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|LCK proto-oncogene, Src family tyrosine kinase|
The SH2 domain of human Lck colored from blue (N-terminus) to red (C-terminus).
|Symbols||; IMD22; LSK; YT16; p56lck; pp58lck|
|External IDs||ChEMBL: GeneCards:|
|RNA expression pattern|
Lck (or lymphocyte-specific protein tyrosine kinase) is a 56 kDa protein that is found inside specialized cells of the immune system called lymphocytes. Lck is a tyrosine kinase, which phosphorylates tyrosine residues of certain proteins involved in the intracellular signaling pathways of these lymphocytes. It is a member of the Src family of tyrosine kinases.
T cell signaling
Lck is most commonly found in T cells. It associates with the cytoplasmic tails of the CD4 and CD8 co-receptors on T helper cells and cytotoxic T cells, respectively, to assist signaling from the T cell receptor (TCR) complex. When the T cell receptor is engaged by the specific antigen presented by MHC, Lck acts to phosphorylate the intracellular chains of the CD3 and ζ-chains of the TCR complex, allowing another cytoplasmic tyrosine kinase called ZAP-70 to bind to them. Lck then phosphorylates and activates ZAP-70, which in turn phosphorylates another molecule in the signaling cascade called LAT (short for Linker of Activated T cells), a transmembrane protein that serves as a docking site for a number of other proteins, the most important of which are Shc-Grb2-SOS, PI3K, and phospholipase C (PLC).
The tyrosine phosphorylation cascade initiated by Lck 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.
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.
Lck tyrosine phosphorylates a number of proteins, the most important of which are the CD3 receptor, CEACAM1, ZAP-70, SLP-76, the IL-2 receptor, Protein kinase C, ITK, PLC, SHC, RasGAP, Cbl, Vav1, and PI3K.
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.
Lck has been shown to interact with:
- Rudd CE, Trevillyan JM, Dasgupta JD, Wong LL, Schlossman SF (Jul 1988). "The CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes". Proceedings of the National Academy of Sciences of the United States of America 85 (14): 5190–4. PMID 2455897.
- Barber EK, Dasgupta JD, Schlossman SF, Trevillyan JM, Rudd CE (May 1989). "The CD4 and CD8 antigens are coupled to a protein-tyrosine kinase (p56lck) that phosphorylates the CD3 complex". Proceedings of the National Academy of Sciences of the United States of America 86 (9): 3277–81. PMID 2470098.
- Rao N, Miyake S, Reddi AL, Douillard P, Ghosh AK, Dodge IL et al. (Mar 2002). "Negative regulation of Lck by Cbl ubiquitin ligase". Proceedings of the National Academy of Sciences of the United States of America 99 (6): 3794–9. doi:10.1073/pnas.062055999. PMID 11904433.
- Poghosyan Z, Robbins SM, Houslay MD, Webster A, Murphy G, Edwards DR (Feb 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. PMID 11741929.
- Bell GM, Fargnoli J, Bolen JB, Kish L, Imboden JB (Jan 1996). "The SH3 domain of p56lck binds to proline-rich sequences in the cytoplasmic domain of CD2". The Journal of Experimental Medicine 183 (1): 169–78. PMC 2192399. PMID 8551220.
- Taher TE, Smit L, Griffioen AW, Schilder-Tol EJ, Borst J, Pals ST (Feb 1996). "Signaling through CD44 is mediated by tyrosine kinases. Association with p56lck in T lymphocytes". The Journal of Biological Chemistry 271 (5): 2863–7. PMID 8576267.
- 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. PMID 9573028.
- Hawash IY, Hu XE, Adal A, Cassady JM, Geahlen RL, Harrison ML (Apr 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. PMID 12007789.
- Foti M, Phelouzat MA, Holm A, Rasmusson BJ, Carpentier JL (Feb 2002). "p56Lck anchors CD4 to distinct microdomains on microvilli". Proceedings of the National Academy of Sciences of the United States of America 99 (4): 2008–13. doi:10.1073/pnas.042689099. PMC 122310. PMID 11854499.
- Marcus SL, Winrow CJ, Capone JP, Rachubinski RA (Nov 1996). "A p56(lck) ligand serves as a coactivator of an orphan nuclear hormone receptor". The Journal of Biological Chemistry 271 (44): 27197–200. PMID 8910285.
- Hanada T, Lin L, Chandy KG, Oh SS, Chishti AH (Oct 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. PMID 9341123.
- Sade H, Krishna S, Sarin A (Jan 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. PMID 14583609.
- Prasad KV, Kapeller R, Janssen O, Repke H, Duke-Cohan JS, Cantley LC et al. (Dec 1993). "Phosphatidylinositol (PI) 3-kinase and PI 4-kinase binding to the CD4-p56lck complex: the p56lck SH3 domain binds to PI 3-kinase but not PI 4-kinase". Molecular and Cellular Biology 13 (12): 7708–17. PMC 364842. PMID 8246987.
- Yu CL, Jin YJ, Burakoff SJ (Jan 2000). "Cytosolic tyrosine dephosphorylation of STAT5. Potential role of SHP-2 in STAT5 regulation". The Journal of Biological Chemistry 275 (1): 599–604. PMID 10617656.
- Chiang GG, Sefton BM (Jun 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. PMID 11294838.
