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Gene Review

ITK  -  IL2-inducible T-cell kinase

Homo sapiens

Synonyms: EMT, IL-2-inducible T-cell kinase, Interleukin-2-inducible T-cell kinase, Kinase EMT, LPFS1, ...
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Disease relevance of ITK

  • This region in humans is frequently deleted in the myelodysplastic syndrome, suggesting possible involvement of ITK in this disorder [1].
  • EMT is related to the B-cell progenitor kinase (BPK), which has recently been implicated in X-linked hypogammaglobulinemia, to the TECI mammalian kinase, which has been implicated in liver neoplasia, to the more widely expressed TECII mammalian kinase, and to the Drosophila melanogaster Dsrc28 kinase [2].
  • OBJECTIVE: We assessed the role of polymorphisms in the TIM family genes and ITK in atopy, eczema, and asthma [3].
  • Novel t(5;9)(q33;q22) fuses ITK to SYK in unspecified peripheral T-cell lymphoma [4].
  • Gene network analysis using an integrated comprehensive workbench, VoyaGene, revealed that a gene encoding a TEC-family kinase, ITK, might be a putative modulator in the host immune response against HHV-6B infection [5].

High impact information on ITK

  • Whereas IL-15(-/-) mice lack CD44(hi)CD122(hi) CD8(+) T cells, mice deficient in the kinase ITK lack CD44(lo)CD122(lo) cells among CD8(+) T cells [6].
  • In contrast to Src kinases, ZAP-70 and ITK failed to induce these events [7].
  • 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 [8].
  • Sequence comparison suggests that EMT is likely the human homologue of a recently identified murine interleukin-2 (IL-2)-inducible T cell kinase (ITK) [2].
  • EMT does not contain the N-terminal myristylation site or the negative regulatory tyrosine phosphorylation site in its carboxyterminus that are found in the SRC family of tyrosine kinases [2].

Biological context of ITK

  • EMT was localized to chromosome 5q31-32, a region that contains the genes for several growth factors and receptors as well as early activation genes, particularly those involved in the hematopoietic system [2].
  • The cDNA of EMT predicts an open reading frame of 1866 bp encoding a protein with a predicted size of 72 Kd, which is in keeping with its size on Western blotting [2].
  • A single 6.2-kb EMT mRNA and 72-Kd protein were detected in T lymphocytes and NK-like cell lines, but were not detected in other cell lineages [2].
  • Thus, whereas ITK-dependent CD44(lo)CD122(lo) CD8(+) T cells appear to represent conventional CD8(+) T cells, IL-15-dependent CD44(hi)CD122(hi) CD8(+) T cells may have functions in both adaptive and innate immunity [6].
  • METHODS: Twenty-one polymorphisms in the TIM-ITK gene cluster were genotyped in 564 children enrolled in the Tucson Children's Respiratory Study. Skin prick tests to common allergens were performed at age 6.1 years (n=508), age 10.8 years (n=539), and age 16.6 years (n=424) [3].

Anatomical context of ITK


Associations of ITK with chemical compounds

  • Three major classes of signalling molecule are regulated by binding of D-3 phosphoinositides to PH domains: guanine-nucleotide-exchange proteins for Rho family GTPases, the TEC family tyrosine kinases such as BTK and ITK in B and T lymphocytes, respectively, and the AGC superfamily of serine/threonine protein kinases [13].
  • We report herein that inhibition of PI3K activity with the specific inhibitors LY294002 and wortmannin markedly decreased EMT activation induced by CD28 cross-linking but not by CD3 cross-linking [14].
  • To address this we studied the ability of truncation mutants and tyrosine to phenylalanine substitution mutants of the CD28 cytoplasmic tail to activate LCK and EMT in Jurkat T leukemia cells [15].
  • In all five translocation-positive cases, the breakpoints were identical fusing the N-terminal pleckstrin homology domain and proline-rich region of ITK to the tyrosine kinase domain of SYK [4].
  • The open-source ITK Insight Software package developed by the National Library of Medicine (USA) contains a multi-resolution, voxel-similarity-based registration algorithm which we selected as our baseline registration method [16].

Regulatory relationships of ITK

  • Further, inhibition of PI3K markedly decreased EMT in vitro autokinase activity induced by activated LCK [14].

Other interactions of ITK

  • The activation of EMT during CD2 signaling suggests an important role for this kinase in CD2 co-stimulation of T cell responses [17].
  • Taken together, it seems that EMT is a member of a new family of intracellular kinases that includes BPK, TECI, and TECII [2].
  • Taken together, the data indicate that the EMT tyrosine kinase is activated following cross-linking of the TCR, a process in which LCK likely plays an important role [18].
  • On a biochemical level, SLP-76 inducibly associated with both Vav and catalytically active ITK, which efficiently phosphorylated a PLC-gamma1 fragment at Tyr(783) in vitro [19].
  • CD28 binds to several intracellular proteins including phosphatidylinositol 3-kinase (Pl3-kinase), the tyrosine kinase ITK and the growth factor receptor-bound protein/Son of Sevenless (GRB-2/SOS) complex [20].

