• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Jul 5, 1994; 91(14): 6374–6378.
PMCID: PMC44204

Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes.

Abstract

Protein-tyrosine kinases (PTKs) are critical enzymes for receptor-mediated signaling in lymphocytes. Because natural killer (NK) cells are large granular lymphocytes with specialized effector function, we set out to identify PTKs preferentially expressed in these cells. One such PTK was identified and molecularly cloned. The predicted amino acid sequence shows that this kinase lacks SH2 or SH3 domains typical of src family kinases but has tandem nonidentical catalytic domains, indicating that it is a member of the Janus family of PTKs. Immunoprecipitation using antiserum generated against a peptide corresponding to the deduced amino acid sequence of this gene revealed a kinase with a molecular weight of approximately 125,000. The pattern of expression of this kinase contrasted sharply with that of other Janus kinases, which are ubiquitously expressed. The kinase described in the present study was found to be more limited in its expression; expression was found in NK cells and an NK-like cell line but not in resting T cells or in other tissues. In contrast, stimulated and transformed T cells expressed the gene, suggesting a role in lymphoid activation. Because of its homology and tissue expression, we have tentatively termed this PTK gene L-JAK for leukocyte Janus kinase.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.6M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Perlmutter RM, Levin SD, Appleby MW, Anderson SJ, Alberola-Ila J. Regulation of lymphocyte function by protein phosphorylation. Annu Rev Immunol. 1993;11:451–499. [PubMed]
  • Klausner RD, Samelson LE. T cell antigen receptor activation pathways: the tyrosine kinase connection. Cell. 1991 Mar 8;64(5):875–878. [PubMed]
  • 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. [PubMed]
  • Keegan AD, Paul WE. Multichain immune recognition receptors: similarities in structure and signaling pathways. Immunol Today. 1992 Feb;13(2):63–68. [PubMed]
  • Taniguchi T, Minami Y. The IL-2/IL-2 receptor system: a current overview. Cell. 1993 Apr 9;73(1):5–8. [PubMed]
  • Minami Y, Kono T, Miyazaki T, Taniguchi T. The IL-2 receptor complex: its structure, function, and target genes. Annu Rev Immunol. 1993;11:245–268. [PubMed]
  • Stahl N, Yancopoulos GD. The alphas, betas, and kinases of cytokine receptor complexes. Cell. 1993 Aug 27;74(4):587–590. [PubMed]
  • Samelson LE, Phillips AF, Luong ET, Klausner RD. 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. [PMC free article] [PubMed]
  • Timson Gauen LK, Kong AN, Samelson LE, Shaw AS. p59fyn tyrosine kinase associates with multiple T-cell receptor subunits through its unique amino-terminal domain. Mol Cell Biol. 1992 Dec;12(12):5438–5446. [PMC free article] [PubMed]
  • Appleby MW, Gross JA, Cooke MP, Levin SD, Qian X, Perlmutter RM. Defective T cell receptor signaling in mice lacking the thymic isoform of p59fyn. Cell. 1992 Sep 4;70(5):751–763. [PubMed]
  • Stein PL, Lee HM, Rich S, Soriano P. pp59fyn mutant mice display differential signaling in thymocytes and peripheral T cells. Cell. 1992 Sep 4;70(5):741–750. [PubMed]
  • Cooke MP, Abraham KM, Forbush KA, Perlmutter RM. Regulation of T cell receptor signaling by a src family protein-tyrosine kinase (p59fyn). Cell. 1991 Apr 19;65(2):281–291. [PubMed]
  • Veillette A, Bookman MA, Horak EM, Bolen JB. The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56lck. Cell. 1988 Oct 21;55(2):301–308. [PubMed]
  • Veillette A, Abraham N, Caron L, Davidson D. The lymphocyte-specific tyrosine protein kinase p56lck. Semin Immunol. 1991 May;3(3):143–152. [PubMed]
