Affinage

Showing LAT — LAT1 is a alias.

LAT

Linker for activation of T-cells family member 1 · UniProt O43561

Length
262 aa
Mass
27.9 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LAT is a palmitoylated integral membrane adapter protein that serves as the central organizing scaffold for signaling downstream of ITAM-coupled immunoreceptors, and its disruption causes a complete block of T cell development at the double-negative thymic stage (PMID:9489702, PMID:10204488). Upon TCR engagement, LAT is phosphorylated on multiple tyrosines by ZAP-70/Syk kinases — a reaction made efficient by Lck, which acts as a molecular bridge through binding a LAT proline-rich motif via its SH3 domain and phospho-ZAP-70 via its SH2 domain (PMID:9489702, PMID:29915297) — and Lck additionally functions as a direct LAT kinase at Y171/Y191 (PMID:16938345). Phosphorylated tyrosines create discrete docking sites: Y132 recruits PLC-γ1 (essential for calcium flux, ERK, and NFAT activation), while Y171/Y191/Y226 bind Grb2 and the Gads adaptor that bridges to SLP-76, coupling LAT to the Ras/MAPK and transcriptional machinery (PMID:10811803, PMID:10021361, PMID:12065840). Palmitoylation at C26/C29 targets LAT to glycolipid-enriched raft microdomains and is required for its phosphorylation, plasma-membrane trafficking, and protein stability (PMID:9729044, PMID:16460687); loss of LAT palmitoylation is itself the upstream lesion underlying T cell anergy (PMID:16713970). Activation drives concatenation of separate TCR and LAT membrane islands into microclusters and self-limiting LAT condensates that propagate signaling through a Zap70–LAT–Src-family positive feedback loop (PMID:20010844, PMID:34161759, PMID:36460640), while the intrinsically slow kinetics of Y132 phosphorylation — set by the adjacent glycine G131 — function as a physiological kinetic-proofreading step for antigen discrimination, such that accelerating mutations (G131D/G135D) degrade ligand discrimination and provoke autoimmunity in vivo (PMID:31611699, PMID:36914891). Beyond T cells, LAT is essential for PLC-γ activation downstream of the platelet collagen receptor GPVI and the mast cell FcεRI, where its loss confers resistance to IgE-mediated anaphylaxis (PMID:10567557, PMID:10843385). Signaling output is restrained by c-Cbl/Cbl-b-mediated ubiquitylation and turnover and by SHP-1 dephosphorylation of Y132 (PMID:17938199, PMID:21282648, PMID:27221712), and a pool of intracellular vesicular LAT is delivered to the immune synapse through VAMP7-, Rab6/Syntaxin-16-, GMAP210-, and IFT20-dependent trafficking (PMID:23666293, PMID:29440364, PMID:31253807, PMID:26715756).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1998 High

    Identified the molecular adapter that converts receptor-proximal kinase activity into multi-pathway signaling, answering how the TCR engages downstream effectors.

    Evidence cDNA cloning with co-immunoprecipitation and dominant-negative overexpression in T cells; genetic complementation in LAT-deficient Jurkat (J.CaM2)

    PMID:9489702 PMID:9846483

    Open questions at the time
    • Did not resolve which tyrosines bind which effectors
    • Mechanism of membrane targeting unaddressed
  2. 1998 High

    Established that lipid-raft localization, conferred by palmitoylation at C26/C29, is a prerequisite for LAT phosphorylation, linking membrane microdomain targeting to function.

    Evidence Palmitoylation assay, detergent-resistant membrane fractionation, and palmitoylation-site mutagenesis with phosphorylation readout

    PMID:9729044

    Open questions at the time
    • Palmitoyl transferase not identified
    • Relative contribution of C26 vs C29 unresolved
  3. 1999 High

    In vivo knockout defined LAT as non-redundant for early T cell development and showed lineage specificity, while complex assembly studies identified Gads as the bridge between LAT and SLP-76.

    Evidence LAT knockout mouse with flow cytometry; co-IP and domain-deletion mutants with NFAT reporter

    PMID:10021361 PMID:10204488

    Open questions at the time
    • Did not separate developmental from peripheral signaling roles
    • Stoichiometry of LAT-Gads-SLP-76 complex unresolved
  4. 1999 High

    Extended LAT's adapter role beyond the TCR to other ITAM receptors, establishing it as a general node for PLC-γ activation in platelets (GPVI) and mast cells (FcεRI).

    Evidence LAT knockout mouse platelets and bone-marrow mast cells with phosphorylation, activation, degranulation, and in vivo anaphylaxis readouts; epistasis with Syk-deficient mice

    PMID:10567557 PMID:10843385

    Open questions at the time
    • Whether adapter wiring differs between cell types not fully defined
  5. 2000 High

    Tyrosine-resolution mapping assigned distinct effectors to specific LAT phosphosites, explaining how one adapter branches into calcium and Ras pathways.

    Evidence Systematic Tyr-to-Phe mutagenesis with reconstitution in LAT-deficient Jurkat, co-IP, calcium flux, ERK/NFAT assays; raft-localization immunoisolation

    PMID:10811803 PMID:11038169

    Open questions at the time
    • Did not address phosphorylation order or kinetics
    • Did not establish in vivo consequences of individual site loss
  6. 2002 High

    A single knock-in point mutation disrupting PLC-γ1 binding revealed a paradoxical role: LAT-PLC-γ1 coupling controls both T cell maturation and peripheral homeostasis, its loss causing lymphoproliferation and autoimmunity.

    Evidence Y136F knock-in mouse with functional T cell, calcium, NFAT, IL-2, and ERK assays; redox-dependent membrane displacement via cysteine mutagenesis

    PMID:11756537 PMID:12065840

    Open questions at the time
    • Mechanism connecting signaling defect to lymphoproliferation incompletely defined
  7. 2004 High

    Defined that LAG exists in plasma-membrane and intracellular vesicular pools with distinct synapse-recruitment kinetics, and that c-Cbl-mediated ubiquitylation drives LAT internalization and downregulation.

