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

• Regulated association between the tyrosine kinase Emt/Itk/Tsk and phospholipase-C gamma 1 in human T lymphocytes [9].
• As predicted, wild-type rat CD2 was able to activate ITK in Jurkat cells [10].
• We have cloned the complete cDNA for a unique human tyrosine kinase that is expressed mainly in T lymphocytes (EMT) and natural killer (NK) cells [2].
• In hematopoietic cells, expression of the EMT gene was associated with T-cell fractions, but Emt was not detected in cord blood CD34+ cells [11].
• Transcytosis by the P6 HeLa cells was inhibited by C57 a9-9 but not by A-14 ITK or anti-CD4 mAb [12].

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

• By fluorescence in situ hybridization, human ITK was mapped to 5q32-q33 [1].
• Ligation of the CD2 co-stimulatory receptor on human T lymphocytes induces tyrosine phosphorylation and activation of the Tec-family tyrosine kinase, ITK [10].
• In an attempt to correlate the morphologic and immunophenotypic findings in extramedullary myeloid cell tumors (EMT), we studied 28 cases with a large panel of antibodies using paraffin section immunohistochemistry [21].
• Indeed, because it has become easier to perform bone marrow transplantation (EMT), the indications of BMT have become broader, making follow-up of patients receiving grafts a widespread practice [22].
• Nine patients received chemotherapy at the time of EMT and had a median survival of 36 weeks [23].

References