  • Rudd CE, Trevillyan JM, Dasgupta JD, Wong LL, Schlossman SF. The CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5190–5194. [PMC free article] [PubMed]
  • Abraham N, Miceli MC, Parnes JR, Veillette A. Enhancement of T-cell responsiveness by the lymphocyte-specific tyrosine protein kinase p56lck. Nature. 1991 Mar 7;350(6313):62–66. [PubMed]
  • Molina TJ, Kishihara K, Siderovski DP, van Ewijk W, Narendran A, Timms E, Wakeham A, Paige CJ, Hartmann KU, Veillette A, et al. Profound block in thymocyte development in mice lacking p56lck. Nature. 1992 May 14;357(6374):161–164. [PubMed]
  • Straus DB, Weiss A. Genetic evidence for the involvement of the lck tyrosine kinase in signal transduction through the T cell antigen receptor. Cell. 1992 Aug 21;70(4):585–593. [PubMed]
  • Chan AC, Irving BA, Fraser JD, Weiss A. The zeta chain is associated with a tyrosine kinase and upon T-cell antigen receptor stimulation associates with ZAP-70, a 70-kDa tyrosine phosphoprotein. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9166–9170. [PMC free article] [PubMed]
  • Wange RL, Kong AN, Samelson LE. A tyrosine-phosphorylated 70-kDa protein binds a photoaffinity analogue of ATP and associates with both the zeta chain and CD3 components of the activated T cell antigen receptor. J Biol Chem. 1992 Jun 15;267(17):11685–11688. [PubMed]
  • Chan AC, Iwashima M, Turck CW, Weiss A. ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain. Cell. 1992 Nov 13;71(4):649–662. [PubMed]
  • Hatakeyama M, Kono T, Kobayashi N, Kawahara A, Levin SD, Perlmutter RM, 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. [PubMed]
  • Kobayashi N, Kono T, Hatakeyama M, Minami Y, Miyazaki T, Perlmutter RM, Taniguchi T. Functional coupling of the src-family protein tyrosine kinases p59fyn and p53/56lyn with the interleukin 2 receptor: implications for redundancy and pleiotropism in cytokine signal transduction. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4201–4205. [PMC free article] [PubMed]
  • Torigoe T, Saragovi HU, Reed JC. Interleukin 2 regulates the activity of the lyn protein-tyrosine kinase in a B-cell line. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2674–2678. [PMC free article] [PubMed]
  • Wilks AF. Two putative protein-tyrosine kinases identified by application of the polymerase chain reaction. Proc Natl Acad Sci U S A. 1989 Mar;86(5):1603–1607. [PMC free article] [PubMed]
  • Wilks AF, Harpur AG, Kurban RR, Ralph SJ, Zürcher G, Ziemiecki A. Two novel protein-tyrosine kinases, each with a second phosphotransferase-related catalytic domain, define a new class of protein kinase. Mol Cell Biol. 1991 Apr;11(4):2057–2065. [PMC free article] [PubMed]
  • Harpur AG, Andres AC, Ziemiecki A, Aston RR, Wilks AF. JAK2, a third member of the JAK family of protein tyrosine kinases. Oncogene. 1992 Jul;7(7):1347–1353. [PubMed]
  • Firmbach-Kraft I, Byers M, Shows T, Dalla-Favera R, Krolewski JJ. tyk2, prototype of a novel class of non-receptor tyrosine kinase genes. Oncogene. 1990 Sep;5(9):1329–1336. [PubMed]
  • Velazquez L, Fellous M, Stark GR, Pellegrini S. A protein tyrosine kinase in the interferon alpha/beta signaling pathway. Cell. 1992 Jul 24;70(2):313–322. [PubMed]
  • Argetsinger LS, Campbell GS, Yang X, Witthuhn BA, Silvennoinen O, Ihle JN, Carter-Su C. Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase. Cell. 1993 Jul 30;74(2):237–244. [PubMed]
  • Witthuhn BA, Quelle FW, Silvennoinen O, Yi T, Tang B, Miura O, Ihle JN. JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell. 1993 Jul 30;74(2):227–236. [PubMed]
  • Müller M, Briscoe J, Laxton C, Guschin D, Ziemiecki A, Silvennoinen O, Harpur AG, Barbieri G, Witthuhn BA, Schindler C, et al. The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction. Nature. 1993 Nov 11;366(6451):129–135. [PubMed]
