LCK

Consequently, lck is targeted by regulatory proteins of T-lymphotropic viruses, especially by the Herpesvirus saimiri (HVS) tyrosine kinase interacting protein (Tip). This oncoprotein physically interacts with lck in HVS transformed T cells and has an impact on its catalytic activity. Together with the identification of defects in the regulation of lck expression or activity in T-cell leukemias, suggests that dysregulation of lck might play a role in neoplastic transformation. However, under certain conditions lck is also involved in the induction of apoptosis. This chemosensitizing effect of lck is independent of T-cell receptor signaling and does not require the kinase activity of Lck. The findings demonstrate that lck might be part of two independent signaling pathways leading to either cell proliferation or apoptosis.

LCK Related Areas

Enzyme>>Protein Kinase>>Intracellular Kinase>>Src (sarcoma) Family Kinase>>Lck

Signal Transduction>>Protein Kinase>>Intracellular Kinase>>Src (sarcoma) Family Kinase>>Lck

Immunology>>Adaptive Immunity>>T Cell>>T Cell Antigen Recognition>>Lck

LCK Alternative Names

LCK, RP4-675E8.4, LSK, YT16, p56lck, pp58lck [Homo sapiens]

Lck, RP23-209C6.8, Hck-3, Lsk, Lskt, p56<lck>, p56Lck [Mus musculus]

Summaries for LCK

Entrez Gene summary for LCK:

This LCK gene is a member of the Src family of protein tyrosine kinases (PTKs). Lck is a key signaling molecule in the selection and maturation of developing T-cells. Lck contains N-terminal sites for myristylation and palmitylation, a PTK domain, and SH2 and SH3 domains which are involved in mediating protein-protein interactions with phosphotyrosine-containing and proline-rich motifs, respectively. The lck protein localizes to the plasma membrane and pericentrosomal vesicles, and binds to cell surface receptors, including CD4 and CD8, and other signaling molecules. Multiple alternatively spliced variants, encoding the same protein, have been described. [provided by RefSeq, Jul 2008]

OMIM - description for LCK:

The LCK gene encodes p56(LCK), a nonreceptor protein-tyrosine kinase of the SRC (190090) oncogene family that is involved in transduction of T-cell receptor (TCR; see 186880)-mediated activation. The p56(LCK) protein is anchored to the plasma membrane and interacts with the intracellular domains of CD4 (186940)/CD8 (see 186910) coreceptors. It is composed of 4 SRC homology (SH) domains that are variably conserved among members of the SRC family (Germani et al., 2003).

Human LCK Protein General Information

 

• Protein names: Tyrosine-protein kinase Lck, Short Name=LCK
• Sequence length: 509 AA.
• Domain: The SH2 domain mediates interaction with SQSTM1. Interaction is regulated by Ser-59 phosphorylation.
• Sequence similarities: Lck belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily. Contains 1 protein kinase domain. Contains 1 SH2 domain. Contains 1 SH3 domain.
• Post-translational modification: Autophosphorylated on Tyr-394, increasing enzymatic activity. Phosphorylated on Tyr-505 by CSK, decreasing activity. Dephosphorylated by PTPRC/CD4
• Subunit structure: LCK interacts with SQSTM1. Interacts with phosphorylated LIME1. Interacts with CBLB and PTPRH. Interacts with RUNX3. Forms a signaling complex with EPHA1, PTK2B AND PI3-KINASE; upon activation by EFNA1 which may regulate T-lymphocyte migration. Associates with ZAP70 and RHOH; these interactions allow LCK-mediated RHOH and CD3 subunit phosphorylation in the presence of functional ZAP70.
• Subcellular location: Cytoplasm. Cell membrane; Lipid-anchor; Cytoplasmic side. Note: Present in lipid rafts in an unactive form
• Tissue specificity: LCK is expressed specifically in lymphoid cells.
• Involvement in disease: Note=A chromosomal aberration involving LCK is found in leukemias. Translocation t(1;7)(p34;q34) with TCRB.
• Catalytic activity: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
• Enzyme regulation: The relative activities of the inhibitory tyrosine-protein kinase CSK and the activating tyrosine-protein phosphatase PTPRC/CD45 determine the level of LCK activity. These interactions allow rapid and efficient activation of LCK in response to TCR stimulation.
• Mass spectrometry: Molecular mass is 57869.42 Da from positions 2 - 509. Determined by MALDI.
• Sequence caution: The sequence CAI22320.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.
  The sequence CAI22321.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.

