Affinage

ITK

Tyrosine-protein kinase ITK/TSK · UniProt Q08881

Round 2 corrected
Length
620 aa
Mass
71.8 kDa
Annotated
2026-04-28
130 papers in source corpus 25 papers cited in narrative 25 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ITK is a Tec-family non-receptor tyrosine kinase that serves as a central integrator of T-cell receptor (TCR) signaling, coupling antigen recognition to downstream effector programs including calcium mobilization, cytokine production, actin polarization, and T-cell differentiation. Activated by Lck-mediated transphosphorylation of Tyr511 upon PI3K-dependent PH-domain-mediated membrane recruitment, ITK assembles into a multivalent signaling complex with SLP-76, LAT, and Grb2 through cooperative SH3/SH2/PH domain interactions and phosphorylates PLCγ1 to drive Ca²⁺ flux and NFAT activation; its catalytic activity is negatively regulated by intramolecular SH3–proline-rich autoinhibition and cyclophilin A-mediated prolyl isomerization of the SH2 domain (PMID:9312162, PMID:10636929, PMID:8985255, PMID:11830645). ITK also performs a kinase-independent scaffolding function by constitutively associating with Vav to direct actin polarization at the immunological synapse, and controls conventional versus innate T-cell lineage commitment, Th2/Th17 cytokine production, Tr1 cell development via the Ras/IRF4 axis, and autoreactive T-cell trafficking to target tissues (PMID:15661896, PMID:19290924, PMID:28635957, PMID:24270545). Loss-of-function mutations in ITK cause fatal EBV-associated lymphoproliferative disease in humans, with absent NKT cells phenocopying the murine knockout (PMID:19425169, PMID:22289921).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1995 Medium

    The identification that Gβγ subunits stimulate ITK kinase activity raised the possibility that ITK integrates signals from heterotrimeric G proteins in addition to receptor tyrosine kinases.

    Evidence Co-transfection and in vitro reconstitution with purified bovine brain Gβγ subunits and immunoprecipitated ITK

    PMID:7567982

    Open questions at the time
    • Single-lab finding not independently replicated
    • Physiological relevance of Gβγ–ITK coupling in primary T cells not established
    • No identification of upstream GPCR
  2. 1996 High

    Mapping the SH3 domain interactome (Sam68, WASP, Grb2, Cbl, Fyn) established ITK as a multi-partner signaling hub whose SH3 domain engages distinct proline-rich effectors upon TCR stimulation.

    Evidence Phage display motif definition and SH3 pulldown from TCR-stimulated Jurkat lysates

    PMID:8810341

    Open questions at the time
    • Functional consequence of each individual SH3 interaction not dissected
    • Relative affinities and competitive binding in vivo unknown
  3. 1997 High

    Three foundational discoveries resolved ITK activation and autoinhibition: NMR revealed the first intramolecular SH3–proline-rich autoinhibitory interaction in a Tec kinase; reconstitution showed Lck transphosphorylates Tyr511 to activate ITK; and Itk-knockout mice demonstrated a non-redundant requirement for optimal antiviral CTL responses.

    Evidence Multidimensional NMR structure with competitive binding assays; baculovirus co-expression with Y511F mutagenesis and in vitro kinase assay; Itk⁻/⁻ mice with LCMV/vaccinia/VSV infection and IL-2 rescue

    PMID:8985255 PMID:9311799 PMID:9312162

    Open questions at the time
    • Full-length structural model of autoinhibited ITK not available
    • Whether Lck is the sole activating kinase in vivo undetermined
    • Mechanism by which ITK loss reduces CTL responses beyond IL-2 signaling not resolved
  4. 1999 High

    The demonstration that ITK's SH2 domain selectively binds phospho-SLP-76 linked ITK recruitment to the adaptor scaffold required for PLCγ phosphorylation and Ca²⁺ mobilization.

