Tyrosin-protein kinase Lck

Last updated
LCK
1lkkA SH2 domain.png
Available structures
PDB Ortholog search: E9PI33 PDBe E9PI33 RCSB
Identifiers
Aliases LCK , LCK proto-oncogene, Src family tyrosine kinase, IMD22, LSK, YT16, p56lck, pp58lck
External IDs OMIM: 153390 MGI: 96756 HomoloGene: 3911 GeneCards: LCK
Orthologs
SpeciesHumanMouse
Entrez

3932

16818

Ensembl

ENSG00000182866

ENSMUSG00000000409

UniProt

P06239

P06240

RefSeq (mRNA)

NM_001042771
NM_005356
NM_001330468

NM_001162432
NM_001162433
NM_010693

RefSeq (protein)

NP_001036236
NP_001317397
NP_005347

NP_001155904
NP_001155905
NP_034823

Location (UCSC) Chr 1: 32.25 – 32.29 Mb Chr 4: 129.44 – 129.47 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Tyrosin-protein kinase Lck (or lymphocyte-specific protein tyrosine kinase) is a 56 kDa protein that is found inside lymphocytes and encoded in the human by the LCK gene. [5] The Lck is a member of Src kinase family (SFK) and is important for the activation of T-cell receptor (TCR) signaling in both naive T cells and effector T cells. The role of Lck is less prominent in the activation or in the maintenance of memory CD8 T cells in comparison to CD4 T cells. In addition, the constitutive activity of the mouse Lck homolog varies among memory T cell subsets. It seems that in mice, in the effector memory T cell (TEM) population, more than 50% of Lck is present in a constitutively active conformation, whereas less than 20% of Lck is present as active form in central memory T cells. These differences are due to differential regulation by SH2 domain–containing phosphatase-1 (Shp-1) and C-terminal Src kinase. [6]

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. [7] The reasons for these differences are not well understood yet.

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, [8] [9] respectively, to assist signaling from the T cell receptor (TCR) complex. T cells are able to respond to pathogen and cancer using T-cell receptor, nevertheless, they can also react to self-antigen causing the onset of autoimmune diseases. The T cells maturation occurs in the thymus and it is regulated by a threshold that defines the limit between the positive and the negative selection of thymocytes. in order to avoid the onset of autoimmune diseases, highly self-reactive T cells are removed during the negative selection, whereas, an amount of weak self-reactive T cells is required to promote an efficient immune response, therefore during the positive selection these cells are chosen for maturation. The threshold for positive and negative selection of developing T cells is regulated by the bound between the Lck and co-receptors. [10]

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. [11]

The initiation of immune response takes place when T cells encounter and recognize their cognate antigen. The antigen-presenting cells (APC) expose on their surface a fraction of the antigen that is recognized either from CD8+ T cells or CD4+ T cells. This binding leads to the activation of TCR signaling cascade in which the immunoreceptor tyrosine-based activation motifs (ITAM) located in the CD3-zeta chains (ζ-chains) of the TCR complex, are phosphorylated by Lck and less extended by Fyn. [12] Both coreceptor-bound and free Lck can phosphorylate the CD3 chains upon TCR activation, evidences suggest that the free form of Lck can be recruited and trigger the TCR signal faster than the coreceptor-bound Lck [7] Additionally, upon T cell activation, a fraction of kinase active Lck, translocate from outside of lipid rafts (LR) to inside lipid rafts where it interacts with and activates LR-resident Fyn, which is involved in further downstream signaling activation. [13] [14] Once ITAM complex is phosphorylated the CD3 chains can be bound by another cytoplasmic tyrosine kinase called ZAP-70. In the case of CD8+ T cells, once ZAP70 binds CD3, the coreceptor associated with Lck binds the MHC stabilizing the TCR-MHC-peptide interaction. The phosphorylated form of ZAP-70 recruits another molecule in the signaling cascade called LAT (Linker for activation of T cells), a transmembrane protein. LAT acts as a scaffold able to regulate the TCR proximal signals in a phosphorylation-dependent manner. [15] The most important proteins recruited by phosphorylated LAT are Shc-Grb2-SOS, PI3K, and phospholipase C (PLC). The residue responsible for the recruitment of phospholipase C-γ1 (PLC-γ1) is Y132. This binding leads to the Tec family kinase ITK-mediated PLC-γ1 phosphorylation and activation that consequentially produce calcium (Ca2+) ions mobilization, 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, NF-κB, 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. In addition to the significance of Lck and Fyn in T cell receptor signaling, these two src kinases have also been shown to be important in TLR-mediated signaling in T cells. [16]

