Affinage

LCK

Tyrosine-protein kinase Lck · UniProt P06239

Length
509 aa
Mass
58.0 kDa
Annotated
2026-06-10
100 papers in source corpus 53 papers cited in narrative 53 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LCK is a Src-family non-receptor tyrosine kinase that initiates and sets the threshold of T cell receptor (TCR) signaling by phosphorylating proximal substrates at the plasma membrane and immunological synapse (PMID:9305640, PMID:29915297). Membrane and lipid-raft targeting depend on N-terminal S-acylation: palmitoylation at Cys3/Cys5 is required for plasma-membrane localization and TCR signal reconstitution, with DHHC2 and the Fas-inducible DHHC21 acting as acyltransferases (PMID:9305640, PMID:26351666, PMID:22034844). LCK is recruited to its activating context through multiple membrane anchors—a zinc-clasp association of its N-terminus with CD4 and CD8 coreceptor tails (PMID:14500983), an electrostatic interaction between the CD3ε basic-residue-rich sequence and the LCK Unique domain plus a ligand-exposed CD3ε RK motif binding the SH3 domain for coreceptor-free recruitment (PMID:32690949, PMID:28659468), and SH2-domain binding to anionic membrane lipids that is needed for engagement of the TCR ζ chain (PMID:27334919). Catalytic output is governed by a conformational switch built on opposing tyrosine phosphorylations: activating autophosphorylation at Tyr394 is indispensable for activity and drives an open conformation that promotes nanoscale clustering of phospho-TCRs while excluding CD45 (PMID:7538674, PMID:29083415, PMID:23202272), whereas Csk-dependent and FAK-recruited Csk-mediated phosphorylation of the inhibitory Tyr505 closes the kinase, a state reversed by CD45 to license thymocyte development (PMID:7523116, PMID:24227778, PMID:10330160, PMID:18981123). Phosphorylation of SH2-domain Tyr192 by Itk/TSAd both blocks CD45 access and redirects substrate/partner specificity toward actin regulators (PMID:28735895, PMID:25492967). A substantial pool of LCK is constitutively active in resting T cells, maintained by the HSP90–CDC37 chaperone system that protects open/active LCK from ubiquitin-dependent degradation (PMID:20541955, PMID:15199125). Negative feedback is imposed by the Cbl E3 ligase, which ubiquitinates active LCK for degradation via the SH3 domain, and by the phosphatases DUSP22/JKAP and SHP-1 acting on Tyr394; conversely UBR2-mediated K63-ubiquitination promotes Tyr394 activation (PMID:11904433, PMID:24714587, PMID:38225265, PMID:30373850). Functionally, LCK bridges phospho-ZAP70 (through its SH2 domain) to LAT (through its SH3 domain) to coordinate downstream adaptor phosphorylation, sets the quantitative signal that directs CD4/CD8 lineage commitment, and shapes Th2 differentiation via GATA-3/T-bet (PMID:29915297, PMID:10755618, PMID:20237292). Beyond the TCR, LCK phosphorylates a range of substrates including PKCθ (Tyr90), STAT3, FOXP3 (Tyr342), WASH (Tyr141) for NK cytotoxicity, and the TRPM8 channel (Tyr1022), and mediates β1-integrin/laminin signaling required for Schwann cell myelination (PMID:10652356, PMID:10617281, PMID:24155921, PMID:27441653, PMID:35665750, PMID:23715271).

Mechanistic history

Synthesis pass · year-by-year structured walk · 30 steps
  1. 1993 Medium

    Established that LCK's non-catalytic SH2/SH3 domains and adaptor functions, not kinase activity alone, drive T cell activation, reframing LCK as more than a catalytic enzyme.

    Evidence CD4-Lck domain-deletion chimeras in antigen-specific T cell hybridoma assays

    PMID:8358792

    Open questions at the time
    • Did not define direct binding partners of each domain
    • Chimera context may not reflect native LCK regulation
  2. 1995 Medium

    Defined the Unique domain as the determinant of physiological substrate specificity, separating intrinsic catalysis from biological output.

    Evidence Unique-domain deletion mutant with kinase assays on physiological vs non-physiological substrates and IL-2 promoter reporter

    PMID:7531706

    Open questions at the time
    • Mechanism by which the Unique domain selects substrates not resolved
    • Membrane/partner context contributions not isolated
  3. 1995 High

    Identified Tyr394 as the activating autophosphorylation site and provided early evidence for a trans-activating kinase, framing how LCK is switched on.

    Evidence H2O2 stimulation of cells with Y394F/kinase-dead Lck mutants and kinase activity readouts

    PMID:7538674

    Open questions at the time
    • Identity of the trans-activating kinase not established
    • Physiological (non-oxidative) trigger not defined here
  4. 1996 Medium

    Demonstrated LCK self-association via SH2/SH3 domains, providing a mechanism for trans-activation between LCK molecules.

    Evidence CD4-Lck chimeras and GST-SH2/SH3 pull-downs in Lck-positive vs Lck-negative T cells

    PMID:8798782

    Open questions at the time
    • Stoichiometry and physiological relevance of dimers unclear
    • Whether dimerization is regulated during signaling not addressed
  5. 1997 High

    Showed that N-terminal palmitoylation is essential for membrane targeting and TCR signaling, separating catalytic competence from spatial positioning.

    Evidence Acylation-mutant LCK reconstituted in LCK-negative T cells with Ca2+ flux, CD69/NFAT and ZAP-70 association readouts

    PMID:9305640

    Open questions at the time
    • Acyltransferase responsible not identified at this stage
    • Dynamics of palmitoylation not addressed
  6. 1999 High

    Established CD45 dephosphorylation of inhibitory Tyr505 as the in vivo activating step required for thymocyte development.

    Evidence Genetic epistasis with CD45-/- mice rescued by LckY505F transgene

    PMID:10330160

    Open questions at the time
    • How CD45 access to LCK is spatially controlled not resolved here
    • Other CD45 substrates contribution not isolated
  7. 1999 Medium

    Connected LCK to downstream transcriptional and lipid-signaling outputs by showing it phosphorylates STAT3 and gates SHP-1/PI3K regulation.

    Evidence Baculovirus reconstitution with EMSA for STAT3; Co-IP and PI3K activity assays for SHP-1/p85

    PMID:10488096 PMID:10617281

    Open questions at the time
    • Direct vs indirect phosphorylation in vivo not fully separated
    • Quantitative contribution to physiological signaling unclear
  8. 2000 High

    Showed that the quantitative level of LCK activity instructs the CD4/CD8 lineage decision, establishing LCK signal strength as a developmental rheostat.

    Evidence Reciprocal dominant-negative and constitutively active Lck transgenic mice on TCR-transgenic backgrounds

    PMID:10755618

    Open questions at the time
    • Molecular threshold sensors downstream of LCK not defined
    • How signal duration vs amplitude is read not resolved
  9. 2000 High

    Identified PKCθ Tyr90 as a direct LCK substrate linking LCK to NFAT activation and proliferation.

