Affinage

LCK

Tyrosine-protein kinase Lck · UniProt P06239

Length
509 aa
Mass
58.0 kDa
Annotated
2026-04-28
100 papers in source corpus 50 papers cited in narrative 50 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LCK is a Src-family non-receptor tyrosine kinase that serves as the principal initiating kinase of T-cell receptor (TCR) signaling, with additional roles in thymocyte lineage commitment, costimulatory receptor signaling, cardiac ischemic preconditioning, and YAP-dependent transcription in cholangiocarcinoma. LCK is held in an autoinhibited state by intramolecular SH2-domain engagement of phospho-Tyr505; CD45 dephosphorylates Tyr505 to permit opening, while autophosphorylation or trans-phosphorylation at Tyr394 is indispensable for full catalytic activity, and a constitutively active pool (~40% in naive T cells) is stabilized by the HSP90–CDC37 chaperone complex (PMID:7512222, PMID:10330160, PMID:7538674, PMID:20541955). Upon TCR ligation, LCK is recruited to CD3ε through ionic Unique-domain–BRS interactions and a noncanonical SH3–RK motif interaction, whereupon it phosphorylates CD3 ITAMs, the adaptor LAT, and DGKα to propagate downstream signaling; its plasma-membrane targeting requires dual acylation (myristoylation at Gly2, palmitoylation at Cys3/Cys5 installed by DHHC2/DHHC21), and delivery to the immunological synapse depends on a Rab11–UNC119–ARL3 endosomal trafficking pathway that preferentially retains active (pY394) LCK at the synapse (PMID:28659468, PMID:32690949, PMID:9305640, PMID:22034844, PMID:30220567, PMID:19592652). LCK activity is negatively regulated by SH2-domain phosphorylation at Tyr192 (blocking CD45 access and maintaining Tyr505 phosphorylation), Cbl-mediated ubiquitination and proteasomal degradation of the open/active conformer, TSAd-mediated substrate diversion, LAG3-induced local pH changes that dissociate LCK from coreceptors, and nitration of Tyr394 by MDSC-derived reactive nitrogen species (PMID:28735895, PMID:11904433, PMID:18541536, PMID:35437325, PMID:30232256).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1989 High

    Identification of Tyr505 as the negative-regulatory phosphorylation site established that LCK kinase activity is tonically suppressed in lymphoid cells, framing the central question of how LCK is activated during TCR signaling.

    Evidence In vitro kinase assays and phosphorylation site mapping in multiple lymphoid cell lines

    PMID:2468122

    Open questions at the time
    • Identity of the Tyr505 kinase (CSK) not addressed here
    • Activation-loop phosphorylation not yet mapped
  2. 1994 High

    The crystal structure of the LCK SH3-SH2 fragment revealed the intramolecular autoinhibitory mechanism whereby the phosphorylated C-terminal tail engages the SH2 domain, providing a structural framework for understanding how Tyr505 phosphorylation suppresses activity.

    Evidence X-ray crystallography of SH3-SH2 fragment with and without phosphotyrosyl tail peptide

    PMID:7512222

    Open questions at the time
    • Full-length kinase structure not determined
    • Dynamics of conformational switching not resolved
  3. 1995 High

    Demonstrating that Tyr394 phosphorylation is required for LCK activation and can be installed in trans by another kinase resolved the question of how LCK achieves full catalytic competence and revealed that activation-loop phosphorylation is a distinct regulatory step from Tyr505 dephosphorylation.

    Evidence H2O2 stimulation with Tyr394 and kinase-dead mutants in LCK-negative cells; in vitro kinase assays

    PMID:7538674

    Open questions at the time
    • Identity of the trans-activating kinase not determined
    • Relative contribution of auto- vs. trans-phosphorylation in physiological TCR triggering unclear
  4. 1997 High

    Establishing that palmitoylation at Cys3/Cys5 is essential for LCK plasma-membrane targeting and TCR signaling solved how a soluble kinase is localized to the signaling-competent membrane compartment.

    Evidence Palmitoylation-site mutants in COS-18 and LCK-negative JCam-1.6 T cells; Ca²⁺ flux, ZAP-70 association, NFAT induction

    PMID:9305640

    Open questions at the time
    • Palmitoyl acyltransferase identity not yet known
    • Dynamic regulation of palmitoylation during signaling not addressed
  5. 1999 High

    Genetic rescue of thymocyte development in CD45-deficient mice by the LCK Y505F mutation established CD45 as the physiological phosphatase that activates LCK, closing a long-standing question about the upstream activator.

