Lck: Wikis


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Lymphocyte-specific protein tyrosine kinase

The SH2 domain of human Lck colored from blue (N-terminus) to red (C-terminus).
Available structures
1bhf, 1bhh, 1cwd, 1cwe, 1fbz, 1h92, 1ijr, 1kik, 1lcj, 1lck, 1lkk, 1lkl, 1q68, 1q69, 1qpc, 1qpd, 1qpe, 1qpj, 1x27, 2iim, 2of2, 2of4, 2ofu, 2ofv, 2og8, 3lck
Symbols LCK; YT16; p56lck; pp58lck
External IDs OMIM153390 MGI96756 HomoloGene3911 GeneCards: LCK Gene
RNA expression pattern
PBB GE LCK 204891 s at tn.png
PBB GE LCK 204890 s at tn.png
More reference expression data
Species Human Mouse
Entrez 3932 16818
Ensembl ENSG00000182866 n/a
UniProt P06239 n/a
RefSeq (mRNA) NM_001042771 XM_992422
RefSeq (protein) NP_001036236 XP_997516
Location (UCSC) Chr 1:
32.49 - 32.52 Mb
PubMed search [1] [2]

Lck (or leukocyte-specific protein tyrosine kinase) is a 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.


Lck and 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 a 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, NFκB, 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 structure

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 substrates

Lck tyrosine phosphorylates a number of proteins, the most important of which are the CD3 receptor, ZAP-70, SLP-76, the IL-2 receptor, Protein kinase C, ITK, PLC, SHC, RasGAP, Cbl, Vav1, and PI3K.

Lck 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.[1]


Lck has been shown to interact with PTPN6,[2][3][4] ZAP-70,[5][6] Syk,[6] P110α,[7][8] ADAM15,[9] CD4,[10][11] CD44,[12][13] PTPRC,[14][15] DLG1,[16] CD2,[17] Protein unc-119 homolog,[18] UBE3A,[19] NOTCH1[7] and COUP-TFII.[20]