    Evidence Live imaging of LAT-GFP/YFP, transferrin colocalization, c-Cbl RING mutants, ubiquitylation assays, and c-Cbl knockout T cells

    PMID:14996932 PMID:17938199

    Open questions at the time
    • Trafficking machinery for the intracellular pool not yet identified
    • Ubiquitin acceptor lysines not mapped
  8. 2006 Medium

    Linked palmitoylation to anergy and protein stability, showing impaired LAT palmitoylation is the upstream lesion in anergic T cells and is required for trafficking and proteasome-resistant stability.

    Evidence Anergy induction in primary CD4+ T cells with palmitoylation/DRM/synapse assays; palmitoylation-site mutants with trafficking and proteasome-inhibitor stability assays

    PMID:16460687 PMID:16713970

    Open questions at the time
    • Enzyme controlling activity-dependent palmitoylation state not identified
    • Second study single-lab
  9. 2009 High

    High-resolution imaging redefined LAT signaling as membrane-island concatenation into microclusters, and identified cytoskeletal 4.1R as a direct negative regulator of LAT phosphorylation.

    Evidence PALM, dual-color FCCS, and TEM in T cells; 4.1R knockout mouse with direct binding and functional assays

    PMID:19190245 PMID:20010844

    Open questions at the time
    • Physical drivers of island concatenation unresolved
    • 4.1R findings single-lab
  10. 2011 Medium

    Distinguished LAT ubiquitylation as a turnover-based signaling checkpoint independent of internalization, showing ubiquitylation-resistant LAT elevates signaling.

    Evidence Lys-to-Arg mutagenesis with ubiquitylation, internalization, and signaling readouts

    PMID:21282648

    Open questions at the time
    • Responsible E3 ligases for specific lysines not all defined
    • Single lab
  11. 2013 Medium

    Resolved how vesicular LAT and modifying enzymes are delivered to the synapse and uncovered LAT's role in negative feedback on upstream kinases, plus TRAF6-mediated positive ubiquitylation.

    Evidence VAMP7 siRNA/knockout with imaging; quantitative phosphoproteomics in LAT-deficient Jurkat; TRAF6 co-IP, knockdown, and Lys88 mutagenesis

    PMID:23514740 PMID:23666293 PMID:24204825

    Open questions at the time
    • Whether vesicle docking vs fusion fully accounts for delivery debated
    • TRAF6 and phosphoproteomic findings single-lab
  12. 2015 High

    Demonstrated that intraflagellar/ciliary trafficking machinery is co-opted to deliver intracellular LAT to the immune synapse, with in vivo functional consequences.

    Evidence Conditional IFT20 T cell knockout mouse with synapse imaging, signaling, proliferation, and in vivo colitis transfer assays

    PMID:26715756

    Open questions at the time
    • How IFT20 selects LAT-bearing vesicles unresolved
  13. 2016 Medium

    Established SHP-1 dephosphorylation of LAT Y132 and Cbl-mediated degradation as inhibitory-receptor-driven brakes in NK cells, extending LAT regulation beyond T cells.

    Evidence SHP-1 substrate identification, phospho-specific antibodies, Cbl knockdown, ubiquitylation-resistant mutants, and NK cytotoxicity assays

    PMID:27221712

    Open questions at the time
    • Direct SHP-1–LAT contact site not mapped
    • Single lab
  14. 2017 Medium

    Revealed receptor-specific LAT phospho-coding, where LFA-1/FAK1 phosphorylates LAT selectively at Y171 to assemble a distinct GRB2-SKAP1 complex regulating T cell–DC dwell times.

    Evidence Co-IP, Y171F mutagenesis, kinase assays, and T cell–DC conjugation/proliferation assays

    PMID:28699640

    Open questions at the time
    • Single lab
    • Crosstalk with canonical TCR-driven LAT signaling not resolved
  15. 2018 High

    Defined the kinase-recruitment logic (Lck bridging ZAP-70 to LAT via a proline-rich motif) and the two-phase, retrograde-trafficking delivery of plasma-membrane and vesicular LAT to the synapse.

    Evidence LAT proline-rich-motif mapping and mutagenesis with development assays; Rab6 knockout mouse and Syntaxin-16 silencing with imaging; lattice light-sheet/TIRF-SIM/CLEM imaging

    PMID:29440364 PMID:29789604 PMID:29915297

    Open questions at the time
    • Coordination between membrane and vesicular pools incompletely defined
  16. 2019 High

    Identified Y132 phosphorylation kinetics, set by adjacent G131, as a rate-limiting kinetic-proofreading step for antigen discrimination, and GMAP210 as a Golgi tether for synaptic LAT delivery.

    Evidence G131D/E mutagenesis with in vitro kinase and PLC-γ1 activation and ligand discrimination assays; GMAP210 co-IP, vesicle rerouting/capture, and imaging

    PMID:31253807 PMID:31611699

    Open questions at the time
    • Molecular basis for slow G131-dependent kinetics not fully resolved
    • GMAP210 findings single-lab
  17. 2021 High

    Showed that clustering itself, not one-to-one Zap70:LAT pairing, drives signaling through a Zap70-LAT-SFK positive feedback loop, and that single pMHC:TCR events can nucleate self-limiting LAT condensates.

    Evidence Optogenetic clustering with single-point control and calcium readouts; single-molecule imaging of pMHC:TCR binding with LAT condensation and G131D analysis

    PMID:34161759 PMID:36460640

    Open questions at the time
    • Composition and material properties of condensates not fully characterized
    • How condensate self-limitation is enforced unresolved
  18. 2023 High

    Provided in vivo proof that slow Y132/Y136 phosphorylation is a physiological proofreading step, with accelerating mutation causing aberrant thymic selection, anergy, and autoimmunity.

