Lck

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
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 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, 2PL0, 2ZM1, 2ZM4, 2ZYB, 3AC1, 3AC2, 3AC3, 3AC4, 3AC5, 3AC8, 3ACJ, 3ACK, 3AD4, 3AD5, 3AD6, 3B2W, 3BRH, 3BYM, 3BYO, 3BYS, 3BYU, 3KMM, 3KXZ, 3LCK, 3MPM, 4D8K, 4C3F
Identifiers
Aliases	LCK, LCK proto-oncogene, Src family tyrosine kinase, IMD22, LSK, YT16, p56lck, pp58lck
External IDs	OMIM: 153390 MGI: 96756 HomoloGene: 3911 GeneCards: LCK
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1p35.2 Start 32,251,239 bp[1] End 32,286,165 bp[1]
Gene location (Mouse) Chr. Chromosome 4 (mouse)[2] Band 4 D2.2|4 63.26 cM Start 129,548,344 bp[2] End 129,573,641 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • transferase activity • nucleotide binding • protein kinase activity • CD4 receptor binding • ATPase binding • SH2 domain binding • CD8 receptor binding • phosphatidylinositol 3-kinase binding • protein C-terminus binding • GO:0001948 protein binding • identical protein binding • protein phosphatase binding • ATP binding • protein kinase binding • phosphatidylinositol-4,5-bisphosphate 3-kinase activity • kinase activity • protein serine/threonine phosphatase activity • non-membrane spanning protein tyrosine kinase activity • phosphotyrosine residue binding • protein tyrosine kinase activity • T cell receptor binding • receptor binding Cellular component • cytoplasm • cytosol • membrane • extrinsic component of cytoplasmic side of plasma membrane • immunological synapse • extracellular exosome • pericentriolar material • membrane raft • cell membrane Biological process • B cell receptor signaling pathway • release of sequestered calcium ion into cytosol • haematopoiesis • phosphorylation • transmembrane receptor protein tyrosine kinase signaling pathway • positive regulation of T cell receptor signaling pathway • T cell costimulation • regulation of defense response to virus by virus • platelet activation • T cell differentiation • regulation of cell proliferation • cellular zinc ion homeostasis • regulation of lymphocyte activation • peptidyl-tyrosine autophosphorylation • T cell receptor signaling pathway • positive regulation of intrinsic apoptotic signaling pathway • leukocyte migration • positive regulation of T cell activation • protein dephosphorylation • innate immune system • phosphatidylinositol phosphorylation • GO:0022415 viral process • protein phosphorylation • activation of cysteine-type endopeptidase activity involved in apoptotic process • response to drug • cell migration • peptidyl-tyrosine phosphorylation • interleukin-7-mediated signaling pathway • positive regulation of protein kinase B signaling • cell differentiation • positive regulation of heterotypic cell-cell adhesion • positive regulation of leukocyte cell-cell adhesion Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	3932	16818
Ensembl	ENSG00000182866	ENSMUSG00000000409
UniProt	P06239	P06240
RefSeq (mRNA)	NM_001042771 NM_005356 NM_001330468	NM_001162432 NM_001162433 NM_010693
RefSeq (protein)	NP_001036236 NP_001317397 NP_005347	NP_001155904 NP_001155905 NP_034823
Location (UCSC)	Chr 1: 32.25 – 32.29 Mb	Chr 4: 129.55 – 129.57 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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,[5][6] 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). Additionally, upon T cell activation, a fraction of kinase active Lck, translocates from outside of lipid rafts (LR) to inside lipid rafts where it interacts with and activates LR-resident Fyn, which is involved in further downstream signaling activation.[7][8]

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. In addition to significance of Lck and Fyn in T cell receptor signaling, these two src kinases have also been shown to be important in TLR-mediated signaling in T cells.[9]

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.

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.

Substrates

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.

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.[10]

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.[11]

Masitinib also inhibits Lck, which may have some impact on its therapeutic effects in canine mastocytoma.[12]

Interactions

Lck has been shown to interact with:

• ADAM15,[13]
• CD2,[14]
• CD44,[15][16]
• CD4,[17][18]
• COUP-TFII,[19]
• DLG1,[20]
• NOTCH1,[21]
• PIK3CA,[21][22]
• PTPN6,[23][24][25]
• PTPRC,[26][27]
• UNC119,[28]
• SYK,[29]
• UBE3A,[30] and
• ZAP70.[29][31]

