Lck

Lck (or lymphocyte-specific protein tyrosine kinase) is a 56 kDa is_associated_with::protein that is found inside specialized cells of the is_associated_with::immune system called is_associated_with::lymphocytes. Lck is a is_associated_with::tyrosine kinase, which is_associated_with::phosphorylates is_associated_with::tyrosine residues of certain is_associated_with::proteins involved in the is_associated_with::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 is_associated_with::T cells. It associates with the is_associated_with::cytoplasmic tails of the is_associated_with::CD4 and is_associated_with::CD8 is_associated_with::co-receptors on is_associated_with::T helper cells and is_associated_with::cytotoxic T cells, respectively, to assist signaling from the is_associated_with::T cell receptor (TCR) complex. When the is_associated_with::T cell receptor is engaged by the specific is_associated_with::antigen presented by MHC, Lck acts to is_associated_with::phosphorylate the intracellular chains of the CD3 and ζ-chains of the TCR complex, allowing another is_associated_with::cytoplasmic is_associated_with::tyrosine is_associated_with::kinase called is_associated_with::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 is_associated_with::transmembrane protein that serves as a docking site for a number of other proteins, the most important of which are Shc-is_associated_with::Grb2-SOS, is_associated_with::PI3K, and is_associated_with::phospholipase C (PLC).

The tyrosine phosphorylation cascade initiated by Lck culminates in the intracellular mobilization of is_associated_with::calcium (Ca2+) is_associated_with::ions and activation of important signaling cascades within the lymphocyte. These include the Ras-MEK-ERK pathway, which goes on to activate certain is_associated_with::transcription factors such as is_associated_with::NFAT, is_associated_with::NF-κB, and AP-1. These transcription factors regulate the production of a plethora of gene products, most notable, is_associated_with::cytokines such as is_associated_with::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 is_associated_with::gene knockout (knock-out mice), is_associated_with::Jurkat cells deficient in Lck (JCaM1.6), and is_associated_with::siRNA-mediated RNA interference.

Structure
Lck is a 56-is_associated_with::kilodalton protein. The is_associated_with::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 is_associated_with::SH3 domain, a is_associated_with::SH2 domain and in the is_associated_with::C-terminal part the is_associated_with::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 is_associated_with::CD3 receptor, is_associated_with::CEACAM1, is_associated_with::ZAP-70, is_associated_with::SLP-76, the is_associated_with::IL-2 receptor, is_associated_with::Protein kinase C, ITK, PLC, SHC, is_associated_with::RasGAP, Cbl, is_associated_with::Vav1, and is_associated_with::PI3K.

Inhibition
In resting T cells, Lck is constitutively inhibited by Csk phosphorylation on tyrosine 505. Lck is also inhibited by is_associated_with::SHP-1 dephosphorylation on tyrosine 394. Lck can also be inhibited by is_associated_with::Cbl ubiquitin ligase, which is part of the is_associated_with::ubiquitin-mediated pathway.

Interactions
Lck has been shown to interact with:


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