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Gene Review

Itk  -  IL2 inducible T cell kinase

Mus musculus

Synonyms: Emt, IL-2-inducible T-cell kinase, Kinase EMT, Kinase TLK, T-cell-specific kinase, ...
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Disease relevance of Itk

  • An optimal Itk SH3 binding motif was derived by screening biased phage display libraries; peptides based on this motif bound with high affinity and selectivity to the Itk SH3 domain [1].
  • Collectively, our data suggest a critical role of Itk in airway mast cell degranulation in vivo that together with an impaired T cell response prevents the development of both acute and late phase inflammatory allergic reactions [2].
  • Moreover, late phase inflammatory changes, including eosinophilia, lymphocyte infiltration, and Th2 cytokine production in the lungs, was eliminated in Itk(-/-) mice [2].
  • Reduction of Itk expression via small interfering RNA treatment of the Jurkat human T lymphoma cell line or human peripheral blood T cells disrupted TCR-induced actin polarization, a defect that correlated with decreased recruitment of the Vav guanine nucleotide exchange factor to the site of Ag contact [3].
  • Interestingly, while LCMV was completely eliminated by day 8 in both Itk-deficient and control mice, VV cleared from itk-/- mice with delayed kinetics [4].

High impact information on Itk

  • Three members of this family, Itk, Rlk, and Tec, are expressed in T cells and activated in response to T cell receptor (TCR) engagement [5].
  • The T-cell-specific tyrosine kinase Itk is a member of the Tec family of non-receptor tyrosine kinases, and is required for signalling through the T-cell antigen receptor (TCR) [6].
  • Although Itk also contains SH3, SH2 and tyrosine kinase domains, it lacks the corresponding regulatory phosphorylation site, and therefore must be regulated by an alternative mechanism [6].
  • Expression of a hypersensitive Erk2 mutant partially corrects the CD8(+) T cell phenotypes in Itk(-/-) mice, arguing that altered signaling permits development of this innate-type CD8(+) cell population [7].
  • Itk(-/-) and Rlk(-/-)Itk(-/-) CD8(+) thymocytes and T cells were CD44(hi), CD122(+), and NK1.1(+); were able to produce interferon-gamma directly ex vivo; and were dependent on interleukin-15 [8].

Biological context of Itk

  • The phenotype of the Itk/Fyn doubly deficient mice was similar to that of Itk deficient mice [9].
  • Itk is a member of the Btk/Tec/Itk family of nonreceptor protein tyrosine kinases (PTKs), and has been implicated in T cell antigen receptor (TCR) signal transduction [9].
  • These proteins are involved in the regulation of signaling processes downstream of the TCR in CD4(+) T cells, particularly in the phosphorylation of phospholipase C-gamma1 after TCR activation; furthermore, both Itk and Rlk are important in CD4(+) T cell development, differentiation, function, and homeostasis [10].
  • Disruption of Tec family signaling in Itk-/- and Rlk-/-Itk-/- mice has multiple effects on T cell development, cytokine production and T-helper cell differentiation [11].
  • The protein/peptide data combined with the association constants for binding of each proline-rich peptide to the corresponding SH3 domain provide an explanation for the opposing modes of self-association within the otherwise closely related Rlk and Itk proteins [12].

Anatomical context of Itk

  • Itk and Fyn make independent contributions to T cell activation [9].
  • Retroviral transfer of Emt (= Itk/Tsk), Btk's closest relative, also partially improved the ability of btk mutant mast cells to secrete mediators [13].
  • Initial studies with T cell lysates indicated that the Itk SH3 domain bound Cbl, Fyn, and other tyrosine phosphoproteins from TCR-stimulated Jurkat cells [1].
  • Recent studies include new work on the roles of the immune synapse in regulating T-cell receptor signaling, the discovery of new functions for the Src-family kinase Fyn and the Tec kinase Itk, particularly in regulation of the actin cytoskeleton, and new insights into positive and negative feedback mechanisms in antigen receptor signaling [14].
  • Coexpression of Emt in COS-7 cells with Ca(2+)-dependent PKC isoforms (alpha, beta I, or beta II) induces an enhancement in tyrosine phosphorylation of Emt [15].

