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Gene Review

Lck  -  lymphocyte protein tyrosine kinase

Mus musculus

Synonyms: Hck-3, LSK, Leukocyte C-terminal Src kinase, Lsk, Lsk-t, ...
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Disease relevance of Lck

  • Constitutive activation of the Janus kinase-STAT pathway in T lymphoma overexpressing the Lck protein tyrosine kinase [1].
  • Dysregulation of Lck expression or Lck kinase activity has been implicated in T cell leukemias from mice to humans, although the mechanism underlying Lck-mediated oncogenesis is still largely unclear [1].
  • We have typed 368 backcross mice for the four proviruses, Nppa, Lck, and D4Smh6b [2].
  • Here we present the characterization of a thymoma from an Lck(-/-) mouse, where the block in thymocyte development is overcome and the transition between the CD4(-)CD8(-) and CD4(+)CD8(+) stages is fully restored [3].
  • The lack of the Lck protein produces a spectrum of retinal pathology that resembles human retinopathy of prematurity (ROP) [4].

High impact information on Lck

  • The lymphocyte-specific cytoplasmic protein-tyrosine kinase p56lck (Lck) is essential for T cell development and activation [5].
  • The main TCR signalling pathways, such as tyrosine kinases Zap-70 and Lck, Ras/mitogen-activated kinases, phospholipase Cgamma-1 and Ca2+ mobilization, were not affected in Cbl-b(-/-) T cells [6].
  • We show here that the sarcoma (Src) family kinase Lck (p56lck) is required for efficient CVB3 replication in T-cell lines and for viral replication and persistence in vivo [7].
  • The protein Lck (p56lck) has a relative molecular mass of 56,000 and belongs to the Src family of tyrosine kinases [8].
  • Lck associates specifically with the cytoplasmic domains of both CD4 and CD8 T-cell surface glycoproteins and interacts with the beta-chain of the interleukin-2 receptor, which implicates Lck activity in signal transduction during thymocyte ontogeny and activation of mature T cells [8].

Biological context of Lck

  • We have previously shown that Lck plays a major role in the tyrosine phosphorylation of the TCR-zeta chain and the ZAP-70 PTK [9].
  • These data suggest that Lck has a functional role in regulation of TCR signal transduction in thymocytes [10].
  • The function of Csk as a repressor of Lck and Fyn activity suggests activation of these PTKs is solely responsible for the phenotype observed in csk-deficient T lineage cells [11].
  • In addition, whereas T cell stimulation results in down-regulation of Lck, no significant change in ZAP-70 or Syk protein is detected [12].
  • We found that as a result of arresting cells in mitosis, forms of Lck were generated that migrated with slower mobilities on SDS-polyacrylamide gels [13].

Anatomical context of Lck


Associations of Lck with chemical compounds


Physical interactions of Lck

  • Finally, Lck derived from unstimulated Jurkat T cells formed stable complexes with the intracellular domain of the Fas receptor [21].
  • Using unstimulated T lymphocytes, we further demonstrated that Lck binds to HS1 in vivo and that HS1 is tyrosine phosphorylated upon TCR stimulation [22].
  • The results presented demonstrate that IL-2 signal transduction results in the functional uncoupling of the TCR complex through altering the subcellular distribution of kinase-active Lck [23].
  • Interestingly, the ability of CD45-AP to interact with Lck in the absence of other lymphoid-specific molecules was proportional to the degree of catalytic activation of p56(lck) [24].

Enzymatic interactions of Lck

  • Consistently, Vav was strongly phosphorylated in Lck-deficient JCAM-1 cells after CD28 ligation [25].
  • TCR/CD3 recruitment is accompanied by the accumulation of a series of prominent tyrosine-phosphorylated substrates and by an increase of the Lck activity in DIMs [26].
  • We examined here whether Tyr-394 in kinase-deficient Lck was phosphorylated following exposure of cells devoid of endogenous Src family kinase activity to H(2)O(2) [27].
  • Biochemically, Itk is directly phosphorylated and activated by Lck [28].
  • Among the NTec2-bound Lyn proteins, only the p56 form seems to be inducibly tyrosine-phosphorylated in response to IL-3 [29].