    Evidence In vitro kinase assay, Co-IP, Y90F mutagenesis and T cell reporter assays

    PMID:10652356

    Open questions at the time
    • Structural basis of LCK-PKCθ docking not defined
    • In vivo requirement not tested
  10. 2002 High

    Defined coreceptor and costimulatory control of LCK activation, showing CD4 recruits and CD28 sustains active LCK, and that Cbl provides ubiquitin-dependent negative feedback.

    Evidence Phosphospecific antibodies with blocking antibodies; Co-IP and Cbl-/- T cell line analysis with SH3 mutants

    PMID:11828322 PMID:11904433

    Open questions at the time
    • How CD28 mechanistically sustains autophosphorylation not resolved
    • Cbl recognition determinants on LCK beyond SH3 contact unclear
  11. 2003 High

    Provided the structural basis for coreceptor selectivity by solving the zinc-clasp that folds CD4/CD8 tails with the LCK N-terminus.

    Evidence Solution NMR structures of CD4-Lck-Zn2+ and CD8α-Lck-Zn2+ ternary complexes

    PMID:14500983

    Open questions at the time
    • Dynamics of clasp assembly during synapse formation not captured
    • Regulation of zinc availability not addressed
  12. 2004 Medium

    Linked LCK conformation to its turnover, showing open/active LCK is degraded unless protected by HSP90, independent of kinase activity.

    Evidence Conformational and kinase mutants in COS-7 with geldanamycin and ubiquitination assays

    PMID:15199125

    Open questions at the time
    • E3 ligase mediating conformation-dependent degradation not identified here
    • Quantitative stability difference in primary cells not measured
  13. 2010 High

    Revealed that a constitutively active LCK pool pre-exists in resting T cells and sets TCR-ζ phosphorylation capacity, shifting the model from de novo activation to pre-poised signaling.

    Evidence Phosphospecific flow cytometry and biochemical fractionation in primary cells with HSP90 inhibition

    PMID:20541955

    Open questions at the time
    • How active LCK is restrained from constitutive signaling not fully resolved
    • Spatial segregation from substrate at rest not defined here
  14. 2010 Medium

    Showed CD45 dephosphorylates the activating Tyr394 in additional contexts (CD44 ligation), establishing CD45 as both an activator and a dampener depending on the targeted tyrosine.

    Evidence CD45+/- T cells with CD44 stimulation, phospho-Y394 blotting and PI3K/PLC readouts

    PMID:18981123

    Open questions at the time
    • How CD45 selects Y394 vs Y505 not mechanistically resolved
    • Generality across receptor contexts unclear
  15. 2012 High

    Demonstrated that LCK conformation directly controls nanoscale clustering, producing CD45-excluding, phospho-TCR-enriched domains that spatially favor signaling.

    Evidence Super-resolution PALM/STORM imaging with conformation-state mutants

    PMID:23202272

    Open questions at the time
    • Trigger that shifts conformation in situ not defined
    • Cluster composition beyond TCR/CD45 not enumerated
  16. 2013 High

    Extended LCK function beyond lymphocytes, showing it transduces laminin/β1-integrin signals required for Schwann cell myelination.

    Evidence LCK inhibition, β1-integrin siRNA, Lck-/- mice and Rac-GTP/paxillin pathway readouts

    PMID:23715271

    Open questions at the time
    • Direct LCK substrates in the Schwann cell pathway not all defined
    • Relationship to TCR-context regulation unknown
  17. 2013 Medium

    Identified FAK-recruited Csk as a TCR-induced brake on LCK, adding a spatial mechanism for inhibitory Tyr505 phosphorylation.

    Evidence FAK suppression in human T cells with Csk recruitment and LCK phosphorylation analysis

    PMID:24227778

    Open questions at the time
    • Direct FAK-Csk-LCK assembly stoichiometry not resolved
    • Distinction between LCK and Fyn effects not fully separated
  18. 2014 High

    Established DUSP22/JKAP as a direct phosphatase inactivating LCK at Tyr394, providing a genetic brake whose loss promotes autoimmunity.

    Evidence In vitro phosphatase assay and JKAP knockout mice with EAE model

    PMID:24714587

    Open questions at the time
    • Spatial regulation of JKAP-LCK encounter not defined
    • Relationship to other Y394 phosphatases not ranked
  19. 2014 Medium

    Showed Tyr192 phosphorylation rewires LCK SH2-domain partner preference toward actin regulators, linking a post-translational mark to substrate-selectivity switching.

    Evidence Phosphopeptide arrays and T cell conjugate assays with Itk/TSAd as upstream kinases

    PMID:25492967

    Open questions at the time
    • Full pY192 interactome not mapped
    • In vivo consequence of altered specificity not established here
  20. 2014 Medium

    Expanded LCK substrate repertoire to FOXP3 (Tyr342) and to receptor-localized activation via SAP at NTB-A, linking LCK to Treg/invasion programs and restimulation-induced cell death.

    Evidence In vitro kinase assays with Y342F mutant and invasion assays; Co-IP with NTB-A ITSM mutants and RICD assays in XLP patient cells

    PMID:24155921 PMID:24688028

    Open questions at the time
    • Physiological setting of FOXP3 phosphorylation by LCK unclear
    • Direct vs SAP-bridged LCK recruitment at NTB-A not fully separated
  21. 2017 High

    Resolved the Tyr192 mechanism as a gate on CD45 access, integrating SH2-domain phosphorylation with the activation switch and thymocyte development.

    Evidence Y192 mutants with Co-IP, phospho-blotting and retrogenic mouse thymocyte assays

    PMID:28735895

    Open questions at the time
    • Kinetics of pY192/CD45 competition in vivo not measured
    • Coordination with pY394/pY505 cycling not fully integrated
  22. 2017 High

    Defined the CD3ε BRS-LCK Unique-domain ionic interaction as an antigen-unlocked targeting mechanism for coreceptor-independent TCR phosphorylation.

    Evidence TCR reconstitution with electrostatic mapping, mutagenesis and phosphorylation assays

    PMID:28659468

    Open questions at the time
    • How antigen mechanically unlocks BRS not resolved
    • Quantitative contribution vs coreceptor route unclear
  23. 2017 Medium

    Defined SH2-domain lipid binding and Rab11-FIP3-controlled endosomal delivery as spatial determinants of LCK function at the synapse.

    Evidence NMR/membrane binding assays with lipid-binding mutants; FIP3 gain/loss-of-function with imaging and signaling readouts

    PMID:27334919 PMID:28235866

    Open questions at the time
    • Interplay between lipid binding and phospho-Tyr docking not resolved
    • Trafficking machinery beyond FIP3 not mapped
  24. 2017 High

    Used genetic code expansion to prove Tyr394 autophosphorylation is indispensable and that LCK self-opens, with coreceptors enhancing activity, providing a quantitative live-cell view of the switch.

