Affinage

ITK

Tyrosine-protein kinase ITK/TSK · UniProt Q08881

Length
620 aa
Mass
71.8 kDa
Annotated
2026-06-10
100 papers in source corpus 54 papers cited in narrative 53 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ITK is a T-cell-lineage-restricted, IL-2-inducible Tec-family non-receptor tyrosine kinase that couples antigen-receptor engagement to phospholipase C-γ1 activation, calcium flux, and downstream transcriptional programs governing T-cell development and effector differentiation (PMID:1280821, PMID:9584150). Activation proceeds by sequential, domain-coordinated steps: PI3-kinase-dependent membrane recruitment through the ITK pleckstrin-homology domain — which binds D3-phosphorylated phosphoinositides and drives membrane clustering — positions ITK at receptor-proximal sites, and this PH-domain function is the critical step in Src/Lck-induced activation (PMID:9326591, PMID:17060314, PMID:22289921). Lck then directly trans-phosphorylates the activation-loop residue Tyr-511, an event required for catalytic activity, while autophosphorylation at Tyr-180 in the SH3 domain and ligand binding by the SH3 domain provide additional layers of regulation (PMID:9312162, PMID:12842872). ITK is recruited into LAT/SLP-76-nucleated signaling complexes through cooperative SH3/SH2 and proline-rich interactions, and ongoing SLP-76 association is required to maintain ITK in an active conformation (PMID:10636929, PMID:17420479). Active ITK selectively phosphorylates PLC-γ1 at Y775/Y783 via a direct, phosphotyrosine-independent docking interaction between the ITK kinase domain and the PLC-γ1 nSH2 domain, driving IP3 production and capacitative calcium entry that ZAP-70 cannot supply (PMID:17420479, PMID:19955438, PMID:9584150). Catalytic output is restrained by cyclophilin A, whose prolyl-isomerase activity exploits a cis/trans conformational switch in the ITK SH2 domain to inhibit kinase activity and modulate substrate recognition (PMID:11830645, PMID:16436281). Beyond its catalytic role, ITK performs a kinase-independent scaffolding function via its PH and SH2 domains to localize Vav to the immune synapse and organize Cdc42-dependent actin polarization at the T-cell–APC interface (PMID:15661896, PMID:21971040). Genetically, ITK is required for proximal TCR signaling, positive thymic selection, NKT cell maturation, and Th2/Th9/Tr1 differentiation, and shapes the conventional-versus-innate CD8+ T-cell fate decision through an mTOR/Pten and IRF4/Eomes axis; its loss promotes innate-like T cells and Treg/Th1 skewing (PMID:8777721, PMID:12055226, PMID:12193707, PMID:15345221, PMID:24534190, PMID:23011795, PMID:28635957). A recurrent t(5;9) translocation fuses the ITK PH and proline-rich region to the SYK kinase domain, generating a constitutively active fusion kinase that drives peripheral T-cell lymphoma (PMID:16341044, PMID:20439541), and ITK is a covalent off-target of the BTK inhibitor ibrutinib (PMID:23886836).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1992 Medium

    Establishing ITK's identity answered whether a dedicated, lineage-restricted tyrosine kinase exists in T cells, defining it as an IL-2-inducible enzyme of the T-cell compartment.

    Evidence Molecular cloning and Northern blot of mouse tissues and cell lines

    PMID:1280821

    Open questions at the time
    • No functional or signaling role defined
    • No domain mechanism established
  2. 1995 High

    Knockout mice answered whether ITK is functionally required, placing it in proximal TCR signaling rather than the distal PMA/ionomycin or IL-2 pathways.

    Evidence Gene targeting, flow cytometry, proliferation assays with TCR/MHC versus PMA+ionomycin/IL-2 stimulation

    PMID:8777721

    Open questions at the time
    • Molecular substrate not identified
    • Step in the TCR cascade not pinpointed
  3. 1997 High

    In vitro reconstitution answered how ITK is switched on, showing Lck directly phosphorylates the activation-loop Tyr-511, and that PI3K-dependent PH-domain membrane recruitment is the critical upstream step.

    Evidence Baculovirus recombinant kinase assays with Y511F mutagenesis; PH-domain deletion and membrane-targeting rescue with PI3K inhibitors

    PMID:9312162 PMID:9326591

    Open questions at the time
    • PH domain has a function beyond membrane targeting that was undefined at the time
    • Direct physiological substrate not yet established
  4. 1998 High

    Biochemical dissection in knockout T cells answered where ITK acts in the cascade, showing it lies downstream of/parallel to ZAP-70 and is required for IP3 generation, PLC-γ1 phosphorylation, and capacitative calcium entry.

    Evidence Calcium flux (fura-2), IP3 measurement, phosphotyrosine blots, thapsigargin in Itk-/- T cells

    PMID:9584150

    Open questions at the time
    • Direct versus indirect PLC-γ1 phosphorylation not resolved
    • Recruitment mechanism into the signaling complex unknown
  5. 1999 High

    Genetic epistasis with Rlk and adaptor/PLC-γ1 association studies answered how ITK is wired into the TCR complex, establishing Tec kinases as critical PLC-γ regulators recruited via SH3/SH2 domains.

    Evidence Rlk/Itk double-knockout mice with IP3/calcium/ERK readouts and in vivo infection; co-IP with PLC-γ1 domain mutants; RIBP yeast two-hybrid and knockout

    PMID:10213685 PMID:10586033 PMID:10587356

    Open questions at the time
    • Direct kinase-substrate relationship with PLC-γ1 not yet proven in vitro
    • Docking interface unmapped
  6. 2000 High

    Mapping ITK's multivalent interactions answered how it is concentrated at the membrane, showing PH-domain raft targeting plus cooperative SH3/SH2 engagement of Syk-phosphorylated SLP-76 and proline-rich binding to Grb2/LAT.

    Evidence Membrane fractionation, co-IP, SH2/SH3 binding assays, NFAT reporter with kinase-dead ITK

    PMID:10636929

    Open questions at the time
    • Whether SLP-76 binding regulates catalytic state not yet shown
    • Stoichiometry of the complex undefined
  7. 2002 High

    Structural and biochemical work answered how ITK catalytic activity is restrained, identifying cyclophilin A prolyl-isomerase-driven cis/trans switching of the SH2 domain as a negative regulator.

    Evidence NMR of the SH2 domain, mutagenesis, co-IP from Jurkat cells, cyclosporin A treatment with phospho-PLC-γ1 readout

    PMID:11830645 PMID:16436281

    Open questions at the time
    • Physiological trigger for CypA engagement in vivo not defined
    • Quantitative contribution to overall ITK output unclear
  8. 2003 High

    Mutational reconstitution in primary T cells answered which regulatory events are functionally required, showing both Tyr-511 trans-phosphorylation, Tyr-180 SH3 autophosphorylation, and SH3 ligand binding are each needed for full function.

    Evidence Retroviral transduction of Itk point mutants into Itk-/- T cells with cytokine and ERK readouts

    PMID:12842872

    Open questions at the time
    • SH3 ligand identity in vivo not pinned down
    • Order of phosphorylation events not resolved
  9. 2005 High

    Separation-of-function experiments answered whether ITK has roles beyond catalysis, defining a kinase-independent scaffolding function that localizes Vav to drive actin polarization.