    Evidence LATG135D knock-in mouse with thymic selection, Listeria infection, autoimmunity, and anergy assays

    PMID:36914891

    Open questions at the time
    • Mechanism linking accelerated kinetics to specific autoimmune manifestations incompletely defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The identity of the palmitoyl transferase/depalmitoylase governing activity-dependent LAT palmitoylation, the structural/biophysical basis of LAT condensate formation and self-limitation, and the molecular determinant of the slow G131-dependent Y132 phosphorylation kinetics remain open.
  • No enzyme assigned to LAT palmitoylation cycling
  • No structural model of the LAT condensate
  • Physical basis of G131-imposed kinetic delay unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0005198 structural molecule activity 3
Localization
GO:0005886 plasma membrane 4 GO:0031410 cytoplasmic vesicle 4 GO:0005794 Golgi apparatus 2
Pathway
R-HSA-168256 Immune System 5 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3
Partners
CBLGRAP2GRB2LCKPLCG1TRAF6VAMP7ZAP70
Complex memberships
LAT-GRB2-SKAP1 complexLAT-Gads-SLP-76 signaling complexLAT-Zap70 membrane condensate

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 LAT (linker for activation of T cells) was cloned as a novel integral membrane protein of 36-38 kDa that is phosphorylated by ZAP-70/Syk protein tyrosine kinases upon TCR engagement, leading to recruitment of multiple signaling molecules including Grb2, PLC-γ1, and the p85 subunit of PI3-kinase. Overexpression of a tyrosine-mutant LAT lacking critical tyrosine residues inhibited T cell activation, demonstrating its essential adapter function. cDNA cloning, co-immunoprecipitation, dominant-negative overexpression in T cells Cell High 9489702
1998 LAT is palmitoylated at cysteines C26 and C29, and this palmitoylation is essential for its localization into glycolipid-enriched membrane microdomains (GEMs/lipid rafts). Loss of palmitoylation abolishes LAT tyrosine phosphorylation upon TCR activation, demonstrating that GEM targeting is required for LAT signaling function. Palmitoylation assay, detergent-resistant membrane fractionation, site-directed mutagenesis of palmitoylation sites, phosphorylation assays Immunity High 9729044
1998 LAT is required for TCR-mediated activation of PLC-γ1 and the Ras pathway. The LAT-deficient Jurkat variant J.CaM2 is defective in calcium increases, Ras activation, and IL-2 expression despite intact TCR-ζ chain and ZAP-70 phosphorylation; reconstitution with LAT restored all signaling events. Genetic complementation in LAT-deficient Jurkat cell line (J.CaM2), calcium flux, Ras activation assay, IL-2 reporter Immunity High 9846483
1999 LAT gene disruption in mice causes a complete block of T cell development at the CD4−CD8− (double-negative) stage in the thymus, with no mature peripheral T cells, while B cell and NK cell populations are grossly normal, establishing LAT as essential for early T cell development. Gene targeting (knockout mouse), flow cytometric analysis of lymphocyte populations Immunity High 10204488
2000 Mapping of LAT tyrosine residues revealed that Tyr171, Tyr191, and Tyr226 are responsible for Grb2 binding; Tyr171 and Tyr191 (but not Tyr226) are required for Gads binding; and Tyr132 alone is required for PLC-γ1 binding. Mutation of Tyr132 abolished calcium flux and blocked ERK and NFAT activation, while Grb2 binding was unaffected, indicating PLC-γ1 activation regulates Ras activation. Tyrosine-to-phenylalanine mutagenesis of LAT, reconstitution in LAT-deficient Jurkat cells, Co-IP, calcium flux, ERK/NFAT assays The Journal of biological chemistry High 10811803
1999 Gads constitutively binds SLP-76 via its C-terminal SH3 domain and a proline-rich region of SLP-76, and inducibly associates with tyrosine-phosphorylated LAT via its SH2 domain upon TCR stimulation. Gads thereby bridges LAT and SLP-76 signaling complexes, promoting NFAT activation synergistically. Co-immunoprecipitation, domain-deletion mutants, NFAT reporter assay Current biology : CB High 10021361
1999 LAT is required for tyrosine phosphorylation of PLC-γ2 and platelet activation downstream of the collagen receptor GPVI. In LAT-deficient platelets, Syk and Btk phosphorylation are maintained but PLC-γ2 phosphorylation, phosphatidic acid formation, PKC substrate phosphorylation, P-selectin expression, and integrin αIIbβ3 activation are markedly reduced in response to CRP. LAT tyrosine phosphorylation is abolished in Syk-deficient platelets, placing LAT downstream of Syk. LAT-knockout mouse platelets, phosphorylation assays, aggregation and secretion assays Molecular and cellular biology High 10567557
2000 LAT is essential for FcεRI-mediated mast cell activation. LAT-deficient mast cells show intact FcεRI, Syk, and Vav phosphorylation but severely reduced SLP-76, PLC-γ1, and PLC-γ2 phosphorylation, calcium mobilization, MAPK activation, degranulation, and cytokine production after FcεRI cross-linking. LAT-deficient mice are resistant to IgE-mediated passive systemic anaphylaxis. LAT-knockout mouse-derived bone marrow mast cells, phosphorylation assays, calcium flux, degranulation assays, anaphylaxis model Immunity High 10843385
1999 LAT is required for TCR-mediated Ca2+ mobilization and optimal tyrosine phosphorylation of PLC-γ1, Vav, and SLP-76, as well as ERK activation, CD69 upregulation, and AP-1/NFAT transcription. The LAT transmembrane domain and palmitoylation at Cys26 (but not Cys29) are required for LAT function and TCR signaling. LAT-deficient Jurkat cell line generation, reconstitution with LAT mutants, phosphorylation assays, calcium flux, transcription reporter assays International immunology High 10360968
2001 TCR engagement triggers actin polymerization-driven T cell spreading requiring LAT. LAT-deficient cells failed to form and maintain the TCR-induced lamellipodia and actin-rich contact rings characteristic of T cell activation, placing LAT upstream of actin cytoskeletal remodeling. Live imaging of T cells on antibody-coated coverslips, LAT-deficient cell lines, actin inhibitors, morphometric analysis Immunity Medium 11290340
2002 A single tyrosine mutation in LAT (Y136F), disrupting PLC-γ1 binding, causes an early block in T cell maturation but subsequently leads to polyclonal lymphoproliferation and autoimmune disease. TCR-induced PLC-γ1 activation, NFAT/calcium signaling, IL-2 production, and cell death were abolished while Erk activation was intact, demonstrating that LAT-PLC-γ1 interaction is critical for integrated signaling controlling T cell development and homeostasis. Knock-in mouse (Y136F point mutation), T cell functional assays, calcium flux, NFAT reporter, IL-2 ELISA, ERK phosphorylation Science (New York, N.Y.) High 12065840