    Evidence CD45-knockout × LCK Y505F transgenic mouse crosses; thymocyte development assays

    PMID:10330160

    Open questions at the time
    • Whether CD45 also dephosphorylates Y394 in vivo under certain contexts not settled here
  6. 2000 High

    Demonstrating that graded LCK activity controls CD4/CD8 lineage commitment established LCK as a signal-strength integrator in thymic selection, extending its role beyond simple TCR triggering.

    Evidence Transgenic mice with dominant-negative and constitutively active LCK, class I– and class II–restricted TCR transgenes

    PMID:10755618

    Open questions at the time
    • Downstream effectors that translate LCK signal strength into lineage fate not fully defined
  7. 2002 High

    Multiple discoveries in this period revealed negative regulation by Cbl-mediated ubiquitination/degradation, cooperative activation by CD4 and CD28 at the APC interface, and a cardiac PKCε–LCK signaling module, broadening the regulatory landscape and tissue context of LCK function.

    Evidence Co-IP/ubiquitination assays in Cbl−/− T cells (PMID:11904433); phosphospecific antibodies in CD4/CD28-deficient T cells (PMID:11828322); co-IP, kinase assays, and LCK-knockout mice in cardiac ischemia models (PMID:11854322)

    PMID:11828322 PMID:11854322 PMID:11904433

    Open questions at the time
    • Cbl-LCK interaction interface not structurally defined
    • How CD28 sustains LCK activation mechanistically remains unclear
    • Cardiac LCK substrates beyond PKCε not identified
  8. 2003 High

    The NMR structure of the zinc-clasp domain formed between LCK and CD4/CD8 cytoplasmic tails solved the atomic basis of coreceptor–LCK coupling and revealed zinc as the essential bridging element.

    Evidence NMR solution structures of CD4–LCK–Zn²⁺ and CD8α–LCK–Zn²⁺ ternary complexes

    PMID:14500983

    Open questions at the time
    • Whether zinc availability modulates LCK–coreceptor coupling in vivo not tested
  9. 2010 High

    Discovery that ~40% of LCK is constitutively active in naive T cells, stabilized by HSP90–CDC37, overturned the model that LCK activation is entirely stimulus-dependent and reframed TCR sensitivity as a function of the pre-existing active LCK pool.

    Evidence Phosphospecific flow cytometry and kinase assays in primary naive T cells; HSP90 inhibitor treatment

    PMID:20541955

    Open questions at the time
    • How the constitutively active pool is set during development is unclear
    • Whether HSP90 inhibition affects TCR sensitivity in vivo not directly tested
  10. 2012 High

    Super-resolution imaging showed that LCK clustering on the plasma membrane is governed by its open/active conformation rather than lipid raft partitioning, revising the prevailing membrane microdomain model of TCR signaling initiation.

    Evidence PALM/STORM with conformation-specific LCK mutants in T cells

    PMID:23202272

    Open questions at the time
    • Molecular determinants of conformation-dependent clustering not identified
    • Quantitative relationship between cluster size and signaling output not defined
  11. 2017 High

    Three concurrent advances established (i) ionic Unique-domain–CD3ε BRS interactions as the direct LCK recruitment mechanism to TCR, (ii) Tyr192 phosphorylation as a feedback loop blocking CD45-mediated activation, and (iii) Tyr394 autophosphorylation as indispensable for catalytic activity, collectively defining the multi-layered regulation of LCK at the TCR.

    Evidence TCR reconstitution with BRS mutagenesis (PMID:28659468); Y192 phosphomutants with CD45 co-IP and retrogenic thymocyte assays (PMID:28735895); genetic code expansion for optical LCK activation (PMID:29083415)

    PMID:28659468 PMID:28735895 PMID:29083415

    Open questions at the time
    • Kinase that phosphorylates Y192 not identified
    • Relative contribution of ionic vs. SH3-mediated CD3ε interactions not quantified
  12. 2018 High

    The UNC119A–ARL3 trafficking mechanism was shown to extract myristoylated LCK from membranes and release it at the synapse, with Y394 phosphorylation inhibiting extraction — explaining how active LCK is spatially focused at the immune synapse.

