transduction | TAS PMID:8364206 Identification, cloning, and characterization of a novel hum... | ACCEPT | Summary: Signal transduction attributed to the cloning paper. Reason: The cloning paper introduces ITK as a candidate signal transducer in T cells; correct but general. Supporting Evidence: PMID:8364206 Signal transduction through the T-cell receptor and cytokine receptors on the surface of T lymphocytes occurs largely via tyrosine phosphorylation of intracellular substrates. |
| GO:0035556 intracellular signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: Intracellular signal transduction from the PH domain InterPro mapping. Reason: Correct but general; ITK relays receptor signals intracellularly to PLCG1. Supporting Evidence: PMID:17420479 ITK efficiently phosphorylated Y(783) and Y(775) of PLC-gamma1, two phosphorylation sites that are critical for its activation, whereas ZAP-70 did not |
| GO:0042110 T cell activation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: T cell activation by ARBA. Reason: ITK contributes to T cell activation through its TCR signaling activity, but T cell activation as a whole is a broad downstream outcome; kept as non-core, consistent with the LCK, ZAP70 and LAT reviews. Supporting Evidence: PMID:18443296 T cells from ITK-deficient mice show decreases in IL-2 production and proliferation and defects in T H 2 cytokine production |
| GO:0042110 T cell activation | TAS PMID:12186560 Phosphorylation of the linker for activation of T-cells by I... | KEEP AS NON CORE | Summary: T cell activation, from the LAT phosphorylation paper. Reason: The paper places ITK-mediated LAT phosphorylation and VAV recruitment within TCR-driven activation; the precise process is TCR signaling, so T cell activation is kept as non-core. Supporting Evidence: PMID:12186560 Itk kinase activity promotes recruitment of Vav to LAT |
| GO:0046629 gamma-delta T cell activation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Gamma-delta T cell activation by ISS from mouse Itk. Reason: Mouse Itk is required for TCR-induced calcium responses in gamma-delta T cells (UniProt, by similarity). This reflects the same TCR-signaling kinase activity in another T cell lineage; kept as non-core. Supporting Evidence: PMID:17420479 ITK efficiently phosphorylated Y(783) and Y(775) of PLC-gamma1, two phosphorylation sites that are critical for its activation, whereas ZAP-70 did not |
| GO:0050852 T cell receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for T cell receptor signaling pathway. Reason: ITK is recruited to the LAT-SLP-76 signalosome, activated by LCK and phosphorylates PLCG1 Y783/Y775 to switch on PIP2 hydrolysis; it performs a step of TCR signaling. Core process. Supporting Evidence: PMID:17420479 ITK efficiently phosphorylated Y(783) and Y(775) of PLC-gamma1, two phosphorylation sites that are critical for its activation, whereas ZAP-70 did not PMID:17420479 We propose that SLP-76 is required for ITK activation; furthermore, an ongoing physical interaction between SLP-76 and ITK is required to maintain ITK in an active conformation Reactome:R-HSA-202248 The phosphorylation of the tyrosine residues and the activation of PLC-gamma1 is mediated by both Syk tyrosine kinase ZAP-70 and Tec kinase ITK. |
| GO:0050852 T cell receptor signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: TCR signaling by ISS from mouse Itk. Reason: Same as the IBA row; core process. Supporting Evidence: PMID:17420479 ITK efficiently phosphorylated Y(783) and Y(775) of PLC-gamma1, two phosphorylation sites that are critical for its activation, whereas ZAP-70 did not PMID:9312162 The major site of Lck phosphorylation on Itk was mapped to the conserved tyrosine (Tyr511) in the activation loop of the Itk kinase domain. |
| GO:0050853 B cell receptor signaling pathway | IBA GO_REF:0000033 | REMOVE | Summary: IBA for B cell receptor signaling pathway, propagated from the Tec-family node seeded by BTK and BMX/TEC. Reason: BCR signaling is a function of BTK in B cells. ITK is expressed in T cells, NK cells and mast cells, not in B cells, so the propagated term does not apply to ITK. The node placement captures a family-level function that diverged by lineage expression. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: PANTHER:PTN000700360 SUPPORTS SOURCE BUT NOT TARGET Tec-family ancestral node that carries both TCR and BCR signaling; each extant member acts in the antigen receptor system of the lineage that expresses it. ITK is expressed in T, NK and mast cells, not B cells, so the BCR branch of the assertion does not apply to it. UniProtKB:Q06187 Β· BTK SUPPORTS SOURCE BUT NOT TARGET BTK is the B cell Tec kinase and genuinely acts in BCR signaling. UniProtKB:P42680 Β· TEC SUPPORTS SOURCE BUT NOT TARGET TEC is expressed in B cells and contributes to BCR signaling; this does not transfer to the T-cell-restricted ITK. Supporting Evidence: PMID:8364206 We have cloned the complete cDNA for a unique human tyrosine kinase that is expressed mainly in T lymphocytes (EMT) and natural killer (NK) cells. PMID:18443296 ITK is expressed in a limited number of cell types, including T cells, NK cells, and mast cells |
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Download this section (compressed HTML)Q: ITK has a kinase-independent scaffolding role in localizing VAV1 for TCR-induced actin polarization (PMID:15661896, PMID:12682224). Should this be captured with an MF term (e.g. a signaling adaptor activity), or is it adequately covered by the SH2 phosphotyrosine binding plus TCR signaling annotations?
Q: Two GOA IPI rows (PMID:18443296, PMID:31585087) name UniProtKB:P10686 as the PLCG1 partner; IntAct flags this interaction as cross-species (Xeno). Should the human annotation be made against human PLCG1 (P19174), or dropped as an enzyme-substrate relationship?
Q: ITK phosphorylates TBX21 (T-bet) Tyr530 to promote its interaction with GATA3 in mouse (UniProt, by similarity). Is this a direct, physiologically relevant ITK substrate in human T helper cells, and how much of the Th2/Th17 versus Treg skewing of ITK deficiency it explains?
Experiment: Reconstitute ITK-knockout primary human CD4+ T cells (or patient-derived cells with LPFS1 variants) with wild-type, kinase-dead, SH2-mutant (R335W) and PH-mutant ITK; measure PLCG1 Y783 phosphorylation, calcium flux, NFAT nuclear translocation, VAV1 recruitment and synapse actin polarization.
Hypothesis: ITK kinase activity and its SH2/PH-dependent scaffolding make separable contributions to calcium/NFAT signaling and actin polarization in human T cells.
Experiment: Use an analog-sensitive ITK allele in human T cells with thiophosphate labelling and phosphoproteomics after TCR stimulation to identify direct substrates, then test candidate sites (e.g. TBX21 Tyr530) by mutation in Th1/Th2/Th17 differentiation assays.
Hypothesis: ITK has direct substrates beyond PLCG1, LAT and SLP-76 that shape T helper differentiation.
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