    Evidence SH2 domain binding assays and co-immunoprecipitation from activated T-cell lysates

    PMID:10556826

    Open questions at the time
    • Stoichiometry and dynamics of the ITK–SLP-76 complex in living cells not measured
    • Contribution of other SLP-76-binding kinases not delineated
  5. 2000 High

    Membrane recruitment was mechanistically resolved: the PH domain targets ITK to PIP₃-enriched lipid rafts containing Lck and LAT, and PTEN opposes this localization—establishing PI3K/PTEN as upstream regulators of ITK spatial activation. Concurrently, cooperative multivalent interactions (PH–PIP₃, proline-rich–Grb2/LAT, SH3/SH2–SLP-76) were shown to assemble ITK into the TCR signalosome, with kinase-dead ITK acting as a dominant negative for NFAT activation.

    Evidence Subcellular fractionation with PTEN re-expression and PI3K inhibition; co-IP and in vitro binding with domain mutants and NFAT reporter assay

    PMID:10636929 PMID:10958690

    Open questions at the time
    • Quantitative contribution of each multivalent interaction to complex stability unmeasured
    • Real-time imaging of ITK membrane dynamics not performed
  6. 2002 High

    The discovery that cyclophilin A inhibits ITK through prolyl isomerization of the SH2 domain introduced a novel post-translational regulatory mechanism and provided an unexpected link between ITK regulation and cyclosporin A pharmacology.

    Evidence NMR structural analysis of the SH2 proline switch, co-IP from Jurkat cells, cyclosporin A disruption of CypA–ITK complex with increased PLCγ1 phosphorylation

    PMID:11830645

    Open questions at the time
    • In vivo contribution of CypA to ITK regulation versus calcineurin inhibition by cyclosporin A not separated
    • Whether other peptidyl-prolyl isomerases regulate ITK is unknown
  7. 2005 High

    Separation of kinase-dependent and kinase-independent functions was achieved: ITK scaffolds Vav recruitment to the immunological synapse via PH and SH2 domains to direct actin polarization independently of its catalytic activity.

    Evidence siRNA knockdown with rescue by wild-type versus kinase-dead and domain-mutant ITK constructs; Vav-CAAX rescue of actin polarization

    PMID:15661896

    Open questions at the time
    • How ITK's scaffolding and kinase functions are temporally coordinated is unresolved
    • Structural basis of the constitutive ITK–Vav interaction undefined
  8. 2009 High

    ITK was established as a master regulator of T-cell lineage fate: Itk⁻/⁻ mice show expansion of innate-like T cells (NKT, γδ) at the expense of conventional αβ T cells, indicating that ITK-dependent TCR signal strength determines the conventional versus innate lineage decision. Simultaneously, human genetics proved ITK essential for EBV control, as homozygous R335W (SH2 domain) caused fatal lymphoproliferative disease with absent NKT cells.

    Evidence Itk⁻/⁻ and Rlk⁻/⁻Itk⁻/⁻ KO mouse models with flow cytometric T-cell subset analysis; human exome sequencing, in silico modeling, Western blot of mutant protein in 293T cells, immunophenotyping

    PMID:19290924 PMID:19425169

    Open questions at the time
    • Molecular threshold of TCR signal strength that toggles lineage fate not quantified
    • Whether ITK deficiency-related lymphoproliferation reflects solely NKT cell absence or additional immune defects is unclear
  9. 2012 High

    Additional human loss-of-function mutations mapped across ITK (PH domain R29H; kinase domain truncations) confirmed genotype–phenotype correlations: the R29H mutation specifically ablates PH domain phosphoinositide binding and all mutations reduce protein half-life, directly connecting lipid-binding-driven membrane recruitment and protein stability to human disease.

    Evidence Calcium flux rescue in murine Itk⁻/⁻ T cells, pulse-chase protein stability assay, PH domain–phosphoinositide binding assay

    PMID:22289921

    Open questions at the time
    • Crystal structure of R29H PH domain not determined
    • Whether reduced half-life is due to misfolding or active degradation pathway not identified
  10. 2013 High

    A non-redundant role for ITK in licensing autoreactive T-cell tissue infiltration (distinct from activation/proliferation) was demonstrated: ITK ablation in Ctla4⁻/⁻ mice blocks self-reactive T-cell egress from lymphoid organs without suppressing their activation, positioning ITK as a specific target for autoimmune tissue destruction.