    Evidence Biochemical binding assays, TIRF imaging, mutagenesis of LCK Y394 and UNC119A-binding residues, siRNA knockdown

    PMID:30220567

    Open questions at the time
    • ARL13B contribution not fully dissected in primary T cells
    • Whether other SFKs use the same trafficking mechanism unknown
  13. 2020 High

    Identification of a noncanonical RK motif in CD3ε that binds the LCK SH3 domain only upon TCR ligation provided a second, stimulus-dependent recruitment mechanism, and the finding that free (coreceptor-unbound) LCK is more active than coreceptor-bound LCK revised the coreceptor-centric model of TCR triggering.

    Evidence Mutagenesis, T cell activation/thymocyte development assays, CAR-T models (PMID:32690949); biochemical fractionation of free vs. bound LCK pools with kinase assays (PMID:32571924)

    PMID:32571924 PMID:32690949

    Open questions at the time
    • Structural basis of SH3–RK interaction not resolved
    • Whether free LCK pool size is dynamically regulated during immune responses unknown
  14. 2022 High

    Multiple studies revealed new regulatory inputs: LAG3-mediated local pH reduction dissociates LCK from coreceptors, disulfiram covalently activates LCK via Cys20/Cys23, and endogenous-level knock-in mice showed CD8-bound LCK is largely dispensable for antiviral/antitumor responses while CD4-bound LCK has a kinase-independent role in CD4 surface stabilization.

    Evidence pH reporters and BiFC at the synapse (PMID:35437325); mass spectrometry/covalent binding assays with in vivo tumor models (PMID:35638332); endogenous knock-in mouse models with immune challenge (PMID:36564464)

    PMID:35437325 PMID:35638332 PMID:36564464

    Open questions at the time
    • Structural mechanism of LAG3-induced pH change not resolved
    • Whether DSF-mediated LCK activation is specific in vivo (off-target effects) not excluded
    • How CD4-LCK kinase-independent stabilization works mechanistically is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length structure of LCK in its membrane-associated state, the identity of the kinase(s) responsible for Tyr192 and trans-Tyr394 phosphorylation in vivo, quantitative understanding of how the free vs. coreceptor-bound LCK pools are dynamically regulated during immune responses, and the structural basis for the noncanonical SH3–RK motif interaction.
  • No full-length membrane-associated LCK structure
  • Y192 kinase unknown
  • Trans-activating Y394 kinase identity unresolved in physiological context
  • Quantitative dynamic modeling of free vs. bound LCK pools lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 14 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 7 GO:0031410 cytoplasmic vesicle 4 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 11 R-HSA-168256 Immune System 10 R-HSA-5357801 Programmed Cell Death 2 R-HSA-1266738 Developmental Biology 1
Partners
CBLCD3ECD45FYNLATSAPTSADUNC119
Complex memberships
CD4/CD8–LCK zinc-clasp complexHSP90–CDC37 chaperone complexTCR-CD3 signaling complex