    Evidence siRNA, kinase-dead and PH/SH2 domain mutants, co-IP, confocal actin imaging, membrane-targeted Vav-CAAX rescue

    PMID:15661896

    Open questions at the time
    • How Vav is held by ITK structurally undefined
    • Relationship to catalytic signaling at the synapse unclear
  10. 2007 High

    Side-by-side in vitro kinase reconstitution answered whether ITK directly phosphorylates PLC-γ1, identifying Y775/Y783 as specific ITK (not ZAP-70) sites and showing SLP-76 association maintains the active conformation.

    Evidence Recombinant ITK vs ZAP-70 kinase assays, co-IP, complex elution/reconstitution, SLP-76 mutants

    PMID:17420479

    Open questions at the time
    • Structural basis of substrate selectivity not yet defined
    • Mechanism of conformational maintenance by SLP-76 unresolved
  11. 2009 High

    NMR structures answered how ITK domains coordinate substrate engagement, revealing a nonclassical SH3/SH2 interface tuned by prolyl isomerization and a phosphotyrosine-independent kinase-domain docking onto the PLC-γ1 nSH2 domain.

    Evidence NMR structure determination of the SH3/SH2 binary complex and of the ITK-PLC-γ1 docking interface with mutagenesis and T-cell signaling assays

    PMID:19361414 PMID:19955438

    Open questions at the time
    • Full-length autoinhibited architecture not solved
    • Allosteric coupling between domains in vivo not quantified
  12. 2006 High

    Phenotypic and genetic-rescue studies answered how ITK governs CD8 T-cell identity, showing Tec kinase loss yields innate-like CD8+ cells correctable by enhanced ERK signaling.

    Evidence Itk-/- and Rlk-/-Itk-/- mice, chimeras, hypersensitive ERK2 transgene rescue; NKT and thymic selection phenotyping

    PMID:12055226 PMID:12193707 PMID:16860760

    Open questions at the time
    • Transcriptional effectors not yet identified at this stage
    • Cell-intrinsic versus -extrinsic contributions partly unresolved
  13. 2012 Medium

    Transcription-factor and pathway analyses answered how ITK signal strength is decoded into fate, linking ITK to IRF4 induction and Eomes suppression and to PH-domain phosphoinositide binding affected by a patient mutation.

    Evidence ITK inhibitor and IRF4-knockout mice for Eomes readout; lipid binding assays, calcium-rescue, and protein stability for the R29H PH-domain mutation

    PMID:22289921 PMID:23011795

    Open questions at the time
    • Direct ITK targets upstream of IRF4 not mapped
    • Clinical genotype-phenotype correlation limited
  14. 2014 High

    Mechanistic pathway dissection answered how ITK biases CD4 differentiation, showing ITK loss derepresses Pten and dampens mTOR, skewing toward Foxp3+ Treg, and that ITK promotes Th9/Tr1 via IL-2/STAT5/IRF4 and Ras/IRF4 axes.

    Evidence Itk-/- mice with mTOR/STAT5/Pten/Myc readouts; STAT5 ChIP at Irf4, constitutively active STAT5 and HRas rescue, ITK inhibitor in human cells

    PMID:24534190 PMID:26936133 PMID:28635957

    Open questions at the time
    • Direct ITK substrates linking to Pten/Myc not identified
    • Hierarchy among parallel differentiation axes unclear
  15. 2021 High

    Single-cell and genome-wide analyses answered which transcriptional outputs ITK preferentially tunes, showing ITK shapes graded NF-κB and AP-1 activation while NFAT1/ERK responses are more digital and ITK-insensitive.

    Evidence ITK inhibitor with single-cell NFAT1/NF-κB/ERK imaging, ATAC-seq, transcriptomics in naïve CD8+ OT-I cells; earlier CD2/IL-2 promoter and NFAT reporter work

    PMID:34452995 PMID:9130632

    Open questions at the time
    • Direct molecular link from ITK to NF-κB/AP-1 not fully mapped
    • Generalizability across T-cell subsets untested
  16. 2010 High

    Characterization of the ITK-SYK fusion answered how ITK contributes to lymphomagenesis, showing the fusion constitutively activates TCR-proximal signaling and drives fully penetrant peripheral T-cell lymphoma requiring SYK activity.

    Evidence Cytogenetics/RT-PCR in patient samples; lipid raft fractionation, in vitro activation assays, conditional transgenic and bone-marrow transplant mouse models with R29C/E42K mutants and SYK inhibition

    PMID:16341044 PMID:20439541 PMID:20670954

    Open questions at the time
    • Contribution of native ITK (versus fusion) to lymphoma unclear
    • Membrane-localization requirement context-dependent
  17. 2015 High

    Inhibitor and pharmacology studies answered whether ITK is a tractable drug target, defining covalent active-site cysteines, ibrutinib off-target inhibition, and in vivo immunomodulatory and trafficking effects.

    Evidence Selective and covalent inhibitors (BMS-509744, PRN694 targeting Cys442), ibrutinib clinical samples and infection models; Itk-/-;Ctla4-/- trafficking studies

    PMID:15323564 PMID:23886836 PMID:24270545 PMID:25593320

    Open questions at the time
    • Long-term immune consequences of chronic ITK inhibition undefined
    • Selectivity over other Tec kinases incomplete
  18. 2024 Medium

    Metabolic profiling answered how ITK couples cytokine cues to T-cell metabolism, showing TNF-α drives glycolytic/mitochondrial reprogramming and Th1/Th17 bias through ITK-Akt-mTOR independently of NF-κB.

    Evidence ITK inhibitor in human naïve CD4+ T cells, Akt phosphorylation, metabolic flux analysis, differentiation assays, RA patient samples

    PMID:38652761

    Open questions at the time
    • Direct ITK substrate in the Akt-mTOR arm not identified
    • In vivo relevance of the TNF-ITK-mTOR axis untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ITK's catalytic and kinase-independent scaffolding functions are integrated within a single full-length autoregulated molecule at the immune synapse, and which direct substrates link ITK to the NF-κB/AP-1 and Pten/mTOR programs, remain open.
  • No full-length autoinhibited structure
  • Direct substrates beyond PLC-γ1 largely uncatalogued
  • Mechanism linking ITK activity to NF-κB and Pten regulation unmapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0008289 lipid binding 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0008092 cytoskeletal protein binding 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-1643685 Disease 3
Partners
CD28GRB2LATLCKPLCG1PPIASLP-76VAV1
Complex memberships
LAT/SLP-76 signalosome

