Abstract
The activity of Src-related protein-tyrosine kinases is repressed by the phosphorylation of a conserved carboxyl-terminal tyrosine by another cytoplasmic protein-tyrosine kinase termed p50csk. In this study, we characterize Ntk, a protein-tyrosine kinase bearing striking similarities to p50csk. Like p50csk, Ntk possesses Src homology 3 and Src homology 2 domains and lacks the consensus tyrosine phosphorylation and myristoylation sites found in members of the Src family. Expression of ntk transcripts was maximal in brain, and was observed at significant levels in thymus and spleen. ntk RNA levels were dramatically reduced upon mitogenic stimulation of normal T lymphocytes and were minimal in transformed T-cell populations. Firm evidence that Ntk is a Csk-related enzyme was provided by the observation that it phosphorylated a Src-related polypeptide on the inhibitory carboxyl-terminal tyrosine. These findings indicate that Ntk is a Csk-related enzyme that may play an inhibitory role in the control of T-cell proliferation.
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- Abraham K. M., Levin S. D., Marth J. D., Forbush K. A., Perlmutter R. M. Thymic tumorigenesis induced by overexpression of p56lck. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3977–3981. doi: 10.1073/pnas.88.9.3977. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Abraham N., Miceli M. C., Parnes J. R., Veillette A. Enhancement of T-cell responsiveness by the lymphocyte-specific tyrosine protein kinase p56lck. Nature. 1991 Mar 7;350(6313):62–66. doi: 10.1038/350062a0. [DOI] [PubMed] [Google Scholar]
- Bergman M., Mustelin T., Oetken C., Partanen J., Flint N. A., Amrein K. E., Autero M., Burn P., Alitalo K. The human p50csk tyrosine kinase phosphorylates p56lck at Tyr-505 and down regulates its catalytic activity. EMBO J. 1992 Aug;11(8):2919–2924. doi: 10.1002/j.1460-2075.1992.tb05361.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bräuninger A., Karn T., Strebhardt K., Rübsamen-Waigmann H. Characterization of the human CSK locus. Oncogene. 1993 May;8(5):1365–1369. [PubMed] [Google Scholar]
- Carrera A. C., Alexandrov K., Roberts T. M. The conserved lysine of the catalytic domain of protein kinases is actively involved in the phosphotransfer reaction and not required for anchoring ATP. Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):442–446. doi: 10.1073/pnas.90.2.442. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
- Chow L. M., Fournel M., Davidson D., Veillette A. Negative regulation of T-cell receptor signalling by tyrosine protein kinase p50csk. Nature. 1993 Sep 9;365(6442):156–160. doi: 10.1038/365156a0. [DOI] [PubMed] [Google Scholar]
- Cooper J. A., Howell B. The when and how of Src regulation. Cell. 1993 Jun 18;73(6):1051–1054. doi: 10.1016/0092-8674(93)90634-3. [DOI] [PubMed] [Google Scholar]
- Gervais F. G., Chow L. M., Lee J. M., Branton P. E., Veillette A. The SH2 domain is required for stable phosphorylation of p56lck at tyrosine 505, the negative regulatory site. Mol Cell Biol. 1993 Nov;13(11):7112–7121. doi: 10.1128/mcb.13.11.7112. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hanks S. K., Quinn A. M. Protein kinase catalytic domain sequence database: identification of conserved features of primary structure and classification of family members. Methods Enzymol. 1991;200:38–62. doi: 10.1016/0076-6879(91)00126-h. [DOI] [PubMed] [Google Scholar]
- Haughn L., Gratton S., Caron L., Sékaly R. P., Veillette A., Julius M. Association of tyrosine kinase p56lck with CD4 inhibits the induction of growth through the alpha beta T-cell receptor. Nature. 1992 Jul 23;358(6384):328–331. doi: 10.1038/358328a0. [DOI] [PubMed] [Google Scholar]