2004 Signaling clusters containing LAT are internalized into distinct intracellular compartments after TCR activation. The ubiquitin ligase c-Cbl mediates LAT ubiquitylation, internalization, and downregulation; c-Cbl RING-domain mutants suppress LAT ubiquitylation and increase cellular LAT levels and basal/TCR-induced LAT phosphorylation. Live fluorescence imaging of LAT-YFP, c-Cbl RING mutant expression, ubiquitylation assay, c-Cbl knockout T cells Molecular and cellular biology High 17938199
2004 LAT exists in two distinct intracellular pools: one at the plasma membrane and one co-distributing with transferrin-labeled intracellular compartments. Distribution between pools is dependent on LAT intracytoplasmic residues. Plasma membrane LAT is recruited to immune synapses within seconds, while the intracellular pool polarizes and recruits over minutes. LAT tyrosines 136, 175, 195, and 235 are required for LAT's own recruitment to the immune synapse. Time-lapse video imaging of LAT-GFP in live T lymphocytes conjugated with APCs, transferrin co-localization, LAT mutant analysis Journal of cell science Medium 14996932
2006 In anergic T cells, LAT is hypophosphorylated due to impaired palmitoylation, resulting in defective LAT recruitment to the immunological synapse and to detergent-resistant membrane fractions. Upstream signaling (CD3ζ and ZAP-70 phosphorylation) remains intact, identifying defective LAT palmitoylation as the upstream target of anergy induction. This effect was independent of Cbl-b. Anergy induction in primary murine CD4+ T cells, palmitoylation assay, DRM fractionation, immunological synapse imaging, phosphorylation assays Immunity High 16713970
2006 Palmitoylation of LAT is required not only for lipid raft targeting but also for LAT trafficking to the plasma membrane and protein stability. Non-palmitoylated LAT mutants failed to traffic to the plasma membrane and were unstable, subject to proteasomal degradation. LAT palmitoylation-site mutants, subcellular fractionation, proteasome inhibitor treatment, protein stability assays Biochemical and biophysical research communications Medium 16460687
2009 TCR and LAT exist in separate protein islands (membrane domains) in resting T cells. Upon T cell activation, these domains concatenate to form signaling microclusters. This was demonstrated using PALM, dual-color fluorescence cross-correlation spectroscopy, and transmission electron microscopy. High-speed photoactivated localization microscopy (PALM), dual-color fluorescence cross-correlation spectroscopy, transmission electron microscopy Nature immunology High 20010844
2011 LAT is ubiquitylated at specific lysine residues, and ubiquitylation-resistant LAT mutants (lysine-to-arginine substitutions) showed normal internalization rates but defective protein turnover. Cells with ubiquitylation-resistant LAT had elevated T cell signaling, establishing LAT ubiquitylation as a checkpoint for attenuating T cell signaling. Site-directed mutagenesis (Lys→Arg), ubiquitylation assay, internalization assay, signaling readouts Proceedings of the National Academy of Sciences of the United States of America Medium 21282648
2013 VAMP7, a vesicular SNARE, is required for recruitment of LAT-containing vesicles to TCR-activation sites and controls phosphorylation of LAT and formation of the TCR-LAT signaling complex. VAMP7 localizes together with LAT on subsynaptic vesicles, and vesicle docking (not fusion with plasma membrane) regulates TCR-induced signaling. siRNA silencing, genetically modified mice (VAMP7-deficient), live imaging, phosphorylation assays, immune synapse analysis Nature immunology High 23666293
2013 TRAF6 is recruited to the immune synapse through direct interaction with LAT via its TRAF domain. TRAF6 promotes LAT ubiquitylation at Lys88 via K63-linked chains and LAT tyrosine phosphorylation and association with ZAP-70, thereby positively regulating TCR/CD28-induced NFAT activation. Co-immunoprecipitation, immune synapse imaging, TRAF6 knockdown, overexpression of catalytically inactive mutant, site-directed mutagenesis of LAT Lys88 Journal of immunology (Baltimore, Md. : 1950) Medium 23514740
2016 SHP-1 directly dephosphorylates LAT (specifically Tyr132) and PLC-γ1/γ2 in NK cells. Dephosphorylation of LAT Tyr132 by SHP-1 abrogates PLC-γ recruitment to the NK-target cell immune synapse, reducing degranulation and target killing. Additionally, LAT is ubiquitylated by c-Cbl and Cbl-b in response to inhibitory receptor engagement, leading to LAT degradation and abrogation of NK cell cytotoxicity. SHP-1 phosphatase substrate identification, phospho-specific antibodies, Cbl knockdown, ubiquitylation assays, LAT mutant (ubiquitylation-resistant) expression, NK cytotoxicity assay Science signaling Medium 27221712
2018 Lck acts as a molecular bridge to facilitate LAT phosphorylation by ZAP-70. A conserved proline-rich motif in LAT mediates binding to the Lck SH3 domain, while Lck SH2 domain binds phospho-ZAP-70, thereby co-localizing ZAP-70 with LAT. Elimination of this proline-rich motif in LAT compromises TCR signaling and T cell development. Identification of LAT proline-rich motif, SH3 binding assay, mutagenesis of LAT proline-rich motif, T cell signaling assays, T cell development analysis Nature immunology High 29915297
2018 LAT internalized from the plasma membrane transits through the Golgi/trans-Golgi network (TGN) before being re-delivered to the immune synapse. This retrograde transport depends on the small GTPase Rab6 and the t-SNARE Syntaxin-16. Knockdown or knockout of Rab6 or Syntaxin-16 impairs LAT recruitment to the immune synapse and TCR-stimulated signaling. Rab6 knockout mouse, Syntaxin-16 silencing, live-cell imaging of LAT trafficking, Golgi colocalization, TCR signaling assays The Journal of experimental medicine High 29440364
2018 Plasma membrane LAT is recruited and phosphorylated at TCR activation sites in the first phase of T cell activation, while vesicular LAT is subsequently recruited dynamically to microclusters via microtubule-directed movement in a second phase. Correlative 3D light and electron microscopy showed absence of vesicles at microclusters at early times but abundance at later times. Lattice light sheet microscopy, TIRF-SIM, correlative 3D light and electron microscopy, live-cell imaging Nature communications High 29789604