Evidence

Reading pass · 53 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 ITK encodes a 72-kDa protein-tyrosine kinase specifically expressed in the T-cell lineage; its mRNA is induced by IL-2 in parallel with IL-2Rα, identifying it as an IL-2-inducible T-cell kinase. Molecular cloning, Northern blot analysis of mouse tissues and cell lines Proceedings of the National Academy of Sciences of the United States of America Medium 1280821
1994 ITK is physically associated with CD28 in Jurkat T cells and undergoes rapid tyrosine phosphorylation and activation within 30 seconds of CD28 ligation, preceding phosphorylation of VAV, placing ITK among the earliest events in CD28 signaling. Co-immunoprecipitation, in vitro kinase assay, Western blot with phosphotyrosine antibodies Proceedings of the National Academy of Sciences of the United States of America Medium 7524075
1995 Itk-deficient mice have decreased numbers of mature thymocytes and reduced T-cell proliferative responses to allogeneic MHC stimulation and anti-TCR cross-linking, but respond normally to PMA plus ionomycin or IL-2, establishing Itk as required for proximal TCR signaling events in T-cell development. Gene targeting (knockout mice), flow cytometry, proliferation assays Immunity High 8777721
1995 ITK binding to CD28 is dependent on the presence of p56Lck; Lck and Fyn phosphorylate CD28 at Tyr-191 of the YMNM motif, inducing increased PI3K and GRB-2 SH2 binding to CD28, whereas ZAP-70 and ITK failed to phosphorylate CD28 at this site, placing ITK downstream of Lck in CD28 costimulatory signaling. Co-expression studies, in vitro kinase assays, SH2 domain binding assays, phosphatase digestion Proceedings of the National Academy of Sciences of the United States of America Medium 7568038
1995 Upon FcεRI cross-linking on mast cells, Itk is activated and its pleckstrin homology domain directly interacts with multiple PKC isoforms in vitro; PKC phosphorylates the PH domain of Itk and PKC isoforms co-immunoprecipitate with Itk in intact mast cells, with PKC inhibition attenuating Itk tyrosine phosphorylation and activity. Co-immunoprecipitation, in vitro kinase assay, GST pulldown, PKC inhibitor treatment Journal of immunology Medium 7561053
1996 The Itk SH3 domain binds to proline-rich sequences in T-cell lysates; under stringent conditions it binds Sam68, Wiskott-Aldrich Syndrome protein (WASP), and hnRNP-K, overlapping but distinct from Src-family SH3 binding sites on these proteins. Phage display library screening, SH3 domain pulldown/binding assays with T-cell lysates and deletion mutants The Journal of biological chemistry Medium 8810341
1996 CD2 ligation induces tyrosine phosphorylation and activation of ITK in Jurkat T cells and peripheral blood T cells; this CD2-mediated activation of ITK requires LCK expression but not surface expression of the CD3 zeta chain. Co-immunoprecipitation, in vitro kinase assay, Jurkat cell mutant panel International immunology Medium 8943565
1997 Lck directly phosphorylates Itk at Tyr-511 in the activation loop of the kinase domain using recombinant baculovirus-expressed proteins; phosphorylation at Tyr-511 is required for Itk kinase activity, as the Y511F mutant is catalytically inactive. Baculovirus co-expression, in vitro kinase assay with recombinant proteins, site-directed mutagenesis The Journal of biological chemistry High 9312162
1997 Src-induced activation of ITK requires PI3-kinase activity and the pleckstrin homology domain of ITK; the PH domain binds D3-phosphorylated inositol phosphates, and membrane targeting of ITK without the PH domain rescues Src-induced activation, demonstrating that PH-domain-mediated membrane recruitment is the critical step. Coexpression in COS cells, PI3K inhibitor treatment, PH domain deletion and membrane-targeting mutants, membrane fractionation Proceedings of the National Academy of Sciences of the United States of America High 9326591
1997 The Itk SH3 domain forms an inducible complex with CD28 mediated by the N-terminal diproline motif of CD28; site-directed mutagenesis of the N-terminal diproline abolishes the association, and N-terminal diproline peptides activate Itk kinase activity to levels similar to CD28 cross-linking. Co-immunoprecipitation, site-directed mutagenesis of CD28 diproline motifs, peptide competition, in vitro kinase assay Journal of immunology High 9317120
1997 Itk negatively regulates CD28-mediated T-cell proliferation: Itk-deficient T cells show severely compromised CD3-mediated proliferation but significantly elevated CD28 co-stimulatory proliferative responses, indicating Itk has distinct roles in CD3 versus CD28 signaling pathways. Knockout mouse T-cell proliferation assays with anti-CD3 and anti-CD28 stimulation The Journal of experimental medicine Medium 9221751
1997 Itk is required for CD2-mediated IL-2 promoter activation and NFAT activation in Jurkat T cells; kinase-inactive Itk mutant expression reduces IL-2 promoter activity and NFAT activation downstream of CD2, TCR/CD3, and CD28 stimulation. Transient transfection of kinase-dead Itk mutant, IL-2 promoter-luciferase reporter assay, NFAT activation assay European journal of immunology Medium 9130632
1998 Itk-deficient T cells release normal calcium from intracellular stores upon TCR stimulation but fail to open plasma membrane calcium channels; TCR-induced IP3 generation and PLC-γ1 tyrosine phosphorylation are substantially reduced, while TCR-ζ and ZAP-70 are phosphorylated normally, establishing that Itk functions downstream of or in parallel to ZAP-70 to facilitate IP3 production and capacitative calcium entry. Calcium flux measurement (fura-2), thapsigargin treatment, IP3 measurement, phosphotyrosine Western blot in Itk-/- T cells The Journal of experimental medicine High 9584150
1999 Combined deletion of Tec kinases Rlk and Itk causes marked defects in TCR-induced proliferation, cytokine production, apoptosis, and adaptive immune responses; molecular events immediately downstream of TCR are intact, but intermediate events including IP3 production, calcium mobilization, and MAP kinase activation are impaired, establishing Tec kinases as critical regulators of PLC-γ activation. Double-knockout mice, in vitro T-cell assays (proliferation, cytokine), IP3 measurement, calcium flux, ERK activation, in vivo Toxoplasma gondii infection model Science High 10213685
1999 A novel adaptor protein RIBP, identified by yeast two-hybrid screening, physically interacts with both Itk and Rlk/Txk; RIBP-knockout mice show impaired TCR-induced T-cell proliferation and defective IL-2 and IFN-γ but not IL-4 production, linking RIBP-Itk interaction to TCR signal transduction. Yeast two-hybrid screen, co-immunoprecipitation, knockout mouse with T-cell functional assays The Journal of experimental medicine Medium 10587356
