The tyrosine phosphorylation cascade initiated by Lck and Fyn culminates in the intracellular mobilization of calcium (Ca2+) ions and activation of important signaling cascades within the lymphocyte. These include the Ras-MEK-ERK pathway, which goes on to activate certain transcription factors such as NFAT, NF-κB, and AP-1. These transcription factors regulate the production of a plethora of gene products, most notable, cytokines such as Interleukin-2 that promote long-term proliferation and differentiation of the activated lymphocytes.
The function of Lck has been studied using several biochemical methods, including gene knockout (knock-out mice), Jurkat cells deficient in Lck (JCaM1.6), and siRNA-mediated RNA interference.
Lck is a 56-kilodalton protein. The N-terminal tail of Lck is myristoylated and palmitoylated, which tethers the protein to the plasma membrane of the cell. The protein furthermore contains a SH3 domain, a SH2 domain and in the C-terminal part the tyrosine kinase domain. The two main phosphorylation sites on Lck are tyrosines 394 and 505. The former is an autophosphorylation site and is linked to activation of the protein. The latter is phosphorylated by Csk, which inhibits Lck because the protein folds up and binds its own SH2 domain. Lck thus serves as an instructive example that protein phosphorylation may result in both activation and inhibition.
In resting T cells, Lck is constitutively inhibited by Csk phosphorylation on tyrosine 505. Lck is also inhibited by SHP-1 dephosphorylation on tyrosine 394. Lck can also be inhibited by Cbl ubiquitin ligase, which is part of the ubiquitin-mediated pathway.
Saractinib, a specific inhibitor of LCK impairs maintenance of human T-ALL cells in vitro as well as in vivo by targeting this tyrosine kinase in cells displaying high level of lipid rafts.
↑Buffière A, Accogli T, Saint-Paul L, Lucchi G, Uzan B, Ballerini P, Bastie JN, Delva L, Pflumio F, Quéré R (February 2018). "Saracatinib impairs maintenance of human T-ALL by targeting the LCK tyrosine kinase in cells displaying high level of lipid rafts". Leukemia. doi:10.1038/s41375-018-0081-5. PMID29535432.
↑Gil da Costa RM (July 2015). "C-kit as a prognostic and therapeutic marker in canine cutaneous mast cell tumours: From laboratory to clinic". Veterinary Journal. 205 (1): 5–10. doi:10.1016/j.tvjl.2015.05.002. PMID26021891.
↑Poghosyan Z, Robbins SM, Houslay MD, Webster A, Murphy G, Edwards DR (February 2002). "Phosphorylation-dependent interactions between ADAM15 cytoplasmic domain and Src family protein-tyrosine kinases". The Journal of Biological Chemistry. 277 (7): 4999–5007. doi:10.1074/jbc.M107430200. PMID11741929.
↑Taher TE, Smit L, Griffioen AW, Schilder-Tol EJ, Borst J, Pals ST (February 1996). "Signaling through CD44 is mediated by tyrosine kinases. Association with p56lck in T lymphocytes". The Journal of Biological Chemistry. 271 (5): 2863–7. doi:10.1074/jbc.271.5.2863. PMID8576267.
↑Ilangumaran S, Briol A, Hoessli DC (May 1998). "CD44 selectively associates with active Src family protein tyrosine kinases Lck and Fyn in glycosphingolipid-rich plasma membrane domains of human peripheral blood lymphocytes". Blood. 91 (10): 3901–8. PMID9573028.
↑Hawash IY, Hu XE, Adal A, Cassady JM, Geahlen RL, Harrison ML (April 2002). "The oxygen-substituted palmitic acid analogue, 13-oxypalmitic acid, inhibits Lck localization to lipid rafts and T cell signaling". Biochimica et Biophysica Acta. 1589 (2): 140–50. doi:10.1016/s0167-4889(02)00165-9. PMID12007789.
↑Marcus SL, Winrow CJ, Capone JP, Rachubinski RA (November 1996). "A p56(lck) ligand serves as a coactivator of an orphan nuclear hormone receptor". The Journal of Biological Chemistry. 271 (44): 27197–200. doi:10.1074/jbc.271.44.27197. PMID8910285.
↑Hanada T, Lin L, Chandy KG, Oh SS, Chishti AH (October 1997). "Human homologue of the Drosophila discs large tumor suppressor binds to p56lck tyrosine kinase and Shaker type Kv1.3 potassium channel in T lymphocytes". The Journal of Biological Chemistry. 272 (43): 26899–904. doi:10.1074/jbc.272.43.26899. PMID9341123.
↑ 16.016.1Sade H, Krishna S, Sarin A (January 2004). "The anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt/PKB-mediated signaling in T cells". The Journal of Biological Chemistry. 279 (4): 2937–44. doi:10.1074/jbc.M309924200. PMID14583609.
↑Yu CL, Jin YJ, Burakoff SJ (January 2000). "Cytosolic tyrosine dephosphorylation of STAT5. Potential role of SHP-2 in STAT5 regulation". The Journal of Biological Chemistry. 275 (1): 599–604. doi:10.1074/jbc.275.1.599. PMID10617656.