  1. ^ Rao et al. Negative regulation of Lck by Cbl ubiquitin ligase. PNAS, 2002,vol. 99, 3794-3799.
  2. ^ Yu, C L; Jin Y J, Burakoff S J (Jan. 2000). "Cytosolic tyrosine dephosphorylation of STAT5. Potential role of SHP-2 in STAT5 regulation". J. Biol. Chem. (UNITED STATES) 275 (1): 599–604. ISSN 0021-9258. PMID 10617656.  
  3. ^ Chiang, G G; Sefton B M (Jun. 2001). "Specific dephosphorylation of the Lck tyrosine protein kinase at Tyr-394 by the SHP-1 protein-tyrosine phosphatase". J. Biol. Chem. (United States) 276 (25): 23173–8. doi:10.1074/jbc.M101219200. ISSN 0021-9258. PMID 11294838.  
  4. ^ Lorenz, U; Ravichandran K S, Pei D, Walsh C T, Burakoff S J, Neel B G (Mar. 1994). "Lck-dependent tyrosyl phosphorylation of the phosphotyrosine phosphatase SH-PTP1 in murine T cells". Mol. Cell. Biol. (UNITED STATES) 14 (3): 1824–34. ISSN 0270-7306. PMID 8114715.  
  5. ^ Pelosi, M; Di Bartolo V, Mounier V, Mège D, Pascussi J M, 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". J. Biol. Chem. (UNITED STATES) 274 (20): 14229–37. ISSN 0021-9258. PMID 10318843.  
  6. ^ a b 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". J. Exp. Med. (UNITED STATES) 181 (6): 1997–2006. ISSN 0022-1007. PMID 7539035.  
  7. ^ a b Sade, Hadassah; Krishna Sudhir, Sarin Apurva (Jan. 2004). "The anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt/PKB-mediated signaling in T cells". J. Biol. Chem. (United States) 279 (4): 2937–44. doi:10.1074/jbc.M309924200. ISSN 0021-9258. PMID 14583609.  
  8. ^ Prasad, K V; Kapeller R, Janssen O, Repke H, Duke-Cohan J S, Cantley L C, Rudd C E (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". Mol. Cell. Biol. (UNITED STATES) 13 (12): 7708–17. ISSN 0270-7306. PMID 8246987.  
  9. ^ Poghosyan, Zaruhi; Robbins Stephen M, Houslay Miles D, Webster Ailsa, Murphy Gillian, Edwards Dylan R (Feb. 2002). "Phosphorylation-dependent interactions between ADAM15 cytoplasmic domain and Src family protein-tyrosine kinases". J. Biol. Chem. (United States) 277 (7): 4999–5007. doi:10.1074/jbc.M107430200. ISSN 0021-9258. PMID 11741929.  
  10. ^ Hawash, Ibrahim Y; Hu X Eric, Adal Adiam, Cassady John M, Geahlen Robert L, Harrison Marietta L (Apr. 2002). "The oxygen-substituted palmitic acid analogue, 13-oxypalmitic acid, inhibits Lck localization to lipid rafts and T cell signaling". Biochim. Biophys. Acta (Netherlands) 1589 (2): 140–50. ISSN 0006-3002. PMID 12007789.  
  11. ^ Foti, Michelangelo; Phelouzat Marie-Anne, Holm Asa, Rasmusson Birgitta J, Carpentier Jean-Louis (Feb. 2002). "p56Lck anchors CD4 to distinct microdomains on microvilli". Proc. Natl. Acad. Sci. U.S.A. (United States) 99 (4): 2008–13. doi:10.1073/pnas.042689099. ISSN 0027-8424. PMID 11854499.  
  12. ^ Taher, T E; Smit L, Griffioen A W, Schilder-Tol E J, Borst J, Pals S T (Feb. 1996). "Signaling through CD44 is mediated by tyrosine kinases. Association with p56lck in T lymphocytes". J. Biol. Chem. (UNITED STATES) 271 (5): 2863–7. ISSN 0021-9258. PMID 8576267.  
  13. ^ Ilangumaran, S; Briol A, Hoessli D C (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 (UNITED STATES) 91 (10): 3901–8. ISSN 0006-4971. PMID 9573028.  
  14. ^ Koretzky, G A; Kohmetscher M, Ross S (Apr. 1993). "CD45-associated kinase activity requires lck but not T cell receptor expression in the Jurkat T cell line". J. Biol. Chem. (UNITED STATES) 268 (12): 8958–64. ISSN 0021-9258. PMID 8473339.  
  15. ^ Ng, D H; Watts J D, Aebersold R, Johnson P (Jan. 1996). "Demonstration of a direct interaction between p56lck and the cytoplasmic domain of CD45 in vitro". J. Biol. Chem. (UNITED STATES) 271 (3): 1295–300. ISSN 0021-9258. PMID 8576115.  
  16. ^ Hanada, T; Lin L, Chandy K G, Oh S S, Chishti A H (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". J. Biol. Chem. (UNITED STATES) 272 (43): 26899–904. ISSN 0021-9258. PMID 9341123.  
  17. ^ Bell, G M; Fargnoli J, Bolen J B, Kish L, Imboden J B (Jan. 1996). "The SH3 domain of p56lck binds to proline-rich sequences in the cytoplasmic domain of CD2". J. Exp. Med. (UNITED STATES) 183 (1): 169–78. ISSN 0022-1007. PMID 8551220.  
  18. ^ Gorska, Magdalena M; Stafford Susan J, Cen Osman, Sur Sanjiv, Alam Rafeul (Feb. 2004). "Unc119, a novel activator of Lck/Fyn, is essential for T cell activation". J. Exp. Med. (United States) 199 (3): 369–79. doi:10.1084/jem. 20030589. ISSN 0022-1007. PMID 14757743.  
  19. ^ Oda, H; Kumar S, Howley P M (Aug. 1999). "Regulation of the Src family tyrosine kinase Blk through E6AP-mediated ubiquitination". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 96 (17): 9557–62. ISSN 0027-8424. PMID 10449731.  
  20. ^ Marcus, S L; Winrow C J, Capone J P, Rachubinski R A (Nov. 1996). "A p56(lck) ligand serves as a coactivator of an orphan nuclear hormone receptor". J. Biol. Chem. (UNITED STATES) 271 (44): 27197–200. ISSN 0021-9258. PMID 8910285.  