- Lorenz U, Ravichandran KS, Pei D, Walsh CT, Burakoff SJ, Neel BG (Mar 1994). "Lck-dependent tyrosyl phosphorylation of the phosphotyrosine phosphatase SH-PTP1 in murine T cells". Molecular and Cellular Biology 14 (3): 1824–34. PMC 358540. PMID 8114715.
- Koretzky GA, Kohmetscher M, Ross S (Apr 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. PMID 8473339.
- Ng DH, Watts JD, Aebersold R, Johnson P (Jan 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. PMID 8576115.
- Gorska MM, Stafford SJ, Cen O, Sur S, Alam R (Feb 2004). "Unc119, a novel activator of Lck/Fyn, is essential for T cell activation". The Journal of Experimental Medicine 199 (3): 369–79. doi:10.1084/jem.20030589. PMC 2211793. PMID 14757743.
- Thome M, Duplay P, Guttinger M, Acuto O (Jun 1995). "Syk and ZAP-70 mediate recruitment of p56lck/CD4 to the activated T cell receptor/CD3/zeta complex". The Journal of Experimental Medicine 181 (6): 1997–2006. PMC 2192070. PMID 7539035.
- Oda H, Kumar S, Howley PM (Aug 1999). "Regulation of the Src family tyrosine kinase Blk through E6AP-mediated ubiquitination". Proceedings of the National Academy of Sciences of the United States of America 96 (17): 9557–62. PMC 22247. PMID 10449731.
- Pelosi M, Di Bartolo V, Mounier V, Mège D, Pascussi JM, Dufour E et al. (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. PMID 10318843.
- Sasaoka T, Kobayashi M (Aug 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. PMID 11075717.
- Goldmann WH (2003). "p56(lck) Controls phosphorylation of filamin (ABP-280) and regulates focal adhesion kinase (pp125(FAK))". Cell Biology International 26 (6): 567–71. doi:10.1006/cbir.2002.0900. PMID 12171035.
- Mustelin T, Taskén K (Apr 2003). "Positive and negative regulation of T-cell activation through kinases and phosphatases". The Biochemical Journal 371 (Pt 1): 15–27. doi:10.1042/BJ20021637. PMC 1223257. PMID 12485116.
- Zamoyska R, Basson A, Filby A, Legname G, Lovatt M, Seddon B (Feb 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. PMID 12614355.
- Summy JM, Gallick GE (Dec 2003). "Src family kinases in tumor progression and metastasis". Cancer Metastasis Reviews 22 (4): 337–58. doi:10.1023/A:1023772912750. PMID 12884910.
- Leavitt SA, SchOn A, Klein JC, Manjappara U, Chaiken IM, Freire E (Feb 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. PMID 14965316.
- Tolstrup M, Ostergaard L, Laursen AL, Pedersen SF, Duch M (Apr 2004). "HIV/SIV escape from immune surveillance: focus on Nef". Current HIV Research 2 (2): 141–51. doi:10.2174/1570162043484924. PMID 15078178.
- Palacios EH, Weiss A (Oct 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. PMID 15489916.
- Joseph AM, Kumar M, Mitra D (Jan 2005). "Nef: "necessary and enforcing factor" in HIV infection". Current HIV Research 3 (1): 87–94. doi:10.2174/1570162052773013. PMID 15638726.
- Levinson AD, Oppermann H, Levintow L, Varmus HE, Bishop JM (Oct 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. PMID 214242.
- Thomas PM, Samelson LE (Jun 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. PMID 1351058.
- Shenoy-Scaria AM, Kwong J, Fujita T, Olszowy MW, Shaw AS, Lublin DM (Dec 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. PMID 1385527.
- Brown R, Meldrum C, Cousins S (Aug 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. PMID 1491632.
- Weber JR, Bell GM, Han MY, Pawson T, Imboden JB (Aug 1992). "Association of the tyrosine kinase LCK with phospholipase C-gamma 1 after stimulation of the T cell antigen receptor". The Journal of Experimental Medicine 176 (2): 373–9. doi:10.1084/jem.176.2.373. PMC 2119313. PMID 1500851.
- Cefai D, Ferrer M, Serpente N, Idziorek T, Dautry-Varsat A, Debre P et al. (Jul 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. PMID 1535086.
- Soula M, Fagard R, Fischer S (Feb 1992). "Interaction of human immunodeficiency virus glycoprotein 160 with CD4 in Jurkat cells increases p56lck autophosphorylation and kinase activity". International Immunology 4 (2): 295–9. doi:10.1093/intimm/4.2.295. PMID 1535787.
- Crise B, Rose JK (Apr 1992). "Human immunodeficiency virus type 1 glycoprotein precursor retains a CD4-p56lck complex in the endoplasmic reticulum". Journal of Virology 66 (4): 2296–301. PMC 289024. PMID 1548763.
- Molina TJ, Kishihara K, Siderovski DP, van Ewijk W, Narendran A, Timms E et al. (May 1992). "Profound block in thymocyte development in mice lacking p56lck". Nature 357 (6374): 161–4. doi:10.1038/357161a0. PMID 1579166.
- Yoshida H, Koga Y, Moroi Y, Kimura G, Nomoto K (Feb 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. PMID 1622897.
- Torigoe T, O'Connor R, Santoli D, Reed JC (Aug 1992). "Interleukin-3 regulates the activity of the LYN protein-tyrosine kinase in myeloid-committed leukemic cell lines". Blood 80 (3): 617–24. PMID 1638019.