Alternative titles; symbols
HGNC Approved Gene Symbol: TXK
Cytogenetic location: 4p12 Genomic coordinates (GRCh38): 4:48,066,393-48,134,250 (from NCBI)
To identify tyrosine kinases of the Btk/Tec type that are expressed in hematopoietic cell lineages, Haire et al. (1994) isolated a gene for a novel, putative cytoplasmic tyrosine kinase from a human peripheral blood cDNA library. The complete nucleotide sequence of the cDNA indicated that it was related most closely to EMT (186973), a tyrosine kinase of T cells, and to the B-cell tyrosine kinase BTK (300300), which is mutated in X-linked agammaglobulinemia in humans (300755) and X-linked immunodeficiency disease (XID) in mice. Other members of this gene family include BMX and TEC (600583). TXK, like BTK, is a member of the TEC subfamily of SRC-type (nonreceptor) tyrosine kinases. Like other members of the TEC subfamily, and unlike other SRC kinases, TXK lacks both the N-terminal myristylation signal and the C-terminal regulatory tyrosine. TXK expression is detected primarily in T cells and some myeloid cell lines, but not in a number of other cell types.
CTLA4 (123890) binds to CD80 (112203) or CD86 (601020) and acts as a negative regulator of T-cell proliferation. It is capable of binding to the SH2 domains of the lipid kinase PI 3-kinase (see PIK3CG; 601232). Schneider et al. (1998) found that, when expressed in COS cells, RLK, but not inactive RLK or active ZAP70 (176947), readily phosphorylated CTLA4 at the YVKM motif.
TXK expression is restricted to the Th1/Th0 subset of T lymphocytes with gamma-interferon (IFNG; 147570)-producing potential. By immunoblot analysis, Takeba et al. (2002) showed that TXK binds to the IFNG promoter in the region -53 to -39 bp from the transcription start site, a site distinct from previously characterized IFNG promoter binding locations. Luciferase reporter analysis indicated that phosphorylated TXK enhances IFNG transcriptional activity severalfold. Comparative sequence analysis established that this DNA-binding motif is conserved not only across mammalian species but also among human Th1 cell-associated protein genes, e.g., CCR5 (601373) and TNF (191160). Takeba et al. (2002) proposed that TXK acts as a Th1 cell-specific transcription factor.
Hwang et al. (2005) reported that TBET (604895) represses Th2 lineage commitment through tyrosine kinase-mediated interaction between itself and GATA3 (131320) that interferes with the binding of GATA3 to its target DNA. Hwang et al. (2005) concluded that their results provide a novel function for tyrosine phosphorylation of a transcription factor in specifying alternate fates of a common progenitor cell. Hwang et al. (2005) showed that TBET phosphorylation is restricted to the TEC kinases ITK (186973) and RLK. Coexpression studies demonstrated that this was most efficiently performed by ITK. In primary CD4 T cells isolated from ITK-, RLK-, or double ITK/RLK-deficient mice, the greatest diminution of TBET tyrosine phosphorylation was seen in the absence of ITK. Furthermore, mutation of TBET at tyrosine residue 525, but not control tyrosine residue 437, resulted in greatly reduced phosphorylation by ITK, revealing that ITK phosphorylates TBET at residue Y525 after T cell receptor stimulation.
By fluorescence in situ hybridization using genomic clones, Haire et al. (1994) assigned the TXK gene to 4p12, the same location reported for TEC. Haire and Litman (1995) demonstrated that the Txk gene maps to mouse chromosome 5.
By homologous recombination, Schaeffer et al. (1999) disrupted the Rlk gene in mice. Heterozygotes were completely normal. Homozygous null Rlk mice showed increased amounts of Itk mRNA. The authors hypothesized that upregulation of related Tec kinases may partially compensate for the lack of Rlk. Schaeffer et al. (1999) therefore generated Rlk -/- Itk -/- mice by interbreeding. Itk-deficient mice have reduced numbers of mature T cells, particularly CD4+ cells, causing a decreased CD4-to-CD8 ratio. Rlk -/- Itk -/- mutants, however, had normal T cell numbers. Both CD4+ and CD8+ cell numbers are increased relative to Itk -/- mice. The persistent abnormal ratio of CD4+ to CD8+ cells suggested an altered regulation of lymphoid development and homeostasis in the double mutants. The double mutants had marked defects in T-cell receptor responses including proliferation, cytokine production, and apoptosis in vitro and adaptive immune responses to Toxoplasma gondii in vivo. Molecular events immediately downstream from the T-cell receptor were intact in Rlk -/- Itk -/- cells, but intermediate events including inositol trisphosphate production, calcium mobilization, and mitogen-activated protein kinase activation were impaired, establishing Tec kinases as critical regulators of T-cell receptor signaling required for phospholipase C-gamma activation.