    Evidence Itk⁻/⁻;Ctla4⁻/⁻ double-KO mice, adoptive transfer, ITK inhibitor treatment, pancreatic islet histology

    PMID:24270545

    Open questions at the time
    • Molecular mechanism by which ITK controls tissue-homing molecule expression not fully defined
    • Whether this trafficking role is kinase-dependent or scaffolding-dependent is unknown
  11. 2015 High

    Pharmacological and genetic studies converged to show ITK controls Th17 differentiation and T-cell transendothelial migration: selective covalent ITK/RLK inhibitor PRN694 blocked Th1/Th17 cytokines and reduced colitis severity, while Itk⁻/⁻ CD4⁺ T cells showed impaired transmigration across brain endothelial barriers and reduced EAE severity with altered Teff/Treg ratios.

    Evidence In vitro Th polarization, adoptive transfer colitis model, PRN694 treatment; Itk⁻/⁻ EAE model with in vitro transendothelial migration assay and actin imaging

    PMID:25568116 PMID:26466958

    Open questions at the time
    • Relative contributions of ITK versus RLK to PRN694 efficacy not separated
    • Actin–CD4 coreceptor displacement mechanism not molecularly defined
  12. 2017 High

    The downstream signaling axis was extended: ITK kinase activity drives Tr1 cell development through Ras-dependent IRF4 expression, as constitutively active HRas and IRF4 overexpression each rescue Tr1 differentiation in Itk⁻/⁻ cells across parasitic and viral infection models.

    Evidence Itk⁻/⁻ mice with constitutively active HRas or IRF4 rescue, in vivo infection models, flow cytometry

    PMID:28635957

    Open questions at the time
    • Direct biochemical link between ITK kinase activity and Ras activation not established
    • Whether ITK–Ras–IRF4 axis operates in human Tr1 cells not confirmed
  13. 2019 High

    Human validation confirmed ITK's role in Th17 biology: a novel ITK loss-of-function patient and ibrutinib treatment both reduced Th17 generation and IL-17A/IL-22/GM-CSF production while increasing IFN-γ, and reduced ILC2/ILC3 populations, extending ITK function beyond adaptive T cells to innate lymphoid cells.

    Evidence Human exome sequencing, ex vivo ibrutinib treatment of human T cells, flow cytometry, cytokine measurement

    PMID:31025232

    Open questions at the time
    • Ibrutinib also inhibits BTK; ITK-selective effects in human cells require confirmation with cleaner tools
    • Whether ILC2/ILC3 reduction is cell-intrinsic or secondary to T-cell dysfunction unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length structure of autoinhibited ITK, the molecular mechanism by which ITK controls tissue-homing programs independently of proliferative signals, the direct biochemical connection between ITK and Ras activation, and whether kinase-dependent versus scaffolding functions can be pharmacologically separated for therapeutic benefit.
  • No full-length autoinhibited structure resolved
  • Kinase-dependent vs. scaffolding functions not pharmacologically separable yet
  • ITK–Ras link lacks direct biochemical reconstitution

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0008289 lipid binding 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 9 R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 3 R-HSA-1266738 Developmental Biology 2
Partners
GRB2LATLCKPLCG1PPIASLP76VAV1WASP