1999 ITK associates with PLC-γ1 in a TCR/CD3-regulated manner in T cells; before activation, the Itk SH3 domain mediates constitutive association with PLC-γ1, while after TCR stimulation the Itk SH2 domain dominates the enhanced interaction; the PLC-γ1 SH3 domain (but not PLC-γ1 SH2 domains) contributes to the complex. Co-immunoprecipitation with domain-specific antibodies and domain deletion mutants in Jurkat and primary T cells Journal of immunology Medium 10586033
1999 Itk co-localizes with TCR/CD3 at the membrane upon CD3ε engagement; deletion of the Itk PH domain abolishes membrane association, activation-induced co-localization with TCR, and subsequent tyrosine phosphorylation; replacing the PH domain with an Lck membrane-targeting sequence restores membrane targeting and co-localization but not activation-induced tyrosine phosphorylation, demonstrating the PH domain has an additional function beyond membrane targeting in enabling Itk phosphorylation. Laser scanning confocal microscopy, PH domain deletion mutants, chimeric membrane-targeted Itk constructs Journal of immunology Medium 10570288
2000 Itk PH domain directs constitutive association with buoyant membrane rafts enriched in Lck and LAT; the Itk proline-rich region binds Grb2 and LAT; the Itk SH3 and SH2 domains cooperatively interact with Syk-phosphorylated SLP-76; SLP-76 contains a predicted SH2 binding motif and binds full-length Itk in vitro; kinase-inactive Itk inhibits SLP-76-dependent NFAT activation, implicating multivalent interactions recruiting Itk to LAT-nucleated signaling complexes. Membrane fractionation, co-immunoprecipitation, SH2/SH3 domain binding assays, in vitro binding, NFAT reporter assay The Journal of biological chemistry High 10636929
2001 Itk SH3 domain interacts with karyopherin α (Rch1α) via its proline-rich motif; TCR-CD3 stimulation increases Itk/Rch1α complex formation and recruits karyopherin β; recombinant Itk (but not Lck, ZAP-70, or Jak3) efficiently phosphorylates Rch1α in vitro; Itk shows constitutive nuclear localization that is upregulated by TCR stimulation or Rch1α overexpression; a Rch1α P242A mutant abolishes the interaction and reduces Itk nuclear localization and TCR-induced IL-2 production. Co-immunoprecipitation, in vitro kinase assay with GST-fusion proteins, mutagenesis, immunofluorescence subcellular localization, IL-2 production assay International immunology Medium 11581171
2001 Noncatalytic domains of Itk contribute to enzymatic activity: deletion of the PH/TH domain reduces catalytic activity ~10-fold; mutation of the proline-rich domain (P158A,P159A) reduces activity ~100-fold; the kinase domain alone is essentially inactive, demonstrating that N-terminal domains are required for efficient catalysis by affecting turnover rate rather than substrate binding. Recombinant protein expression and purification, steady-state kinetic analysis (kcat, Km), in vitro kinase assay with SAM68 substrate Protein expression and purification High 11437596
2002 Cyclophilin A (CypA) inhibits Itk catalytic activity through its peptidyl-prolyl isomerase activity; NMR structural studies show a proline-dependent conformational switch in the Itk SH2 domain regulates substrate recognition and mediates interaction with CypA; CypA and Itk form a stable complex in Jurkat T cells that is disrupted by cyclosporin A; cyclosporin A treatment increases phosphorylation of Itk and its substrate PLC-γ1. NMR spectroscopy, mutagenesis, co-immunoprecipitation from Jurkat cells, cyclosporin A treatment, phosphorylation Western blot Proceedings of the National Academy of Sciences of the United States of America High 11830645
2002 Itk is required for efficient NKT cell maturation; Itk-deficient mice have reduced NKT cell numbers with a predominantly immature phenotype, and progressive decrease of NKT cells in older mice, establishing a role for Itk in NKT cell development and peripheral maintenance. CD1d tetramer staining, flow cytometry, Itk-/- mice Journal of immunology Medium 12193707
2002 Absence of Itk impairs positive thymic selection at multiple stages but does not affect CD4/CD8 lineage commitment; fewer TCR transgenic T cells develop without Itk, but those that do appear normal in lineage markers. Itk-/- mice crossed to TCR transgenic lines on multiple MHC backgrounds, flow cytometry Journal of immunology Medium 12055226
2003 Itk autophosphorylates at Tyr-180 in the SH3 domain; mutation of either the trans-phosphorylation site (Y511F) or the autophosphorylation site (Y180F) impairs full restoration of cytokine production and ERK activation in Itk-deficient primary T cells; an SH3 point mutant unable to bind ligand also fails to restore function, demonstrating both phosphorylation events and SH3 ligand binding are required for Itk function. Retroviral transduction of Itk point mutants into Itk-/- primary T cells, cytokine production assay, ERK activation Western blot The Journal of biological chemistry High 12842872
2004 Selective small-molecule ITK inhibitors (BMS-488516 and BMS-509744) potently inhibit Itk kinase activity and reduce TCR-induced PLC-γ1 tyrosine phosphorylation, calcium mobilization, IL-2 secretion, and T-cell proliferation in human and mouse cells; BMS-509744 reduces lung inflammation in an ovalbumin mouse asthma model, validating ITK as a target downstream of PLCγ in TCR signaling. In vitro kinase assay, biochemical T-cell signaling assays (PLCγ1 phosphorylation, calcium flux), IL-2 ELISA, proliferation assay, in vivo mouse asthma model Biochemistry High 15323564
2004 Itk signaling promotes Th2 differentiation by negatively regulating T-bet expression; in the absence of skewing cytokines with low-avidity ligands, wild-type T cells preferentially express GATA-3 and become Th2, while Itk-/- T cells produce T-bet and become IFN-γ-producing cells; Itk expression is upregulated during Th2 differentiation while Rlk disappears from Th2 cells. Itk-/- mice, in vitro T-cell differentiation assays, cytokine measurement, RT-PCR for T-bet and GATA-3 Immunity Medium 15345221
2004 ITK is activated by CXCL12/SDF-1α stimulation through CXCR4 via Src and PI3K activities; ITK regulates CXCR4-mediated T-cell migration and adhesion by altering actin polymerization, as ITK-null T cells show defective CXCL12-induced actin polymerization, migration, and adhesion. Kinase activation assay, Src and PI3K inhibitors, migration assay, adhesion assay, actin polymerization assay in Itk-/- T cells The Journal of biological chemistry Medium 15123627
2005 Itk has a kinase-independent scaffolding function in TCR-induced actin polarization; siRNA-mediated knockdown of Itk or expression of kinase-inactive Itk rescues actin polarization defect; PH domain and SH2 domain mutations abolish this activity; Itk is constitutively associated with Vav and loss of Itk disrupts Vav localization to the immune synapse and Vav-SLP-76 interactions without altering bulk Vav tyrosine phosphorylation; membrane-targeted Vav-CAAX rescues the actin polarization defect. siRNA knockdown, kinase-dead mutant rescue, confocal microscopy for actin polarization, co-immunoprecipitation, membrane-targeted Vav-CAAX rescue experiment Journal of immunology High 15661896
