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FLASH GENE
Symbol LCK contributors: mct/pgu - updated : 16-02-2016
HGNC name lymphocyte-specific protein tyrosine kinase
HGNC id 6524
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • a SH3, controling T lymphocyte activation by regulating MAPK pathway induction
  • a SH2 domains mediating interaction with SQSTM1, interaction regulated by ser-58 phosphorylation
  • a kinase domain alone is sufficient to bind SOCS1
    • HOMOLOGY
    Homologene
    FAMILY
  • protein kinase superfamily
  • Tyr protein kinase family
  • SRC subfamily
    • CATEGORY protooncogene
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus
    text
  • may be recruited to the plasma membrane by RHOH, which also binds CSK, resulting in LCK inactivation
  • oncogenic LCK kinase translocates to the nucleus and binds to the LMO2 gene promoter
    • basic FUNCTION
  • playing an essential role for the selection and maturation of developing T-cell in the thymus and in mature T-cell function
  • plays a key role in targeting HIV-1 Gag to the plasma membrane in T cells
  • protects cells from glucocorticoid-induced apoptosis and its inhibition enhances sensitivity to dexamethasone
  • role for LCK in the regulation of Th2-type immunity
  • plays essential roles in development, antigen-induced T cell activation, and proliferation
  • essential for activation of mature T cells
  • non-receptor tyrosine kinase, critically involved in fractionated radiation-induced expansion of the glioma-initiating cell population and decreased cellular sensitivity to anticancer treatments
  • LCK signaling is required, at the immunological synapse, for the centrosome to dock at the plasma membrane
  • plays a key role in T cell signal transduction and is tightly regulated by phosphorylation and dephosphorylation
  • oncogenic LCK can initiate multiple signaling cascades that are likely to be controlled by the spatial localization of the oncoprotein
  • regulation of the cellular location and activation of LCK in maturing thymocytes is a key regulatory mechanism to prevent T-cell responses to self-antigens
  • major role for LCK in proximal and distal B-cell receptor-mediated signaling in chronic lymphocytic leukemia cells
  • mediates ITGB1 signalling to regulate Schwann cell migration and myelination
  • plays a crucial role in the T-cell response by transducing early activation signals triggered by TCR (T-cell receptor) engagement
  • T cell receptor (TCR) phosphorylation requires the kinase LCK and phosphatase PTPRC
  • LCK, which plays a unique role in enforcing MHC restriction, is essential for thymic development in presence or absence of CBL, ensuring MHC restriction of T cells derived from either pathway
  • is an Src family kinases (SFKs) that is central to the initiation of T cell activation in response to ligand binding to the T cell receptor (TCR) and is also critical for later signaling processes
  • kinase activity of LCK requires both the phosphorylation of an activating tyrosine residue and the dephosphorylation of an inhibitory tyrosine residue
  • kinase activity of ZAP70 stimulates negative feedback pathways that target LCK and thereby modulate the phosphorylation patterns of the immunoreceptor tyrosine-based activation motifs (ITAMs) of the CD3 and zeta chain components of the TCR
  • novel function of nuclear LCK in promoting human leukemic T cell survival through interaction with a tumor suppressor
  • is a key T-cell kinase and widely implicated in blood malignancies
  • role of mitochondrial LCK in metabolic reprogramming of leukemic cells
    • CELLULAR PROCESS cell life, proliferation/growth
    PHYSIOLOGICAL PROCESS development
    text T cell development and function
    PATHWAY
    metabolism
    signaling signal transduction
    RAS signaling pathway
    a component
  • ITGB2/LCK/ZAP70 complex is in position to initiate the rapid adhesion strengthening and migration necessary for T-lymphocyte responses when stimulated vasculature is encountered at sites of infection or injury
    • INTERACTION
    DNA
    RNA
    small molecule nucleotide,
  • ATP
    • protein
  • mediating phosphorylation of DOK proteins
  • interaction between PRKD2 and LCK (LCK regulated the activity of PRKD2 by tyrosine phosphorylation, which in turn may have modulated the physiological functions of PKD2 during TCR-induced T cell activation)
  • anchoring CD4 to lipid microdomains (rafts) on microvilli
  • interacts with RASSF5 through its C-terminal Src homology 2 binding motif and LCK-mediated phosphorylation is critical for the efficient translocation of RASSF5 into the nuclear compartment
  • SH2D2A through its interaction with both ITK and LCK, primes ITK for LCK mediated phosphorylation and thereby regulates CXCL12 induced T cell migration and actin cytoskeleton rearrangements
  • RHOH binds and modulates LCK, the non-receptor tyrosine kinase crucial in initiating pre-TCR and TCR signallings
  • LAT promotes TCR signal initiation, suggesting that this adaptor may contribute to maintain active LCK in proximity of their substrates
  • ITGB2 is constitutively associated with the protein tyrosine kinases LCK and ZAP70
  • oncogenic LCK may activate LMO2 promoter through direct interaction
  • oncogenic LCK and JAK2 may utilize different mechanisms to upregulate LMO2 levels during oncogenic transformation
  • DLG1, which acts as a scaffold for many signaling molecules including the TCR and LCK, could mediate the cellular redistribution of LCK during T-cell maturation
  • upregulates FOXP3 by tyrosine phosphorylation, resulting in decreased MMP9, SKP2, and VEGFA expression, and suppressed cellular invasion
  • PTK2 negatively regulates LCK function downstream of the T cell antigen receptor
  • spatial regulation of LCK by PTPRC and GM1 ganglioside determines the outcome of apoptotic response to LGALS1 and this local regulation may occur only upon intimate effector (LGALS1 expressing) cell-T-cell attachment
  • prominent immunoregulatory function of LGALS1, is induction of apoptosis in activated T-cells by a process depending on the activity of SRC family tyrosine kinase, LCK
  • both SLAMF6-associated LCK phosphorylation and kinase activity were enhanced in restimulated T cells, amplifying proximal TCR signaling
  • SH2D1A facilitates recruitment and activation of LCK at SLAMF6 receptors during restimulation-induced cell death
  • IGF2R specifically controls the balance between active and inactive LCK in resting T cells, which guarantees operative T cell effector functions
  • in T-cells, cholesterol-dependent membrane domains function in the regulation of the Src family kinase LCK by sequestering LCK from its activator PTPRC
  • in a kinase-independent manner, mitochondrial LCK interferes with mitochondrial translational machinery through competitive binding to GADD45GIP1
    • cell & other
  • membrane associated
    • REGULATION
    inhibited by negatively regulated by CB1 ubiquitin ligase
    SOCS6 (negative regulator of LCK)
    repressed by dexamethasone that downregulates LCK, which, in turn, suppresses lymphocyte activation by inhibiting pro-survival calcium oscillations
    Other regulated by SOCS1 (important role of SOCS in regulating LCK functions)
    ASSOCIATED DISORDERS
    corresponding disease(s) IMD22
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   translocation    
    breakpoint in T-cell acute lymphoblastic leukemia with translocations t(1;7)(p34;q34
    constitutional     --low  
    in one case of SCID(severe combined immunodeficiency)
    tumoral     --over  
    in lymphomas of germinal center origin (e.g. follicular lymphoma) and also many mantle cell lymphomas, chronic lymphocytic leukemia (CLL) and most T-cell neoplasms
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerhemopathy 
    small-molecule inhibitors of Lck, such as dasatinib, may function to reverse glucocorticoid resistance in some lymphoid malignancies
    ANIMAL & CELL MODELS