Abstract
T lymphocytes are activated by interactions with antigens, lymphokines, and cell adhesion molecules. Tyrosine phosphorylation has been implicated as important in signaling through each of these pathways, but except for p56lck, a member of the Src family that associates with CD4 and CD8, the protein-tyrosine kinases involved have not been defined. We describe here a tyrosine kinase gene that we have designated itk (for IL-2-inducible T-cell kinase). The itk gene specifies a 72-kDa protein-tyrosine kinase that is related to members of the Src family but lacks two features characteristic of Src kinases: an N-terminal myristoylation consensus sequence and a regulatory tyrosine residue near the C terminus. Analysis of mouse tissues and cell lines indicates that itk is specifically expressed in the T-cell lineage, suggesting that the tyrosine kinase encoded by itk functions in a signal transduction pathway unique to T lymphocytes. On addition of IL-2 to responsive T cells, itk RNA increases in parallel with that of IL-2R alpha, implicating itk in T-cell activation.
Full text
PDF




Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Appleby M. W., Gross J. A., Cooke M. P., Levin S. D., Qian X., Perlmutter R. M. Defective T cell receptor signaling in mice lacking the thymic isoform of p59fyn. Cell. 1992 Sep 4;70(5):751–763. doi: 10.1016/0092-8674(92)90309-z. [DOI] [PubMed] [Google Scholar]
- Baker P. E., Gillis S., Smith K. A. Monoclonal cytolytic T-cell lines. J Exp Med. 1979 Jan 1;149(1):273–278. doi: 10.1084/jem.149.1.273. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Blackman M. A., Tigges M. A., Minie M. E., Koshland M. E. A model system for peptide hormone action in differentiation: interleukin 2 induces a B lymphoma to transcribe the J chain gene. Cell. 1986 Nov 21;47(4):609–617. doi: 10.1016/0092-8674(86)90625-2. [DOI] [PubMed] [Google Scholar]
- Chan A. C., Irving B. A., Weiss A. New insights into T-cell antigen receptor structure and signal transduction. Curr Opin Immunol. 1992 Jun;4(3):246–251. doi: 10.1016/0952-7915(92)90072-m. [DOI] [PubMed] [Google Scholar]
- Cooke M. P., Abraham K. M., Forbush K. A., Perlmutter R. M. Regulation of T cell receptor signaling by a src family protein-tyrosine kinase (p59fyn). Cell. 1991 Apr 19;65(2):281–291. doi: 10.1016/0092-8674(91)90162-r. [DOI] [PubMed] [Google Scholar]
- Cooke M. P., Perlmutter R. M. Expression of a novel form of the fyn proto-oncogene in hematopoietic cells. New Biol. 1989 Oct;1(1):66–74. [PubMed] [Google Scholar]
- Depper J. M., Leonard W. J., Drogula C., Krönke M., Waldmann T. A., Greene W. C. Interleukin 2 (IL-2) augments transcription of the IL-2 receptor gene. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4230–4234. doi: 10.1073/pnas.82.12.4230. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dymecki S. M., Zwollo P., Zeller K., Kuhajda F. P., Desiderio S. V. Structure and developmental regulation of the B-lymphoid tyrosine kinase gene blk. J Biol Chem. 1992 Mar 5;267(7):4815–4823. [PubMed] [Google Scholar]
- Fearon E. R., Pardoll D. M., Itaya T., Golumbek P., Levitsky H. I., Simons J. W., Karasuyama H., Vogelstein B., Frost P. Interleukin-2 production by tumor cells bypasses T helper function in the generation of an antitumor response. Cell. 1990 Feb 9;60(3):397–403. doi: 10.1016/0092-8674(90)90591-2. [DOI] [PubMed] [Google Scholar]
- Gregory R. J., Kammermeyer K. L., Vincent W. S., 3rd, Wadsworth S. G. Primary sequence and developmental expression of a novel Drosophila melanogaster src gene. Mol Cell Biol. 1987 Jun;7(6):2119–2127. doi: 10.1128/mcb.7.6.2119. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hanks S. K., Quinn A. M., Hunter T. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science. 1988 Jul 1;241(4861):42–52. doi: 10.1126/science.3291115. [DOI] [PubMed] [Google Scholar]
- Hatakeyama M., Kono T., Kobayashi N., Kawahara A., Levin S. D., Perlmutter R. M., Taniguchi T. Interaction of the IL-2 receptor with the src-family kinase p56lck: identification of novel intermolecular association. Science. 1991 Jun 14;252(5012):1523–1528. doi: 10.1126/science.2047859. [DOI] [PubMed] [Google Scholar]
- Hatakeyama M., Mori H., Doi T., Taniguchi T. A restricted cytoplasmic region of IL-2 receptor beta chain is essential for growth signal transduction but not for ligand binding and internalization. Cell. 1989 Dec 1;59(5):837–845. doi: 10.1016/0092-8674(89)90607-7. [DOI] [PubMed] [Google Scholar]
- Irving B. A., Weiss A. The cytoplasmic domain of the T cell receptor zeta chain is sufficient to couple to receptor-associated signal transduction pathways. Cell. 1991 Mar 8;64(5):891–901. doi: 10.1016/0092-8674(91)90314-o. [DOI] [PubMed] [Google Scholar]
