Affinage

SLC7A5

Large neutral amino acids transporter small subunit 1 · UniProt Q01650

Length
507 aa
Mass
55.0 kDa
Annotated
2026-04-28
100 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC7A5 (LAT1) is a Na⁺-independent large neutral amino acid antiporter that serves as the obligate transport-competent subunit of the LAT1–CD98/4F2hc (SLC3A2) heterodimer, coupling essential amino acid import to mTORC1 signaling, immune cell activation, and tumor metabolism. Cryo-EM structures show LAT1 adopts an inward-open conformation and engages CD98 through a disulfide bond plus extensive transmembrane and extracellular contacts; reconstituted LAT1 alone catalyzes histidine/leucine antiport, whereas CD98 is transport-inactive but required for plasma membrane trafficking via N-glycosylation-dependent export (PMID:30867591, PMID:26256001, PMID:36028562). Transport activity is modulated by cholesterol-mediated stabilization of the inward-open state, ATP binding at Lys204, Nedd4-2-dependent ubiquitylation of N-terminal lysines triggering endocytosis, and TRIM35-mediated ubiquitylation that increases transporter levels (PMID:33028978, PMID:31728037, PMID:39304904). Beyond amino acid import—which fuels mTORC1 in contexts driven by HIF-2α, FOXC1, YAP/TAZ, oncogenic KRAS, and c-Myc/SRC2—LAT1 transports gabapentin, pregabalin, and methylmercury-cysteine conjugates across the blood–brain barrier and placenta, and directly modulates Kv1.2 potassium channel gating to influence neuronal excitability and neuropathic pain (PMID:23567998, PMID:30356053, PMID:38946582, PMID:33414552, PMID:38755144).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1998 High

    Identifying the molecular identity of the CD98 light chain as SLC7A5/LAT1 established the subunit composition of the heterodimeric amino acid transporter.

    Evidence Mass spectrometry peptide sequencing plus reciprocal co-immunoprecipitation of tagged E16 with anti-CD98hc antibody

    PMID:9837878

    Open questions at the time
    • Functional contribution of each subunit to transport not yet resolved
    • Stoichiometry of the complex unknown
  2. 2000 Medium

    Demonstrating that SLC7A5 mRNA is selectively induced by arginine deprivation (but not glutamine) in normal hepatocytes—with this adaptive response lost in transformed cells—provided early evidence for amino acid-responsive transcriptional regulation of LAT1.

    Evidence Amino acid deprivation experiments in primary rat hepatocytes and transformed hepatic cell lines with mRNA quantification

    PMID:10681508

    Open questions at the time
    • Transcription factor mediating arginine-responsive induction not identified
    • Mechanism of lost regulation in transformed cells unknown
  3. 2005 High

    Identification of CD147 as an associate of the CD98–LAT1 complex revealed a metabolic supercomplex at the cell surface linking amino acid transport with monocarboxylate transport and proliferation control.

    Evidence Chemical cross-linking/mass spectrometry and reciprocal co-IP, with RNAi of CD147/CD98hc reducing proliferation and activating AMPK

    PMID:15901826

    Open questions at the time
    • Whether CD147 directly modulates LAT1 transport kinetics not tested
    • Structural basis of the supercomplex unknown
  4. 2012 High

    Establishing that HIF-2α directly binds the Slc7a5 promoter to upregulate LAT1 expression linked oxygen sensing to mTORC1 activation via amino acid import, explaining mTORC1 hyperactivity in VHL-deficient tumors.

    Evidence ChIP at Slc7a5 promoter, HIF-2α gain/loss-of-function, mTORC1 and amino acid transport assays in VHL-deficient cells and hypoxic tissues

    PMID:23103253

    Open questions at the time
    • Other HIF-2α-independent transcriptional regulators of Slc7a5 not fully mapped
    • Whether HIF-2α regulation is tissue-specific not resolved
  5. 2013 High

    Demonstrating that gabapentin is a LAT1 substrate with saturable kinetics explained its blood–brain barrier permeation and opened the concept that LAT1 transports clinically relevant drugs.

    Evidence Radiolabeled gabapentin uptake in brain endothelial cells and LAT1-transfected HEK293, plus siRNA knockdown and pharmacological inhibition

    PMID:23567998

    Open questions at the time
    • In vivo contribution of LAT1 vs. other routes for gabapentin CNS entry not quantified
  6. 2015 High

    Reconstitution of purified recombinant LAT1 alone in proteoliposomes proved it is the sole transport-competent subunit—catalyzing Na⁺-independent histidine/leucine antiport—while CD98 contributes no intrinsic transport activity, resolving a longstanding question about subunit roles.

    Evidence Proteoliposome reconstitution of recombinant hLAT1 and hCD98 tested separately with radiolabeled substrates

    PMID:26256001

    Open questions at the time
    • Role of CD98 in trafficking vs. allosteric modulation of LAT1 not fully distinguished
  7. 2015 Medium

    Linking LAT1-imported methionine to S-adenosylmethionine production and EZH2-dependent histone methylation revealed an epigenetic feedback loop in which amino acid supply controls chromatin state.

