LCK (lymphocyte-specific protein tyrosine kinase)

2005-05-01   Deepak Pralhad Patil , Gopal Chandra Kundu 

CSIR-JRF,c\\\/o Dr. G. C. Kundu, National Center for Cell Science, NCCS Complex, Ganeshkhind, Pune(Maharastra)-411007, India

Identity

HGNC
LOCATION
1p35.1
IMAGE
Atlas Image
LEGEND
Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics
LOCUSID
ALIAS
IMD22,LSK,YT16,p56lck,pp58lck
FUSION GENES

DNA/RNA

Atlas Image

Description

DNA sequence is located on chromosome no.1 on the arm 1(p).

Transcription

Consists of 13 exons and 12 introns spanning 12.3 kb.

Pseudogene

Unknown

Proteins

Atlas Image

Description

The kinase p56lck (509 aa) is a T-lymphocyte-specific member of the Src family of non-receptor protein tyrosine kinase. Lck is a 56 kDa phosphoprotein expressed in variety of lymphoid and non-lymphoid cell lineages. Lck contain myristylation sequence, unique amino-terminal regions, followed by Src homology domains SH3 and SH2, a tyrosine kinase catalytic domain, and C-terminal regulatory domain. Lck associates with the inner face of the plasma membrane through its amino-terminus. This interaction is mediated by both myristic acid and palmitic acid that are bound to the amino terminal glycine and Cys-3 and/or Cys-5. The Unique region of Lck represents the domain possessing the greatest sequence diversity within this group of enzymes. This domain is thought to be involved in the interaction of the Lck with specific cellular proteins including Lck substrate. In T-cells it is known, to mediate association with the cytoplasmic tail of T-cell coreceptors CD4 and CD8a. SH3 (Src homology 3) domain is mainly implicated in the regulation of protein-protein interactions, recognizing proline-rich region found in guanine nucleotide exchange factors and GTPase activating proteins. SH2 (Src homology 2) domain of Lck recognizes phosphorylated tyrosine residues on other proteins thereby facilitating the formation of tyrosine phosphorylation-induced multimeric complexes. The tyrosine kinase domain is the catalytic domain of Lck catalyzing the transfer of the gamma-phosphate from ATP to tyrosine residues on proteins. The catalytic domain contains a site of autophosphorylation (Tyr-394), which plays an important role in regulating the protein kinase activity. A C-terminal regulatory domain is also seen containing the major site of tyrosine phosphorylation in vivo (Tyr-505). Phosphorylation of Csk (C-terminal Src kinase) at Tyr-505 leads to inactivation of Lck. Lck is also activated by oxidative stress. Reoxygenation after hypoxia induces Lck kinase activity.

Expression

Expressed in variety of lymphoid and non-lymphoid cell lineages (Breast cancer tissues and other cancers too).

Localisation

Cell membrane

Function

  • T-cell development,
  • T-cell activation.
  • Homology

    Shares sequence homology with other Src family kinases (Src, Hck, Fyn, Blk, Lyn, Fgr, Yes, and Yrk).

    Mutations

    Note

    Not reported yet

    Implicated in

    Entity name
    Breast cancer, T-cell Leukemia, Colon carcinoma.
    Oncogenesis
    Upregulation of Lck is seen in many cases of Breast cancer. It is also overexpressed in lymphoma, colon cancer. Rearrangement of LCK gene is also reported in murine lymphoma cell line. Oncogenic activation of Lck due translocation of the LCK gene is reported in the human HSB2 T-cell leukemia with t(1;7)(p34;q34) with LCK/ TCRB involvement. Lck regulates cell motility through NF-KB mediated uPA secretion following hypoxia and reoxygenation in Breast cancer.
    Disease
    Type 1 Diabetes
    Prognosis
    T-cell mediated Type diabetes (Autoimmune disease) shows defect in TCR/CD3-mediated T-cell activation due to the abnormal expression of LCK.