Regulatory relationships of Lck

  • Csk recruited to rafts would then be activated and inhibit the kinase activity of Lck to keep resting T cells in a quiescent state [30].
  • One candidate is Fyn, a Src kinase coexpressed with Lck in immature and mature T cells [14].
  • Lck regulates the tyrosine phosphorylation of the T cell receptor subunits and ZAP-70 in murine thymocytes [10].
  • Regulation of Fyn through translocation of activated Lck into lipid rafts [31].
  • Lck dependence of signaling pathways activated by gamma-irradiation and CD3 epsilon engagement in RAG-1(-/-)-immature thymocytes [32].

Other interactions of Lck

  • The engagement of these receptors leads to the activation of Lck and Fyn, which are protein tyrosine kinases (PTKs) of the Src family [33].
  • These observations reveal that Fyn can subserve some Lck-like functions in T cell development [14].
  • Antagonist stimulation increased tyrosine phosphorylation and kinase activity of Fyn severalfold, whereas little or no increase in Lck and ZAP-70 activity was observed [15].
  • Because HS1 associates with the p56(lck) and p59(lyn) tyrosine kinases in vitro and in vivo, and becomes tyrosine phosphorylated upon various receptor stimulations, our present data suggest that HS1 mediates linkage between Lck or Lyn and Grb2 in lymphoid lineage cells [34].
  • Differentiation of ES cells to embryoid bodies was associated with rapid transcriptional silencing of Hck and Lck and with the loss of the corresponding kinase proteins [35].

Analytical, diagnostic and therapeutic context of Lck

  • Immunoprecipitation studies of anti-Fas-stimulated human Jurkat and murine 2B4.11 T cells revealed activation of the Src-family tyrosine kinases Lck and Fyn [21].
  • To determine how this distribution is achieved, we analyzed the location of Lck in lymphoid and in transfected nonlymphoid cells by immunofluorescence [18].
  • Lck is required for activation-induced T cell death after TCR ligation with partial agonists [36].
  • Lck gene expression was identified after isolating and sequencing the specific 5' and 3' part of the cDNA obtained by RT-PCR [4].
  • In vivo studies showed that cardioprotection elicited either by cardiac-specific transgenic activation of PKCepsilon or by ischemic preconditioning enhances the formation of PKCepsilon-Lck modules [37].