    Evidence Photocaged active-site lysine LCK with FRET biosensor imaging and live-cell kinetics, CD4/CD8 cotransfection

    PMID:29083415

    Open questions at the time
    • In vivo relevance of measured kinetics not tested
    • Coupling to clustering not directly imaged here
  25. 2018 High

    Defined the bridging function of LCK between phospho-ZAP70 and LAT, explaining how proximal phosphorylation is spatially coordinated.

    Evidence Co-IP, phosphoproteomics, LAT proline-rich-motif mutants and retrogenic mice

    PMID:29915297

    Open questions at the time
    • Stoichiometry of the ZAP70-LCK-LAT assembly not defined
    • Dynamics of bridge formation during signaling unresolved
  26. 2018 Medium

    Identified TAOK3 as protecting LCK from premature SHP-1 inactivation and ICOS transmembrane-domain-driven LCK recruitment for costimulation, broadening LCK's receptor inputs.

    Evidence TAOK3 knockdown with LCK-SHP-1 Co-IP; ICOS TMD-swap mutants with PI3K recruitment and calcium flux

    PMID:30373850 PMID:30523347

    Open questions at the time
    • Mechanism of TAOK3 control over SHP-1 access not resolved
    • Direct vs indirect LCK-ICOS contact not structurally defined
  27. 2020 High

    Established a ligand-exposed CD3ε RK motif binding the LCK SH3 domain and showed free LCK is more active than coreceptor-bound LCK, refining the model of how LCK is positioned and activated at the TCR.

    Evidence Biochemical binding/mutagenesis with thymocyte and CAR-T assays; single-molecule tracking comparing free vs CD8α-bound LCK pools

    PMID:32571924 PMID:32690949

    Open questions at the time
    • Balance between coreceptor-bound and free LCK in vivo not quantified
    • How the two recruitment modes are coordinated unclear
  28. 2022 Medium

    Identified CD146 as a coreceptor-free LCK SH3 partner and LAG3 as a coreceptor-LCK dissociator via local pH, mechanistically explaining both LCK recruitment and inhibitory checkpoint disengagement.

    Evidence Co-IP and direct binding with CD146 knockout mice; LAG3 cytoplasmic mutants with pH-sensor imaging and CD4/CD8-LCK dissociation measurement

    PMID:34491908 PMID:35437325

    Open questions at the time
    • Physiological balance between CD146 and other coreceptor-free routes unclear
    • Generality of pH-driven dissociation beyond LAG3 unknown
  29. 2022 Medium

    Extended LCK substrates to the TRPM8 channel (Tyr1022) with reciprocal feedback on LCK Tyr505, and identified disulfiram as a covalent LCK activator, opening pharmacological tuning of LCK.

    Evidence In vitro kinase assay/electrophysiology for TRPM8; covalent binding and tumor models for disulfiram

    PMID:35638332 PMID:35665750

    Open questions at the time
    • Physiological context of LCK-TRPM8 signaling unclear
    • Selectivity of disulfiram for LCK over other targets not fully established
  30. 2024 High

    Defined UBR2-mediated K63-ubiquitination at Lys99/Lys276 as a positive driver of LCK Tyr394 activation, counter-regulated by DUSP22, with disease relevance in SLE T cells.

    Evidence scRNA-seq, K63-linkage ubiquitination biochemistry, UBR2 knockout, DUSP22 phosphatase assays and SLE patient samples

    PMID:38225265

    Open questions at the time
    • How K63-ubiquitin promotes Y394 phosphorylation mechanistically not resolved
    • Interplay with Cbl K48-degradation pathway not integrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple, overlapping recruitment routes (coreceptor zinc-clasp, CD3ε BRS/RK, CD146, lipid binding) and the layered post-translational controls (Y394/Y505/Y192, K63/K48 ubiquitination, palmitoylation) are quantitatively integrated to set a single activation threshold in vivo remains unresolved.
  • No unified quantitative model linking conformation, ubiquitination, localization and clustering
  • Relative weighting of free vs coreceptor-bound LCK pools in physiological responses unknown
  • Full substrate repertoire and its context-dependence incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016740 transferase activity 3 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 2 GO:0008289 lipid binding 1
Localization
GO:0005886 plasma membrane 4 GO:0005739 mitochondrion 1 GO:0005768 endosome 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3
Partners
CBLCD3ECD4CD45CD8DUSP22LATZAP70
Complex memberships
CD4/CD8-LCK zinc-clasp coreceptor complexHSP90-CDC37 chaperone-LCK complexTCR-linked HSP90-LCK-FYN-glucocorticoid receptor complexZAP70-LCK-LAT proximal signaling assembly