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 activity regulation

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. [17] 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. [18] 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 [19] 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. [7] 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 [7]

Structure

Lck is a 56-kilodalton protein. The 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 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 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. [20]

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. [21] Moreover, mice with an unbalanced amount of lck show altered lung function which can consequentially leads to the onset of asthma.   [22]

Substrates

Lck tyrosine phosphorylates a number of proteins, the most important of which are the CD3 receptor, CEACAM1, ZAP-70, SLP-76, the IL-2 receptor, Protein kinase C, ITK, PLC, SHC, RasGAP, Cbl, Vav1, and PI3K.

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. [23]

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. [24]

Masitinib also inhibits Lck, which may have some impact on its therapeutic effects in canine mastocytoma. [25]

HSP90 inhibitor NVP-BEP800 has been described to affect stability of the LCK kinase and growth of T-cell acute lymphoblastic leukemias. [26]

Interactions

Lck has been shown to interact with:

See also

Related Research Articles

<span class="mw-page-title-main">CD4</span> Marker on immune cells

In molecular biology, CD4 is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as helper T cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984. In humans, the CD4 protein is encoded by the CD4 gene.

<span class="mw-page-title-main">T-cell receptor</span> Protein complex on the surface of T cells that recognizes antigens

The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding between TCR and antigen peptides is of relatively low affinity and is degenerate: that is, many TCRs recognize the same antigen peptide and many antigen peptides are recognized by the same TCR.

CD8 is a transmembrane glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). Along with the TCR, the CD8 co-receptor plays a role in T cell signaling and aiding with cytotoxic T cell-antigen interactions.

<span class="mw-page-title-main">PTPRC</span> Mammalian protein found in Homo sapiens

Protein tyrosine phosphatase, receptor type, C also known as PTPRC is an enzyme that, in humans, is encoded by the PTPRC gene. PTPRC is also known as CD45 antigen, which was originally called leukocyte common antigen (LCA).

In immunology, a naive T cell (Th0 cell) is a T cell that has differentiated in the thymus, and successfully undergone the positive and negative processes of central selection in the thymus. Among these are the naive forms of helper T cells (CD4+) and cytotoxic T cells (CD8+). Any naive T cell is considered immature and, unlike activated or memory T cells, has not encountered its cognate antigen within the periphery. After this encounter, the naive T cell is considered a mature T cell.

<span class="mw-page-title-main">ZAP70</span> Protein-coding gene in the species Homo sapiens

ZAP-70 is a protein normally expressed near the surface membrane of lymphocytes. It is most prominently known to be recruited upon antigen binding to the T cell receptor (TCR), and it plays a critical role in T cell signaling.

<span class="mw-page-title-main">Tyrosine-protein kinase SYK</span>

Tyrosine-protein kinase SYK, also known as spleen tyrosine kinase, is an enzyme which in humans is encoded by the SYK gene.

<span class="mw-page-title-main">Lymphocyte cytosolic protein 2</span> Protein-coding gene in the species Homo sapiens

Lymphocyte cytosolic protein 2, also known as LCP2 or SLP-76, is a signal-transducing adaptor protein expressed in T cells and myeloid cells and is important in the signaling of T-cell receptors (TCRs). As an adaptor protein, SLP-76 does not have catalytic functions, primarily binding other signaling proteins to form larger signaling complexes. It is a key component of the signaling pathways of receptors with immunoreceptor tyrosine-based activation motifs (ITAMs) such as T-cell receptors, its precursors, and receptors for the Fc regions of certain antibodies. SLP-76 is expressed in T-cells and related lymphocytes like natural killer cells.

<span class="mw-page-title-main">Linker for activation of T cells</span> Protein-coding gene in the species Homo sapiens

The Linker for activation of T cells, also known as linker of activated T cells or LAT, is a protein involved in the T-cell antigen receptor signal transduction pathway which in humans is encoded by the LAT gene. Alternative splicing results in multiple transcript variants encoding different isoforms.

<span class="mw-page-title-main">FYN</span> Mammalian protein found in Homo sapiens

Proto-oncogene tyrosine-protein kinase Fyn is an enzyme that in humans is encoded by the FYN gene.

<span class="mw-page-title-main">LYN</span> Mammalian protein found in Homo sapiens

Tyrosine-protein kinase Lyn is a protein that in humans is encoded by the LYN gene.