  1. Constitutive activation of the Janus kinase-STAT pathway in T lymphoma overexpressing the Lck protein tyrosine kinase. Yu, C.L., Jove, R., Burakoff, S.J. J. Immunol. (1997) [Pubmed]
  2. Genetic map of the region surrounding the retrovirus restriction locus, Fv1, on mouse chromosome 4. Stoye, J.P., Kaushik, N., Jeremiah, S., Best, S. Mamm. Genome (1995) [Pubmed]
  3. Restoration of thymic development in an Lck(-/-) thymoma overexpressing ZAP-70. Ulivieri, C., Majolini, M.B., Baldari, C.T. Mol. Immunol. (2000) [Pubmed]
  4. Retinal dysplasia in mice lacking p56lck. Omri, B., Blancher, C., Neron, B., Marty, M.C., Rutin, J., Molina, T.J., Pessac, B., Crisanti, P. Oncogene (1998) [Pubmed]
  5. A kinase-independent function of Lck in potentiating antigen-specific T cell activation. Xu, H., Littman, D.R. Cell (1993) [Pubmed]
  6. Cbl-b regulates the CD28 dependence of T-cell activation. Chiang, Y.J., Kole, H.K., Brown, K., Naramura, M., Fukuhara, S., Hu, R.J., Jang, I.K., Gutkind, J.S., Shevach, E., Gu, H. Nature (2000) [Pubmed]
  7. The tyrosine kinase p56lck is essential in coxsackievirus B3-mediated heart disease. Liu, P., Aitken, K., Kong, Y.Y., Opavsky, M.A., Martino, T., Dawood, F., Wen, W.H., Kozieradzki, I., Bachmaier, K., Straus, D., Mak, T.W., Penninger, J.M. Nat. Med. (2000) [Pubmed]
  8. Profound block in thymocyte development in mice lacking p56lck. Molina, T.J., Kishihara, K., Siderovski, D.P., van Ewijk, W., Narendran, A., Timms, E., Wakeham, A., Paige, C.J., Hartmann, K.U., Veillette, A. Nature (1992) [Pubmed]
  9. Tyrosine phosphorylation of Pyk2 is selectively regulated by Fyn during TCR signaling. Qian, D., Lev, S., van Oers, N.S., Dikic, I., Schlessinger, J., Weiss, A. J. Exp. Med. (1997) [Pubmed]
  10. Lck regulates the tyrosine phosphorylation of the T cell receptor subunits and ZAP-70 in murine thymocytes. van Oers, N.S., Killeen, N., Weiss, A. J. Exp. Med. (1996) [Pubmed]
  11. Autonomous maturation of alpha/beta T lineage cells in the absence of COOH-terminal Src kinase (Csk). Schmedt, C., Tarakhovsky, A. J. Exp. Med. (2001) [Pubmed]
  12. Differential expression of ZAP-70 and Syk protein tyrosine kinases, and the role of this family of protein tyrosine kinases in TCR signaling. Chan, A.C., van Oers, N.S., Tran, A., Turka, L., Law, C.L., Ryan, J.C., Clark, E.A., Weiss, A. J. Immunol. (1994) [Pubmed]
  13. The protein-tyrosine kinase Lck associates with and is phosphorylated by Cdc2. Pathan, N.I., Geahlen, R.L., Harrison, M.L. J. Biol. Chem. (1996) [Pubmed]
  14. Fyn can partially substitute for Lck in T lymphocyte development. Groves, T., Smiley, P., Cooke, M.P., Forbush, K., Perlmutter, R.M., Guidos, C.J. Immunity (1996) [Pubmed]
  15. T-cell receptor antagonists induce Vav phosphorylation by selective activation of Fyn kinase. Huang, J., Tilly, D., Altman, A., Sugie, K., Grey, H.M. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  16. Microdomain-dependent regulation of Lck and Fyn protein-tyrosine kinases in T lymphocyte plasma membranes. Ilangumaran, S., Arni, S., van Echten-Deckert, G., Borisch, B., Hoessli, D.C. Mol. Biol. Cell (1999) [Pubmed]
  17. Functional requirements for signaling through the stimulatory and inhibitory mouse NKR-P1 (CD161) NK cell receptors. Ljutic, B., Carlyle, J.R., Filipp, D., Nakagawa, R., Julius, M., Zúñiga-Pflücker, J.C. J. Immunol. (2005) [Pubmed]
  18. Intrinsic signals in the unique domain target p56(lck) to the plasma membrane independently of CD4. Bijlmakers, M.J., Isobe-Nakamura, M., Ruddock, L.J., Marsh, M. J. Cell Biol. (1997) [Pubmed]
  19. Subdomain X of the kinase domain of Lck binds CD45 and facilitates dephosphorylation. Felberg, J., Lefebvre, D.C., Lam, M., Wang, Y., Ng, D.H., Birkenhead, D., Cross, J.L., Johnson, P. J. Biol. Chem. (2004) [Pubmed]