Associations of Itk with chemical compounds

  • The Tec family tyrosine kinase, Itk, is critical for PLC-gamma1 activation downstream of the TCR [16].
  • Notably, airway mast cell degranulation in Itk(-/-) mice was severely impaired, despite wild-type levels of allergen-specific IgE and IgG1 [2].
  • Mature T cells from Itk-deficient mice had reduced proliferative responses to allogeneic MHC stimulation and to anti-TCR cross-linking, but responded normally to stimulation with phorbol ester plus ionomycin or with IL-2 [17].
  • The Tec family kinase Itk is an important regulator of Ca(2+) mobilization and is required for in vivo responses to Th2-inducing agents [3].
  • This is in contrast to the corresponding fragment of Itk, for which the proline-rich ligand/SH3 interaction occurs exclusively in an intramolecular fashion and no intermolecular binding is observed [12].
  • Function can be restored in Itk-deficient NKT cells by provision of calcium signals using ionomycin [18].

Physical interactions of Itk


Enzymatic interactions of Itk

  • Biochemically, Itk is directly phosphorylated and activated by Lck [20].

Regulatory relationships of Itk


Other interactions of Itk

  • However the Itk/Fyn doubly deficient mice exhibited a more severe defect in TCR-induced proliferation of thymocytes and peripheral T cells than did mice deficient in either kinase alone [9].
  • We also show that Tec can phosphorylate p62(dok), one CD28-specific substrate, whereas Itk cannot [21].
  • The sequence of rlk showed that it is most closely related to the subfamily of cytoplasmic tyrosine kinases that includes the Btk, Itk, and Tec proteins [24].
  • Itk functions to control actin polymerization at the immune synapse through localized activation of Cdc42 and WASP [25].
  • The Itk/Lck doubly deficient mice exhibited a phenotype similar to that of Lck-deficient mice [9].