    Evidence LAT1/EZH2 shRNA knockdown, SAM metabolite measurement, and demonstration that EZH2 loss de-represses RXRα which then reduces LAT1 transcription

    PMID:25979827

    Open questions at the time
    • Whether this feedback operates in non-tumor cells unknown
    • Quantitative contribution of LAT1 vs. other methionine transporters to SAM pools not established
  8. 2016 High

    CRISPR/TALEN knockout of LAT1 across six cancer cell lines and in xenografts showed LAT1 transport activity—not CD98 expression—is the growth-limiting step, triggering amino acid stress (ATF4/GCN2) and ablating mTORC1 signaling and tumor growth.

    Evidence LAT1 and CD98 knockout in six cell lines, leucine transport, mTORC1 signaling, xenograft tumors, JPH203 pharmacological inhibition

    PMID:27302165

    Open questions at the time
    • Compensatory upregulation of other amino acid transporters not systematically assessed
  9. 2016 High

    Discovery that CD69 physically associates with the LAT1–CD98 complex on γδ T cells to regulate tryptophan uptake and AhR-dependent IL-22 secretion connected LAT1 to immune regulation and psoriasis pathogenesis.

    Evidence Co-IP of CD69 with LAT1–CD98, L-Trp uptake measurements, AhR reporter, IL-22 in CD69-deficient mice

    PMID:27376471

    Open questions at the time
    • Whether CD69–LAT1 interaction is direct or mediated by CD98 not resolved
    • Structural basis of the trimolecular complex unknown
  10. 2017 High

    Identification of C407 as a critical residue for dithiazole/dithiazine-mediated covalent inhibition provided the first pharmacologically validated functional residue in LAT1's substrate pathway.

    Evidence C407A mutagenesis in proteoliposome transport assays with kinetic analysis and molecular docking

    PMID:28709952

    Open questions at the time
    • Role of C407 in normal catalytic cycle (not just inhibitor binding) unclear
  11. 2017 High

    Showing that cholesterol depletion reduces LAT1 Vmax established that membrane lipid environment modulates transporter throughput, complemented later by reconstitution data showing cholesterol increases substrate affinity at the internal site.

    Evidence Cell-based cholesterol depletion with L-DOPA uptake kinetics (2017); proteoliposome assays with cholesterol/ATP and K204Q mutagenesis (2020)

    PMID:28272458 PMID:33028978

    Open questions at the time
    • Structural basis of cholesterol binding site on LAT1 not resolved
    • Physiological relevance of ATP–K204 interaction in vivo unknown
  12. 2018 High

    Mass spectrometric identification of LAT1 as a Kv1.2 channel partner, combined with electrophysiology showing LAT1 hyperpolarizes Kv1.2 activation by −47 mV and accelerates inactivation, revealed a non-canonical ion channel regulatory function independent of amino acid transport.

    Evidence Mass spectrometry of Kv1.2 complexes, whole-cell patch clamp in co-expression system, epilepsy mutant characterization

    PMID:30356053

    Open questions at the time
    • Whether transport activity is required for Kv1.2 regulation not determined
    • In vivo neuronal relevance confirmed only later in diabetic neuropathy models
  13. 2018 Medium

    Demonstrating that LAT1-mediated leucine import drives mTORC1-dependent glycolytic reprogramming and IL-1β production in human monocytes extended LAT1's role from tumor metabolism to innate immune inflammatory signaling.

    Evidence SLC7A5 siRNA and pharmacological inhibition in human monocytes/macrophages with mTORC1 and cytokine readouts

    PMID:29422900

    Open questions at the time
    • Contribution of LAT1 vs. other leucine transporters in macrophage activation not quantified
  14. 2019 High

    Cryo-EM structures of the LAT1–4F2hc complex at 3.3 Å resolution revealed the inward-open conformation, the disulfide bond (C164–C109) linking subunits, and extensive extracellular/transmembrane/intracellular contacts, providing the first atomic framework for understanding substrate selectivity and inhibitor design.

    Evidence Cryo-EM at 3.3/3.5 Å with and without inhibitor BCH, combined with transport assays

    PMID:30867591

    Open questions at the time
    • Outward-open conformation not captured
    • Substrate-bound transition states not resolved
  15. 2019 High

    Mapping Nedd4-2-mediated ubiquitylation to N-terminal lysines K19/K25/K30 upon PKC activation established a regulated endocytic pathway for LAT1 turnover, explaining how signaling controls surface transporter abundance.

    Evidence Systematic mutagenesis of cytosolic lysines, Nedd4-2 siRNA, endocytosis assays in HeLa cells

    PMID:31728037

    Open questions at the time
    • Whether Nedd4-2-mediated regulation operates in all LAT1-expressing tissues unknown
    • Deubiquitinase(s) that counteract this modification not identified
  16. 2021 High

    Genetic deletion of Slc7a5 in KRAS-mutant colorectal cancer models abrogated tumorigenesis by collapsing amino acid pools and bulk protein synthesis, directly demonstrating that oncogenic KRAS depends on LAT1 for nutrient supply; combined LAT1 loss and mTORC1 inhibition eliminated established tumors.