↑Chiang GG, Sefton BM (June 2001). "Specific dephosphorylation of the Lck tyrosine protein kinase at Tyr-394 by the SHP-1 protein-tyrosine phosphatase". The Journal of Biological Chemistry. 276 (25): 23173–8. doi:10.1074/jbc.M101219200. PMID11294838.
↑Koretzky GA, Kohmetscher M, Ross S (April 1993). "CD45-associated kinase activity requires lck but not T cell receptor expression in the Jurkat T cell line". The Journal of Biological Chemistry. 268 (12): 8958–64. PMID8473339.
↑Ng DH, Watts JD, Aebersold R, Johnson P (January 1996). "Demonstration of a direct interaction between p56lck and the cytoplasmic domain of CD45 in vitro". The Journal of Biological Chemistry. 271 (3): 1295–300. doi:10.1074/jbc.271.3.1295. PMID8576115.
↑Pelosi M, Di Bartolo V, Mounier V, Mège D, Pascussi JM, Dufour E, Blondel A, Acuto O (May 1999). "Tyrosine 319 in the interdomain B of ZAP-70 is a binding site for the Src homology 2 domain of Lck". The Journal of Biological Chemistry. 274 (20): 14229–37. doi:10.1074/jbc.274.20.14229. PMID10318843.
Sasaoka T, Kobayashi M (August 2000). "The functional significance of Shc in insulin signaling as a substrate of the insulin receptor". Endocrine Journal. 47 (4): 373–81. doi:10.1507/endocrj.47.373. PMID11075717.
Zamoyska R, Basson A, Filby A, Legname G, Lovatt M, Seddon B (February 2003). "The influence of the src-family kinases, Lck and Fyn, on T cell differentiation, survival and activation". Immunological Reviews. 191: 107–18. doi:10.1034/j.1600-065X.2003.00015.x. PMID12614355.
Leavitt SA, SchOn A, Klein JC, Manjappara U, Chaiken IM, Freire E (February 2004). "Interactions of HIV-1 proteins gp120 and Nef with cellular partners define a novel allosteric paradigm". Current Protein & Peptide Science. 5 (1): 1–8. doi:10.2174/1389203043486955. PMID14965316.
Tolstrup M, Ostergaard L, Laursen AL, Pedersen SF, Duch M (April 2004). "HIV/SIV escape from immune surveillance: focus on Nef". Current HIV Research. 2 (2): 141–51. doi:10.2174/1570162043484924. PMID15078178.
Palacios EH, Weiss A (October 2004). "Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation". Oncogene. 23 (48): 7990–8000. doi:10.1038/sj.onc.1208074. PMID15489916.
Levinson AD, Oppermann H, Levintow L, Varmus HE, Bishop JM (October 1978). "Evidence that the transforming gene of avian sarcoma virus encodes a protein kinase associated with a phosphoprotein". Cell. 15 (2): 561–72. doi:10.1016/0092-8674(78)90024-7. PMID214242.
Thomas PM, Samelson LE (June 1992). "The glycophosphatidylinositol-anchored Thy-1 molecule interacts with the p60fyn protein tyrosine kinase in T cells". The Journal of Biological Chemistry. 267 (17): 12317–22. PMID1351058.
Shenoy-Scaria AM, Kwong J, Fujita T, Olszowy MW, Shaw AS, Lublin DM (December 1992). "Signal transduction through decay-accelerating factor. Interaction of glycosyl-phosphatidylinositol anchor and protein tyrosine kinases p56lck and p59fyn 1". Journal of Immunology. 149 (11): 3535–41. PMID1385527.
Brown R, Meldrum C, Cousins S (August 1992). "Are sense-antisense peptide interactions between HIV-1 (gp120), CD4, and the proto oncogene product p56lck important?". Medical Hypotheses. 38 (4): 322–4. doi:10.1016/0306-9877(92)90025-8. PMID1491632.
Cefai D, Ferrer M, Serpente N, Idziorek T, Dautry-Varsat A, Debre P, Bismuth G (July 1992). "Internalization of HIV glycoprotein gp120 is associated with down-modulation of membrane CD4 and p56lck together with impairment of T cell activation". Journal of Immunology. 149 (1): 285–94. PMID1535086.
Molina TJ, Kishihara K, Siderovski DP, van Ewijk W, Narendran A, Timms E, Wakeham A, Paige CJ, Hartmann KU, Veillette A (May 1992). "Profound block in thymocyte development in mice lacking p56lck". Nature. 357 (6374): 161–4. doi:10.1038/357161a0. PMID1579166.
Yoshida H, Koga Y, Moroi Y, Kimura G, Nomoto K (February 1992). "The effect of p56lck, a lymphocyte specific protein tyrosine kinase, on the syncytium formation induced by human immunodeficiency virus envelope glycoprotein". International Immunology. 4 (2): 233–42. doi:10.1093/intimm/4.2.233. PMID1622897.
Torigoe T, O'Connor R, Santoli D, Reed JC (August 1992). "Interleukin-3 regulates the activity of the LYN protein-tyrosine kinase in myeloid-committed leukemic cell lines". Blood. 80 (3): 617–24. PMID1638019.