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 The kinase activity of Tsk/Itk is stimulated by G protein βγ subunits, demonstrated by co-transfection assays and in vitro reconstitution with purified bovine brain Gβγ subunits and immunoprecipitated Tsk, indicating Itk can act as an effector of heterotrimeric G proteins. Co-transfection assay and in vitro reconstitution with purified Gβγ subunits Proceedings of the National Academy of Sciences of the United States of America Medium 7567982
1996 The Itk SH3 domain binds specific proline-rich ligands including Sam68, Wiskott-Aldrich Syndrome protein (WASP), hnRNP-K, Grb-2, Cbl, and Fyn from TCR-stimulated Jurkat T cells, with the optimal SH3 binding motif defined by phage display library screening. Phage display library screening, SH3 domain pulldown from T cell lysates, deletion variant analysis The Journal of biological chemistry High 8810341
1997 The Itk SH3 domain and proline-rich region interact intramolecularly, as determined by multidimensional NMR structure of an Itk fragment, representing the first example of intramolecular SH3-ligand interaction in a Tec family kinase. This interaction prevents the SH3 domain and proline-rich region from binding protein ligands (Sam68 and Grb-2), constituting an autoinhibitory mechanism. Multidimensional NMR structure determination, competitive binding assays Nature High 8985255
1997 Lck directly transphosphorylates Itk on Tyr511 within the activation loop of the kinase domain, leading to increased Itk kinase activity. This was demonstrated by co-expression of recombinant Itk and Lck in a baculovirus system, and mutation of Tyr511 to Phe abolished Itk kinase activity. Baculovirus co-expression of recombinant proteins, in vitro kinase assay, site-directed mutagenesis The Journal of biological chemistry High 9312162
1997 Itk-deficient mice exhibit reduced primary cytotoxic T-lymphocyte (CTL) responses (by 2–6 fold) to LCMV, vaccinia virus, and VSV infection, while antiviral B cell antibody responses are unaffected. Exogenous IL-2 rescues in vitro CTL responses in Itk-deficient cells, indicating Itk is required for optimal T-cell but not B-cell antiviral immunity. Genetic knockout mouse model, ex vivo CTL assay, cytokine rescue experiment Journal of virology High 9311799
1999 The SH2 domains of Btk and Itk selectively bind tyrosine-phosphorylated SLP-65 (in B cells) and SLP-76 (in T cells), respectively, in activated lymphocytes. This restricted SH2 binding specificity is required for phospholipase C-γ phosphorylation and Ca²⁺ mobilization downstream of antigen receptors. SH2 domain binding assays with T/B cell lysates, co-immunoprecipitation from activated lymphocytes European journal of immunology High 10556826
2000 The Itk pleckstrin homology (PH) domain directs constitutive association with buoyant membrane rafts (primary sites of TCR activation) enriched in Lck and LAT. Deficiency of PTEN in Jurkat cells leads to elevated PI-3,4,5-P₃ at the plasma membrane, causing constitutive membrane localization of Itk and hyperresponsiveness to TCR stimulation. PTEN re-expression or PI3K inhibition redistributes Itk to the cytosol and normalizes signaling. Subcellular fractionation, Western blotting, PI3K inhibitor treatment, PTEN re-expression Molecular and cellular biology High 10958690
2000 Itk forms multivalent interactions with the TCR-proximal signaling complex: (1) its PH domain inositide-binding pocket recruits Itk to buoyant membrane rafts where Lck and LAT reside, enabling transphosphorylation; (2) the proline-rich region binds Grb2 and LAT; (3) SH3 and SH2 domains cooperatively interact with Syk-phosphorylated SLP-76. Kinase-inactive Itk antagonizes SLP-76-dependent NF-AT activation in a PH/proline-rich/SH2-dependent manner. Co-immunoprecipitation, in vitro binding assays, dominant-negative Itk constructs, NF-AT reporter assay The Journal of biological chemistry High 10636929
2002 The peptidyl-prolyl isomerase cyclophilin A (CypA) inhibits Itk catalytic activity through its isomerase activity. NMR structural studies combined with mutagenesis reveal a proline-dependent conformational switch within the Itk SH2 domain that regulates substrate recognition and mediates interactions with the CypA active site. CypA and Itk form a stable complex in Jurkat T cells that is disrupted by cyclosporin A treatment, and phosphorylation of Itk and PLCγ1 is increased following cyclosporin A treatment. NMR structural analysis, mutational analysis, co-immunoprecipitation from Jurkat T cells, cyclosporin A treatment, kinase activity assay Proceedings of the National Academy of Sciences of the United States of America High 11830645