    Bibliography

    Pubmed IDLast YearTitleAuthors
    154899102004Structure and regulation of Src family kinases.Boggon TJ et al
    24767061989Alterations in the expression of pp60c-src and p56lck associated with butyrate-induced differentiation of human colon carcinoma cells.Foss FM et al
    75386741995Activation of the Lck tyrosine protein kinase by hydrogen peroxide requires the phosphorylation of Tyr-394.Hardwick JS et al
    146991202004Tyrosine kinase, p56lck-induced cell motility, and urokinase-type plasminogen activator secretion involve activation of epidermal growth factor receptor/extracellular signal regulated kinase pathways.Mahabeleshwar GH et al
    110679482000Specific deficiency of p56lck expression in T lymphocytes from type 1 diabetic patients.Nervi S et al
    21163901990lck suppresses gene expression from various promoters including human T-cell leukemia virus type I promoter.Ohta M et al
    154899162004Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation.Palacios EH et al

    Other Information

    Locus ID:

    NCBI: 3932
    MIM: 153390
    HGNC: 6524
    Ensembl: ENSG00000182866

    Variants:

    dbSNP: 3932
    ClinVar: 3932
    TCGA: ENSG00000182866
    COSMIC: LCK

    RNA/Proteins

    Gene IDTranscript IDUniprot
    ENSG00000182866ENST00000333070P06239
    ENSG00000182866ENST00000333070A0A0S2Z3T3
    ENSG00000182866ENST00000336890P06239
    ENSG00000182866ENST00000336890A0A0S2Z3Y8
    ENSG00000182866ENST00000373557E9PAP0
    ENSG00000182866ENST00000373562F8W6B9
    ENSG00000182866ENST00000373564Q573B4
    ENSG00000182866ENST00000461712E9PQ10
    ENSG00000182866ENST00000477031E9PI33
    ENSG00000182866ENST00000482949E9PKQ8
    ENSG00000182866ENST00000495610E9PJ92
    ENSG00000182866ENST00000619559P06239
    ENSG00000182866ENST00000619559A0A0S2Z3Y8

    Expression (GTEx)