Further reading

  • Sasaoka T, Kobayashi M (2000). "The functional significance of Shc in insulin signaling as a substrate of the insulin receptor.". Endocr. J. 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 Biol. Int. 26 (6): 567–71. doi:10.1006/cbir.2002.0900. PMID 12171035.  
  • Mustelin T, Taskén K (2003). "Positive and negative regulation of T-cell activation through kinases and phosphatases.". Biochem. J. 371 (Pt 1): 15–27. doi:10.1042/BJ20021637. PMID 12485116.  
  • Zamoyska R, Basson A, Filby A, et al. (2003). "The influence of the src-family kinases, Lck and Fyn, on T cell differentiation, survival and activation.". Immunol. Rev. 191: 107–18. doi:10.1034/j.1600-065X.2003.00015.x. PMID 12614355.  
  • Summy JM, Gallick GE (2004). "Src family kinases in tumor progression and metastasis.". Cancer Metastasis Rev. 22 (4): 337–58. doi:10.1023/A:1023772912750. PMID 12884910.  
  • Leavitt SA, SchOn A, Klein JC, et al. (2004). "Interactions of HIV-1 proteins gp120 and Nef with cellular partners define a novel allosteric paradigm.". Curr. Protein Pept. Sci. 5 (1): 1–8. doi:10.2174/1389203043486955. PMID 14965316.  
  • Tolstrup M, Ostergaard L, Laursen AL, et al. (2004). "HIV/SIV escape from immune surveillance: focus on Nef.". Curr. HIV Res. 2 (2): 141–51. doi:10.2174/1570162043484924. PMID 15078178.  
  • Palacios EH, Weiss A (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 (2005). "Nef: "necessary and enforcing factor" in HIV infection.". Curr. HIV Res. 3 (1): 87–94. doi:10.2174/1570162052773013. PMID 15638726.  
  • Levinson AD, Oppermann H, Levintow L, et al. (1979). "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 (1992). "The glycophosphatidylinositol-anchored Thy-1 molecule interacts with the p60fyn protein tyrosine kinase in T cells.". J. Biol. Chem. 267 (17): 12317–22. PMID 1351058.  
  • Shenoy-Scaria AM, Kwong J, Fujita T, et al. (1992). "Signal transduction through decay-accelerating factor. Interaction of glycosyl-phosphatidylinositol anchor and protein tyrosine kinases p56lck and p59fyn 1.". J. Immunol. 149 (11): 3535–41. PMID 1385527.  
  • Brown R, Meldrum C, Cousins S (1993). "Are sense-antisense peptide interactions between HIV-1 (gp120), CD4, and the proto oncogene product p56lck important?". Med. Hypotheses 38 (4): 322–4. doi:10.1016/0306-9877(92)90025-8. PMID 1491632.  
  • Weber JR, Bell GM, Han MY, et al. (1992). "Association of the tyrosine kinase LCK with phospholipase C-gamma 1 after stimulation of the T cell antigen receptor.". J. Exp. Med. 176 (2): 373–9. doi:10.1084/jem.176.2.373. PMID 1500851.  
  • Cefai D, Ferrer M, Serpente N, et al. (1992). "Internalization of HIV glycoprotein gp120 is associated with down-modulation of membrane CD4 and p56lck together with impairment of T cell activation.". J. Immunol. 149 (1): 285–94. PMID 1535086.  
  • Soula M, Fagard R, Fischer S (1992). "Interaction of human immunodeficiency virus glycoprotein 160 with CD4 in Jurkat cells increases p56lck autophosphorylation and kinase activity.". Int. Immunol. 4 (2): 295–9. doi:10.1093/intimm/4.2.295. PMID 1535787.  
  • Crise B, Rose JK (1992). "Human immunodeficiency virus type 1 glycoprotein precursor retains a CD4-p56lck complex in the endoplasmic reticulum.". J. Virol. 66 (4): 2296–301. PMID 1548763.  
  • Molina TJ, Kishihara K, Siderovski DP, et al. (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, et al. (1992). "The effect of p56lck, a lymphocyte specific protein tyrosine kinase, on the syncytium formation induced by human immunodeficiency virus envelope glycoprotein.". Int. Immunol. 4 (2): 233–42. doi:10.1093/intimm/4.2.233. PMID 1622897.  
  • Torigoe T, O'Connor R, Santoli D, Reed JC (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.  

See also

External links



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