Evidence

Reading pass · 53 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 S-acylation (palmitoylation) of LCK at Cys3 and Cys5 at the N-terminus is required for plasma membrane targeting and TCR signaling; a non-S-acylated LCK mutant is catalytically active but cannot reach the plasma membrane and fails to phosphorylate CD8-zeta or reconstitute TCR signaling in LCK-negative T cells. Transient transfection of COS-18 cells and LCK-negative JCam-1.6 T cells with LCK acylation mutants; functional assays including Ca2+ flux, CD69/NFAT induction, ZAP-70 association The EMBO journal High 9305640
2003 LCK associates with CD4 and CD8 coreceptor cytoplasmic tails via a zinc-coordinated 'zinc clasp' heterodimeric domain; both coreceptor tails and the LCK N-terminus are unstructured in isolation but fold together in the presence of Zn2+. Solution NMR structure determination of ternary CD4-Lck-Zn2+ and CD8alpha-Lck-Zn2+ complexes Science High 14500983
1995 Phosphorylation of Tyr394 (the activating autophosphorylation site) is required for H2O2-induced activation of LCK; additionally, a kinase other than LCK itself can phosphorylate Tyr394, suggesting a trans-activating kinase exists. In vivo H2O2 treatment of cells expressing Lck mutants (Y394F, kinase-inactive); kinase activity assays; expression in LCK-negative cells Proceedings of the National Academy of Sciences High 7538674
1994 LCK can autophosphorylate at both Tyr394 (activating) and Tyr505 (inhibitory) in vitro; autophosphorylation at Tyr505 may represent an accessory mechanism for self-downregulation of kinase activity. Recombinant GST-Lck expression in E. coli with phosphosite mutants (Y394F, Y505F, K273E, double mutant); in vivo and in vitro autophosphorylation assays; phosphopeptide mapping European journal of biochemistry High 7523116
2002 CD4 recruits LCK to the T cell–APC interface (immunological synapse), while CD28 sustains LCK autophosphorylation; TCR cross-linking alone is insufficient to stimulate LCK autophosphorylation. Phosphospecific antisera to activated LCK; stimulation of T cells with antigen-presenting cells; blocking antibodies to CD4 and CD28 Nature immunology Medium 11828322
2002 Cbl ubiquitin ligase negatively regulates LCK by ubiquitinating it upon TCR/CD4 co-ligation, leading to LCK degradation; LCK kinase activity and Cbl RING finger (E3 ligase) activity are both required for LCK ubiquitination; the LCK SH3 domain mediates Cbl-LCK association. Co-immunoprecipitation; Cbl-/- T cell line analysis; co-expression in 293T cells; reporter assays; SH3 domain mutants Proceedings of the National Academy of Sciences High 11904433
1999 CD45 dephosphorylation of the inhibitory Tyr505 of LCK is required for thymocyte development; expression of the constitutively active Y505F LCK mutant rescues thymocyte development in CD45-deficient mice. Genetic epistasis: CD45-/- mice crossed with LckY505F transgenic mice and DO11.10 TCR transgenic mice; T cell functional assays (CD69, IL-2, proliferation) Molecular and cellular biology High 10330160
2002 PKCepsilon forms a signaling module with LCK in cardiac cells: PKCepsilon interacts with, phosphorylates, and activates LCK; disruption of PKCepsilon-LCK modules by Lck gene ablation abrogates cardioprotection from ischemic preconditioning. Functional proteomics; co-immunoprecipitation; transgenic cardiac-specific PKCepsilon activation; Lck knockout mice; infarct size measurement The Journal of clinical investigation Medium 11854322
2010 Constitutively active LCK is present in unstimulated naive T cells and thymocytes (~40% of total LCK); the amount of active LCK does not change after TCR/coreceptor engagement but determines the extent of TCR-zeta phosphorylation; maintenance of active LCK requires the HSP90-CDC37 chaperone complex. Phosphospecific antibodies; flow cytometry; biochemical fractionation; HSP90 inhibitor treatment; quantification in primary cells Immunity High 20541955
2018 LCK acts as a molecular bridge facilitating ZAP70-dependent LAT phosphorylation: LCK SH2 domain binds phospho-ZAP70, while its SH3 domain binds a conserved proline-rich motif in LAT, co-localizing ZAP70 and LAT; elimination of the LAT proline-rich motif compromises TCR signaling and T cell development. Co-immunoprecipitation; phosphoproteomic mass spectrometry; LAT mutants; retrogenic mice; T cell signaling assays Nature immunology High 29915297
2014 The phosphatase JKAP/DUSP22 directly inactivates LCK by dephosphorylating Tyr394; JKAP-knockout T cells display enhanced proliferation and cytokine production; JKAP-deficient mice are more susceptible to EAE. In vitro phosphatase assay; JKAP knockout mice; T cell proliferation and cytokine assays; EAE model; adoptive transfer Nature communications High 24714587
2021 Asparagine directly binds to LCK and modulates its phosphorylation at Tyr394 and Tyr505, thereby enhancing LCK kinase activity and TCR signaling in CD8+ T cells, independently of metabolic flux changes. Binding assays; phospho-specific immunoblotting; Asn restriction experiments; SLC1A5 inhibition; in vitro and in vivo T cell activation assays Nature cell biology Medium 33420490
2012 LCK conformational state controls its nanoscale clustering: open/active conformation induces LCK clustering; closed/inactive conformation prevents clustering; conformation-driven clusters contain phosphorylated TCRs but exclude the phosphatase CD45. Super-resolution microscopy (PALM/STORM); LCK conformation-state mutants; single-molecule imaging in T cells Nature immunology High 23202272
2020 A previously unknown RK motif in the CD3ε cytoplasmic tail binds to the LCK SH3 domain in a noncanonical manner; this motif is accessible only upon TCR ligation, allowing ligand-induced LCK recruitment; binding augments local LCK activity, CD3 phosphorylation, and T cell activation. Biochemical binding assays; mutagenesis; cell-based T cell activation assays; thymocyte development assays; CAR-T cell in vitro and in vivo efficacy Nature immunology High 32690949
2017 The ionic interaction between the basic residue-rich sequence (BRS) of CD3ε and acidic residues in the Unique domain of LCK selectively targets LCK to CD3ε and controls TCR phosphorylation initiation upon antigen stimulation; CD3ε BRS is membrane-sequestered at rest and unlocked by antigen stimulation. TCR reconstitution system; electrostatic interaction mapping; mutagenesis; phosphorylation assays Proceedings of the National Academy of Sciences High 28659468
2022 LAG3 causes dissociation of LCK from the CD4 or CD8 co-receptor via its acidic tandem glutamic acid-proline repeat in the cytoplasmic tail lowering local pH at the immune synapse, resulting in loss of co-receptor-TCR signaling. Co-immunoprecipitation; pH sensor imaging; LAG3 cytoplasmic domain mutants; T cell activation assays; CD4/CD8-LCK dissociation measurement Nature immunology High 35437325
1999 SHP-1 co-immunoprecipitates with the p85 regulatory subunit of PI3K in T cells; this interaction is increased by TCR ligation and requires Lck-mediated phosphorylation of SHP-1 at Tyr564; SHP-1 then dephosphorylates p85 and reduces PI3K activity and Akt phosphorylation. Co-immunoprecipitation; constitutively active Lck co-expression; SHP-1 truncation mutants; PI3K enzyme activity assay; pAkt immunoblotting The Journal of biological chemistry Medium 10488096
2000 Lck tyrosine phosphorylates PKCtheta at Tyr90 in its regulatory domain, both in vitro and in intact T cells; this phosphorylation is required for PKCtheta-dependent enhancement of T cell proliferation and NFAT activation; Lck associates with the regulatory domain of PKCtheta constitutively, enhanced by T cell activation, via both SH2 and SH3 domains. In vitro kinase assay; co-immunoprecipitation; site-directed mutagenesis (Y90F); T cell reporter assays The Journal of biological chemistry High 10652356