Evidence

Reading pass · 50 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 Crystal structure of the Lck SH3-SH2 regulatory domain fragment revealed how the phosphorylated C-terminal tail binds at the intermolecular SH3/SH2 contact, establishing the structural basis for autoinhibitory regulation of Lck activity. X-ray crystallography of SH3-SH2 fragment alone and in complex with phosphotyrosyl tail peptide Nature High 7512222
1997 S-acylation (palmitoylation) of Lck on Cys3 and Cys5 is essential for its plasma membrane targeting; non-S-acylated Lck fails to localize to the plasma membrane and cannot phosphorylate CD8-zeta or support TCR signaling, even though it retains catalytic activity. Transient transfection of COS-18 cells and Lck-negative JCam-1.6 T cells with Lck palmitoylation-site mutants; Ca2+ flux, ZAP-70 association, CD69/NFAT induction assays The EMBO Journal High 9305640
2003 Lck N-terminus and CD4/CD8 cytoplasmic tails are intrinsically unstructured but co-fold with zinc to form a compact heterodimeric 'zinc clasp' domain; zinc is the essential bridging atom for coreceptor-Lck interaction, and complex formation masks the CD4 dileucine endocytosis motif. NMR solution structure of ternary CD4-Lck-Zn2+ and CD8α-Lck-Zn2+ complexes; in vitro zinc-chelation binding assays Science High 14500983 9830036
1993 Lck has a kinase-independent function in potentiating antigen-specific T cell activation; deletion of the kinase domain from a CD4-Lck chimera enhanced activity, while combined SH2 and kinase domain mutations abolished it, indicating distinct domain contributions. Chimeric CD4-Lck fusion proteins with kinase-domain deletions and point mutations analyzed in antigen-specific T cell hybridoma assays Cell High 8358792
1989 Phosphorylation of Lck at the negative-regulatory site Tyr505 is present in lymphoid cells and correlates with suppressed kinase activity; elevated Lck protein levels rather than altered specific activity account for increased tyrosine phosphorylation in LSTRA cells. In vitro kinase assays, phosphorylation site mapping in multiple lymphoid cell lines Oncogene High 2468122
1995 Phosphorylation of Lck at Tyr394 (the activation loop/autophosphorylation site) is required for H2O2-induced activation of Lck; a separate kinase (not Lck itself) can phosphorylate Tyr394 in catalytically inactive Lck mutants, indicating a trans-activating kinase exists upstream. In vivo H2O2 stimulation with Lck Tyr394 and kinase-dead mutants in Lck-negative cells; in vitro kinase assays PNAS High 7538674
1996 Phosphorylation of Lck SH2 domain at Tyr192 reduces its affinity for phosphotyrosyl ligands and negatively regulates Lck participation in TCR signaling; acidic substitution at Tyr192 mimics the phosphorylated state. In vitro SH2 domain binding assays with phosphopeptides; mutagenesis; T cell activation assays Journal of Biological Chemistry High 8798764
2002 Cbl ubiquitin ligase associates with Lck, ubiquitinates it in a manner requiring both Lck kinase activity and Cbl RING-finger ubiquitin ligase activity, and promotes Lck degradation; Cbl-mediated negative regulation of Lck is independent of ZAP-70. Co-immunoprecipitation, ubiquitination assays in 293T cells and T cell lines including Cbl-/- T cells, reporter assays PNAS High 11904433
2002 Lck autophosphorylation is induced by CD4 and CD28 cooperation during APC stimulation: CD4 recruits Lck to the T cell-APC interface, while CD28 sustains Lck activation; TCR cross-linking alone or CD45 is not required. Phosphospecific antisera to Lck, T cell stimulation with APCs, CD4- and CD28-deficient murine T cells Nature Immunology High 11828322
2010 In naive T cells, up to ~40% of total Lck is constitutively active independent of TCR/coreceptor engagement; constitutively active Lck stability is maintained by the HSP90-CDC37 chaperone complex; the amount of pre-activated Lck determines the extent of TCR-zeta phosphorylation. Phosphospecific flow cytometry, biochemical kinase assays, HSP90 inhibition, primary naive T cells and thymocytes from lymphoid organs Immunity High 20541955
2012 Lck clustering on the plasma membrane is controlled by its conformational state: the open/active conformation promotes Lck clustering and excludes CD45 from TCR-signaling clusters, while the closed/inactive conformation prevents clustering; lipid raft association is neither sufficient nor necessary. Single-molecule localization microscopy (PALM/STORM) with conformation-specific Lck mutants in T cells Nature Immunology High 23202272