<span class="mw-page-title-main">PTPN22</span> Protein-coding gene in the species Homo sapiens

Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a cytoplasmatic protein encoded by gene PTPN22 and a member of PEST family of protein tyrosine phosphatases. This protein is also called "PEST-domain Enriched Phosphatase" ("PEP") or "Lymphoid phosphatase" ("LYP"). The name LYP is used strictly for the human protein encoded by PTPN22, but the name PEP is used only for its mouse homolog. However, both proteins have similar biological functions and show 70% identity in amino acid sequence. PTPN22 functions as a negative regulator of T cell receptor (TCR) signaling, which maintains homeostasis of T cell compartment.

<span class="mw-page-title-main">INPP5D</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">FYB</span> Protein-coding gene in the species Homo sapiens

FYN binding protein (FYB-120/130), also known as FYB, ADAP, and SLAP-130 is a protein that is encoded by the FYB gene in humans. The protein is expressed in T cells, monocytes, mast cells, macrophages, NK cells, but not B cells. FYB is a multifunctional protein involved in post-activation T cell signaling, lymphocyte cytokine production, cell adhesion, and actin remodeling.

Christopher Edward Rudd, is a Canadian-born immunologist-biochemist. He is currently Professor of Medicine at the Universite de Montreal and Director, Immunology-Oncology at the Centre de Recherche Hôpital Maisonneuve-Rosemont (CR-HMR).

A non-receptor tyrosine kinase (nRTK) is a cytosolic enzyme that is responsible for catalysing the transfer of a phosphate group from a nucleoside triphosphate donor, such as ATP, to tyrosine residues in proteins. Non-receptor tyrosine kinases are a subgroup of protein family tyrosine kinases, enzymes that can transfer the phosphate group from ATP to a tyrosine residue of a protein (phosphorylation). These enzymes regulate many cellular functions by switching on or switching off other enzymes in a cell.

Kinetic-segregation is a model proposed for the mechanism of T-cell receptor (TCR) triggering. It offers an explanation for how TCR binding to its ligand triggers T-cell activation, based on size-sensitivity for the molecules involved. Simon J. Davis and Anton van der Merwe, University of Oxford, proposed this model in 1996. According to the model, TCR signalling is initiated by segregation of phosphatases with large extracellular domains from the TCR complex when binding to its ligand, allowing small kinases to phosphorylate intracellular domains of the TCR without inhibition. Its might also be applicable to other receptors of the Non-catalytic tyrosine-phosphorylated receptors family such as CD28.

<span class="mw-page-title-main">Tyrosine-protein kinase CSK</span> Kinase enzyme that phosphorylates Src-family kinases

Tyrosine-protein kinase CSK also known as C-terminal Src kinase is an enzyme that, in humans, is encoded by the CSK gene. This enzyme phosphorylates tyrosine residues located in the C-terminal end of Src-family kinases (SFKs) including SRC, HCK, FYN, LCK, LYN and YES1.

CD8.4 is a murine chimeric coreceptor. The extracellular and transmembrane part of the coreceptor is from wild-type CD8 coreceptor, whereas the intracellular domain from CD4 coreceptor. This model was created to examine role of coreceptor coupling to Lck as the CD4 and CD8 coreceptors have an Lck-binding site in their intracellular domain. CD4 coreceptor has higher coupling to Lck in thymocytes than CD8 coreceptor. CD8.4 coreceptor has similar coupling to Lck as CD4 coreceptor, while the MHC I-binding site remains identical to wild-type CD8. This chimeric coreceptor therefore enables addressing influence of different coupling to Lck on TCR signaling.

Non-catalytic tyrosine-phosphorylated receptors (NTRs), also called immunoreceptors or Src-family kinase-dependent receptors, are a group of cell surface receptors expressed by leukocytes that are important for cell migration and the recognition of abnormal cells or structures and the initiation of an immune response. These transmembrane receptors are not grouped into the NTR family based on sequence homology, but because they share a conserved signalling pathway utilizing the same signalling motifs. A signaling cascade is initiated when the receptors bind their respective ligand resulting in cell activation. For that tyrosine residues in the cytoplasmic tail of the receptors have to be phosphorylated, hence the receptors are referred to as tyrosine-phosphorylated receptors. They are called non-catalytic receptors, as the receptors have no intrinsic tyrosine kinase activity and cannot phosphorylate their own tyrosine residues. Phosphorylation is mediated by additionally recruited kinases. A prominent member of this receptor family is the T-cell receptor.

References

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