General information above from UniProt

Function for LCK Protein

UniProtKB:

Lck is non-receptor tyrosine-protein kinase that plays an essential role in the selection and maturation of developing T-cells in the thymus and in the function of mature T-cells. Lck plays a key role in T-cell antigen receptor (TCR)-linked signal transduction pathways. Lck is constitutively associated with the cytoplasmic portions of the CD4 and CD8 surface receptors. Association of the TCR with a peptide antigen-bound MHC complex facilitates the interaction of CD4 and CD8 with MHC class II and class I molecules, respectively, thereby recruiting the associated LCK protein to the vicinity of the TCR/CD3 complex. Lck then phosphorylates tyrosines residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the cytoplasmic tails of the TCR-gamma chains and CD3 subunits, initiating the TCR/CD3 signaling pathway. Once stimulated, the TCR recruits the tyrosine kinase ZAP70, that becomes phosphorylated and activated by lck. Following this, a large number of signaling molecules are recruited, ultimately leading to lymphokine production. Lck also contributes to signaling by other receptor molecules. Lck associates directly with the cytoplasmic tail of CD2, which leads to hyperphosphorylation and activation of lck. Lck also plays a role in the IL2 receptor-linked signaling pathway that controls the T-cell proliferative response. Binding of IL2 to its receptor results in increased activity of LCK. It is expressed at all stages of thymocyte development and is required for the regulation of maturation events that are governed by both pre-TCR and mature alpha beta TCR. Lck phosphorylates other substrates including RUNX3, PTK2B/PYK2, the microtubule-associated protein MAPT, RHOH or TYROBP.

Genatlas:

• Lck plays an essential role for the selection and maturation of developing T-cell in the thymus and in mature T-cell function
• Lck plays a key role in targeting HIV-1 Gag to the plasma membrane in T cells (Pubmed 18714047)
• Lck protects cells from glucocorticoid-induced apoptosis and its inhibition enhances sensitivity to dexamethasone (Pubmed 20300113)
• role for lck in the regulation of Th2-type immunity (Pubmed 20729329)
• Lck plays essential roles in development, antigen-induced T cell activation, and proliferation (Pubmed 20007709)
• Lck is essential for activation of mature T cells (Pubmed 20007709)
• non-receptor tyrosine kinase, lck is critically involved in fractionated radiation-induced expansion of the glioma-initiating cell population and decreased cellular sensitivity to anticancer treatments (Pubmed 20971076)
• Lck signaling is required, at the immunological synapse, for the centrosome to dock at the plasma membrane(Pubmed 21339332)
• Lck plays a key role in T cell signal transduction and is tightly regulated by phosphorylation and dephosphorylation (Pubmed 21234523)

Phenotype Information for LCK

• Gene/Locus: LCK
• Phenotype: SCID due to LCK deficiency

Phenotype Information for LCK from OMIM (Online Mendelian Inheritance in Man)

Drugs for LCK

Target	Drug Name	Disease	Drug Status
LCK	Dasatinib	Chronic myelogenous leukemia	Launched
LCK	Dasatinib	Solid tumours, multiple myeloma	Phase II
LCK	VX-680	Chronic Myelogenous Leukemia; Leukemia; Lymphoblastic, Acute, Philadelphia-Positive	Terminated in Phase I
LCK	VX-680	Leukemia	Terminated in Phase II

Drugs for LCK from TTD (Therapeutic Targets Database)