2004 Two selective small-molecule inhibitors of Itk (BMS-488516 and BMS-509744) potently inhibit Itk kinase activity and block TCR-induced PLCγ1 tyrosine phosphorylation, calcium mobilization, IL-2 secretion, and T-cell proliferation in vitro in human and mouse cells. BMS-509744 significantly diminishes lung inflammation in a mouse model of ovalbumin-induced allergic asthma, validating Itk as a therapeutic target for Th2-mediated inflammatory diseases. In vitro kinase assay, calcium mobilization assay, cytokine ELISA, T-cell proliferation assay, murine ovalbumin asthma model Biochemistry High 15323564
2005 Itk has a kinase-independent scaffolding function in TCR-induced actin polarization: Itk is constitutively associated with the Vav guanine nucleotide exchange factor, and loss of Itk (by siRNA) reduces Vav recruitment to the antigen contact site and disrupts actin polarization. Both wild-type and kinase-inactive Itk rescue actin polarization defects, but Itk with mutations in the PH or SH2 domains cannot. Membrane-targeted Vav (Vav-CAAX) rescues the Itk siRNA phenotype. siRNA knockdown, re-expression of wild-type and mutant Itk, co-immunoprecipitation, actin polarization imaging, Vav-CAAX rescue Journal of immunology High 15661896
2007 SLP-76 not only recruits ITK but also directly maintains ITK kinase activity: the SLP-76/ITK complex interaction is required for both initiation and maintenance of ITK kinase activity, enabling ITK to phosphorylate PLCγ1. This places SLP-76 as more than a neutral adaptor — it actively sustains ITK catalytic function for downstream TCR-stimulated Ca²⁺ mobilization. Biochemical analysis of SLP-76/ITK complex, kinase activity assays Science's STKE Medium 17652306
2009 ITK is required for Th2 cytokine production (IL-4, IL-5, IL-13), actin reorganization, PLCγ activation, calcium mobilization, and NFAT transcription factor activation downstream of TCR, CD28, CD2, CXCR4, and FcεR signaling in T cells, NKT cells, and mast cells. Genetic Itk knockout studies, pharmacological inhibition studies reviewed Current topics in medicinal chemistry Medium 19689375
2009 In the absence of Itk (and Rlk), TCR signaling is impaired with defects in MAPK activation, Ca²⁺ mobilization, and actin polymerization. Itk and Rlk regulate the development of conventional vs. innate CD4⁺ and CD8⁺ T-cell lineages; Itk-deficient mice show altered NKT and γδ T-cell populations, indicating signaling strength via Itk determines conventional versus innate lymphocyte lineage commitment. Genetic knockout mouse models (Itk⁻/⁻, Rlk⁻/⁻Itk⁻/⁻), T-cell subset phenotyping Immunological reviews High 19290924
2009 Homozygous missense mutation R335W in the SH2 domain of ITK causes fatal EBV-associated lymphoproliferative disease in two girls. The R335W mutation destabilizes the ITK SH2 domain (in silico modeling) and renders the protein nearly undetectable by Western blot when expressed in 293T cells, indicating protein instability. Patients show NKT cell absence and high eomesodermin in CD8⁺ cells, phenocopying murine Itk deficiency. SNP array linkage analysis, whole-exome sequencing, in silico protein modeling, Western blot of mutant ITK in 293T cells, flow cytometric immunophenotyping The Journal of clinical investigation High 19425169
2010 ITK functions downstream of the TCR to regulate phospholipase C-gamma (PLCγ), with its kinase activity, domain interactions (PH, SH3, SH2, kinase domain), and substrate recognition mechanisms established. ITK controls development of conventional versus innate αβ and γδ T-cell subsets, and regulates effector T-cell differentiation and cytokine gene expression. Reviewed crystallographic structures, enzymatic studies, genetic models Cold Spring Harbor perspectives in biology High 20519342
2010 The ITK-SYK fusion kinase (from chromosomal translocation t(5;9)(q33;q22) in peripheral T cell lymphoma) constitutively associates with lipid rafts in T cells and drives antigen-independent phosphorylation of TCR-proximal proteins, activating downstream pathways mimicking TCR ligation (CD69 upregulation, IL-2 production, thymocyte deletion, peripheral T-cell activation). Conditional expression of ITK-SYK in mice induces highly malignant peripheral T cell lymphomas with 100% penetrance. Conditional transgenic mouse model, biochemical fractionation (lipid rafts), phosphoprotein analysis, T-cell activation assays, in vivo lymphoma model The Journal of experimental medicine High 20439541