Analytical, diagnostic and therapeutic context of ITK


  1. Mapping of the gene for the tyrosine kinase Itk to a region of conserved synteny between mouse chromosome 11 and human chromosome 5q. Janis, E.M., Siliciano, J.D., Isaac, D.D., Griffin, C.A., Hawkins, A.L., Kozak, C.A., Desiderio, S. Genomics (1994) [Pubmed]
  2. Identification, cloning, and characterization of a novel human T-cell-specific tyrosine kinase located at the hematopoietin complex on chromosome 5q. Gibson, S., Leung, B., Squire, J.A., Hill, M., Arima, N., Goss, P., Hogg, D., Mills, G.B. Blood (1993) [Pubmed]
  3. Association of atopy and eczema with polymorphisms in T-cell immunoglobulin domain and mucin domain-IL-2-inducible T-cell kinase gene cluster in chromosome 5 q 33. Graves, P.E., Siroux, V., Guerra, S., Klimecki, W.T., Martinez, F.D. J. Allergy Clin. Immunol. (2005) [Pubmed]
  4. Novel t(5;9)(q33;q22) fuses ITK to SYK in unspecified peripheral T-cell lymphoma. Streubel, B., Vinatzer, U., Willheim, M., Raderer, M., Chott, A. Leukemia (2006) [Pubmed]
  5. Estimating immunoregulatory gene networks in human herpesvirus type 6-infected T cells. Takaku, T., Ohyashiki, J.H., Zhang, Y., Ohyashiki, K. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  6. ITK and IL-15 support two distinct subsets of CD8+ T cells. Dubois, S., Waldmann, T.A., Müller, J.R. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  7. 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. Raab, M., Cai, Y.C., Bunnell, S.C., Heyeck, S.D., Berg, L.J., Rudd, C.E. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  8. 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. August, A., Gibson, S., Kawakami, Y., Kawakami, T., Mills, G.B., Dupont, B. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  9. Regulated association between the tyrosine kinase Emt/Itk/Tsk and phospholipase-C gamma 1 in human T lymphocytes. Perez-Villar, J.J., Kanner, S.B. J. Immunol. (1999) [Pubmed]
  10. CD2-mediated activation of the Tec-family tyrosine kinase ITK is controlled by proline-rich stretch-4 of the CD2 cytoplasmic tail. King, P.D., Sadra, A., Teng, J.M., Bell, G.M., Dupont, B. Int. Immunol. (1998) [Pubmed]
  11. Human Emt tyrosine kinase is specifically expressed both in mature T-lymphocytes and T-cell associated hematopoietic malignancies. Kaukonen, J., Savolainen, E.R., Palotie, A. Leuk. Lymphoma (1999) [Pubmed]
  12. Human immunodeficiency virus type 1 (HIV-1) infection and transcytosis activity of a HIV-1 susceptible clone from HeLa cell. Morizono, K., Harada, S. Microbiol. Immunol. (1998) [Pubmed]
  13. Phosphoinositide 3-kinase signalling pathways. Cantrell, D.A. J. Cell. Sci. (2001) [Pubmed]
  14. Phosphatidylinositol 3-kinase is required for CD28 but not CD3 regulation of the TEC family tyrosine kinase EMT/ITK/TSK: functional and physical interaction of EMT with phosphatidylinositol 3-kinase. Lu, Y., Cuevas, B., Gibson, S., Khan, H., LaPushin, R., Imboden, J., Mills, G.B. J. Immunol. (1998) [Pubmed]
  15. Analysis of CD28 cytoplasmic tail tyrosine residues as regulators and substrates for the protein tyrosine kinases, EMT and LCK. King, P.D., Sadra, A., Teng, J.M., Xiao-Rong, L., Han, A., Selvakumar, A., August, A., Dupont, B. J. Immunol. (1997) [Pubmed]
  16. Registration of MR and CT images of the liver: comparison of voxel similarity and surface based registration algorithms. Christina Lee, W.C., Tublin, M.E., Chapman, B.E. Computer methods and programs in biomedicine. (2005) [Pubmed]
  17. CD2 signaling in T cells involves tyrosine phosphorylation and activation of the Tec family kinase, EMT/ITK/TSK. King, P.D., Sadra, A., Han, A., Liu, X.R., Sunder-Plassmann, R., Reinherz, E.L., Dupont, B. Int. Immunol. (1996) [Pubmed]
  18. The EMT/ITK/TSK (EMT) tyrosine kinase is activated during TCR signaling: LCK is required for optimal activation of EMT. Gibson, S., August, A., Kawakami, Y., Kawakami, T., Dupont, B., Mills, G.B. J. Immunol. (1996) [Pubmed]
  19. Dual Role of SLP-76 in Mediating T Cell Receptor-induced Activation of Phospholipase C-{gamma}1. Beach, D., Gonen, R., Bogin, Y., Reischl, I.G., Yablonski, D. J. Biol. Chem. (2007) [Pubmed]
  20. CD28 co-stimulatory regimes differ in their dependence on phosphatidylinositol 3-kinase: common co-signals induced by CD80 and CD86. Cefai, D., Cai, Y.C., Hu, H., Rudd, C. Int. Immunol. (1996) [Pubmed]
  21. Extramedullary myeloid cell tumors. An immunohistochemical and morphologic study of 28 cases. Traweek, S.T., Arber, D.A., Rappaport, H., Brynes, R.K. Am. J. Surg. Pathol. (1993) [Pubmed]
  22. Cutaneous graft-versus-host disease. Aractingi, S., Chosidow, O. Archives of dermatology. (1998) [Pubmed]
  23. Extramedullary myeloid cell tumors in myelodysplastic-syndromes: not a true indication of impending acute myeloid leukemia. Byrd, J.C., Edenfield, W.J., Dow, N.S., Aylesworth, C., Dawson, N. Leuk. Lymphoma (1996) [Pubmed]
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