2006 Itk and Rlk deficiency causes CD8+ single-positive thymocytes and peripheral CD8+ T cells to acquire an innate-like phenotype (CD44hi, CD122+, NK1.1+, rapid IFN-γ production, IL-15-dependent, eomesodermin-expressing); expression of a hypersensitive ERK2 mutant partially corrects CD8+ T cell phenotypes in Itk-/- mice, establishing that altered Tec kinase signaling allows development of innate-type CD8+ cells. Itk-/- and Rlk-/-Itk-/- mice, flow cytometry, cytokine production, hematopoietic chimeras, hypersensitive ERK2 transgene rescue Immunity High 16860759 16860760
2006 The t(5;9)(q33;q22) translocation found in 17% of unspecified PTCL fuses the N-terminal PH domain and proline-rich region of ITK to the tyrosine kinase domain of SYK, creating an ITK-SYK fusion kinase that drives oncogenesis. Molecular cytogenetics (FISH), RT-PCR, sequencing of breakpoints in patient samples Leukemia Medium 16341044
2006 Itk forms membrane clusters of at least two molecules within 80 Å upon membrane recruitment via its PH domain; clustering requires PH domain integrity but not the proline-rich region, SH3, SH2 domains, or kinase activity; these clusters form specifically in membrane regions co-occupied by receptors that recruit PI3K. FRET microscopy, domain deletion mutants, membrane fractionation The Journal of biological chemistry Medium 17060314
2006 NMR structure of the Itk SH2 domain bound to a phosphotyrosine peptide reveals that prolyl cis/trans isomerization controls two distinct SH2 conformers; the trans conformer preferentially binds the phosphopeptide; the BG loop in the free trans conformer is pre-arranged for pY+3 contacts; pY binding propagates structural changes to the CD loop and αB helix, providing the structural basis for CypA-regulated conformational switching. NMR spectroscopy, trans-hydrogen bond scalar coupling analysis, structure determination Journal of molecular biology High 16436281
2007 SLP-76 is required for TCR-induced tyrosine phosphorylation and activation of ITK (but not ZAP-70); ITK specifically and efficiently phosphorylates PLC-γ1 at Y783 and Y775 in vitro whereas ZAP-70 does not; a fraction of active ITK binds SLP-76 in stimulated cells, and catalytic activity is lost upon mild elution from the SLP-76 complex but restored upon reconstitution, establishing that ongoing SLP-76 association is required to maintain ITK in an active conformation. In vitro kinase assay with recombinant proteins (ITK vs ZAP-70 side-by-side), co-immunoprecipitation from TCR-stimulated cells, complex elution and reconstitution, SLP-76 mutant analysis Proceedings of the National Academy of Sciences of the United States of America High 17420479
2007 Itk differentially regulates distinct NK cell-activating pathways in a catalytic-activity-dependent manner: enhanced Itk expression increases calcium mobilization, granule release, and cytotoxicity via the ITAM-containing FcR, but decreases cytotoxicity and granule release downstream of the NKG2D receptor; a kinase-dead Itk mutant abolishes both effects. Itk overexpression and knockdown in human NK cells, cytotoxicity assays, calcium flux, granule release assay, kinase-dead mutant Journal of immunology Medium 17339454
2008 Loss of ITK function (via ITK-specific siRNA, kinase-inactive mutant, or ITK inhibitor) markedly reduces intracellular HIV p24 levels; ITK inhibition partially blocks HIV viral entry (correlating with decreased actin polarization to gp120) and reduces HIV transcription; overexpression of ITK increases viral transcription and virus-like particle formation; ITK does not affect CD4 or CXCR4 expression. siRNA knockdown, kinase-inactive ITK mutant, ITK inhibitor, HIV infection assay, p24 ELISA, actin polarization imaging, viral transcription assay Proceedings of the National Academy of Sciences of the United States of America Medium 18443296
2009 NMR structure of the binary Itk SH3/SH2 complex reveals a nonclassical interaction independent of phosphotyrosine motifs and proline-rich sequences; the higher-affinity cis SH2 conformer (controlled by prolyl isomerization) is preorganized to form a hydrophobic interface with the SH3 domain; autophosphorylation in the Itk SH3 domain is predicted to increase intermolecular SH3/SH2 affinity. NMR spectroscopy, structure determination of SH3/SH2 binary complex Journal of molecular biology High 19361414
2009 Itk phosphorylation and activation of PLC-γ1 requires a direct phosphotyrosine-independent docking interaction between the Itk kinase domain and the nSH2 domain of PLC-γ1; disruption of this docking interface by mutagenesis attenuates T-cell signaling. NMR spectroscopy, mutagenesis of docking interface, T-cell signaling assays Proceedings of the National Academy of Sciences of the United States of America High 19955438
2009 Itk signaling in γδ T cells controls IgE production in vivo; Itk-/- γδ T cells produce high levels of Th2 cytokines when stimulated through the γδ TCR; Itk-/-Tcrd-/- mice have normal IgE levels; activated Itk-/- γδ T cells upregulate costimulatory molecules for B cell help; increased Vγ1.1+Vδ6.3+ γδ NKT cells with increased PLZF expression are found in Itk-/- mice. Itk-/- and Itk-/-Tcrd-/- mice, serum IgE measurement, γδ T cell isolation and stimulation, cytokine assay, flow cytometry Proceedings of the National Academy of Sciences of the United States of America Medium 19416854
2010 ITK-SYK fusion kinase constitutively associates with lipid rafts in T cells and triggers antigen-independent phosphorylation of TCR-proximal signaling proteins, leading to activation of downstream pathways that mimic regular TCR ligation (CD69 upregulation, IL-2 production in vitro, thymocyte deletion and T-cell activation in vivo); conditional expression in mice induces highly malignant PTCL with 100% penetrance. Lipid raft fractionation, phosphorylation assays, in vitro T-cell activation assays, conditional transgenic mouse model The Journal of experimental medicine High 20439541
2010 ITK-SYK-induced T-cell lymphoproliferative disease in mice requires SYK kinase activity; membrane localization of ITK-SYK via its PH domain is not required for disease development (PH domain R29C mutant enhances rather than abolishes disease); CBL binding to membrane-associated ITK-SYK (E42K mutant) delays disease development. Bone marrow transplantation model, SYK kinase inhibitor treatment, point mutants (R29C, E42K) in mouse disease model Cancer research Medium 20670954
2011 Loss of Itk alters the spatiotemporal distribution of 14 of 16 signaling sensors at the T cell–APC interface; Cdc42 activation at the center of the interface is impaired (total active Cdc42 unchanged); reconstitution with interface-targeted active Cdc42 restores actin accumulation in Itk-/- T cells; Itk controls central localization of SLAT, which contributes to Cdc42 activation at the interface. Live-cell imaging with signaling biosensors/sensors, Itk-/- mice, targeted active Cdc42 rescue construct, confocal microscopy Science signaling High 21971040
