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.