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, 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 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 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

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, the most important of which 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. [Rao et al. Negative regulation of Lck by Cbl ubiquitin ligase. PNAS, 2002,vol. 99, 3794-3799.]

References

Further reading

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*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=
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*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=
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*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=
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*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=
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*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=
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*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

* Tyrosine kinase
* T cell

External links

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