2011 Itk and Btk double-knockout mast cells show severely impaired FcεRI-induced degranulation and cytokine secretion, with significant reduction in PLC-γ2 phosphorylation, impaired calcium responses, and altered NFAT1 nuclear localization; network analysis suggests Itk plays both positive and negative roles while Btk primarily plays a positive role in mast cell FcεRI cytokine secretion. Itk/Btk double-KO mice, BMMC generation, degranulation assay, cytokine ELISA, calcium flux, PLC-γ2 phosphorylation Western blot, NFAT1 nuclear localization imaging The Journal of biological chemistry High 21212279
2012 The Itk PH domain binds most prominently to phosphatidylinositol monophosphates (PI(3)P, PI(4)P, PI(5)P) and to a lesser extent to PIP2 and PIP3; an ITK R29H patient mutation (in the PH domain) dramatically reduces these phosphoinositide interactions, abolishes rescue of calcium flux in Itk-/- T cells, and reduces protein half-life. Lipid binding assay (phosphoinositide strips/liposome binding), calcium flux rescue assay in Itk-/- T cells, pulse-chase protein stability assay Leukemia Medium 22289921
2012 ITK signaling promotes IRF4 upregulation in CD8+ T cells following TCR stimulation; ITK inhibitor treatment impairs IRF4 induction; in IRF4-deficient CD8+ T cells, TCR activation leads to rapid Eomesodermin upregulation (further enhanced by IL-4), establishing that ITK-IRF4 signaling normally suppresses Eomes and regulates conventional vs innate CD8+ T-cell fate. Small-molecule ITK inhibitor, IRF4-knockout mice, ITK inhibitor treatment, flow cytometry and RT-PCR for IRF4 and Eomes expression Proceedings of the National Academy of Sciences of the United States of America Medium 23011795
2013 Ibrutinib irreversibly inhibits ITK in T cells (in addition to BTK in B cells); ibrutinib treatment drives a Th1-selective pressure by ablating Th2 immunity; ITK is confirmed as a covalent irreversible target of ibrutinib in T cells using clinical trial samples and disease models. In silico docking, biochemical kinase assays, molecular analysis of T cells from ibrutinib clinical trial patients, Leishmania and Listeria infection models Blood High 23886836
2013 CD28 and ITK signals regulate autoreactive T-cell trafficking to tissues; loss of ITK in Ctla4-/- mice does not block T-cell activation but causes self-reactive T cells to accumulate in secondary lymphoid organs instead of entering tissues; ITK inhibitors phenocopy the null mutant and prevent pancreatic islet infiltration by diabetogenic T cells. Itk-/-;Ctla4-/- double-knockout mice, adoptive transfer, ITK inhibitor treatment in type 1 diabetes mouse model, tissue histology Nature medicine High 24270545
2014 Itk deficiency increases sensitivity to IL-2 signaling and skews CD4+ T-cell differentiation toward Foxp3+ Treg cells; Itk-/- T cells show reduced TCR-induced mTOR target phosphorylation and impaired mTOR activation by IL-2; TCR stimulation normally represses Pten in a dose-dependent manner, but in the absence of Itk, Pten is not repressed, uncoupling STAT5 and PI3K signaling; Itk-deficient cells show impaired TCR-mediated induction of Myc and miR-19b (known Pten repressors). Itk-/- mice, in vitro Th17/Treg differentiation, mTOR target phosphorylation (S6K, 4EBP1), STAT5 phosphorylation, Pten expression, Myc/miR-19b expression, in vivo Treg development The Journal of experimental medicine High 24534190
2015 PRN694 covalently binds to Cys442 of ITK (and Cys350 of RLK) in the kinase domain, blocking kinase activity with extended target residence time; it prevents TCR- and Fc receptor-induced cellular activation, inhibits T-cell proliferation, blocks proinflammatory cytokine release, inhibits Th17 cell activation, and shows in vivo pharmacodynamic effects reducing delayed-type hypersensitivity. Molecular modeling, biochemical kinase assay, cysteine-targeting covalent binding characterization, in vitro T-cell functional assays, ex vivo T-PLL cell assays, in vivo DTH model The Journal of biological chemistry High 25593320
2016 Itk is required for Th9 differentiation via TCR-mediated induction of IL-2 and IRF4; Itk-/- CD4+ T cells under Th9 conditions fail to produce IL-9 and have reduced IRF4 levels; IL-9 and IRF4 expression are rescued by exogenous IL-2 or constitutively active STAT5 but not NFATc1; STAT5 binds the Irf4 promoter; Itk inhibition also reduces IL-9 expression in human T cells. Itk-/- mice, Th9 in vitro differentiation, cytokine measurement, STAT5 ChIP at Irf4 promoter, constitutively active STAT5 rescue, ITK inhibitor in human T cells, mouse asthma model Nature communications High 26936133
2016 TCR signaling activates an ITK-NF-κB-GATA-3 axis that promotes chemotherapy resistance in T-cell lymphomas; pharmacological inhibition of ITK prevents activation of this signaling axis and overcomes chemotherapy resistance. Genetic and pharmacological inhibition of ITK in primary T-cell lymphoma cells and patient-derived cell lines, NF-κB and GATA-3 activation assays, chemotherapy resistance assays Clinical cancer research Medium 27780854
2017 ITK signaling through the Ras/IRF4 pathway is required for functional Tr1 cell development; ITK kinase activity is required for mouse and human Tr1 differentiation; expression of constitutively active HRas rescues IRF4 expression and Tr1 differentiation in Itk-/- cells; IRF4 expression also rescues Tr1 suppressive function in Itk-/- cells. Itk-/- mice, in vitro and in vivo Tr1 differentiation, constitutively active HRas rescue, IRF4 rescue, ITK kinase inhibitor in human T cells Nature communications High 28635957
2021 ITK preferentially aids NF-κB activation downstream of the TCR; NF-κB shows dynamic graded activation in response to TCR signal strength that is dampened by ITK inhibitor; ITK inhibitor-treated cells show reduced AP-1 factors (Fos, Fosb), NF-κB response gene transcripts, and IL-2 transcripts; ATAC-seq shows ITK-sensitive genomic regions are enriched for NF-κB and AP-1 motifs; NFAT1 and Erk1/2 activation is digital and less sensitive to ITK inhibition. ITK inhibitor treatment, single-cell nuclear NFAT1/NF-κB/Erk1/2 imaging, ATAC-seq, gene expression analysis in naïve CD8+ OT-I cells Proceedings of the National Academy of Sciences of the United States of America High 34452995
2024 TNF-α released by activated human naïve CD4+ T cells stimulates metabolic reprogramming (increased glycolysis, amino acid uptake, glutamine oxidation, mitochondrial biogenesis) through ITK-mediated activation of Akt-mTOR signaling, independently of NF-κB; TNF-α also drives Th1 and Th17 but not Treg differentiation via this ITK-Akt-mTOR axis. Human naïve CD4+ T-cell activation assays, ITK inhibitor, Akt phosphorylation measurement, metabolic flux analysis, T-cell differentiation assays, RA patient samples Science signaling Medium 38652761