2019 Phosphorylation of LAT at Y132 (the PLC-γ1 recruitment site) by ZAP-70 is rate-limiting for T cell ligand discrimination. The slow phosphorylation kinetics at Y132 are governed by an adjacent glycine residue (G131). Substituting G131 with aspartate or glutamate accelerates Y132 phosphorylation, increases PLC-γ1 activation speed and magnitude, and enhances T cell sensitivity to weak agonists and self-peptides, disrupting ligand discrimination. Site-directed mutagenesis (G131D/E), in vitro kinase assay, PLC-γ1 activation assay, T cell ligand discrimination assays Nature immunology High 31611699
2009 Cytoskeletal protein 4.1R binds directly to LAT and inhibits its phosphorylation by ZAP-70. 4.1R-deficient CD4+ T cells show enhanced LAT phosphorylation and ERK activation, hyperproliferation, and increased IL-2/IFN-γ production. 4.1R is recruited to the immunological synapse upon TCR stimulation. 4.1R-knockout mouse, direct binding assay (4.1R–LAT), phosphorylation assays, T cell functional assays Blood Medium 19190245
2019 The golgin GMAP210 tethers LAT-containing vesicles to the Golgi and facilitates their specific delivery to the immune synapse. Upon T cell activation, GMAP210 interactions with LAT-containing VAMP7-decorated vesicles increase, and GMAP210 co-migrates with LAT to the immune synapse. Overexpression of GMAP210 domains disrupts LAT delivery, and GMAP210 similarly controls LAT delivery to cilia in a heterologous model. Co-immunoprecipitation, vesicle rerouting and capture assay, live-cell imaging, domain overexpression, immune synapse analysis Nature communications Medium 31253807
2015 IFT20, an intraflagellar transport protein, controls polarized delivery of intracellular LAT to the immune synapse in primary CD4+ T cells. In IFT20-deficient T cells, centrosome polarization and cell spreading were normal, but LAT recruitment to the immune synapse was reduced, impairing TCR signaling, T cell activation, and proliferation in vitro and antigen-specific responses in vivo. Conditional IFT20-knockout mouse in T cells, immune synapse imaging, TCR signaling assays, in vivo T cell response and colitis transfer models Proceedings of the National Academy of Sciences of the United States of America High 26715756
2021 Zap70 and LAT form membrane-localized condensates/clusters during T cell activation, and signaling from these clusters requires a positive feedback loop among Zap70, LAT, and Src-family kinases that bind phosphorylated LAT to further activate Zap70. Optogenetically induced LAT clustering (but not one-to-one Zap70:LAT heterodimers) is sufficient to drive downstream signaling and calcium responses. Optogenetic clustering system with single-point mutation control, synthetic Zap70:LAT cluster expression in fibroblasts, calcium response assay in T cells Cell reports High 34161759
2022 A single pMHC:TCR binding event is sufficient to trigger a LAT condensate. LAT condensate formation is self-limiting and neither size nor lifetime correlates with the originating pMHC:TCR binding duration; only the probability of condensate formation is related to binding dwell time. A LAT mutation facilitating Y132 phosphorylation (G131D) shortens the delay to condensation and alters T cell antigen specificity. Single-molecule imaging of pMHC:TCR binding events combined with LAT condensation monitoring, LAT G131D mutant analysis Nature communications High 36460640
2023 Accelerating Y136 (mouse; equivalent to human Y132) phosphorylation by the adjacent Gly135Asp substitution in LAT (LATG135D) disrupts ligand discrimination in vivo, causing excessive thymic negative selection, T cell anergy, altered effector/memory balance during infection, and autoimmunity features, demonstrating that the normally slow phosphorylation kinetics of this site constitute a physiological proofreading step. LATG135D knock-in mouse, thymic selection assays, infection model (Listeria), autoimmunity phenotyping, T cell anergy assays Nature immunology High 36914891
2017 LFA-1 cross-linking activates FAK1/PYK2, which phosphorylates LAT selectively at Y171, promoting formation of a LAT-GRB2-SKAP1 complex distinct from canonical LAT-Gads-SLP-76 complexes. This LFA-1-FAK1-LAT-Y171 pathway decreases T cell–dendritic cell dwell times and reduces T cell conjugation and proliferation. Co-immunoprecipitation, site-directed mutagenesis (LAT Y171F), kinase assays, T cell–DC conjugation assay, proliferation assay Nature communications Medium 28699640
2013 Absence of LAT results in augmented and persistent tyrosine phosphorylation of CD3ζ and ZAP-70 (revealed by quantitative phosphoproteomics), demonstrating that LAT signaling hub participates in negative feedback to modulate upstream phosphorylation events, in addition to its established role in positive signal propagation. MS-based quantitative phosphoproteomics comparing LAT-sufficient and LAT-deficient Jurkat T cells PloS one Medium 24204825
2000 Raft-localized LAT, but not palmitoylation-deficient non-raft LAT mutant, selectively accumulates in TCR-enriched plasma membrane immunoisolates in a tyrosine phosphorylation-dependent manner, forming a structural scaffold for TCR signal transduction proteins. Other raft markers (Lck, Fyn, GM1, cholesterol) do not concentrate similarly, indicating protein-mediated selective anchoring. Plasma membrane immunoisolation, palmitoylation-deficient LAT mutant, Western blotting for signaling proteins and lipid markers The Journal of cell biology Medium 11038169
2002 Redox balance alterations (reduced intracellular glutathione) cause membrane displacement of LAT associated with a conformational change detectable by gel electrophoresis, leading to abrogated TCR-mediated signaling. Mutation of redox-sensitive cysteine residues in LAT produces redox-insensitive mutants that remain membrane-anchored under oxidative stress conditions and restore TCR signaling. Glutathione depletion, native vs. non-reducing denaturing PAGE, cysteine mutagenesis, TCR signaling assays Molecular and cellular biology Medium 11756537
2006 LAT is a dual substrate for both Lck and Syk/ZAP-70 kinases. LAT phosphorylation is absent in Lck-deficient cells; Lck co-precipitates with LAT; and in vitro kinase assays with purified Lck demonstrate direct phosphorylation of LAT by Lck at ITAM-like motifs Y171/Y191. Lck-deficient cell line, co-immunoprecipitation, in vitro kinase assay with purified proteins Leukemia research Medium 16938345