    0
    50
    100
    150

    Pathways

    PathwaySourceExternal ID
    Natural killer cell mediated cytotoxicityKEGGko04650
    T cell receptor signaling pathwayKEGGko04660
    Primary immunodeficiencyKEGGko05340
    Natural killer cell mediated cytotoxicityKEGGhsa04650
    T cell receptor signaling pathwayKEGGhsa04660
    Primary immunodeficiencyKEGGhsa05340
    Osteoclast differentiationKEGGko04380
    Osteoclast differentiationKEGGhsa04380
    HTLV-I infectionKEGGko05166
    HTLV-I infectionKEGGhsa05166
    NF-kappa B signaling pathwayKEGGhsa04064
    NF-kappa B signaling pathwayKEGGko04064
    DiseaseREACTOMER-HSA-1643685
    Diseases of signal transductionREACTOMER-HSA-5663202
    PI3K/AKT Signaling in CancerREACTOMER-HSA-2219528
    Constitutive Signaling by Aberrant PI3K in CancerREACTOMER-HSA-2219530
    Infectious diseaseREACTOMER-HSA-5663205
    HIV InfectionREACTOMER-HSA-162906
    Host Interactions of HIV factorsREACTOMER-HSA-162909
    The role of Nef in HIV-1 replication and disease pathogenesisREACTOMER-HSA-164952
    Nef and signal transductionREACTOMER-HSA-164944
    Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adaptersREACTOMER-HSA-164938
    Nef Mediated CD4 Down-regulationREACTOMER-HSA-167590
    Immune SystemREACTOMER-HSA-168256
    Adaptive Immune SystemREACTOMER-HSA-1280218
    TCR signalingREACTOMER-HSA-202403
    Phosphorylation of CD3 and TCR zeta chainsREACTOMER-HSA-202427
    Translocation of ZAP-70 to Immunological synapseREACTOMER-HSA-202430
    Generation of second messenger moleculesREACTOMER-HSA-202433
    Downstream TCR signalingREACTOMER-HSA-202424
    Costimulation by the CD28 familyREACTOMER-HSA-388841
    CD28 co-stimulationREACTOMER-HSA-389356
    CD28 dependent PI3K/Akt signalingREACTOMER-HSA-389357
    CD28 dependent Vav1 pathwayREACTOMER-HSA-389359
    CTLA4 inhibitory signalingREACTOMER-HSA-389513
    PD-1 signalingREACTOMER-HSA-389948
    Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
    Downstream signaling events of B Cell Receptor (BCR)REACTOMER-HSA-1168372
    PIP3 activates AKT signalingREACTOMER-HSA-1257604
    Negative regulation of the PI3K/AKT networkREACTOMER-HSA-199418
    Innate Immune SystemREACTOMER-HSA-168249
    DAP12 interactionsREACTOMER-HSA-2172127
    DAP12 signalingREACTOMER-HSA-2424491
    Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
    Role of LAT2/NTAL/LAB on calcium mobilizationREACTOMER-HSA-2730905
    Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
    Signaling by InterleukinsREACTOMER-HSA-449147
    Interleukin-2 signalingREACTOMER-HSA-451927
    HemostasisREACTOMER-HSA-109582
    Platelet activation, signaling and aggregationREACTOMER-HSA-76002
    GPVI-mediated activation cascadeREACTOMER-HSA-114604
    Cell surface interactions at the vascular wallREACTOMER-HSA-202733
    PECAM1 interactionsREACTOMER-HSA-210990
    Signal TransductionREACTOMER-HSA-162582
    Signaling by EGFRREACTOMER-HSA-177929
    GAB1 signalosomeREACTOMER-HSA-180292
    Signalling by NGFREACTOMER-HSA-166520
    NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
    PI3K/AKT activationREACTOMER-HSA-198203
    Signaling by PDGFREACTOMER-HSA-186797
    Downstream signal transductionREACTOMER-HSA-186763
    Signaling by SCF-KITREACTOMER-HSA-1433557
    Regulation of KIT signalingREACTOMER-HSA-1433559
    PI5P, PP2A and IER3 Regulate PI3K/AKT SignalingREACTOMER-HSA-6811558
    Th1 and Th2 cell differentiationKEGGko04658
    Th1 and Th2 cell differentiationKEGGhsa04658
    Th17 cell differentiationKEGGko04659
    Th17 cell differentiationKEGGhsa04659

    Protein levels (Protein atlas)

    Not detected
    Low
    Medium
    High

    References

    Pubmed IDYearTitleCitations
    158671542005Calculation of absolute protein-ligand binding free energy from computer simulations.165
    205419552010Constitutively active Lck kinase in T cells drives antigen receptor signal transduction.144
    232022722013Conformational states of the kinase Lck regulate clustering in early T cell signaling.74
    203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
    204214942010Tandem fluorescence imaging of dynamic S-acylation and protein turnover.49
    119044332002Negative regulation of Lck by Cbl ubiquitin ligase.48
    145009832003A zinc clasp structure tethers Lck to T cell coreceptors CD4 and CD8.44
    205386122010Autoimmune-associated PTPN22 R620W variation reduces phosphorylation of lymphoid phosphatase on an inhibitory tyrosine residue.44
    178979562007Lateral compartmentalization of T cell receptor versus CD45 by galectin-N-glycan binding and microfilaments coordinate basal and activation signaling.42
    146238722004Lck dephosphorylation at Tyr-394 and inhibition of T cell antigen receptor signaling by Yersinia phosphatase YopH.40

    Citation

    Deepak Pralhad Patil ; Gopal Chandra Kundu

    LCK (lymphocyte-specific protein tyrosine kinase)

    Atlas Genet Cytogenet Oncol Haematol. 2005-05-01

    Online version: http://atlasgeneticsoncology.org/gene/14/lckid14ch1p34