2013 T cell activation induces conformational changes in Lck (opening of 20% of Lck molecules) at sites of TCR engagement, which correlates with increased Lck enzymatic activity toward TCR complex substrates. Fluorescence lifetime imaging microscopy (FLIM) with Lck biosensors in live human T cells; parallel biochemical analysis of TCR complexes Science Signaling High 23423439
2017 Lck interacts with CD3ε via ionic interactions between the acidic residues in the Lck Unique domain and the basic residue-rich sequence (BRS) of CD3ε; antigen stimulation unlocks the membrane-sequestered BRS motif, enabling Lck recruitment and TCR phosphorylation. TCR reconstitution system, mutagenesis of CD3ε BRS and Lck Unique domain, biochemical phosphorylation assays PNAS High 28659468
2020 A previously unknown receptor kinase (RK) motif in the CD3ε cytoplasmic tail binds the Lck SH3 domain in a noncanonical manner; this motif is accessible only upon TCR ligation, and its binding to Lck SH3 locally augments Lck activity and CD3 phosphorylation. Biochemical binding assays, mutagenesis, T cell activation and thymocyte development assays, CAR-T in vitro and in vivo tumor models Nature Immunology High 32690949
2017 Phosphorylation of Lck SH2 domain at Tyr192 inhibits CD45 association with Lck and prevents CD45-mediated dephosphorylation of the C-terminal inhibitory Tyr505, thereby establishing a negative feedback loop that controls the pool of active Lck available for TCR signaling. Phosphospecific mutant analysis, co-immunoprecipitation of CD45-Lck, retrogenic mouse thymocyte development assays Molecular Cell High 28735895
1999 CD45 dephosphorylates the inhibitory Tyr505 of Lck; expression of the Lck Y505F mutation in CD45-deficient mice rescues thymocyte development, establishing CD45 as the phosphatase that activates Lck during T cell development. Genetic epistasis: CD45-deficient mice crossed with Lck Y505F transgenic mice; thymocyte development and T cell activation assays Molecular and Cellular Biology High 10330160
2002 PKCε forms a functional signaling module with Lck in cardiac cells: PKCε interacts with, phosphorylates, and activates Lck; disruption of PKCε-Lck modules by Lck gene ablation abrogates cardioprotection induced by PKCε activation or ischemic preconditioning. Co-immunoprecipitation, in vitro kinase assays, Lck knockout mice, ischemic preconditioning models Journal of Clinical Investigation High 11854322
1996 HIV-1 Nef physically interacts with Lck via SH2 and SH3 domain interactions (requiring Nef proline-rich motif and tyrosine phosphorylation), and this interaction depresses Lck kinase activity in vitro and in intact T cells. In vitro binding with recombinant Lck SH2/SH3 domains, co-immunoprecipitation from T cells, in vitro kinase assays Journal of Biological Chemistry High 8626429
2009 Lck is transported to the plasma membrane via a Rab11 endosomal compartment; this trafficking depends on the adaptor protein UNC119, which regulates Rab11 GTPase activation and recruits myosin 5B to organize endosomal complexes; the UNC119-Rab11 pathway is essential for immunological synapse formation and T cell activation. Subcellular fractionation, live imaging, siRNA knockdown, dominant-negative Rab11, co-immunoprecipitation in T cells Journal of Immunology High 19592652
2018 UNC119A extracts membrane-bound LCK by sequestering its myristoyl group; release at the target membrane (immune synapse) is controlled by the ciliary GTPases ARL3/ARL13B; LCK Y394 phosphorylation inhibits UNC119A binding to the LCK kinase domain, focusing active LCK to the immune synapse. Biochemical binding assays, cell imaging (confocal/TIRF), mutagenesis of LCK Y394 and UNC119A-binding residues, siRNA knockdown Developmental Cell High 30220567
2017 Autophosphorylation of the LCK active-site loop (Tyr394) is indispensable for catalytic activity; CD4 and CD8 coreceptors enhance LCK activity; LCK can stimulate its own activation by adopting a more open conformation. Genetic code expansion (photocaged lysine) to generate LCK* for temporal optical control; in-cell phosphorylation kinetics by biochemistry and imaging Nature Structural & Molecular Biology High 29083415