2011 Itk is required for the development of invariant NKT αβ cells and a smaller population of NKT-like γδ T cells; Itk-regulated signaling pathways produce different developmental outcomes (conventional vs. innate lineage) in these cell subsets, suggesting the same Itk-regulated TCR signaling pathway is interpreted differently depending on cellular context. Itk genetic knockout mouse models, T-cell subset flow cytometric analysis The FEBS journal Medium 21362141
2012 Loss-of-function mutations in ITK distributed across the entire protein (missense R29H; nonsense/indel D500T,F501L,M503X) cause EBV-associated lymphoproliferative disorders. Wild-type ITK but not mutants rescues defective calcium flux in murine Itk⁻/⁻ T cells. The R29H mutation in the PH domain dramatically reduces binding to phosphatidylinositol monophosphates (PI(3)P, PI(4)P, PI(5)P) and higher-order PIP species. Mutations reduce ITK protein half-life by 25–69% compared to wild-type (t½ = 107 min). Calcium flux rescue assay in murine Itk⁻/⁻ T cells, pulse-chase protein stability assay, PH domain phosphoinositide binding assay Leukemia High 22289921
2013 CD28-activated ITK specifically licenses autoreactive T cells to traffic from secondary lymphoid organs into target tissues to mount destructive autoimmune responses. Concurrent ablation of ITK in Ctla4⁻/⁻ mice blocks tissue infiltration by self-reactive T cells without preventing their activation or proliferation in lymphoid organs. ITK inhibitors phenocopy the null mutant and prevent pancreatic islet infiltration by diabetogenic T cells. Genetic double-knockout (Itk⁻/⁻;Ctla4⁻/⁻) mice, adoptive transfer, ITK inhibitor treatment, pancreatic islet histology Nature medicine High 24270545
2015 ITK inhibitor PRN694 (selective covalent inhibitor of ITK and RLK) blocks Th1 and Th17 differentiation and cytokine production in vitro. In a T-cell adoptive transfer colitis model, in vivo PRN694 administration markedly reduces disease progression, T-cell infiltration into the intestinal lamina propria, IFN-γ production, and P-selectin binding and CXCL11/CCL20-directed migration of Th1/Th17 cells. In vitro Th polarization assay, adoptive transfer colitis model, flow cytometry, cytokine ELISA, migration assay Journal of immunology High 26466958
2015 Itk signaling promotes experimental autoimmune encephalomyelitis (EAE): Itk⁻/⁻ mice show reduced disease severity, and adoptive transfer of Itk⁻/⁻ CD4⁺ T cells produces lower disease severity in T cell-deficient recipients. Itk⁻/⁻ CD4⁺ T cells show defective response to myelin antigen, displacement of filamentous actin from the CD4 co-receptor, impaired transmigration across brain endothelial barriers, and reduced Th1/Th17 cytokine production with skewed Teff/Treg ratios. KO mouse model, adoptive transfer, EAE induction, in vitro transendothelial migration assay, actin imaging, cytokine measurement The Journal of neuroscience High 25568116
2017 ITK kinase activity is required for TCR-induced development of Type 1 regulatory T (Tr1) cells in various organs and mucosal tissues during parasitic and viral infections. Downstream of ITK, Ras activity is responsible for Tr1 cell induction: constitutively active HRas rescues IRF4 expression and Tr1 cell differentiation in Itk⁻/⁻ cells. The transcription factor IRF4 mediates ITK's effect on Tr1 cell differentiation, as IRF4 overexpression restores Tr1 development and suppressive function of Itk-deficient cells. Itk⁻/⁻ mouse model, constitutively active HRas rescue, IRF4 overexpression rescue, in vivo infection models, flow cytometry Nature communications High 28635957
2019 Both genetic loss-of-function (novel ITK mutation) and chemical inhibition of ITK (ibrutinib) result in reduced Th17 generation and IL-17A/IL-22/GM-CSF production in humans, with reciprocally increased IFN-γ (Th1) production. ITK deficiency in a human patient also reduces peripheral ILC2 and ILC3 populations. IBrutinib blocks Th17 generation and augments FoxP3 expression at low doses in Treg cultures. Whole exome sequencing, flow cytometry, cytokine measurement, ibrutinib pharmacological inhibition of ex vivo human T cells Journal of clinical immunology High 31025232
2020 ITK signals downstream of TCR differentially control effector T-cell differentiation: the Ras/MAPK pathway downstream of ITK controls TH17, Foxp3⁺ Treg, and Tr1 cell fate decisions, supporting a model in which ITK signaling strength controls a T-cell effector differentiation decision point. Genetic KO studies, constitutively active Ras rescue, IRF4 expression analysis (reviewed mechanistic findings) Biochemical Society transactions Medium 32049330