2015 Fas receptor engagement leads to a rapid and transient increase in LCK palmitoylation; this dynamic palmitoylation is required for downstream Fas signaling (ZAP70, PLC-γ1 activation) and Fas-mediated apoptosis; DHHC21 is the palmitoyl acyl transferase responsible. Palmitoylation assay; DHHC21 knockdown; inhibition of palmitoylation; apoptosis assay; downstream signaling readouts Proceedings of the National Academy of Sciences Medium 26351666
2011 DHHC2, a DHHC family protein S-acyltransferase localized to the ER and Golgi, palmitoylates LCK in T cells; DHHC2 knockdown reduces LCK S-acylation and partially delocalizes LCK from membranes. siRNA knockdown of DHHC2; S-acylation assay; subcellular fractionation; LckN10-GFP overexpression reporter Molecular membrane biology Medium 22034844
2004 Activated LCK conformations (open/active) are targeted for ubiquitination and degradation, while HSP90 binding rescues active LCK from degradation; both processes are triggered by conformational changes (open SH2/SH3), not by kinase activity or phosphorylation at S42/S59 or Y394; the Src inhibitor PP2 (binding ATP site) reduces ubiquitination and Hsp90 dependence. Lck conformational and kinase mutants expressed in COS-7 cells; Hsp90 inhibitor geldanamycin; ubiquitination assays; western blotting in T cells Molecular and cellular biology Medium 15199125
2017 A phosphosite at Y192 within the LCK SH2 domain inhibits CD45 association with LCK in cells, preventing CD45-mediated dephosphorylation of the C-terminal inhibitory tail (Y505), thus blocking LCK adoption of the active open conformation; Y192 mutation blocks proximal TCR signaling and thymocyte development. Y192 mutant LCK; co-immunoprecipitation; phosphospecific immunoblotting; retrogenic mice; thymocyte development assays Molecular cell High 28735895
1996 Cdc2 kinase associates with LCK through the LCK SH3 domain (only active Cdc2 associates) and phosphorylates LCK in vitro at mitosis, shifting its electrophoretic mobility; this association is selective and not shared by Csk or Syk. Co-immunoprecipitation with anti-Lck and anti-Cdc2 antibodies; Suc1-agarose affinity; in vitro kinase assay; mitotic cell arrest The Journal of biological chemistry Medium 8910336
2000 Quantitative differences in LCK signal (activity level) control the CD4/CD8 lineage decision in thymocytes: reduced LCK activity causes class II-restricted thymocytes to develop into CD8 T cells; increased LCK activity causes class I-restricted thymocytes to develop into CD4 T cells. Transgenic mice with altered Lck activity (dominant-negative or constitutively active); TCR transgenic backgrounds; thymocyte lineage analysis Immunity High 10755618
2013 LCK mediates Th2 differentiation through regulation of T-bet and GATA-3 expression; in lck-/- Th2 cells, GATA-3 is reduced and T-bet is aberrantly elevated, leading to IFN-gamma production; overexpression of GATA-3 restores IL-4 expression in lck-/- Th2 cells. Lck knockout mouse model; Th1/Th2 skewing; cytokine assays; transcription factor expression analysis; GATA-3 overexpression rescue Journal of immunology Medium 20237292
1999 Lck directly activates STAT3 by tyrosine phosphorylation, enhancing STAT3 DNA binding activity; this was demonstrated in a baculovirus reconstitution system and in mammalian cells expressing constitutively active Lck. Baculovirus co-expression of Lck and STAT3; exogenous Lck addition to STAT3; Lck-specific inhibitor PP1; constitutively active Lck stable cell lines; EMSA Cellular signalling Medium 10617281
2013 LCK mediates β1-integrin signaling in Schwann cells downstream of laminin: LCK activation by laminin/β1-integrin drives a paxillin/CrkII/Rac-GTP pathway to induce lamellipodia; LCK-/- mice show delays in myelination, thinner myelin with abnormal g-ratios, and aberrant myelin outfoldings. LCK inhibitor in Schwann cells; siRNA knockdown of β1-integrin; Lck-/- mice; myelination assays; Rac-GTP pull-down Nature communications High 23715271
1998 Tyrosine-phosphorylated paxillin associates with LCK via the LCK SH2 domain in T cells following CD45 or CD3 stimulation; paxillin phosphorylation is dependent on LCK expression. Co-immunoprecipitation; GST-SH2 domain pull-down; LCK-deficient T cell reconstitution; western blotting The Journal of biological chemistry Medium 9488700
2006 Glucocorticoid receptor is part of a TCR-linked multiprotein complex containing HSP90, LCK, and FYN; short-term glucocorticoid treatment causes dissociation of this complex, resulting in impaired LCK/FYN activation and TCR signaling; HSP90 is required for complex assembly. Co-immunoprecipitation; GC receptor siRNA; HSP90 siRNA; LCK/FYN activity assays; T cell stimulation EMBO reports Medium 16888650
2017 Autophosphorylation of the LCK activation-loop (Y394) is indispensable for catalytic activity; LCK can stimulate its own activation by adopting a more open conformation; CD4 and CD8 coreceptors enhance LCK kinase activity. Genetic code expansion (photocaged lysine replacing active-site K) to generate LCK*; FRET biosensor imaging; biochemical phosphorylation kinetics in live cells; CD4/CD8 cotransfection Nature structural & molecular biology High 29083415
2014 LCK phosphorylates FOXP3 at Tyr342, stabilizing FOXP3 expression; phospho-FOXP3 then suppresses LCK-induced MMP9, SKP2, and VEGF-A expression; the Y342F FOXP3 mutant abolishes suppression of MMP9 and cell invasion. Co-immunoprecipitation; in vitro kinase assay; site-directed mutagenesis (Y342F); invasion assays; western blotting PloS one Medium 24155921
2008 LCK-dependent activation of FYN requires LCK to be kinase-active and partition to lipid rafts, mediated by the C-terminal YQPQP sequence; only LR-associated kinase-active LCK co-immunoprecipitates with and activates FYN. Lipid raft fractionation; Co-immunoprecipitation; Lck C-terminal truncation and kinase mutants in NIH 3T3 and T cells; FYN kinase activity assay; IL-2 reporter The Journal of biological chemistry Medium 18660530
2016 The Lck SH2 domain binds anionic plasma membrane lipids (including PI(4,5)P2 and PI(3,4,5)P3) through a surface-exposed basic/aromatic/hydrophobic site distinct from the phospho-Tyr binding pocket; mutation of lipid-binding residues greatly reduces LCK interaction with TCR zeta chain and overall TCR signaling activity. NMR analysis; electrostatic potential calculation; mutational studies; membrane binding assays; TCR signaling assays The Journal of biological chemistry Medium 27334919
1996 The LCK SH3 domain enables LCK to dimerize (interact with itself via SH2/SH3 domains); kinase-dead CD4-Lck lacking catalytic domain can enhance tyrosine phosphorylation by recruiting endogenous active Lck via SH2/SH3 interactions; this dimerization requires endogenous LCK. CD4-Lck chimeras in Lck-positive and Lck-negative (JCam1.6) T cells; GST-SH2/SH3 pull-down from T cell lysates; tyrosine phosphorylation assays The Journal of biological chemistry Medium 8798782
2017 Rab11-FIP3 controls Lck subcellular localization and delivery to the immunological synapse; FIP3 overexpression or silencing modifies Lck endosomal localization and alters TCR-proximal signaling (zeta, ZAP70, LAT phosphorylation, Ca2+ flux, IL-2 expression), as well as steady-state TCR-CD3 surface expression. FIP3 overexpression and siRNA silencing in human T cells; confocal microscopy; signaling assays (phosphotyrosine, Ca2+ flux); IL-2 reporter; flow cytometry Journal of immunology Medium 28235866