2015 Fas receptor engagement triggers rapid and transient palmitoylation of Lck; inhibiting Lck palmitoylation blocks proximal Fas signaling (Zap70 and PLC-γ1 activation) and renders cells resistant to Fas-mediated apoptosis; DHHC21 is the palmitoyl acyl transferase responsible for Lck palmitoylation downstream of Fas. Acyl-RAC assay for palmitoylation, siRNA knockdown of DHHC21, downstream signaling assays, apoptosis assays PNAS High 26351666
2011 DHHC2 is the protein S-acyltransferase responsible for palmitoylating Lck in T cells; DHHC2 localizes to the ER and Golgi and siRNA-mediated knockdown decreases Lck S-acylation and causes partial membrane dislocation of Lck. siRNA knockdown of DHHC2, overexpression of DHHC2, acylation assays, subcellular fractionation Molecular Membrane Biology Medium 22034844
2021 Asparagine (Asn) directly binds LCK and modulates phosphorylation at Tyr394 (activating) and Tyr505 (inhibitory), thereby enhancing LCK kinase activity and downstream TCR signaling in CD8+ T cells; this is independent of Asn's effects on cellular metabolism. Direct binding assays (LCK-Asn), phosphorylation assays (anti-pY394, anti-pY505), dietary Asn restriction, ASNase treatment, SLC1A5 inhibition, in vitro and in vivo T cell activation assays Nature Cell Biology High 33420490
2022 Disulfiram (DSF) covalently binds Cys20/Cys23 residues of LCK, enhancing Tyr394 phosphorylation and LCK kinase activity, thereby boosting effector T cell function and anti-tumor immunity. Covalent binding assays (mass spectrometry/biochemistry), Tyr394 phosphorylation assays, in vitro kinase assays, in vivo mouse tumor models The EMBO Journal High 35638332
2022 LAG3 associates with TCR-CD3 complexes and its cytoplasmic acidic glutamic acid-proline repeats lower local pH at the immune synapse, causing dissociation of Lck from CD4 or CD8 co-receptor, resulting in loss of co-receptor-TCR signaling. Co-immunoprecipitation, pH-sensitive reporters at the synapse, Lck-coreceptor proximity assays (split-GFP/BiFC), T cell activation assays in human CD4+ and CD8+ T cells Nature Immunology High 35437325
2020 Coreceptor-bound Lck has lower kinase activity and less Y394 activating phosphorylation compared to free (coreceptor-unbound) Lck; free Lck mediates higher T cell activation; coreceptor-Lck coupling is independent of TCR activation. Biochemical fractionation, Y394 phosphospecific western blotting, in vitro kinase assays, T cell activation readouts in OT-I hybridoma cells PNAS High 32571924
2014 Initial TCR triggering is induced by free Lck (not CD8-associated Lck): early CD3ζ-CD8 interaction (within seconds) is independent of CD8-MHC binding but requires CD8 association with Lck; later CD3ζ-CD8 interactions require CD8-MHC binding. TIRF/FRET microscopy at single-cell level during TCR engagement, CD8/Lck association mutants Nature Communications High 25427562
2022 CD8-bound Lck is largely dispensable for cytotoxic T cell antiviral and antitumor responses but facilitates CD8+ T cell responses to suboptimal antigens via kinase-dependent mechanism; CD4-bound Lck is required for helper T cell development and function via a kinase-independent stabilization of surface CD4. Endogenous-level knock-in mouse models with modified LCK (CD4-binding or CD8-binding abolished), antiviral and antitumor in vivo assays Nature Immunology High 36564464
1999 SHP-1 co-immunoprecipitates with the PI3K p85 subunit in a manner dependent on Lck phosphorylation of SHP-1 at Tyr564; SHP-1 dephosphorylates p85 and reduces PI3K activity downstream of Lck in T cells. Co-immunoprecipitation, constitutively active Lck co-expression in COS7 cells, PI3K enzyme activity assays, SHP-1 mutagenesis Journal of Biological Chemistry High 10488096
1994 Lck localizes to the plasma membrane and to pericentrosomal vesicles co-localizing with the cation-independent mannose 6-phosphate receptor in T cells; its distribution is distinct from Fyn, which associates with the centrosome. Immunofluorescence and confocal microscopy in Jurkat T cells and T lymphoblasts Journal of Cell Biology Medium 7513706
2008 Lck-dependent tyrosine phosphorylation of DGKα at Tyr335 is required for DGKα membrane localization during TCR activation; pY335-DGKα is exclusively plasma membrane-associated and this phosphorylation is regulated by Lck downstream of TCR engagement. Phosphospecific antibody to pY335-DGKα, Lck-deficient and reconstituted T cells, subcellular fractionation, in vitro kinase assay with Lck and DGKα Journal of Immunology High 18424699