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 EMT: 2016. Cell 3694 27368099
2018 EMT in cancer. Nature reviews. Cancer 1594 29326430
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2018 Identification of the tumour transition states occurring during EMT. Nature 1139 29670281
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2013 The Role of Snail in EMT and Tumorigenesis. Current cancer drug targets 739 24168186
2012 Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell 708 22939624
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2016 EMT, cell plasticity and metastasis. Cancer metastasis reviews 682 27878502
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2014 KRAS and YAP1 converge to regulate EMT and tumor survival. Cell 650 24954536
2005 A quantitative protein interaction network for the ErbB receptors using protein microarrays. Nature 568 16273093
2005 High-throughput mapping of a dynamic signaling network in mammalian cells. Science (New York, N.Y.) 553 15761153
2012 EMT-activating transcription factors in cancer: beyond EMT and tumor invasiveness. Cellular and molecular life sciences : CMLS 441 22945800
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2012 Regulation of EMT by TGFβ in cancer. FEBS letters 429 22710176
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2016 Role of EMT in Metastasis and Therapy Resistance. Journal of clinical medicine 404 26828526
2016 Epithelial-mesenchymal transition (EMT) and metastasis: yes, no, maybe? Current opinion in cell biology 399 27371787
2016 Tumor Budding: The Name is EMT. Partial EMT. Journal of clinical medicine 391 27136592
1996 Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases. Science (New York, N.Y.) 391 8629002
2017 EMT: Mechanisms and therapeutic implications. Pharmacology & therapeutics 378 28834698
2010 The epithelial-mesenchymal transition (EMT) phenomenon. Annals of oncology : official journal of the European Society for Medical Oncology 346 20943648
2021 Epithelial-Mesenchymal Transition (EMT): The Type-2 EMT in Wound Healing, Tissue Regeneration and Organ Fibrosis. Cells 332 34201858
2009 Role of epithelial-to-mesenchymal transition (EMT) in drug sensitivity and metastasis in bladder cancer. Cancer metastasis reviews 325 20012924
2021 Vimentin Is at the Heart of Epithelial Mesenchymal Transition (EMT) Mediated Metastasis. Cancers 318 34638469
2007 Fibrosis and cancer: do myofibroblasts come also from epithelial cells via EMT? Journal of cellular biochemistry 281 17211838
2000 Deficiency of PTEN in Jurkat T cells causes constitutive localization of Itk to the plasma membrane and hyperresponsiveness to CD3 stimulation. Molecular and cellular biology 276 10958690
2013 Multilayer control of the EMT master regulators. Oncogene 274 23604123
2010 The role of Notch signaling pathway in epithelial-mesenchymal transition (EMT) during development and tumor aggressiveness. Current drug targets 271 20041844
2011 The EMT regulator slug and lung carcinogenesis. Carcinogenesis 270 21665887
1996 Regulation of Btk function by a major autophosphorylation site within the SH3 domain. Immunity 261 8630736
2005 The epithelial-mesenchymal transition (EMT) and colorectal cancer progression. Cancer biology & therapy 257 15846061
2017 EMT transcription factors in cancer development re-evaluated: Beyond EMT and MET. Biochimica et biophysica acta. Reviews on cancer 238 28669750
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
1997 Regulatory intramolecular association in a tyrosine kinase of the Tec family. Nature 234 8985255