- June C. H., Fletcher M. C., Ledbetter J. A., Schieven G. L., Siegel J. N., Phillips A. F., Samelson L. E. Inhibition of tyrosine phosphorylation prevents T-cell receptor-mediated signal transduction. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7722–7726. doi: 10.1073/pnas.87.19.7722. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kamps M. P., Sefton B. M. Acid and base hydrolysis of phosphoproteins bound to immobilon facilitates analysis of phosphoamino acids in gel-fractionated proteins. Anal Biochem. 1989 Jan;176(1):22–27. doi: 10.1016/0003-2697(89)90266-2. [DOI] [PubMed] [Google Scholar]
- Kmiecik T. E., Shalloway D. Activation and suppression of pp60c-src transforming ability by mutation of its primary sites of tyrosine phosphorylation. Cell. 1987 Apr 10;49(1):65–73. doi: 10.1016/0092-8674(87)90756-2. [DOI] [PubMed] [Google Scholar]
- Kozak M. Structural features in eukaryotic mRNAs that modulate the initiation of translation. J Biol Chem. 1991 Oct 25;266(30):19867–19870. [PubMed] [Google Scholar]
- MacDonald H. R., Lees R. K., Bron C., Sordat B., Miescher G. T cell antigen receptor expression in athymic (nu/nu) mice. Evidence for an oligoclonal beta chain repertoire. J Exp Med. 1987 Jul 1;166(1):195–209. doi: 10.1084/jem.166.1.195. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Marth J. D., Peet R., Krebs E. G., Perlmutter R. M. A lymphocyte-specific protein-tyrosine kinase gene is rearranged and overexpressed in the murine T cell lymphoma LSTRA. Cell. 1985 Dec;43(2 Pt 1):393–404. doi: 10.1016/0092-8674(85)90169-2. [DOI] [PubMed] [Google Scholar]
- Merida I., Gaulton G. N. Protein tyrosine phosphorylation associated with activation of the interleukin 2 receptor. J Biol Chem. 1990 Apr 5;265(10):5690–5694. [PubMed] [Google Scholar]
- Nada S., Okada M., MacAuley A., Cooper J. A., Nakagawa H. Cloning of a complementary DNA for a protein-tyrosine kinase that specifically phosphorylates a negative regulatory site of p60c-src. Nature. 1991 May 2;351(6321):69–72. doi: 10.1038/351069a0. [DOI] [PubMed] [Google Scholar]
- Saltzman E. M., Thom R. R., Casnellie J. E. Activation of a tyrosine protein kinase is an early event in the stimulation of T lymphocytes by interleukin-2. J Biol Chem. 1988 May 25;263(15):6956–6959. [PubMed] [Google Scholar]
- Samelson L. E., Fletcher M. C., Ledbetter J. A., June C. H. Activation of tyrosine phosphorylation in human T cells via the CD2 pathway. Regulation by the CD45 tyrosine phosphatase. J Immunol. 1990 Oct 15;145(8):2448–2454. [PubMed] [Google Scholar]
- Samelson L. E., Phillips A. F., Luong E. T., Klausner R. D. Association of the fyn protein-tyrosine kinase with the T-cell antigen receptor. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4358–4362. doi: 10.1073/pnas.87.11.4358. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shaw G., Kamen R. A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell. 1986 Aug 29;46(5):659–667. doi: 10.1016/0092-8674(86)90341-7. [DOI] [PubMed] [Google Scholar]
- Simon M. A., Kornberg T. B., Bishop J. M. Three loci related to the src oncogene and tyrosine-specific protein kinase activity in Drosophila. Nature. 1983 Apr 28;302(5911):837–839. doi: 10.1038/302837a0. [DOI] [PubMed] [Google Scholar]
- Stein P. L., Lee H. M., Rich S., Soriano P. pp59fyn mutant mice display differential signaling in thymocytes and peripheral T cells. Cell. 1992 Sep 4;70(5):741–750. doi: 10.1016/0092-8674(92)90308-y. [DOI] [PubMed] [Google Scholar]
- Takeshita T., Asao H., Ohtani K., Ishii N., Kumaki S., Tanaka N., Munakata H., Nakamura M., Sugamura K. Cloning of the gamma chain of the human IL-2 receptor. Science. 1992 Jul 17;257(5068):379–382. doi: 10.1126/science.1631559. [DOI] [PubMed] [Google Scholar]
- Tanaka A., Gibbs C. P., Arthur R. R., Anderson S. K., Kung H. J., Fujita D. J. DNA sequence encoding the amino-terminal region of the human c-src protein: implications of sequence divergence among src-type kinase oncogenes. Mol Cell Biol. 1987 May;7(5):1978–1983. doi: 10.1128/mcb.7.5.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Taniguchi T., Kobayashi T., Kondo J., Takahashi K., Nakamura H., Suzuki J., Nagai K., Yamada T., Nakamura S., Yamamura H. Molecular cloning of a porcine gene syk that encodes a 72-kDa protein-tyrosine kinase showing high susceptibility to proteolysis. J Biol Chem. 1991 Aug 25;266(24):15790–15796. [PubMed] [Google Scholar]
- Towler D. A., Gordon J. I., Adams S. P., Glaser L. The biology and enzymology of eukaryotic protein acylation. Annu Rev Biochem. 1988;57:69–99. doi: 10.1146/annurev.bi.57.070188.000441. [DOI] [PubMed] [Google Scholar]
- Vandenberghe P., Freeman G. J., Nadler L. M., Fletcher M. C., Kamoun M., Turka L. A., Ledbetter J. A., Thompson C. B., June C. H. Antibody and B7/BB1-mediated ligation of the CD28 receptor induces tyrosine phosphorylation in human T cells. J Exp Med. 1992 Apr 1;175(4):951–960. doi: 10.1084/jem.175.4.951. [DOI] [PMC free article] [PubMed] [Google Scholar]