2014 SAP facilitates recruitment and activation of LCK (but not FYN) at NTB-A receptors during TCR restimulation; NTB-A-associated LCK activity is enhanced in SAP-dependent manner, amplifying proximal TCR signaling and restimulation-induced cell death (RICD); both NTB-A ITSM motifs are required. Co-immunoprecipitation; NTB-A ITSM mutants; SAP siRNA; LCK kinase activity assay; RICD assay in XLP patient T cells Journal of immunology Medium 24688028
2022 CD146 directly interacts with the SH3 domain of coreceptor-free LCK via its cytoplasmic domain; CD146 dimerization upon TCR ligation recruits LCK and promotes LCK autophosphorylation; CD146 deficiency impairs thymocyte development and peripheral T cell activation. Co-immunoprecipitation; direct binding assays; CD146 knockout mice; thymocyte development analysis; LCK autophosphorylation assay The Journal of clinical investigation Medium 34491908
2024 UBR2 E3 ubiquitin ligase induces Lys63-linked ubiquitination of LCK at Lys99 and Lys276, followed by Tyr394 phosphorylation and activation during TCR signaling; DUSP22 dephosphorylates UBR2, leading to its degradation and thus indirectly limiting LCK activation; UBR2-mediated K63-ubiquitination of LCK is elevated in SLE patient T cells. Single-cell RNA sequencing; co-immunoprecipitation; ubiquitination assays (K63 linkage); UBR2 knockout; DUSP22 phosphatase assays; LCK kinase activity; SLE patient samples Nature communications High 38225265
2013 FAK negatively regulates LCK activity in T cells by recruiting C-terminal Src kinase (Csk) to the membrane/receptor complex after TCR activation; in the absence of FAK, inhibitory phosphorylation of LCK (and/or Fyn) is impaired, resulting in augmented TCR signaling. FAK inhibition/suppression in primary human T cells; Csk recruitment assay; LCK phosphorylation analysis; TCR signaling assays Journal of immunology Medium 24227778
2018 Lck transmembrane domain of ICOS promotes LCK association with ICOS; this TMD-enabled LCK association is required for both PI3K-p85 recruitment to ICOS and calcium mobilization costimulation; ICOS cytoplasmic domain is dispensable for calcium costimulation. ICOS TMD swap mutants; co-immunoprecipitation; PI3K recruitment assay; calcium flux; in vivo TFH/GC formation Cellular & molecular immunology Medium 30523347
2016 LCK interacts with WASH and induces WASH phosphorylation at Y141; this Lck-mediated phosphorylation is required for lytic granule polarization and NK cell cytotoxicity. Co-immunoprecipitation; WASH Y141F mutant; WASH knockdown; lytic granule polarization assay; cytotoxicity assay Cell death & disease Medium 27441653
2022 Disulfiram (DSF) covalently binds to Cys20/Cys23 residues of LCK and enhances LCK Tyr394 phosphorylation, promoting LCK kinase activity and effector T cell function; this mechanism enhances anti-tumor immunity in vivo. Covalent binding assays; phospho-specific immunoblotting; LCK kinase activity assay; T cell functional assays; murine tumor models The EMBO journal Medium 35638332
2015 Lck interacts with CRIF1 in mitochondria in a kinase-independent manner; mitochondrial Lck competitively interferes with CRIF1-Tid1 interaction (components of intramitochondrial translation machinery), repressing oxidative phosphorylation in leukemic T cells. Subcellular fractionation; confocal microscopy; proteomics; co-immunoprecipitation; proximity ligation assay; shRNA silencing of CRIF1; mitochondrial respiration assays BMC cancer Medium 26210498
2014 Phosphorylation of Y192 in the LCK SH2 domain (promoted by Itk and TSAd) changes LCK substrate specificity by altering SH2 domain-binding partner preference; pY192-LCK preferentially binds regulators of the actin cytoskeleton; Itk and TSAd promote TCR-dependent Y192 phosphorylation. Phosphopeptide arrays; biochemical assays; T cell-cell conjugate assays; Y192 mutants; Itk/TSAd expression in T cells Science signaling Medium 25492967
2018 TAOK3 (a serine/threonine kinase) prevents premature SHP-1-mediated inactivation of LCK following TCR engagement; TAOK3-deficient T cells show enhanced LCK-SHP-1 interaction and rapid TCR signal termination; TAOK3 reconstitution corrects this defect. TAOK3 knockdown in human T cells; LCK-SHP-1 co-immunoprecipitation; TCR signaling assays; IL-2 production; superantigen (LCK-independent) control Journal of immunology Medium 30373850
2020 Free (coreceptor-unbound) LCK shows higher activating Y394 phosphorylation, higher mobility, and greater kinase activity than CD8α-bound LCK in T hybridoma cells; free LCK mediates higher T cell activation than coreceptor-bound LCK. Single-molecule tracking; phospho-specific immunoblotting; kinase activity assays; T cell activation assays comparing free vs. coreceptor-bound LCK pools Proceedings of the National Academy of Sciences Medium 32571924
2010 CD4-associated LCK activity stimulated by antagonist MHC-peptide complexes acts in a dominant negative mode to override stimulatory signals from agonist ligands; anti-CD4 antibody blocks the antagonist effect, implicating CD4-Lck activation in negative signaling. T cell stimulation with agonist/antagonist peptides; LCK kinase activity assay; CD4 blocking antibody; inositol phospholipid hydrolysis assay Proceedings of the National Academy of Sciences Medium 8816805
2010 SOCS1 and SOCS3 expression attenuates Lck kinase activity and reduces STAT5 phosphorylation in Lck-transformed leukemia cells; SOCS1 gene silencing in Lck-transformed LSTRA cells occurs via DNA hypermethylation. Ectopic SOCS1/SOCS3 expression; LCK kinase activity assay; STAT5 phosphorylation; methylation analysis; cell proliferation and apoptosis assays International journal of oncology Medium 20372794
2022 LCK directly interacts with TRPM8 and phosphorylates it at Y1022; this phosphorylation promotes TRPM8 multimerization and enhances channel current density; phospho-TRPM8-Y1022 inhibits LCK Tyr505 phosphorylation in feedback regulation of LCK activity. Co-immunoprecipitation; in vitro kinase assay; Y1022F mutant; electrophysiology (TRPM8 current); multimerization assay; LCK ubiquitination analysis Cell death & disease Medium 35665750
2010 CD45 dephosphorylates LCK at Y394 upon CD44 ligation, dampening the amplitude of Src kinase-dependent signaling and determining the morphological outcome (round vs. elongated spreading) in T cells; CD45-/- cells show sustained Y394 phosphorylation and enhanced PI3K/PLC activation. CD45+/- T cells; CD44 antibody stimulation; confocal microscopy; phospho-Y394 immunoblotting; PI3K/PLC activity assays; actin visualization Journal of immunology Medium 18981123
2010 CD44 directly interacts with LCK (but not FYN) through the membrane-proximal region of the CD44 cytoplasmic domain in a zinc-dependent manner; this zinc-inducible interaction requires the first 13 amino acids of the CD44 cytoplasmic domain and the non-catalytic regions of LCK. Direct binding assay with recombinant purified proteins; zinc chelation (1,10-phenanthroline); progressive deletion mutagenesis; co-immunoprecipitation Molecular immunology Medium 20417561
1993 A kinase-dead Lck chimera (CD4-LckΔkinase) is more active than full-length in an antigen-specific T cell assay; SH2 or SH3 domain mutations moderately reduce activity; combined SH2+SH3 mutations largely abolish activity; indicating distinct, independent contributions of LCK domains to T cell activation. CD4-Lck chimeras with domain deletions/mutations; antigen-specific T cell hybridoma assays; T cell activation readouts Cell Medium 8358792
1995 The unique (specific) domain of LCK is not required for intrinsic kinase activity or ATP binding, but is required for phosphorylation of physiological substrates and for induction of the IL-2 promoter, demonstrating that the unique domain determines substrate specificity. Unique domain deletion mutant; kinase activity assay with physiological and non-physiological substrates; IL-2 promoter reporter assay The Journal of biological chemistry Medium 7531706