2006 LAT serves as a direct substrate for both Lck and Syk kinases; Lck co-precipitates with LAT and directly phosphorylates LAT in vitro at ITAM-like motifs Y171/Y191, enabling downstream Grb2, PLC-γ1, and c-Cbl recruitment. Co-immunoprecipitation, in vitro kinase assay with purified Lck and LAT, Lck-deficient J.CaM1.6 cells Leukemia Research Medium 16938345
2008 Kinase-active Lck residing in lipid rafts activates co-localized Fyn via proximity-mediated transphosphorylation; Lck C-terminal sequence QPQP is required for Lck partitioning into lipid rafts and subsequent Fyn activation. Lipid raft fractionation, reciprocal co-immunoprecipitation of Lck-Fyn, Lck C-terminal truncation mutants, Fyn kinase assays, IL-2 reporter Journal of Biological Chemistry High 18660530
2018 LCK phosphorylates YAP at Tyr357, promoting YAP nuclear localization and transcriptional activity in cholangiocarcinoma cells, independent of LATS1/2-mediated serine phosphorylation; LCK was identified as the SFK most responsible for YAPY357 phosphorylation by siRNA screening. siRNA screen of SFKs, CRISPR/Cas9 LCK deletion, site-directed mutagenesis (YAPY357F), phospho-YAP357 assays, nuclear fractionation, PDX models Molecular Cancer Research High 29903769
2018 MDSCs nitrate LCK at Tyr394 via reactive nitrogen species, inhibiting T cell activation; wild-type but not nitrated LCK rescues IL-2 production in LCK-deficient human T cells. Nitroproteomic mass spectrometry, functional reconstitution with wild-type vs. nitrated LCK in LCK-deficient T cells, in vivo mouse prostate cancer model PNAS High 30232256
2004 Hsp90 monitors and stabilizes activated Lck; conformational opening (due to activating mutations Y505F or W97A) increases both Lck ubiquitination and Hsp90 dependence; PP2 (ATP-site binding) reduces ubiquitination, indicating that activation-induced kinase domain conformation triggers both processes. Geldanamycin (Hsp90 inhibitor) treatment, Lck activation mutants, ubiquitination assays in COS-7 cells and T cells Molecular and Cellular Biology High 15199125
2008 T-cell specific adapter protein (TSAd) is phosphorylated by Lck at three C-terminal tyrosines (Tyr280, Tyr290, Tyr305) that serve as docking sites for the Lck SH2 domain; multivalent TSAd-Lck interaction diverts Lck from other substrates and modulates proximal TCR signaling. Mutagenesis, in vitro kinase assays, SH2 domain binding affinity measurements, TCR signaling assays in T cells Journal of Biological Chemistry High 18541536
2016 Anionic plasma membrane lipids (PIP2, PIP3) bind the Lck SH2 domain at a site distinct from the phosphotyrosine-binding pocket; mutation of lipid-binding residues in the SH2 domain reduces Lck interaction with the TCR ζ chain and impairs TCR signaling. NMR analysis of SH2-lipid interaction, electrostatic calculation, mutagenesis, co-immunoprecipitation with TCR ζ chain, T cell signaling assays Journal of Biological Chemistry High 27334919
2014 SAP (SLAM-associated protein) facilitates recruitment and activation of LCK (but not FYN) at NTB-A receptors upon TCR restimulation; this SAP-NTB-A-LCK complex amplifies proximal TCR signaling to promote restimulation-induced cell death (RICD). Co-immunoprecipitation, LCK phosphorylation and kinase activity assays, SAP-deficient patient T cells, SAP siRNA knockdown Journal of Immunology High 24688028
2017 FIP3 (Rab11 family interacting protein-3) controls Lck subcellular localization and its delivery to the immunological synapse via Rab11 endosomes; FIP3-dependent Lck localization controls early TCR signaling (phosphorylation of TCRζ, ZAP70, LAT) and IL-2 gene expression. FIP3 overexpression and silencing, subcellular imaging, Rab11 interaction mutants, TCR signaling assays in human T cells Journal of Immunology High 28235866
2000 Lck activity controls CD4/CD8 lineage commitment in the thymus: reduced Lck activity redirects class II-restricted TCR thymocytes to the CD8 lineage, and increased Lck activity redirects class I-restricted TCR thymocytes to the CD4 lineage. Transgenic mice with altered Lck activity (dominant-negative and constitutively active), class I- and class II-restricted TCR transgenes Immunity High 10755618
2004 CD28 stimulation (via its COOH-terminal PxxPP motif) induces recruitment of Lck into detergent-resistant membrane domains and its accumulation at the immunological synapse in human T cells; this is independent of CD4. CD4- and CD28-deficient murine T cells, CD28 proline-to-alanine mutants, lipid raft isolation, confocal imaging at the immunological synapse Journal of Immunology High 15494485