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood 690 23886836
1999 Requirement for Tec kinases Rlk and Itk in T cell receptor signaling and immunity. Science (New York, N.Y.) 311 10213685
1992 itk, a T-cell-specific tyrosine kinase gene inducible by interleukin 2. Proceedings of the National Academy of Sciences of the United States of America 255 1280821
1998 T cell receptor-initiated calcium release is uncoupled from capacitative calcium entry in Itk-deficient T cells. The Journal of experimental medicine 254 9584150
1995 Altered T cell receptor signaling and disrupted T cell development in mice lacking Itk. Immunity 253 8777721
2001 The Tec family of cytoplasmic tyrosine kinases: mammalian Btk, Bmx, Itk, Tec, Txk and homologs in other species. BioEssays : news and reviews in molecular, cellular and developmental biology 238 11340625
2002 Regulation of the tyrosine kinase Itk by the peptidyl-prolyl isomerase cyclophilin A. Proceedings of the National Academy of Sciences of the United States of America 234 11830645
2000 Biochemical interactions integrating Itk with the T cell receptor-initiated signaling cascade. The Journal of biological chemistry 215 10636929
2010 T-cell signaling regulated by the Tec family kinase, Itk. Cold Spring Harbor perspectives in biology 214 20519342
1994 CD28 is associated with and induces the immediate tyrosine phosphorylation and activation of the Tec family kinase ITK/EMT in the human Jurkat leukemic T-cell line. Proceedings of the National Academy of Sciences of the United States of America 213 7524075
2006 Novel t(5;9)(q33;q22) fuses ITK to SYK in unspecified peripheral T-cell lymphoma. Leukemia 201 16341044
1994 BMX, a novel nonreceptor tyrosine kinase gene of the BTK/ITK/TEC/TXK family located in chromosome Xp22.2. Oncogene 171 7970727
2014 Itk-mediated integration of T cell receptor and cytokine signaling regulates the balance between Th17 and regulatory T cells. The Journal of experimental medicine 163 24534190
2006 Altered development of CD8+ T cell lineages in mice deficient for the Tec kinases Itk and Rlk. Immunity 159 16860760
1995 p56Lck and p59Fyn regulate CD28 binding to phosphatidylinositol 3-kinase, growth factor receptor-bound protein GRB-2, and T cell-specific protein-tyrosine kinase ITK: implications for T-cell costimulation. Proceedings of the National Academy of Sciences of the United States of America 158 7568038
2006 The Tec family tyrosine kinases Itk and Rlk regulate the development of conventional CD8+ T cells. Immunity 154 16860759
1996 Identification of Itk/Tsk Src homology 3 domain ligands. The Journal of biological chemistry 150 8810341
1997 Src-induced activation of inducible T cell kinase (ITK) requires phosphatidylinositol 3-kinase activity and the Pleckstrin homology domain of inducible T cell kinase. Proceedings of the National Academy of Sciences of the United States of America 146 9326591
2004 Signaling through Itk promotes T helper 2 differentiation via negative regulation of T-bet. Immunity 138 15345221
1997 Lck phosphorylates the activation loop tyrosine of the Itk kinase domain and activates Itk kinase activity. The Journal of biological chemistry 138 9312162
2010 The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma. The Journal of experimental medicine 120 20439541
2002 NK T cell precursors exhibit differential cytokine regulation and require Itk for efficient maturation. Journal of immunology (Baltimore, Md. : 1950) 117 12193707
2009 Tec kinase Itk in gammadeltaT cells is pivotal for controlling IgE production in vivo. Proceedings of the National Academy of Sciences of the United States of America 113 19416854
2009 Tec kinases regulate T-lymphocyte development and function: new insights into the roles of Itk and Rlk/Txk. Immunological reviews 112 19290923
2005 Kinase-independent functions for Itk in TCR-induced regulation of Vav and the actin cytoskeleton. Journal of immunology (Baltimore, Md. : 1950) 108 15661896
2012 Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases. Leukemia 100 22289921
2004 Selective Itk inhibitors block T-cell activation and murine lung inflammation. Biochemistry 98 15323564
2008 The Tec kinases Itk and Rlk regulate NKT cell maturation, cytokine production, and survival. Journal of immunology (Baltimore, Md. : 1950) 94 18292523
2012 TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8+ T-cell differentiation. Proceedings of the National Academy of Sciences of the United States of America 83 23011795
1995 Activation and interaction with protein kinase C of a cytoplasmic tyrosine kinase, Itk/Tsk/Emt, on Fc epsilon RI cross-linking on mast cells. Journal of immunology (Baltimore, Md. : 1950) 83 7561053
2014 Interleukin-2-inducible T-cell kinase (ITK) deficiency - clinical and molecular aspects. Journal of clinical immunology 82 25339095
2015 Inhibition of BTK and ITK with Ibrutinib Is Effective in the Prevention of Chronic Graft-versus-Host Disease in Mice. PloS one 80 26348529
2016 Itk is required for Th9 differentiation via TCR-mediated induction of IL-2 and IRF4. Nature communications 79 26936133
2007 Differential regulation of human NK cell-mediated cytotoxicity by the tyrosine kinase Itk. Journal of immunology (Baltimore, Md. : 1950) 75 17339454
2007 SLP-76 mediates and maintains activation of the Tec family kinase ITK via the T cell antigen receptor-induced association between SLP-76 and ITK. Proceedings of the National Academy of Sciences of the United States of America 73 17420479
2004 Expression and function of Tec, Itk, and Btk in lymphocytes: evidence for a unique role for Tec. Molecular and cellular biology 73 14993283
2006 ITK and IL-15 support two distinct subsets of CD8+ T cells. Proceedings of the National Academy of Sciences of the United States of America 72 16880398
1999 RIBP, a novel Rlk/Txk- and itk-binding adaptor protein that regulates T cell activation. The Journal of experimental medicine 72 10587356
2017 ITK signalling via the Ras/IRF4 pathway regulates the development and function of Tr1 cells. Nature communications 65 28635957
2003 Itk phosphorylation sites are required for functional activity in primary T cells. The Journal of biological chemistry 65 12842872
2009 The Tec kinases Itk and Rlk regulate conventional versus innate T-cell development. Immunological reviews 64 19290924
2004 Regulation of CXC chemokine receptor 4-mediated migration by the Tec family tyrosine kinase ITK. The Journal of biological chemistry 64 15123627
2011 Tec family kinases Itk and Rlk / Txk in T lymphocytes: cross-regulation of cytokine production and T-cell fates. The FEBS journal 63 21362139
2013 Inhibitors of BTK and ITK: state of the new drugs for cancer, autoimmunity and inflammatory diseases. Scandinavian journal of immunology 60 23672610
2008 Selective targeting of ITK blocks multiple steps of HIV replication. Proceedings of the National Academy of Sciences of the United States of America 60 18443296
2010 The ITK-SYK fusion oncogene induces a T-cell lymphoproliferative disease in mice mimicking human disease. Cancer research 57 20670954
2020 Role of the IL-2 inducible tyrosine kinase ITK and its inhibitors in disease pathogenesis. Journal of molecular medicine (Berlin, Germany) 56 32808093
2016 Fragment Molecular Orbital Method Applied to Lead Optimization of Novel Interleukin-2 Inducible T-Cell Kinase (ITK) Inhibitors. Journal of medicinal chemistry 56 26950250
2007 A key role for Itk in both IFN gamma and IL-4 production by NKT cells. Journal of immunology (Baltimore, Md. : 1950) 55 17579028
2009 ITK inhibitors in inflammation and immune-mediated disorders. Current topics in medicinal chemistry 53 19689375