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell 1007 9489702
1998 LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation. Immunity 698 9729044
2009 TCR and Lat are expressed on separate protein islands on T cell membranes and concatenate during activation. Nature immunology 502 20010844
1999 Essential role of LAT in T cell development. Immunity 452 10204488
1998 LAT is required for TCR-mediated activation of PLCgamma1 and the Ras pathway. Immunity 407 9846483
1999 Identification of a membrane protein, LAT-2, that Co-expresses with 4F2 heavy chain, an L-type amino acid transport activity with broad specificity for small and large zwitterionic amino acids. The Journal of biological chemistry 342 10391915
2000 Association of Grb2, Gads, and phospholipase C-gamma 1 with phosphorylated LAT tyrosine residues. Effect of LAT tyrosine mutations on T cell angigen receptor-mediated signaling. The Journal of biological chemistry 330 10811803
2001 Dynamic actin polymerization drives T cell receptor-induced spreading: a role for the signal transduction adaptor LAT. Immunity 328 11290340
2000 LAT is essential for Fc(epsilon)RI-mediated mast cell activation. Immunity 279 10843385
1999 The hematopoietic-specific adaptor protein gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors. Current biology : CB 254 10021361
1999 Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene. Nature genetics 240 10080182
2002 A LAT mutation that inhibits T cell development yet induces lymphoproliferation. Science (New York, N.Y.) 234 12065840
1999 Functional analysis of LAT in TCR-mediated signaling pathways using a LAT-deficient Jurkat cell line. International immunology 209 10360968
1989 Herpes simplex virus latent RNA (LAT) is not required for latent infection in the mouse. Proceedings of the National Academy of Sciences of the United States of America 163 2552449
1999 LAT is required for tyrosine phosphorylation of phospholipase cgamma2 and platelet activation by the collagen receptor GPVI. Molecular and cellular biology 153 10567557
2001 High resolution mapping of mast cell membranes reveals primary and secondary domains of Fc(epsilon)RI and LAT. The Journal of cell biology 146 11489921
2018 Lck promotes Zap70-dependent LAT phosphorylation by bridging Zap70 to LAT. Nature immunology 135 29915297
2000 Selective accumulation of raft-associated membrane protein LAT in T cell receptor signaling assemblies. The Journal of cell biology 129 11038169
2015 The linker for activation of T cells (LAT) signaling hub: from signaling complexes to microclusters. The Journal of biological chemistry 112 26354432
2004 Dynamic recruitment of the adaptor protein LAT: LAT exists in two distinct intracellular pools and controls its own recruitment. Journal of cell science 103 14996932
2009 Loss of the LAT adaptor converts antigen-responsive T cells into pathogenic effectors that function independently of the T cell receptor. Immunity 99 19682930
2005 LAT-mediated signaling in CD4+CD25+ regulatory T cell development. The Journal of experimental medicine 98 16380508
2003 LAT regulates gammadelta T cell homeostasis and differentiation. Nature immunology 98 12970761
2013 VAMP7 controls T cell activation by regulating the recruitment and phosphorylation of vesicular Lat at TCR-activation sites. Nature immunology 95 23666293
2007 c-Cbl-mediated regulation of LAT-nucleated signaling complexes. Molecular and cellular biology 94 17938199
2012 HSV-1 genome subnuclear positioning and associations with host-cell PML-NBs and centromeres regulate LAT locus transcription during latency in neurons. PLoS pathogens 86 22912575
2001 A PAK1-PIX-PKL complex is activated by the T-cell receptor independent of Nck, Slp-76 and LAT. The EMBO journal 86 11157752
2015 Oriented Cell Division in the C. elegans Embryo Is Coordinated by G-Protein Signaling Dependent on the Adhesion GPCR LAT-1. PLoS genetics 82 26505631
2002 Effect of redox balance alterations on cellular localization of LAT and downstream T-cell receptor signaling pathways. Molecular and cellular biology 82 11756537
2019 Slow phosphorylation of a tyrosine residue in LAT optimizes T cell ligand discrimination. Nature immunology 81 31611699
2006 Impaired activation and localization of LAT in anergic T cells as a consequence of a selective palmitoylation defect. Immunity 80 16713970
2004 Vav1 transduces T cell receptor signals to the activation of the Ras/ERK pathway via LAT, Sos, and RasGRP1. The Journal of biological chemistry 80 14764585
2000 LAT, the linker for activation of T cells: a bridge between T cell-specific and general signaling pathways. Science's STKE : signal transduction knowledge environment 79 11752630
1999 Perturbed regulation of ZAP-70 and sustained tyrosine phosphorylation of LAT and SLP-76 in c-Cbl-deficient thymocytes. Journal of immunology (Baltimore, Md. : 1950) 77 10358158
