- Lck
Lck (or leukocyte-specific protein tyrosine kinase) is a
protein that is found inside specialized cells of theimmune system calledlymphocytes . Lck is atyrosine kinase , whichphosphorylate styrosine residues of certainprotein s involved in theintracellular 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 cell s. It associates with the cytoplasmic tails of theCD4 andCD8 co-receptors onT helper cells andcytotoxic T cells , respectively, to assist signaling from the T cell receptor (TCR) complex. When theT cell receptor is engaged by the specificantigen presented by MHC, Lck acts tophosphorylate the intracellular chains of the CD3 and ζ-chains of the TCR complex, allowing anothercytoplasm ictyrosine kinase calledZAP-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), atransmembrane protein that serves as a docking site for a number of other proteins, the most important of which are Shc-Grb2 -SOS,PI3K , andphospholipase C (PLC).The tyrosine phosphorylation cascade initiated by Lck culminates in the intracellular mobilization of a
calcium (Ca2+)ion s and activation of important signaling cascades within the lymphocyte. These include theRas -MEK-ERK pathway, which goes on to activate certaintranscription factor s such asNFAT , NFκB, andAP-1 . These transcription factors regulate the production of aplethora of gene products, most notable,cytokine s such asInterleukin-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 cell s deficient in Lck (JCaM1.6), andsiRNA -mediated RNA interference.Lck structure
Lck is a 56-
kilodalton protein. TheN-terminal tail of of Lck is myristoylated and palmitoylated, which tethers the protein the the plasma membrane of the cell. The protein furthermore contains aSH3 domain , aSH2 domain and in theC-terminal part thetyrosine 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 byCsk , 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 , theIL-2 receptor ,Protein kinase C ,ITK ,PLC ,SHC ,RasGAP , Cbl,Vav1 , andPI3K .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 byCbl ubiquitin ligase , which is part of theubiquitin -mediated pathway. [Rao et al. Negative regulation of Lck by Cbl ubiquitin ligase. PNAS, 2002,vol. 99, 3794-3799.]References
Further reading
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citations =
*cite journal | author=Sasaoka T, Kobayashi M |title=The functional significance of Shc in insulin signaling as a substrate of the insulin receptor. |journal=Endocr. J. |volume=47 |issue= 4 |pages= 373–81 |year= 2000 |pmid= 11075717 |doi=
*cite journal | author=Goldmann WH |title=p56(lck) Controls phosphorylation of filamin (ABP-280) and regulates focal adhesion kinase (pp125(FAK)). |journal=Cell Biol. Int. |volume=26 |issue= 6 |pages= 567–71 |year= 2003 |pmid= 12171035 |doi=
*cite journal | author=Mustelin T, Taskén K |title=Positive and negative regulation of T-cell activation through kinases and phosphatases. |journal=Biochem. J. |volume=371 |issue= Pt 1 |pages= 15–27 |year= 2003 |pmid= 12485116 |doi= 10.1042/BJ20021637
*cite journal | author=Zamoyska R, Basson A, Filby A, "et al." |title=The influence of the src-family kinases, Lck and Fyn, on T cell differentiation, survival and activation. |journal=Immunol. Rev. |volume=191 |issue= |pages= 107–18 |year= 2003 |pmid= 12614355 |doi=
*cite journal | author=Summy JM, Gallick GE |title=Src family kinases in tumor progression and metastasis. |journal=Cancer Metastasis Rev. |volume=22 |issue= 4 |pages= 337–58 |year= 2004 |pmid= 12884910 |doi=
*cite journal | author=Leavitt SA, SchOn A, Klein JC, "et al." |title=Interactions of HIV-1 proteins gp120 and Nef with cellular partners define a novel allosteric paradigm. |journal=Curr. Protein Pept. Sci. |volume=5 |issue= 1 |pages= 1–8 |year= 2004 |pmid= 14965316 |doi=