Broussard et al. (2006) found that Cd8-positive T cells from mice lacking Itk or both Itk and Rlk expressed memory markers (e.g., Cd44 (107269) and Cd122 (146710)) and rapidly produced Ifng. Itk deficiency greatly increased the number of cells selected by MHC class Ib. Broussard et al. (2006) concluded that the absence of TEC kinases prevents conventional CD8-positive T-cell development and leads to generation of a large population of nonconventional innate-type CD8-positive T cells. Atherly et al. (2006) presented similar findings.
Atherly, L. O., Lucas, J. A., Felices, M., Yin, C. C., Reiner, S. L., Berg, L. J. The Tec family kinases Itk and Rlk regulate the development of conventional CD8+ T cells. Immunity 25: 79-91, 2006. [PubMed: 16860759] [Full Text: https://doi.org/10.1016/j.immuni.2006.05.012]
Broussard, C., Fleischacker, C., Horai, R., Chetana, M., Venegas, A. M., Sharp, L. L., Hedrick, S. M., Fowlkes, B. J., Schwartzberg, P. L. Altered development of CD8+ T cell lineages in mice deficient for the Tec kinases Itk and Rlk. Immunity 25: 93-104, 2006. Note: Erratum: Immunity 25: 849 only, 2006. [PubMed: 16860760] [Full Text: https://doi.org/10.1016/j.immuni.2006.05.011]
Haire, R. N., Litman, G. W. The murine form of TXK, a novel TEC kinase expressed in thymus maps to chromosome 5. Mammalian Genome 6: 476-480, 1995. [PubMed: 7579892] [Full Text: https://doi.org/10.1007/BF00360659]
Haire, R. N., Ohta, Y., Lewis, J. E., Fu, S. M., Kroisel, P., Litman, G. W. TXK, a novel human tyrosine kinase expressed in T cells shares sequence identity with Tec family kinases and maps to 4p12. Hum. Molec. Genet. 3: 897-901, 1994. [PubMed: 7951233] [Full Text: https://doi.org/10.1093/hmg/3.6.897]
Hwang, E. S., Szabo, S. J., Schwartzberg, P. L., Glimcher, L. H. T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science 307: 430-433, 2005. [PubMed: 15662016] [Full Text: https://doi.org/10.1126/science.1103336]
Schaeffer, E. M., Debnath, J., Yap, G., McVicar, D., Liao, X. C., Littman, D. R., Sher, A., Varmus, H. E., Lenardo, M. J., Schwartzberg, P. L. Requirement for Tec kinases Rlk and Itk in T cell receptor signaling and immunity. Science 284: 638-641, 1999. [PubMed: 10213685] [Full Text: https://doi.org/10.1126/science.284.5414.638]
Schneider, H., Schwartzberg, P. L., Rudd, C. E. Resting lymphocyte kinase (Rlk/Txk) phosphorylates the YVKM motif and regulates PI 3-kinase binding to T-cell antigen CTLA-4. Biochem. Biophys. Res. Commun. 252: 14-19, 1998. [PubMed: 9813138] [Full Text: https://doi.org/10.1006/bbrc.1998.9559]
Takeba, Y., Nagafuchi, H., Takeno, M., Kashiwakura, J., Suzuki, N. Txk, a member of nonreceptor tyrosine kinase of Tec family, acts as a Th1 cell-specific transcription factor and regulates IFN-gamma gene transcription. J. Immun. 168: 2365-2370, 2002. [PubMed: 11859127] [Full Text: https://doi.org/10.4049/jimmunol.168.5.2365]