1991 Identification of a novel latency-specific splice donor signal within the herpes simplex virus type 1 2.0-kilobase latency-associated transcript (LAT): translation inhibition of LAT open reading frames by the intron within the 2.0-kilobase LAT. Journal of virology 77 1658375
2001 Protein tyrosine phosphatase CD148-mediated inhibition of T-cell receptor signal transduction is associated with reduced LAT and phospholipase Cgamma1 phosphorylation. Molecular and cellular biology 76 11259588
2002 Differential requirement for LAT and SLP-76 in GPVI versus T cell receptor signaling. The Journal of experimental medicine 72 11901197
2005 Mutation of the phospholipase C-gamma1-binding site of LAT affects both positive and negative thymocyte selection. The Journal of experimental medicine 69 15795236
2000 Involvement of LAT, Gads, and Grb2 in compartmentation of SLP-76 to the plasma membrane. The Journal of experimental medicine 68 10993915
2004 HSV LAT and neuronal survival. International reviews of immunology 62 14690860
2000 Functional analysis of novel mutations in y(+)LAT-1 amino acid transporter gene causing lysinuric protein intolerance (LPI). Human molecular genetics 62 10655553
2012 Mycobacterium tuberculosis ManLAM inhibits T-cell-receptor signaling by interference with ZAP-70, Lck and LAT phosphorylation. Cellular immunology 59 22507872
2004 LAT: a T lymphocyte adapter protein that couples the antigen receptor to downstream signaling pathways. BioEssays : news and reviews in molecular, cellular and developmental biology 59 14696041
2002 Neither LAT nor open reading frame P mutations increase expression of spliced or intron-containing ICP0 transcripts in mouse ganglia latently infected with herpes simplex virus. Journal of virology 56 11967293
2016 Early onset combined immunodeficiency and autoimmunity in patients with loss-of-function mutation in LAT. The Journal of experimental medicine 55 27242165
1999 Evidence that phospholipase C-gamma2 interacts with SLP-76, Syk, Lyn, LAT and the Fc receptor gamma-chain after stimulation of the collagen receptor glycoprotein VI in human platelets. European journal of biochemistry 55 10469124
2016 Dephosphorylation of the adaptor LAT and phospholipase C-γ by SHP-1 inhibits natural killer cell cytotoxicity. Science signaling 54 27221712
2020 Multi-gene phylogeny and taxonomy of Amauroderma s.lat. (Ganodermataceae). Persoonia 52 33116341
2009 Both FcgammaRIV and FcgammaRIII are essential receptors mediating type II and type III autoimmune responses via FcRgamma-LAT-dependent generation of C5a. European journal of immunology 52 19795417
2015 IFT20 controls LAT recruitment to the immune synapse and T-cell activation in vivo. Proceedings of the National Academy of Sciences of the United States of America 51 26715756
2011 Enhanced T-cell signaling in cells bearing linker for activation of T-cell (LAT) molecules resistant to ubiquitylation. Proceedings of the National Academy of Sciences of the United States of America 51 21282648
2000 The adapter protein LAT enhances fcgamma receptor-mediated signal transduction in myeloid cells. The Journal of biological chemistry 51 10781611
2010 The role of the LAT-PLC-gamma1 interaction in T regulatory cell function. Journal of immunology (Baltimore, Md. : 1950) 50 20130215
1999 Cutting edge: a role for the adaptor protein LAT in human NK cell-mediated cytotoxicity. Journal of immunology (Baltimore, Md. : 1950) 50 10072481
2005 Role of the LAT adaptor in T-cell development and Th2 differentiation. Advances in immunology 49 16102570
2022 Discrete LAT condensates encode antigen information from single pMHC:TCR binding events. Nature communications 48 36460640
2001 Mechanisms of signaling by the hematopoietic-specific adaptor proteins, SLP-76 and LAT and their B cell counterpart, BLNK/SLP-65. Advances in immunology 48 11680012
2018 Rab6-dependent retrograde traffic of LAT controls immune synapse formation and T cell activation. The Journal of experimental medicine 47 29440364
2000 Signaling via LAT (linker for T-cell activation) and Syk/ZAP70 is required for ERK activation and NFAT transcriptional activation following CD2 stimulation. Blood 46 10979964
2016 Aryl hydrocarbon receptor (AHR) regulation of L-Type Amino Acid Transporter 1 (LAT-1) expression in MCF-7 and MDA-MB-231 breast cancer cells. Biochemical pharmacology 42 26944194
2016 LAT-1 activity of meta-substituted phenylalanine and tyrosine analogs. Bioorganic & medicinal chemistry letters 42 27106710
2006 Palmitoylation of LAT contributes to its subcellular localization and stability. Biochemical and biophysical research communications 42 16460687
2005 Single and combined deletions of the NTAL/LAB and LAT adaptors minimally affect B-cell development and function. Molecular and cellular biology 40 15899851
2009 Cytoskeletal protein 4.1R negatively regulates T-cell activation by inhibiting the phosphorylation of LAT. Blood 38 19190245
2023 A Story of Kinases and Adaptors: The Role of Lck, ZAP-70 and LAT in Switch Panel Governing T-Cell Development and Activation. Biology 37 37759563
