Lck

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Lymphocyte-specific protein tyrosine kinase
1lkkA SH2 domain.png
The SH2 domain of human Lck colored from blue (N-terminus) to red (C-terminus).
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols LCK ; LSK; YT16; p56lck; pp58lck
External IDs OMIM153390 MGI96756 HomoloGene3911 ChEMBL: 258 GeneCards: LCK Gene
EC number 2.7.10.2
RNA expression pattern
PBB GE LCK 204891 s at tn.png
PBB GE LCK 204890 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 3932 16818
Ensembl ENSG00000182866 ENSMUSG00000000409
UniProt P06239 P06240
RefSeq (mRNA) NM_001042771 NM_001162432
RefSeq (protein) NP_001036236 NP_001155904
Location (UCSC) Chr 1:
32.72 – 32.75 Mb
Chr 4:
129.55 – 129.57 Mb
PubMed search [1] [2]

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.

Lck and T cell signaling[edit]

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.

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[edit]

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[edit]

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.

Lck inhibition[edit]

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]

Interactions[edit]

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]

See also[edit]

References[edit]

  1. ^ Rao, et al. (2002). "Negative regulation of Lck by Cbl ubiquitin ligase". PNAS 99: 3794–3799. 
  2. ^ Yu, C L; Jin Y J; Burakoff S J (January 2000). "Cytosolic tyrosine dephosphorylation of STAT5. Potential role of SHP-2 in STAT5 regulation". J. Biol. Chem. (UNITED STATES) 275 (1): 599–604. doi:10.1074/jbc.275.1.599. ISSN 0021-9258. PMID 10617656. 
  3. ^ Chiang, G G; Sefton B M (June 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 (March 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. PMC 358540. 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. doi:10.1074/jbc.274.20.14229. ISSN 0021-9258. PMID 10318843. 
  6. ^ a b Thome, M; Duplay P; Guttinger M; Acuto O (June 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. doi:10.1084/jem.181.6.1997. ISSN 0022-1007. PMC 2192070. PMID 7539035. 
  7. ^ a b Sade, Hadassah; Krishna Sudhir; Sarin Apurva (January 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 (December 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. PMC 364842. PMID 8246987. 
  9. ^ Poghosyan, Zaruhi; Robbins Stephen M; Houslay Miles D; Webster Ailsa; Murphy Gillian; Edwards Dylan R (February 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 (April 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. doi:10.1016/S0167-4889(02)00165-9. ISSN 0006-3002. PMID 12007789. 
  11. ^ Foti, Michelangelo; Phelouzat Marie-Anne; Holm Asa; Rasmusson Birgitta J; Carpentier Jean-Louis (February 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. PMC 122310. PMID 11854499. 
  12. ^ Taher, T E; Smit L; Griffioen A W; Schilder-Tol E J; Borst J; Pals S T (February 1996). "Signaling through CD44 is mediated by tyrosine kinases. Association with p56lck in T lymphocytes". J. Biol. Chem. (UNITED STATES) 271 (5): 2863–7. doi:10.1074/jbc.271.5.2863. 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 (April 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 (January 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. doi:10.1074/jbc.271.3.1295. ISSN 0021-9258. PMID 8576115. 
  16. ^ Hanada, T; Lin L; Chandy K G; Oh S S; Chishti A H (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". J. Biol. Chem. (UNITED STATES) 272 (43): 26899–904. doi:10.1074/jbc.272.43.26899. ISSN 0021-9258. PMID 9341123. 
  17. ^ Bell, G M; Fargnoli J; Bolen J B; Kish L; Imboden J B (January 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. doi:10.1084/jem.183.1.169. ISSN 0022-1007. PMC 2192399. PMID 8551220. 
  18. ^ Gorska, Magdalena M; Stafford Susan J; Cen Osman; Sur Sanjiv; Alam Rafeul (February 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. PMC 2211793. PMID 14757743. 
  19. ^ Oda, H; Kumar S; Howley P M (August 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. doi:10.1073/pnas.96.17.9557. ISSN 0027-8424. PMC 22247. PMID 10449731. 
  20. ^ Marcus, S L; Winrow C J; Capone J P; Rachubinski R A (November 1996). "A p56(lck) ligand serves as a coactivator of an orphan nuclear hormone receptor". J. Biol. Chem. (UNITED STATES) 271 (44): 27197–200. doi:10.1074/jbc.271.44.27197. ISSN 0021-9258. PMID 8910285. 

Further reading[edit]

External links[edit]