  20. Regulation of the low molecular weight phosphotyrosine phosphatase by phosphorylation at tyrosines 131 and 132. Tailor, P., Gilman, J., Williams, S., Couture, C., Mustelin, T. J. Biol. Chem. (1997) [Pubmed]
  21. Activation of Src-family tyrosine kinases during Fas-induced apoptosis. Schlottmann, K.E., Gulbins, E., Lau, S.M., Coggeshall, K.M. J. Leukoc. Biol. (1996) [Pubmed]
  22. Distinct binding patterns of HS1 to the Src SH2 and SH3 domains reflect possible mechanisms of recruitment and activation of downstream molecules. Takemoto, Y., Sato, M., Furuta, M., Hashimoto, Y. Int. Immunol. (1996) [Pubmed]
  23. Interleukin 2-mediated uncoupling of T cell receptor alpha/beta from CD3 signaling. Haughn, L., Leung, B., Boise, L., Veillette, A., Thompson, C., Julius, M. J. Exp. Med. (1998) [Pubmed]
  24. Interactions of CD45-associated protein with the antigen receptor signaling machinery in T-lymphocytes. Veillette, A., Soussou, D., Latour, S., Davidson, D., Gervais, F.G. J. Biol. Chem. (1999) [Pubmed]
  25. Fyn and ZAP-70 are required for Vav phosphorylation in T cells stimulated by antigen-presenting cells. Michel, F., Grimaud, L., Tuosto, L., Acuto, O. J. Biol. Chem. (1998) [Pubmed]
  26. Engagement of T cell receptor triggers its recruitment to low-density detergent-insoluble membrane domains. Montixi, C., Langlet, C., Bernard, A.M., Thimonier, J., Dubois, C., Wurbel, M.A., Chauvin, J.P., Pierres, M., He, H.T. EMBO J. (1998) [Pubmed]
  27. Phosphorylation of a Src kinase at the autophosphorylation site in the absence of Src kinase activity. Chiang, G.G., Sefton, B.M. J. Biol. Chem. (2000) [Pubmed]
  28. The absence of Itk inhibits positive selection without changing lineage commitment. Lucas, J.A., Atherly, L.O., Berg, L.J. J. Immunol. (2002) [Pubmed]
  29. Tec protein-tyrosine kinase directly associates with Lyn protein-tyrosine kinase through its N-terminal unique domain. Mano, H., Sato, K., Yazaki, Y., Hirai, H. Oncogene (1994) [Pubmed]
  30. Cutting edge: Fyn is essential for tyrosine phosphorylation of Csk-binding protein/phosphoprotein associated with glycolipid-enriched microdomains in lipid rafts in resting T cells. Yasuda, K., Nagafuku, M., Shima, T., Okada, M., Yagi, T., Yamada, T., Minaki, Y., Kato, A., Tani-Ichi, S., Hamaoka, T., Kosugi, A. J. Immunol. (2002) [Pubmed]
  31. Regulation of Fyn through translocation of activated Lck into lipid rafts. Filipp, D., Zhang, J., Leung, B.L., Shaw, A., Levin, S.D., Veillette, A., Julius, M. J. Exp. Med. (2003) [Pubmed]
  32. Lck dependence of signaling pathways activated by gamma-irradiation and CD3 epsilon engagement in RAG-1(-/-)-immature thymocytes. Wu, G., Danska, J.S., Guidos, C.J. Int. Immunol. (1996) [Pubmed]
  33. Csk controls antigen receptor-mediated development and selection of T-lineage cells. Schmedt, C., Saijo, K., Niidome, T., Kühn, R., Aizawa, S., Tarakhovsky, A. Nature (1998) [Pubmed]
  34. Growth factor receptor-bound protein 2 (Grb2) association with hemopoietic specific protein 1: linkage between Lck and Grb2. Takemoto, Y., Furuta, M., Sato, M., Findell, P.R., Ramble, W., Hashimoto, Y. J. Immunol. (1998) [Pubmed]
  35. SRC family kinase activity is required for murine embryonic stem cell growth and differentiation. Meyn, M.A., Schreiner, S.J., Dumitrescu, T.P., Nau, G.J., Smithgall, T.E. Mol. Pharmacol. (2005) [Pubmed]
  36. Lck is required for activation-induced T cell death after TCR ligation with partial agonists. Yu, X.Z., Levin, S.D., Madrenas, J., Anasetti, C. J. Immunol. (2004) [Pubmed]
  37. Formation of protein kinase C(epsilon)-Lck signaling modules confers cardioprotection. Ping, P., Song, C., Zhang, J., Guo, Y., Cao, X., Li, R.C., Wu, W., Vondriska, T.M., Pass, J.M., Tang, X.L., Pierce, W.M., Bolli, R. J. Clin. Invest. (2002) [Pubmed]
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