2018 Plasma membrane LAT activation precedes vesicular recruitment defining two phases of early T-cell activation. Nature communications 36 29789604
2010 The importance of LAT in the activation, homeostasis, and regulatory function of T cells. The Journal of biological chemistry 35 20837489
2007 Prevalence of ZAP-70, LAT, SLP-76, and DNA methyltransferase 1 expression in CD4+ T cells of patients with systemic lupus erythematosus. Clinical rheumatology 35 17492476
2017 Tonic LAT-HDAC7 Signals Sustain Nur77 and Irf4 Expression to Tune Naive CD4 T Cells. Cell reports 34 28538176
2008 Phospholipid scramblase 1 modulates a selected set of IgE receptor-mediated mast cell responses through LAT-dependent pathway. The Journal of biological chemistry 33 18579528
2009 The essential role of LAT in thymocyte development during transition from the double-positive to single-positive stage. Journal of immunology (Baltimore, Md. : 1950) 32 19380807
2017 LFA-1 activates focal adhesion kinases FAK1/PYK2 to generate LAT-GRB2-SKAP1 complexes that terminate T-cell conjugate formation. Nature communications 31 28699640
2012 The adaptor protein LAT serves as an integration node for signaling pathways that drive T cell activation. Wiley interdisciplinary reviews. Systems biology and medicine 30 23150273
2000 Functional complementation of BLNK by SLP-76 and LAT linker proteins. The Journal of biological chemistry 30 10934198
2006 Evidence of LAT as a dual substrate for Lck and Syk in T lymphocytes. Leukemia research 29 16938345
2023 A single-amino acid substitution in the adaptor LAT accelerates TCR proofreading kinetics and alters T-cell selection, maintenance and function. Nature immunology 28 36914891
2015 miR-155 Controls Lymphoproliferation in LAT Mutant Mice by Restraining T-Cell Apoptosis via SHIP-1/mTOR and PAK1/FOXO3/BIM Pathways. PloS one 28 26121028
2008 Differential roles for the adapters Gads and LAT in platelet activation by GPVI and CLEC-2. Journal of thrombosis and haemostasis : JTH 28 18826392
2013 Quantitative phosphoproteome analysis unveils LAT as a modulator of CD3ζ and ZAP-70 tyrosine phosphorylation. PloS one 27 24204825
1998 The real LAT steps forward. Trends in cell biology 27 9695835
2009 Latency-associated transcript (LAT) exon 1 controls herpes simplex virus species-specific phenotypes: reactivation in the guinea pig genital model and neuron subtype-specific latent expression of LAT. Journal of virology 26 19641003
2021 Adapting T Cell Receptor Ligand Discrimination Capability via LAT. Frontiers in immunology 25 33936119
2015 GRB2 Nucleates T Cell Receptor-Mediated LAT Clusters That Control PLC-γ1 Activation and Cytokine Production. Frontiers in immunology 25 25870599
2013 TNFR-associated factor 6 regulates TCR signaling via interaction with and modification of LAT adapter. Journal of immunology (Baltimore, Md. : 1950) 25 23514740
2001 The transmembrane adapter LAT plays a central role in immune receptor signalling. Oncogene 25 11607829
2021 L-type amino acid transporter (LAT) 1 expression in 18F-FET-negative gliomas. EJNMMI research 23 34905134
2013 LAT-1 functions as a promotor in gastric cancer associated with clinicopathologic features. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 23 23809372
2009 Regulation of lymphocyte development and activation by the LAT family of adapter proteins. Immunological reviews 23 19909357
2003 Appearance of the LAT protein at an early stage of B-cell development and its possible role. Immunology 21 12807480
2018 Glycerol monolaurate induces filopodia formation by disrupting the association between LAT and SLP-76 microclusters. Science signaling 20 29717064
2012 Role of LAT in the granule-mediated cytotoxicity of CD8 T cells. Molecular and cellular biology 20 22566687
2010 Role of the L-amino acid transporter-1 (LAT-1) in mouse trophoblast cell invasion. Placenta 20 20421131
2001 A perspective: regulation of IgE receptor-mediated mast cell responses by a LAT-organized plasma membrane-localized signaling complex. International archives of allergy and immunology 20 11306950
1997 The latency associated transcripts (LAT) of herpes simplex virus: still no end in sight. Journal of neurovirology 20 9372452
2022 Kinetic frustration by limited bond availability controls the LAT protein condensation phase transition on membranes. Science advances 19 36322659
2021 Positive feedback between the T cell kinase Zap70 and its substrate LAT acts as a clustering-dependent signaling switch. Cell reports 19 34161759
2019 Tethering of vesicles to the Golgi by GMAP210 controls LAT delivery to the immune synapse. Nature communications 19 31253807
2010 LAT signaling pathology: an "autoimmune" condition without T cell self-reactivity. Trends in immunology 19 20542732
2009 LAT-1 expression in pre- and post-implantation embryos and placenta. Placenta 19 19193433
2000 The role of SLP-76 and LAT in lymphocyte development. Current opinion in immunology 19 10712938

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