Lck
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, most importantly 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 notably cytokines such as Interleukin-2 that promotes 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) or siRNA-mediated RNA interference.
Lck structure
Lck is a 56 kilodalton protein. The N-terminal tail of of Lck is myristoylated and palmitoylated which tethers the protein the 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 where the most important 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]
References
- ↑ Rao et al. Negative regulation of Lck by Cbl ubiquitin ligase. PNAS, 2002,vol. 99, 3794-3799.
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. 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. 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. PMID 12614355.
- Summy JM, Gallick GE (2004). "Src family kinases in tumor progression and metastasis". Cancer Metastasis Rev. 22 (4): 337–58. 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. 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. 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. 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. 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. 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. 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. 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. 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
- lck+Kinase at the US National Library of Medicine Medical Subject Headings (MeSH)
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