See also

• Tyrosine kinase
• T cell

References

1. GRCh38: Ensembl release 89: ENSG00000182866 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000000409 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Rudd CE, Trevillyan JM, Dasgupta JD, Wong LL, Schlossman SF (July 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. doi:10.1073/pnas.85.14.5190. PMC 281714. PMID 2455897.
6. 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. doi:10.1073/pnas.86.9.3277. PMC 287114. PMID 2470098.
7. Filipp D, Zhang J, Leung BL, Shaw A, Levin SD, Veillette A, Julius M (May 2003). "Regulation of Fyn through translocation of activated Lck into lipid rafts". The Journal of Experimental Medicine. 197 (9): 1221–7. doi:10.1084/jem.20022112. PMC 2193969. PMID 12732664.
8. Filipp D, Moemeni B, Ferzoco A, Kathirkamathamby K, Zhang J, Ballek O, Davidson D, Veillette A, Julius M (September 2008). "Lck-dependent Fyn activation requires C terminus-dependent targeting of kinase-active Lck to lipid rafts". The Journal of Biological Chemistry. 283 (39): 26409–22. doi:10.1074/jbc.M710372200. PMC 3258908. PMID 18660530.
9. Sharma N, Akhade AS, Qadri A (April 2016). "Src kinases central to T-cell receptor signaling regulate TLR-activated innate immune responses from human T cells". Innate Immunity. 22 (3): 238–244. doi:10.1177/1753425916632305. PMID 26888964.
10. Rao N, Miyake S, Reddi AL, Douillard P, Ghosh AK, Dodge IL, Zhou P, Fernandes ND, Band H (March 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. PMC 122603. PMID 11904433.
11. 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. 32 (9): 2062–2065. doi:10.1038/s41375-018-0081-5. PMID 29535432.
12. Gil da Costa RM (July 2015). "C-kit as a prognostic and therapeutic marker in canine cutaneous mast cell tumours: From laboratory to clinic" (PDF). Veterinary Journal. 205 (1): 5–10. doi:10.1016/j.tvjl.2015.05.002. PMID 26021891.
13. 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. PMID 11741929.
14. Bell GM, Fargnoli J, Bolen JB, Kish L, Imboden JB (January 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. doi:10.1084/jem.183.1.169. PMC 2192399. PMID 8551220.
15. 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. PMID 8576267.
16. 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. doi:10.1182/blood.V91.10.3901. PMID 9573028.
17. 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 (BBA) - Molecular Cell Research. 1589 (2): 140–50. doi:10.1016/s0167-4889(02)00165-9. PMID 12007789.
18. Foti M, Phelouzat MA, Holm A, Rasmusson BJ, Carpentier JL (February 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.
19. 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. PMID 8910285.
20. 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. PMID 9341123.
21. Sade 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. PMID 14583609.
22. Prasad KV, Kapeller R, Janssen O, Repke H, Duke-Cohan JS, Cantley LC, Rudd CE (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". Molecular and Cellular Biology. 13 (12): 7708–17. doi:10.1128/mcb.13.12.7708. PMC 364842. PMID 8246987.
23. 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. PMID 10617656.
24. 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. PMID 11294838.
25. Lorenz U, Ravichandran KS, Pei D, Walsh CT, Burakoff SJ, Neel BG (March 1994). "Lck-dependent tyrosyl phosphorylation of the phosphotyrosine phosphatase SH-PTP1 in murine T cells". Molecular and Cellular Biology. 14 (3): 1824–34. doi:10.1128/mcb.14.3.1824. PMC 358540. PMID 8114715.
26. 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. PMID 8473339.
27. 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. PMID 8576115.
28. Gorska MM, Stafford SJ, Cen O, Sur S, Alam R (February 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.
29. 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". The Journal of Experimental Medicine. 181 (6): 1997–2006. doi:10.1084/jem.181.6.1997. PMC 2192070. PMID 7539035.
30. Oda H, Kumar S, Howley PM (August 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. doi:10.1073/pnas.96.17.9557. PMC 22247. PMID 10449731.
31. 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. PMID 10318843.

Further reading

• 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. 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 (April 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 (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. PMID 12614355.
• Summy JM, Gallick GE (December 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 (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. PMID 14965316.
• 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. PMID 15078178.
• 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. PMID 15489916.
• Joseph AM, Kumar M, Mitra D (January 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 (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. PMID 214242.
• 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. PMID 1351058.
• 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. PMID 1385527.
• Weber JR, Bell GM, Han MY, Pawson T, Imboden JB (August 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, 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. PMID 1535086.
• Soula M, Fagard R, Fischer S (February 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 (April 1992). "Human immunodeficiency virus type 1 glycoprotein precursor retains a CD4-p56lck complex in the endoplasmic reticulum". Journal of Virology. 66 (4): 2296–301. doi:10.1128/JVI.66.4.2296-2301.1992. PMC 289024. PMID 1548763.
• 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. PMID 1579166.
• 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. PMID 1622897.
• 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. doi:10.1182/blood.V80.3.617.617. PMID 1638019.

External links

• lck+Kinase at the US National Library of Medicine Medical Subject Headings (MeSH)
• Overview of all the structural information available in the PDB for UniProt: P06239 (Tyrosine-protein kinase Lck) at the PDBe-KB.