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation. Oncogene 547 15489916
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 286 20541955
1993 A kinase-independent function of Lck in potentiating antigen-specific T cell activation. Cell 232 8358792
2003 A zinc clasp structure tethers Lck to T cell coreceptors CD4 and CD8. Science (New York, N.Y.) 203 14500983
2021 Asparagine enhances LCK signalling to potentiate CD8+ T-cell activation and anti-tumour responses. Nature cell biology 173 33420490
2012 Conformational states of the kinase Lck regulate clustering in early T cell signaling. Nature immunology 173 23202272
2022 LAG3 associates with TCR-CD3 complexes and suppresses signaling by driving co-receptor-Lck dissociation. Nature immunology 167 35437325
2003 The influence of the src-family kinases, Lck and Fyn, on T cell differentiation, survival and activation. Immunological reviews 160 12614355
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
2002 Regulation of Lck activity by CD4 and CD28 in the immunological synapse. Nature immunology 157 11828322
2000 Lck activity controls CD4/CD8 T cell lineage commitment. Immunity 145 10755618
2002 Formation of protein kinase C(epsilon)-Lck signaling modules confers cardioprotection. The Journal of clinical investigation 139 11854322
2018 Lck promotes Zap70-dependent LAT phosphorylation by bridging Zap70 to LAT. Nature immunology 135 29915297
2006 Glucocorticoids cause rapid dissociation of a T-cell-receptor-associated protein complex containing LCK and FYN. EMBO reports 123 16888650
2002 Negative regulation of Lck by Cbl ubiquitin ligase. Proceedings of the National Academy of Sciences of the United States of America 123 11904433
2014 The phosphatase JKAP/DUSP22 inhibits T-cell receptor signalling and autoimmunity by inactivating Lck. Nature communications 122 24714587
1999 SHP-1 regulates Lck-induced phosphatidylinositol 3-kinase phosphorylation and activity. The Journal of biological chemistry 122 10488096
2019 Beyond TCR Signaling: Emerging Functions of Lck in Cancer and Immunotherapy. International journal of molecular sciences 116 31315298
1988 Structure and expression of lck transcripts in human lymphoid cells. Journal of cellular biochemistry 105 3265417
1992 Functional dissection of the lck proximal promoter. Molecular and cellular biology 104 1588967
2000 Regulation of protein kinase Ctheta function during T cell activation by Lck-mediated tyrosine phosphorylation. The Journal of biological chemistry 99 10652356
2020 Noncanonical binding of Lck to CD3ε promotes TCR signaling and CAR function. Nature immunology 97 32690949
2017 Ionic CD3-Lck interaction regulates the initiation of T-cell receptor signaling. Proceedings of the National Academy of Sciences of the United States of America 92 28659468
1991 Chromosomal translocations joining LCK and TCRB loci in human T cell leukemia. The Journal of experimental medicine 83 1680958
2015 Rapid and transient palmitoylation of the tyrosine kinase Lck mediates Fas signaling. Proceedings of the National Academy of Sciences of the United States of America 79 26351666
2003 Increased ubiquitination and reduced expression of LCK in T lymphocytes from patients with systemic lupus erythematosus. Arthritis and rheumatism 71 12746907
1989 A function for the lck proto-oncogene. Trends in biochemical sciences 66 2683259
2013 LCK is an important mediator of B-cell receptor signaling in chronic lymphocytic leukemia cells. Molecular cancer research : MCR 58 23505068
2006 Hypoxia regulates cross-talk between Syk and Lck leading to breast cancer progression and angiogenesis. The Journal of biological chemistry 58 16474166
1999 Expression of the p56(Lck) Y505F mutation in CD45-deficient mice rescues thymocyte development. Molecular and cellular biology 57 10330160
2017 A Phosphosite within the SH2 Domain of Lck Regulates Its Activation by CD45. Molecular cell 56 28735895
2018 Exploration of the therapeutic aspects of Lck: A kinase target in inflammatory mediated pathological conditions. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 55 30372858
1998 Paxillin phosphorylation and association with Lck and Pyk2 in anti-CD3- or anti-CD45-stimulated T cells. The Journal of biological chemistry 55 9488700
1998 Requirement for p56(lck) tyrosine kinase activation in Th subset differentiation. International immunology 55 9645606
2017 Encoding optical control in LCK kinase to quantitatively investigate its activity in live cells. Nature structural & molecular biology 54 29083415
2024 CD28 Costimulation Augments CAR Signaling in NK Cells via the LCK/CD3ζ/ZAP70 Signaling Axis. Cancer discovery 52 38900051
2006 Differential requirement for Lck during primary and memory CD8+ T cell responses. Proceedings of the National Academy of Sciences of the United States of America 51 17060632
1997 Lck is necessary and sufficient for Fas-ligand expression and apoptotic cell death in mature cycling T cells. Journal of immunology (Baltimore, Md. : 1950) 49 9126969
2000 T cell-specific adapter protein inhibits T cell activation by modulating Lck activity. Journal of immunology (Baltimore, Md. : 1950) 45 10975797
2002 Conserved regulation of the lymphocyte-specific expression of lck in the Fugu and mammals. Proceedings of the National Academy of Sciences of the United States of America 44 11867707
2004 Regulation of the Src family kinase Lck by Hsp90 and ubiquitination. Molecular and cellular biology 43 15199125
2021 How the Discovery of the CD4/CD8-p56lck Complexes Changed Immunology and Immunotherapy. Frontiers in cell and developmental biology 42 33791292
2006 The differential expression of LCK and BAFF-receptor and their role in apoptosis in human lymphomas. Haematologica 41 16769579
2020 Lck bound to coreceptor is less active than free Lck. Proceedings of the National Academy of Sciences of the United States of America 40 32571924
2010 Lck and the nature of the T cell receptor trigger. Trends in immunology 40 21190897
2022 Disulfiram bolsters T-cell anti-tumor immunity through direct activation of LCK-mediated TCR signaling. The EMBO journal 39 35638332
2022 Unique roles of co-receptor-bound LCK in helper and cytotoxic T cells. Nature immunology 39 36564464
1989 Selective expression of alternative lck mRNAs in human malignant cell lines. Molecular and cellular biology 38 2779553
2023 CD28-CAR-T cell activation through FYN kinase signaling rather than LCK enhances therapeutic performance. Cell reports. Medicine 37 36696897
2022 Therapeutic targeting of LCK tyrosine kinase and mTOR signaling in T-cell acute lymphoblastic leukemia. Blood 37 35544598
1999 The Src-family kinase Lck can induce STAT3 phosphorylation and DNA binding activity. Cellular signalling 36 10617281
2013 Focal adhesion kinase negatively regulates Lck function downstream of the T cell antigen receptor. Journal of immunology (Baltimore, Md. : 1950) 35 24227778