  • Watling D, Guschin D, Müller M, Silvennoinen O, Witthuhn BA, Quelle FW, Rogers NC, Schindler C, Stark GR, Ihle JN, et al. Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-gamma signal transduction pathway. Nature. 1993 Nov 11;366(6451):166–170. [PubMed]
  • Shuai K, Ziemiecki A, Wilks AF, Harpur AG, Sadowski HB, Gilman MZ, Darnell JE. Polypeptide signalling to the nucleus through tyrosine phosphorylation of Jak and Stat proteins. Nature. 1993 Dec 9;366(6455):580–583. [PubMed]
  • Silvennoinen O, Ihle JN, Schlessinger J, Levy DE. Interferon-induced nuclear signalling by Jak protein tyrosine kinases. Nature. 1993 Dec 9;366(6455):583–585. [PubMed]
  • Fu XY. A transcription factor with SH2 and SH3 domains is directly activated by an interferon alpha-induced cytoplasmic protein tyrosine kinase(s). Cell. 1992 Jul 24;70(2):323–335. [PubMed]
  • Pellegrini S, Schindler C. Early events in signalling by interferons. Trends Biochem Sci. 1993 Sep;18(9):338–342. [PubMed]
  • Trinchieri G. Biology of natural killer cells. Adv Immunol. 1989;47:187–376. [PubMed]
  • Robertson MJ, Ritz J. Biology and clinical relevance of human natural killer cells. Blood. 1990 Dec 15;76(12):2421–2438. [PubMed]
  • Rodewald HR, Moingeon P, Lucich JL, Dosiou C, Lopez P, Reinherz EL. A population of early fetal thymocytes expressing Fc gamma RII/III contains precursors of T lymphocytes and natural killer cells. Cell. 1992 Apr 3;69(1):139–150. [PubMed]
  • Lanier LL, Spits H, Phillips JH. The developmental relationship between NK cells and T cells. Immunol Today. 1992 Oct;13(10):392–395. [PubMed]
  • Einspahr KJ, Abraham RT, Binstadt BA, Uehara Y, Leibson PJ. Tyrosine phosphorylation provides an early and requisite signal for the activation of natural killer cell cytotoxic function. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6279–6283. [PMC free article] [PubMed]
  • O'Shea JJ, Weissman AM, Kennedy IC, Ortaldo JR. Engagement of the natural killer cell IgG Fc receptor results in tyrosine phosphorylation of the zeta chain. Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):350–354. [PMC free article] [PubMed]
  • Vivier E, Morin P, O'Brien C, Druker B, Schlossman SF, Anderson P. Tyrosine phosphorylation of the Fc gamma RIII(CD16): zeta complex in human natural killer cells. Induction by antibody-dependent cytotoxicity but not by natural killing. J Immunol. 1991 Jan 1;146(1):206–210. [PubMed]
  • O'Shea JJ, McVicar DW, Kuhns DB, Ortaldo JR. A role for protein tyrosine kinase activity in natural cytotoxicity as well as antibody-dependent cellular cytotoxicity. Effects of herbimycin A. J Immunol. 1992 Apr 15;148(8):2497–2502. [PubMed]
  • Siliciano JD, Morrow TA, Desiderio SV. 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. [PMC free article] [PubMed]
  • Hanks SK, Quinn AM, Hunter T. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science. 1988 Jul 1;241(4861):42–52. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Gene
    Gene
    Gene links
  • Gene (nucleotide)
    Gene (nucleotide)
    Records in Gene identified from shared sequence links
  • GEO Profiles
    GEO Profiles
    Related GEO records
  • HomoloGene
    HomoloGene
    HomoloGene links
  • MedGen
    MedGen
    Related information in MedGen
  • Nucleotide
    Nucleotide
    Published Nucleotide sequences
  • OMIM
    OMIM
    OMIM record citing PubMed
  • Pathways + GO
    Pathways + GO
    Pathways, annotations and biological systems (BioSystems) that cite the current article.
  • Protein
    Protein
    Published protein sequences
  • PubMed
    PubMed
    PubMed citations for these articles
  • Taxonomy
    Taxonomy
    Related taxonomy entry
  • Taxonomy Tree
    Taxonomy Tree

Recent Activity

    Your browsing activity is empty.

    Activity recording is turned off.

    Turn recording back on

    See more...