Lck

For other uses, see LCK.

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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). 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.

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.

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.

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.

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

Interactions

Lck has been shown to interact with:

• ADAM15,
• CD2,
• CD44,
• CD4,
• COUP-TFII,
• DLG1,
• NOTCH1,
• PIK3CA,
• PTPN6,
• PTPRC,
• UNC119,
• SYK,
• UBE3A, and
• ZAP70.

See also

• Tyrosine kinase
• T cell

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.
• 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. PMID 1491632.
• 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. 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. PMID 1638019.

External links

• lck+Kinase at the US National Library of Medicine Medical Subject Headings (MeSH)