Lck

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Lck (or lymphocyte-specific protein tyrosine kinase) is a 56

Lck is responsible for the initiation of the TCR signaling cascade inside the cell by phosphorylating immunoreceptor tyrosine-based activation motifs (ITAM) within the TCR-associated chains.

Lck can be found in different forms in immune cells: free in the cytosol or bound to the plasma membrane (PM) through myristoylation and palmitoylation. Due to the presence of the conserved CxxC motif (C20 and C23) in the zinc clasp structure, Lck is able to bind the cell surface coreceptors CD8 and\or CD4.

Bound and free Lck have different properties: free Lck has more pronounced kinase activity in comparison to bound Lck, and moreover, the free form produces a higher level of T cell activation.^[6] The reasons for these differences are not well understood yet.

T cell signaling

Lck is most commonly found in

There are two main pools of T cells which mediate adaptive immune responses: CD4+ T cells (or helper T cells), and CD8+ T-cells (or cytotoxic T cells) which are MHCII-and MHCI restricted respectively. Despite their role in the immune system is different their activation is similar. Cytotoxic T cells are directly involved in the individuation and in the removal of infected cells, whereas helper T cells modulate other immune cells to supply the response.^[10]

The initiation of immune response takes place when T cells encounter and recognize their cognate antigen. The

The activity of the Lck can be positively or negatively regulated by the presence of other proteins such as the membrane protein CD146, the transmembrane tyrosine phosphatase CD45 and C-terminal Src kinase (Csk). In mice, CD146 directly interacts with the SH3 domain of coreceptor-free LCK via its cytoplasmic domain, promoting the LCK autophosphorylation.^[16] There is very little understanding of the role of CD45 isoforms, it is known that they are cell type-specific, and that they depend on the state of activation and differentiation of cells. In naïve T cells in humans, CD45RA isoform is more frequent, whereas when cells are activated the CD45R0 isoform is expressed in higher concentrations. Mice express low levels of high molecular weight isoforms (CD45RABC) in thymocytes or peripheral T cells. Low levels of CD45RB are typical in primed cells, while high levels of CD45RB are found in both naïve and primed cells.^[17] In general, CD45 acts to promote the active form of LCK by dephosphorylating a tyrosine (Y192) in its inhibitory C-terminal tail. The consequent trans-autophosphorylation of the tyrosine in the lck activation loop (Y394), stabilizes its active form promoting its open conformation^[18] which further enhances the kinase activity and substrate binding. The Dephosphorylation of the Y394 site can also be regulated by SH2 domain-containing phosphatase 1 (SHP-1), PEST-domain enriched tyrosine phosphatase (PEP), and protein tyrosine phosphatase-PEST.^[6] In contrast, Csk has an opposite role to that of CD45, it phosphorylated the Y505 of Lck promoting the closed conformation with inhibited kinase activity. When both Y394 and Y505 are unphosphorylated the lck show a basal kinase activity, vice versa, when phosphorylated, lck show similar activity to the Y394 single phosphorylated Lck ^[6]

Structure

Lck is a 56-

Lck and disease

Mutations in Lck are liked to a various range of diseases such as SCID (Severe combined immunodeficiency) or CIDs. In these pathologies, the dysfunctional activation of the lck leads to T cell activation failure. Many pathologies are linked to the overexpression of Lck such as cancer, asthma, diabetes 1, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, inflammatory bowel diseases (Crohn's disease and ulcerative colitis), organ graft rejection, atherosclerosis, hypersensitivity reactions, polyarthritis, dermatomyositis. The increase of the lck in colonic epithelial cells can lead to colorectal cancer. The lck play a role also in the Thymoma, an auto-immune disorder which involve thymus. Tumorigenesis is enhanced by abnormal proliferation of immature thymocytes due to low levels of Lck.^[19]

Lymphoid protein tyrosine phosphatase (lyp), is one of the suppressor of  lck activity and mutations in this  protein are correlated with the onset of diabetes 1. Increased activity of lck promote the onset of the diabetes 1.

Regarding respiratory diseases, asthma is associated with the activation of th2 type of t cell whose differentiation is mediated by lck.^[20] Moreover, mice with an unbalanced amount of lck show altered lung function which can consequentially leads to the onset of asthma.  ^[21]

Substrates

Lck tyrosine phosphorylates a number of proteins, the most important of which are the

Inhibition

In resting T cells, Lck is constitutively inhibited by Csk phosphorylation on tyrosine 505. Lck is also inhibited by

Saractinib, a specific inhibitor of LCK impairs maintenance of human T-ALL cells in vitro as well as in vivo by targeting this tyrosine kinase in cells displaying high level of lipid rafts.[23]

Masitinib also inhibits Lck, which may have some impact on its therapeutic effects in canine mastocytoma.^[24]

HSP90 inhibitor NVP-BEP800 has been described to affect stability of the LCK kinase and growth of T-cell acute lymphoblastic leukemias.^[25]

Interactions

Lck has been shown to

See also

• Tyrosine kinase
• T cell

References