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

• CypA bound Itk via the PPIase active site [19].

Enzymatic interactions of Itk

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

Regulatory relationships of Itk

• Signaling through Itk promotes T helper 2 differentiation via negative regulation of T-bet [16].
• Itk is expressed primarily in T cells and activated by TCR/CD3, CD28, and CD2 [21].
• Under these suboptimal TCR stimulation conditions, ICAM-2 could also enhance the recruitment of signaling molecules in Itk-/-, but not Rlk-/-Itk-/- T cells [22].
• Kinase-independent functions for Itk in TCR-induced regulation of Vav and the actin cytoskeleton [3].
• Defective Fas ligand expression and activation-induced cell death in the absence of IL-2-inducible T cell kinase [23].

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

• To determine whether Itk has an analogous role in T lymphocytes, we used gene targeting to prepare mice lacking expression of Itk [17].
• By Southern blot analysis of DNA from the progeny of two multilocus crosses, murine Itk was mapped to Chromosome 11 [26].
• 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 [27].
• Differential roles of Lck and Itk in T cell response to antigen recognition revealed by calcium imaging and electron microscopy [28].

References