2020 Concomitant overexpression of mir-182-5p and mir-182-3p raises the possibility of IL-17-producing Treg formation in breast cancer by targeting CD3d, ITK, FOXO1, and NFATs: A meta-analysis and experimental study. Cancer science 52 33283362
1997 The SH3 domain of Itk/Emt binds to proline-rich sequences in the cytoplasmic domain of the T cell costimulatory receptor CD28. Journal of immunology (Baltimore, Md. : 1950) 52 9317120
2016 T-cell Receptor Signaling Activates an ITK/NF-κB/GATA-3 axis in T-cell Lymphomas Facilitating Resistance to Chemotherapy. Clinical cancer research : an official journal of the American Association for Cancer Research 51 27780854
2006 Discovery and SAR of 2-amino-5-(thioaryl)thiazoles as potent and selective Itk inhibitors. Bioorganic & medicinal chemistry letters 50 16682193
2011 Itk controls the spatiotemporal organization of T cell activation. Science signaling 45 21971040
1999 Regulated association between the tyrosine kinase Emt/Itk/Tsk and phospholipase-C gamma 1 in human T lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 45 10586033
2015 Targeting interleukin-2-inducible T-cell kinase (ITK) and resting lymphocyte kinase (RLK) using a novel covalent inhibitor PRN694. The Journal of biological chemistry 43 25593320
2002 The absence of Itk inhibits positive selection without changing lineage commitment. Journal of immunology (Baltimore, Md. : 1950) 43 12055226
2003 Rosmarinic acid inhibits Ca2+-dependent pathways of T-cell antigen receptor-mediated signaling by inhibiting the PLC-gamma 1 and Itk activity. Blood 42 12511421
1999 Emt/Itk associates with activated TCR complexes: role of the pleckstrin homology domain. Journal of immunology (Baltimore, Md. : 1950) 41 10570288
2021 Hierarchy of signaling thresholds downstream of the T cell receptor and the Tec kinase ITK. Proceedings of the National Academy of Sciences of the United States of America 40 34452995
2006 Tec kinases Itk and Rlk are required for CD8+ T cell responses to virus infection independent of their role in CD4+ T cell help. Journal of immunology (Baltimore, Md. : 1950) 40 16424186
1997 Antiviral immune responses in Itk-deficient mice. Journal of virology 40 9311799
2019 Genetic Deficiency and Biochemical Inhibition of ITK Affect Human Th17, Treg, and Innate Lymphoid Cells. Journal of clinical immunology 39 31025232
2011 Absence of Tec family kinases interleukin-2 inducible T cell kinase (Itk) and Bruton's tyrosine kinase (Btk) severely impairs Fc epsilonRI-dependent mast cell responses. The Journal of biological chemistry 39 21212279
1997 Itk negatively regulates induction of T cell proliferation by CD28 costimulation. The Journal of experimental medicine 39 9221751
2011 Screening the PRF1, UNC13D, STX11, SH2D1A, XIAP, and ITK gene mutations in Chinese children with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Pediatric blood & cancer 38 21674762
2006 Molecular details of Itk activation by prolyl isomerization and phospholigand binding: the NMR structure of the Itk SH2 domain bound to a phosphopeptide. Journal of molecular biology 38 16436281
2015 Itk signals promote neuroinflammation by regulating CD4+ T-cell activation and trafficking. The Journal of neuroscience : the official journal of the Society for Neuroscience 37 25568116
2015 Inhibition of the kinase ITK in a mouse model of asthma reduces cell death and fails to inhibit the inflammatory response. Science signaling 37 26628680
2011 Discovery and structure-activity relationship of 3-aminopyrid-2-ones as potent and selective interleukin-2 inducible T-cell kinase (Itk) inhibitors. Journal of medicinal chemistry 37 21391610
2024 TNF-α signals through ITK-Akt-mTOR to drive CD4+ T cell metabolic reprogramming, which is dysregulated in rheumatoid arthritis. Science signaling 36 38652761
2013 CD28 and ITK signals regulate autoreactive T cell trafficking. Nature medicine 36 24270545
2009 Proline isomerization preorganizes the Itk SH2 domain for binding to the Itk SH3 domain. Journal of molecular biology 36 19361414
2011 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. The FEBS journal 35 21518255
2008 Selective expression rather than specific function of Txk and Itk regulate Th1 and Th2 responses. Journal of immunology (Baltimore, Md. : 1950) 35 18941202
1996 CD2 signaling in T cells involves tyrosine phosphorylation and activation of the Tec family kinase, EMT/ITK/TSK. International immunology 35 8943565
1997 Itk, a T cell-specific tyrosine kinase, is required for CD2-mediated interleukin-2 promoter activation in the human T cell line Jurkat. European journal of immunology 33 9130632
2021 Targeting ITK signaling for T cell-mediated diseases. iScience 31 34368657
2019 ITK inhibition induced in vitro and in vivo anti-tumor activity through downregulating TCR signaling pathway in malignant T cell lymphoma. Cancer cell international 31 30814910
2015 Lipid and Protein Co-Regulation of PI3K Effectors Akt and Itk in Lymphocytes. Frontiers in immunology 31 25821452
2015 A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression. Journal of immunology (Baltimore, Md. : 1950) 30 26466958
2008 Differential sensitivity to Itk kinase signals for T helper 2 cytokine production and chemokine-mediated migration. Journal of immunology (Baltimore, Md. : 1950) 30 18322190
2009 Itk tyrosine kinase substrate docking is mediated by a nonclassical SH2 domain surface of PLCgamma1. Proceedings of the National Academy of Sciences of the United States of America 29 19955438
2001 Characterization of Itk tyrosine kinase: contribution of noncatalytic domains to enzymatic activity. Protein expression and purification 28 11437596
2021 BTK inhibitors, irrespective of ITK inhibition, increase efficacy of a CD19/CD3-bispecific antibody in CLL. Blood 27 34046681
2008 Phylogeny of Tec family kinases identification of a premetazoan origin of Btk, Bmx, Itk, Tec, Txk, and the Btk regulator SH3BP5. Advances in genetics 27 19161832
2006 Itk and Th2 responses: action but no reaction. Trends in immunology 27 16931156
2006 Tec kinase Itk forms membrane clusters specifically in the vicinity of recruiting receptors. The Journal of biological chemistry 27 17060314
2020 Tuning T helper cell differentiation by ITK. Biochemical Society transactions 26 32049330
2018 Comparison of interleukin-2-inducible kinase (ITK) inhibitors and potential for combination therapies for T-cell lymphoma. Scientific reports 26 30242208
2011 Tec family kinases: Itk signaling and the development of NKT αβ and γδ T cells. The FEBS journal 26 21362141
2008 Discovery of potent inhibitors of interleukin-2 inducible T-cell kinase (ITK) through structure-based drug design. Bioorganic & medicinal chemistry letters 26 19111460
2007 Keeping the (kinase) party going: SLP-76 and ITK dance to the beat. Science's STKE : signal transduction knowledge environment 25 17652306
2001 Itk/Emt: a link between T cell antigen receptor-mediated Ca2+ events and cytoskeletal reorganization. Trends in immunology 25 11286686
2001 Nuclear localization of the tyrosine kinase Itk and interaction of its SH3 domain with karyopherin alpha (Rch1alpha). International immunology 25 11581171
2022 Inherited human ITK deficiency impairs IFN-γ immunity and underlies tuberculosis. The Journal of experimental medicine 24 36326697
2020 BTK/ITK dual inhibitors: Modulating immunopathology and lymphopenia for COVID-19 therapy. Journal of leukocyte biology 24 32640487
2012 Regulation of T-cell responses and disease by tec kinase Itk. International reviews of immunology 24 22449075
2010 Itk inhibitors: a patent review. Expert opinion on therapeutic patents 24 20218931

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