2018 Epithelial mesenchymal transition (EMT): a universal process in lung diseases with implications for cystic fibrosis pathophysiology. Respiratory research 230 30021582
2010 Snail: More than EMT. Cell adhesion & migration 216 20168078
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 213 20519342
2009 Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation. The Journal of clinical investigation 212 19425169
2019 The basics of epithelial-mesenchymal transition (EMT): A study from a structure, dynamics, and functional perspective. Journal of cellular physiology 207 30723913
2019 Role of AKT and mTOR signaling pathways in the induction of epithelial-mesenchymal transition (EMT) process. Biochimie 206 31401189
2020 Association of the Epithelial-Mesenchymal Transition (EMT) with Cisplatin Resistance. International journal of molecular sciences 203 32503307
1999 Interaction of SLP adaptors with the SH2 domain of Tec family kinases. European journal of immunology 198 10556826
2020 Context specificity of the EMT transcriptional response. Nature communications 178 32358524
2010 Cadherins in the human placenta--epithelial-mesenchymal transition (EMT) and placental development. Placenta 178 20659767
2004 Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry. Analytical chemistry 174 15144186
1999 Socs1 binds to multiple signalling proteins and suppresses steel factor-dependent proliferation. The EMBO journal 166 10022833
2016 Anoikis and EMT: Lethal "Liaisons" during Cancer Progression. Critical reviews in oncogenesis 163 27915969
2009 Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling. Gut 157 19240061
2018 Epithelial-Mesenchymal Transition (EMT) and Prostate Cancer. Advances in experimental medicine and biology 153 30229551
1996 Identification of Itk/Tsk Src homology 3 domain ligands. The Journal of biological chemistry 150 8810341
2017 AXL-Driven EMT State as a Targetable Conduit in Cancer. Cancer research 138 28667075
1997 Lck phosphorylates the activation loop tyrosine of the Itk kinase domain and activates Itk kinase activity. The Journal of biological chemistry 138 9312162
2014 The mammalian-membrane two-hybrid assay (MaMTH) for probing membrane-protein interactions in human cells. Nature methods 131 24658140
2021 Epithelial-Mesenchymal Transition (EMT) as a Therapeutic Target. Cells, tissues, organs 128 33401271
2001 PKCbeta modulates antigen receptor signaling via regulation of Btk membrane localization. The EMBO journal 125 11598012
1995 Activation of Tsk and Btk tyrosine kinases by G protein beta gamma subunits. Proceedings of the National Academy of Sciences of the United States of America 122 7567982
2019 Role of Metabolic Reprogramming in Epithelial⁻Mesenchymal Transition (EMT). International journal of molecular sciences 120 31027222
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
2021 Paralog knockout profiling identifies DUSP4 and DUSP6 as a digenic dependence in MAPK pathway-driven cancers. Nature genetics 116 34857952
2014 In silico prediction of physical protein interactions and characterization of interactome orphans. Nature methods 112 25402006
2013 Epithelial mesenchymal transition (EMT) in prostate growth and tumor progression. Translational andrology and urology 112 25346895
2002 Discovery of aminothiazole inhibitors of cyclin-dependent kinase 2: synthesis, X-ray crystallographic analysis, and biological activities. Journal of medicinal chemistry 110 12190313
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