2010 Enforced SOCS1 and SOCS3 expression attenuates Lck-mediated cellular transformation. International journal of oncology 34 20372794
2016 Lipids Regulate Lck Protein Activity through Their Interactions with the Lck Src Homology 2 Domain. The Journal of biological chemistry 33 27334919
2018 Transmembrane domain-mediated Lck association underlies bystander and costimulatory ICOS signaling. Cellular & molecular immunology 32 30523347
1995 Lck unique domain influences Lck specificity and biological function. The Journal of biological chemistry 32 7531706
2013 The role of membrane rafts in Lck transport, regulation and signalling in T-cells. The Biochemical journal 31 23931554
2002 Lck tyrosine kinase is important for activation of the CD11a/CD18-integrins in human T lymphocytes. European journal of immunology 31 12115650
2021 Identification of lymphocyte cell-specific protein-tyrosine kinase (LCK) as a driver for invasion and migration of oral cancer by tumor heterogeneity exploitation. Molecular cancer 30 34116687
2013 Lck tyrosine kinase mediates β1-integrin signalling to regulate Schwann cell migration and myelination. Nature communications 30 23715271
2019 Biophysical basis underlying dynamic Lck activation visualized by ZapLck FRET biosensor. Science advances 29 31223643
2013 Phosphorylation of FOXP3 by LCK downregulates MMP9 expression and represses cell invasion. PloS one 29 24155921
2010 Lck mediates Th2 differentiation through effects on T-bet and GATA-3. Journal of immunology (Baltimore, Md. : 1950) 29 20237292
2001 Identification and characterization of a transcriptional regulator for the lck proximal promoter. The Journal of biological chemistry 28 11278409
1997 Differential contribution of Lck and Fyn protein tyrosine kinases to intraepithelial lymphocyte development. European journal of immunology 28 9045930
2021 CD146 bound to LCK promotes T cell receptor signaling and antitumor immune responses in mice. The Journal of clinical investigation 27 34491908
1998 Mutation of the Lck-binding motif of Tip enhances lymphoid cell activation by herpesvirus saimiri. Journal of virology 27 9525577
2014 Lck mediates signal transmission from CD59 to the TCR/CD3 pathway in Jurkat T cells. PloS one 25 24454946
2014 SAP facilitates recruitment and activation of LCK at NTB-A receptors during restimulation-induced cell death. Journal of immunology (Baltimore, Md. : 1950) 25 24688028
2011 DHHC2 is a protein S-acyltransferase for Lck. Molecular membrane biology 25 22034844
2022 LCK inhibition downregulates YAP activity and is therapeutic in patient-derived models of cholangiocarcinoma. Journal of hepatology 24 36162702
2017 Rab11-FIP3 Regulation of Lck Endosomal Traffic Controls TCR Signal Transduction. Journal of immunology (Baltimore, Md. : 1950) 24 28235866
2014 The kinase Itk and the adaptor TSAd change the specificity of the kinase Lck in T cells by promoting the phosphorylation of Tyr192. Science signaling 24 25492967
2010 Role of lymphocyte-specific protein tyrosine kinase (LCK) in the expansion of glioma-initiating cells by fractionated radiation. Biochemical and biophysical research communications 24 20971076
2008 Small molecule inhibitors of Lck: the search for specificity within a kinase family. Mini reviews in medicinal chemistry 24 18537718
2022 Betulinic acid prevents liver fibrosis by binding Lck and suppressing Lck in HSC activation and proliferation. Journal of ethnopharmacology 23 35714879
2022 Transcriptomic profiling of iris tissue highlights LCK signaling and T cell-mediated immunity in Behcet's uveitis. Journal of autoimmunity 23 36191467
1997 Lck-independent triggering of T-cell antigen receptor signal transduction by staphylococcal enterotoxins. The Journal of biological chemistry 23 9169445
1996 The role of CD4-Lck in T-cell receptor antagonism: evidence for negative signaling. Proceedings of the National Academy of Sciences of the United States of America 23 8816805
2016 WASH has a critical role in NK cell cytotoxicity through Lck-mediated phosphorylation. Cell death & disease 22 27441653
2005 Short-interfering RNA-mediated Lck knockdown results in augmented downstream T cell responses. Journal of immunology (Baltimore, Md. : 1950) 22 16301647
2015 LCK over-expression drives STAT5 oncogenic signaling in PAX5 translocated BCP-ALL patients. Oncotarget 21 25595912
2008 Lck-dependent Fyn activation requires C terminus-dependent targeting of kinase-active Lck to lipid rafts. The Journal of biological chemistry 21 18660530
2001 The Src-protein tyrosine kinase Lck is required for IL-1-mediated costimulatory signaling in Th2 cells. Journal of immunology (Baltimore, Md. : 1950) 21 11739499
1994 Tyr394 and Tyr505 are autophosphorylated in recombinant Lck protein-tyrosine kinase expressed in Escherichia coli. European journal of biochemistry 21 7523116
2024 The phosphatase DUSP22 inhibits UBR2-mediated K63-ubiquitination and activation of Lck downstream of TCR signalling. Nature communications 20 38225265
2017 NOD1 deficiency impairs CD44a/Lck as well as PI3K/Akt pathway. Scientific reports 20 28592872
2017 The Src family kinase LCK cooperates with oncogenic FLT3/ITD in cellular transformation. Scientific reports 20 29062038
2008 CD45 down-regulates Lck-mediated CD44 signaling and modulates actin rearrangement in T cells. Journal of immunology (Baltimore, Md. : 1950) 20 18981123
1996 The protein-tyrosine kinase Lck associates with and is phosphorylated by Cdc2. The Journal of biological chemistry 20 8910336
2016 Distinct Mechanisms Regulate Lck Spatial Organization in Activated T Cells. Frontiers in immunology 19 27014263
2010 CD44 interacts directly with Lck in a zinc-dependent manner. Molecular immunology 19 20417561
1996 Role of the Lck Src homology 2 and 3 domains in protein tyrosine phosphorylation. The Journal of biological chemistry 19 8798782
2022 The LCK-14-3-3ζ-TRPM8 axis regulates TRPM8 function/assembly and promotes pancreatic cancer malignancy. Cell death & disease 18 35665750
2020 The role of competing mechanisms on Lck regulation. Immunologic research 18 32794043
2020 Tyrosine 192 within the SH2 domain of the Src-protein tyrosine kinase p56Lck regulates T-cell activation independently of Lck/CD45 interactions. Cell communication and signaling : CCS 18 33225946
2018 TAOK3 Regulates Canonical TCR Signaling by Preventing Early SHP-1-Mediated Inactivation of LCK. Journal of immunology (Baltimore, Md. : 1950) 18 30373850
2015 Lymphocyte-specific protein tyrosine kinase (Lck) interacts with CR6-interacting factor 1 (CRIF1) in mitochondria to repress oxidative phosphorylation. BMC cancer 18 26210498
1991 Partial purification and characterization of the lck protein-tyrosine kinase from bovine thymus. The Biochemical journal 18 1953650

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