Analytical, diagnostic and therapeutic context of Itk


  1. Identification of Itk/Tsk Src homology 3 domain ligands. Bunnell, S.C., Henry, P.A., Kolluri, R., Kirchhausen, T., Rickles, R.J., Berg, L.J. J. Biol. Chem. (1996) [Pubmed]
  2. Interleukin-2-inducible T cell kinase regulates mast cell degranulation and acute allergic responses. Forssell, J., Sideras, P., Eriksson, C., Malm-Erjefält, M., Rydell-Törmänen, K., Ericsson, P.O., Erjefält, J.S. Am. J. Respir. Cell Mol. Biol. (2005) [Pubmed]
  3. Kinase-independent functions for Itk in TCR-induced regulation of Vav and the actin cytoskeleton. Dombroski, D., Houghtling, R.A., Labno, C.M., Precht, P., Takesono, A., Caplen, N.J., Billadeau, D.D., Wange, R.L., Burkhardt, J.K., Schwartzberg, P.L. J. Immunol. (2005) [Pubmed]
  4. Antiviral immune responses in Itk-deficient mice. Bachmann, M.F., Littman, D.R., Liao, X.C. J. Virol. (1997) [Pubmed]
  5. Tec family kinases in T lymphocyte development and function. Berg, L.J., Finkelstein, L.D., Lucas, J.A., Schwartzberg, P.L. Annu. Rev. Immunol. (2005) [Pubmed]
  6. Regulatory intramolecular association in a tyrosine kinase of the Tec family. Andreotti, A.H., Bunnell, S.C., Feng, S., Berg, L.J., Schreiber, S.L. Nature (1997) [Pubmed]
  7. Altered development of CD8+ T cell lineages in mice deficient for the Tec kinases Itk and Rlk. Broussard, C., Fleischecker, C., Horai, R., Chetana, M., Venegas, A.M., Sharp, L.L., Hedrick, S.M., Fowlkes, B.J., Schwartzberg, P.L. Immunity (2006) [Pubmed]
  8. The Tec family tyrosine kinases Itk and Rlk regulate the development of conventional CD8+ T cells. Atherly, L.O., Lucas, J.A., Felices, M., Yin, C.C., Reiner, S.L., Berg, L.J. Immunity (2006) [Pubmed]
  9. Itk and Fyn make independent contributions to T cell activation. Liao, X.C., Littman, D.R., Weiss, A. J. Exp. Med. (1997) [Pubmed]
  10. Tec kinases Itk and Rlk are required for CD8+ T cell responses to virus infection independent of their role in CD4+ T cell help. Atherly, L.O., Brehm, M.A., Welsh, R.M., Berg, L.J. J. Immunol. (2006) [Pubmed]
  11. The role of Tec family kinases in T cell development and function. Lucas, J.A., Miller, A.T., Atherly, L.O., Berg, L.J. Immunol. Rev. (2003) [Pubmed]
  12. Determinants of intra versus intermolecular self-association within the regulatory domains of Rlk and Itk. Laederach, A., Cradic, K.W., Fulton, D.B., Andreotti, A.H. J. Mol. Biol. (2003) [Pubmed]
  13. Involvement of Bruton's tyrosine kinase in FcepsilonRI-dependent mast cell degranulation and cytokine production. Hata, D., Kawakami, Y., Inagaki, N., Lantz, C.S., Kitamura, T., Khan, W.N., Maeda-Yamamoto, M., Miura, T., Han, W., Hartman, S.E., Yao, L., Nagai, H., Goldfeld, A.E., Alt, F.W., Galli, S.J., Witte, O.N., Kawakami, T. J. Exp. Med. (1998) [Pubmed]
  14. Fine-tuning lymphocyte regulation: what's new with tyrosine kinases and phosphatases? Cannons, J.L., Schwartzberg, P.L. Curr. Opin. Immunol. (2004) [Pubmed]
  15. Activation and interaction with protein kinase C of a cytoplasmic tyrosine kinase, Itk/Tsk/Emt, on Fc epsilon RI cross-linking on mast cells. Kawakami, Y., Yao, L., Tashiro, M., Gibson, S., Mills, G.B., Kawakami, T. J. Immunol. (1995) [Pubmed]
  16. Signaling through Itk promotes T helper 2 differentiation via negative regulation of T-bet. Miller, A.T., Wilcox, H.M., Lai, Z., Berg, L.J. Immunity (2004) [Pubmed]
  17. Altered T cell receptor signaling and disrupted T cell development in mice lacking Itk. Liao, X.C., Littman, D.R. Immunity (1995) [Pubmed]
  18. A key role for Itk in both IFN gamma and IL-4 production by NKT cells. Au-Yeung, B.B., Fowell, D.J. J. Immunol. (2007) [Pubmed]
  19. Cyclophilin A regulates TCR signal strength in CD4+ T cells via a proline-directed conformational switch in Itk. Colgan, J., Asmal, M., Neagu, M., Yu, B., Schneidkraut, J., Lee, Y., Sokolskaja, E., Andreotti, A., Luban, J. Immunity (2004) [Pubmed]
  20. The absence of Itk inhibits positive selection without changing lineage commitment. Lucas, J.A., Atherly, L.O., Berg, L.J. J. Immunol. (2002) [Pubmed]
  21. The role of Tec protein-tyrosine kinase in T cell signaling. Yang, W.C., Ghiotto, M., Barbarat, B., Olive, D. J. Biol. Chem. (1999) [Pubmed]
  22. Tec kinases regulate TCR-mediated recruitment of signaling molecules and integrin-dependent cell adhesion. Finkelstein, L.D., Shimizu, Y., Schwartzberg, P.L. J. Immunol. (2005) [Pubmed]
  23. Defective Fas ligand expression and activation-induced cell death in the absence of IL-2-inducible T cell kinase. Miller, A.T., Berg, L.J. J. Immunol. (2002) [Pubmed]
  24. Identification of Rlk, a novel protein tyrosine kinase with predominant expression in the T cell lineage. Hu, Q., Davidson, D., Schwartzberg, P.L., Macchiarini, F., Lenardo, M.J., Bluestone, J.A., Matis, L.A. J. Biol. Chem. (1995) [Pubmed]
  25. Itk functions to control actin polymerization at the immune synapse through localized activation of Cdc42 and WASP. Labno, C.M., Lewis, C.M., You, D., Leung, D.W., Takesono, A., Kamberos, N., Seth, A., Finkelstein, L.D., Rosen, M.K., Schwartzberg, P.L., Burkhardt, J.K. Curr. Biol. (2003) [Pubmed]
  26. 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]
  27. Localization of the human IL-2-inducible T-cell kinase gene (ITK) to chromosome band 5q34 and the mouse gene (Itk) to chromosome 15 by fluorescence in situ hybridization. Tate, G., Okuyama, M., Okamoto, M., Futaki, G., Kimura, S., Endo, Y., Mitsuya, T., Katagiri, M. Cytogenet. Cell Genet. (1996) [Pubmed]
  28. Differential roles of Lck and Itk in T cell response to antigen recognition revealed by calcium imaging and electron microscopy. Donnadieu, E., Lang, V., Bismuth, G., Ellmeier, W., Acuto, O., Michel, F., Trautmann, A. J. Immunol. (2001) [Pubmed]
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