- Hay J. M., Kaswin R., Trémolières F., Maillard J. N. Perforations caecales au cours des dilatations idiopathiques aiguës du côlon. Nouv Presse Med. 1976 Jan 3;5(1):16–18. [PubMed] [Google Scholar]
- Imamoto A., Soriano P. Disruption of the csk gene, encoding a negative regulator of Src family tyrosine kinases, leads to neural tube defects and embryonic lethality in mice. Cell. 1993 Jun 18;73(6):1117–1124. doi: 10.1016/0092-8674(93)90641-3. [DOI] [PubMed] [Google Scholar]
- Ito H., Fukuda Y., Murata K., Kimura A. Transformation of intact yeast cells treated with alkali cations. J Bacteriol. 1983 Jan;153(1):163–168. doi: 10.1128/jb.153.1.163-168.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Klausner R. D., Samelson L. E. T cell antigen receptor activation pathways: the tyrosine kinase connection. Cell. 1991 Mar 8;64(5):875–878. doi: 10.1016/0092-8674(91)90310-u. [DOI] [PubMed] [Google Scholar]
- Leo O., Foo M., Sachs D. H., Samelson L. E., Bluestone J. A. Identification of a monoclonal antibody specific for a murine T3 polypeptide. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1374–1378. doi: 10.1073/pnas.84.5.1374. [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]
- 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]
- Nada S., Yagi T., Takeda H., Tokunaga T., Nakagawa H., Ikawa Y., Okada M., Aizawa S. Constitutive activation of Src family kinases in mouse embryos that lack Csk. Cell. 1993 Jun 18;73(6):1125–1135. doi: 10.1016/0092-8674(93)90642-4. [DOI] [PubMed] [Google Scholar]
- Okada M., Nada S., Yamanashi Y., Yamamoto T., Nakagawa H. CSK: a protein-tyrosine kinase involved in regulation of src family kinases. J Biol Chem. 1991 Dec 25;266(36):24249–24252. [PubMed] [Google Scholar]
- Okada M., Nakagawa H. A protein tyrosine kinase involved in regulation of pp60c-src function. J Biol Chem. 1989 Dec 15;264(35):20886–20893. [PubMed] [Google Scholar]
- Partanen J., Armstrong E., Bergman M., Mäkelä T. P., Hirvonen H., Huebner K., Alitalo K. cyl encodes a putative cytoplasmic tyrosine kinase lacking the conserved tyrosine autophosphorylation site (Y416src). Oncogene. 1991 Nov;6(11):2013–2018. [PubMed] [Google Scholar]
- Sabe H., Knudsen B., Okada M., Nada S., Nakagawa H., Hanafusa H. Molecular cloning and expression of chicken C-terminal Src kinase: lack of stable association with c-Src protein. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2190–2194. doi: 10.1073/pnas.89.6.2190. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shalloway D., Zelenetz A. D., Cooper G. M. Molecular cloning and characterization of the chicken gene homologous to the transforming gene of Rous sarcoma virus. Cell. 1981 May;24(2):531–541. doi: 10.1016/0092-8674(81)90344-5. [DOI] [PubMed] [Google Scholar]
- Siliciano J. D., Morrow T. A., Desiderio S. V. itk, a T-cell-specific tyrosine kinase gene inducible by interleukin 2. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11194–11198. doi: 10.1073/pnas.89.23.11194. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Veillette A., Abraham N., Caron L., Davidson D. The lymphocyte-specific tyrosine protein kinase p56lck. Semin Immunol. 1991 May;3(3):143–152. [PubMed] [Google Scholar]
- Veillette A., Davidson D. Src-related protein tyrosine kinases and T-cell receptor signalling. Trends Genet. 1992 Feb;8(2):61–66. doi: 10.1016/0168-9525(92)90351-4. [DOI] [PubMed] [Google Scholar]
- Veillette A., Foss F. M., Sausville E. A., Bolen J. B., Rosen N. Expression of the lck tyrosine kinase gene in human colon carcinoma and other non-lymphoid human tumor cell lines. Oncogene Res. 1987 Sep-Oct;1(4):357–374. [PubMed] [Google Scholar]
- Weiss A. T cell antigen receptor signal transduction: a tale of tails and cytoplasmic protein-tyrosine kinases. Cell. 1993 Apr 23;73(2):209–212. doi: 10.1016/0092-8674(93)90221-b. [DOI] [PubMed] [Google Scholar]