2018 ICOS transmembrane domain (TMD) promotes association with Lck; TMD-enabled Lck association is required for p85 recruitment to ICOS and PI3K activation, as well as costimulation of calcium mobilization; TMD-replaced ICOS (with intact cytoplasmic domain) fails to support TFH development in vivo. ICOS TMD replacement mutants, co-immunoprecipitation of ICOS-Lck, PI3K/calcium signaling assays, in vivo TFH/GC formation in mice Cellular & Molecular Immunology High 30523347
2008 Lck unique domain directly interacts with HIV-1 Gag in infected T cells, and Lck palmitoylation (membrane targeting) is critical for facilitating HIV-1 Gag plasma membrane localization; loss of Lck reduces HIV-1 particle release. Co-immunoprecipitation of Lck and Gag, Lck palmitoylation mutants, HIV-1 replication assays in Lck-deficient T cells and HeLa cells Journal of Immunology Medium 18714047
2016 WASH interacts with Lck and is phosphorylated by Lck at Tyr141; this phosphorylation is required for lytic granule polarization and NK cell cytotoxicity. Co-immunoprecipitation, in vitro kinase assay with Lck and WASH, Y141F mutation, siRNA knockdown, lytic granule polarization assays Cell Death & Disease Medium 27441653
1995 The Lck unique domain is required for phosphorylation of physiological substrates and induction of the IL-2 promoter, but not for intrinsic kinase activity toward non-physiological substrates, indicating it determines substrate specificity. Lck unique-domain deletion mutants, in vitro kinase assays with enolase and physiological substrates, IL-2 promoter reporter assays Journal of Biological Chemistry Medium 7531706
2006 LAT is a direct substrate for Lck: Lck co-precipitates with LAT and phosphorylates it in vitro; LAT phosphorylation is absent in Lck-deficient J.CaM1.6 cells. In vitro kinase assay with purified Lck and LAT, co-immunoprecipitation, Lck-deficient cell line reconstitution Leukemia Research Medium 16938345
2008 CD45 dephosphorylates Lck at Y394 (activating site) in the context of CD44-mediated signaling, reducing sustained Lck activation and limiting PI3K and PLC activation downstream; CD45 is recruited to CD44 clusters to dampen Lck-mediated spreading signals. CD45-positive vs. CD45-negative T cell lines, Y394 phosphospecific western blot, F-actin and cell spreading imaging, PI3K/PLC inhibitors Journal of Immunology Medium 18981123
2003 Lck is required for mitochondrial apoptosis pathways: Lck-deficient JCaM1.6 cells show no cytochrome c release, no mitochondrial potential breakdown, and no caspase-9/-3 activation upon irradiation, all restored by Lck re-expression; Lck is dispensable for death-receptor-triggered apoptosis. Lck-deficient vs. Lck-reconstituted Jurkat cell lines, apoptosis assays (cytochrome c, ΔΨm, caspase activation) after irradiation and CD95/TRAIL stimulation Oncogene Medium 12527887

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 S-acylation of LCK protein tyrosine kinase is essential for its signalling function in T lymphocytes. The EMBO journal 299 9305640
2010 Constitutively active Lck kinase in T cells drives antigen receptor signal transduction. Immunity 285 20541955
1994 Structure of the regulatory domains of the Src-family tyrosine kinase Lck. Nature 256 7512222
1993 A kinase-independent function of Lck in potentiating antigen-specific T cell activation. Cell 231 8358792
2003 A zinc clasp structure tethers Lck to T cell coreceptors CD4 and CD8. Science (New York, N.Y.) 201 14500983
1988 Translational activation of the lck proto-oncogene. Nature 198 3347254
2012 Conformational states of the kinase Lck regulate clustering in early T cell signaling. Nature immunology 171 23202272
2021 Asparagine enhances LCK signalling to potentiate CD8+ T-cell activation and anti-tumour responses. Nature cell biology 170 33420490
1994 Distinct intracellular localization of Lck and Fyn protein tyrosine kinases in human T lymphocytes. The Journal of cell biology 163 7513706
1995 Activation of the Lck tyrosine protein kinase by hydrogen peroxide requires the phosphorylation of Tyr-394. Proceedings of the National Academy of Sciences of the United States of America 160 7538674
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