*cite journal | author=Tolstrup M, Ostergaard L, Laursen AL, "et al." |title=HIV/SIV escape from immune surveillance: focus on Nef. |journal=Curr. HIV Res. |volume=2 |issue= 2 |pages= 141–51 |year= 2004 |pmid= 15078178 |doi=
*cite journal | author=Palacios EH, Weiss A |title=Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation. |journal=Oncogene |volume=23 |issue= 48 |pages= 7990–8000 |year= 2004 |pmid= 15489916 |doi= 10.1038/sj.onc.1208074
*cite journal | author=Joseph AM, Kumar M, Mitra D |title=Nef: "necessary and enforcing factor" in HIV infection. |journal=Curr. HIV Res. |volume=3 |issue= 1 |pages= 87–94 |year= 2005 |pmid= 15638726 |doi=
*cite journal | author=Levinson AD, Oppermann H, Levintow L, "et al." |title=Evidence that the transforming gene of avian sarcoma virus encodes a protein kinase associated with a phosphoprotein. |journal=Cell |volume=15 |issue= 2 |pages= 561–72 |year= 1979 |pmid= 214242 |doi=
*cite journal | author=Thomas PM, Samelson LE |title=The glycophosphatidylinositol-anchored Thy-1 molecule interacts with the p60fyn protein tyrosine kinase in T cells. |journal=J. Biol. Chem. |volume=267 |issue= 17 |pages= 12317–22 |year= 1992 |pmid= 1351058 |doi=
*cite journal | author=Shenoy-Scaria AM, Kwong J, Fujita T, "et al." |title=Signal transduction through decay-accelerating factor. Interaction of glycosyl-phosphatidylinositol anchor and protein tyrosine kinases p56lck and p59fyn 1. |journal=J. Immunol. |volume=149 |issue= 11 |pages= 3535–41 |year= 1992 |pmid= 1385527 |doi=
*cite journal | author=Brown R, Meldrum C, Cousins S |title=Are sense-antisense peptide interactions between HIV-1 (gp120), CD4, and the proto oncogene product p56lck important? |journal=Med. Hypotheses |volume=38 |issue= 4 |pages= 322–4 |year= 1993 |pmid= 1491632 |doi=
*cite journal | author=Weber JR, Bell GM, Han MY, "et al." |title=Association of the tyrosine kinase LCK with phospholipase C-gamma 1 after stimulation of the T cell antigen receptor. |journal=J. Exp. Med. |volume=176 |issue= 2 |pages= 373–9 |year= 1992 |pmid= 1500851 |doi=
*cite journal | author=Cefai D, Ferrer M, Serpente N, "et al." |title=Internalization of HIV glycoprotein gp120 is associated with down-modulation of membrane CD4 and p56lck together with impairment of T cell activation. |journal=J. Immunol. |volume=149 |issue= 1 |pages= 285–94 |year= 1992 |pmid= 1535086 |doi=
*cite journal | author=Soula M, Fagard R, Fischer S |title=Interaction of human immunodeficiency virus glycoprotein 160 with CD4 in Jurkat cells increases p56lck autophosphorylation and kinase activity. |journal=Int. Immunol. |volume=4 |issue= 2 |pages= 295–9 |year= 1992 |pmid= 1535787 |doi=
*cite journal | author=Crise B, Rose JK |title=Human immunodeficiency virus type 1 glycoprotein precursor retains a CD4-p56lck complex in the endoplasmic reticulum. |journal=J. Virol. |volume=66 |issue= 4 |pages= 2296–301 |year= 1992 |pmid= 1548763 |doi=
*cite journal | author=Molina TJ, Kishihara K, Siderovski DP, "et al." |title=Profound block in thymocyte development in mice lacking p56lck. |journal=Nature |volume=357 |issue= 6374 |pages= 161–4 |year= 1992 |pmid= 1579166 |doi= 10.1038/357161a0
*cite journal | author=Yoshida H, Koga Y, Moroi Y, "et al." |title=The effect of p56lck, a lymphocyte specific protein tyrosine kinase, on the syncytium formation induced by human immunodeficiency virus envelope glycoprotein. |journal=Int. Immunol. |volume=4 |issue= 2 |pages= 233–42 |year= 1992 |pmid= 1622897 |doi=
*cite journal | author=Torigoe T, O'Connor R, Santoli D, Reed JC |title=Interleukin-3 regulates the activity of the LYN protein-tyrosine kinase in myeloid-committed leukemic cell lines. |journal=Blood |volume=80 |issue= 3 |pages= 617–24 |year= 1992 |pmid= 1638019 |doi=See also
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Tyrosine kinase
*T cell External links
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