    Evidence Conditional Slc7a5 knockout in Kras/Apc-mutant mouse intestinal epithelium, metabolic flux analysis, protein synthesis assays, tumor growth

    PMID:33414552

    Open questions at the time
    • Whether LAT1 dependency generalizes to all KRAS-driven cancers not tested
  17. 2022 High

    Systematic mutagenesis of CD98 N-glycosylation sites showed that glycosylation is required for CD98 trafficking to the plasma membrane and consequently for LAT1 surface localization and transport activity, clarifying the obligatory chaperone-like role of CD98.

    Evidence Quadruple N-glycosylation mutant of CD98 with biotinylation, trafficking, and transport assays

    PMID:36028562

    Open questions at the time
    • Whether partial glycosylation retains function not fully characterized
  18. 2023 High

    Demonstrating that SRC2 is recruited by c-Myc to the Slc7a5 promoter in CD4+ T cells—with SRC2 loss preventing Slc7a5 upregulation and forced Slc7a5 expression rescuing proliferation—placed LAT1 as a critical effector of Myc-driven T cell activation.

    Evidence T cell-specific SRC2 KO mice, Slc7a5 rescue, proliferation/cytokine assays, EAE and colitis models

    PMID:37094160

    Open questions at the time
    • Direct ChIP evidence for SRC2 at the Slc7a5 promoter not shown in this study
  19. 2023 Medium

    LAT1 deficiency in CD4+ T cells impaired immune synapse formation by reducing CD3ζ and phospho-tyrosine recruitment, revealing a structural or signaling role for LAT1 in TCR complex organization beyond nutrient supply.

    Evidence T cell-specific LAT1 deletion, TIRF microscopy of immune synapse, RNA-seq, arthritis models

    PMID:37229811

    Open questions at the time
    • Whether synapse defect is secondary to amino acid deprivation vs. direct scaffolding not distinguished
    • Mechanism linking LAT1 to CD3ζ recruitment not identified
  20. 2024 Medium

    Multiple transcriptional and post-transcriptional regulators of SLC7A5 were identified: FOXC1 drives endothelial LAT1 expression for mTOR-dependent angiogenesis; YAP/TAZ transcriptionally activates SLC7A5 to confer KRAS inhibitor resistance; IGF2BP2 stabilizes SLC7A5 mRNA via m6A; and TRIM35 ubiquitylation upregulates LAT1 protein to promote cardiac fibrosis.

    Evidence Endothelial Foxc1 KO with mTOR agonist rescue (PMID:38755144); YAP/TAZ/TEAD knockdown in KRAS inhibitor-resistant cells (PMID:39704172); MeRIP/RIP and metabolite assays for IGF2BP2 (PMID:38281999); TRIM35 co-IP/ubiquitination assays with cardiac fibroblast KO mice (PMID:39304904)

    PMID:38281999 PMID:38755144 PMID:39304904 PMID:39704172

    Open questions at the time
    • Many of these regulatory axes demonstrated in single labs and specific tissue contexts
    • Whether TRIM35-mediated ubiquitylation stabilizes LAT1 (non-degradative) or enhances trafficking is unclear
  21. 2024 Medium

    In diabetic neuropathy, LAT1 upregulation (via ATF4) reduces Kv1.2 membrane localization, increases neuronal excitability, and causes neuropathic pain—validated by pharmacological LAT1 inhibition alleviating allodynia—connecting the earlier Kv1.2-regulatory function to a disease-relevant in vivo phenotype.

    Evidence RNA-seq, proteomics, Kv1.2 immunofluorescence, electrophysiology, behavioral pain assays in HFD/STZ and db/db mice treated with JPH203

    PMID:38946582

    Open questions at the time
    • Whether LAT1-Kv1.2 interaction is direct in sensory neurons or mediated by amino acid depletion not fully resolved
    • Contribution of transport-independent vs. transport-dependent mechanisms to neuropathic pain unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of outward-open and substrate-occluded conformations, how LAT1 simultaneously executes amino acid antiport and Kv1.2 channel regulation, whether transport-independent scaffolding functions exist at the immune synapse, and identification of deubiquitinases that oppose Nedd4-2-mediated LAT1 turnover.
  • Outward-open and occluded structures not captured
  • Transport-dependent vs. -independent Kv1.2 regulation not mechanistically separated
  • Deubiquitinase for LAT1 not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 7 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 5 GO:0005768 endosome 2
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-382551 Transport of small molecules 6 R-HSA-168256 Immune System 4 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-9609507 Protein localization 3
Partners
BSGCD69IGF2BP2KCNB1NEDD4LSLC3A2TRIM35
Complex memberships
CD147-CD98-LAT1 metabolic supercomplexLAT1-CD98/4F2hc heterodimer

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 Cryo-EM structures of human LAT1-4F2hc alone and in complex with inhibitor 2-amino-2-norbornanecarboxylic acid revealed that LAT1 adopts an inward-open conformation, interacts with 4F2hc via a disulfide bond plus extensive extracellular, transmembrane, and intracellular contacts, and that 4F2hc is essential for transport activity of the complex. Cryo-EM structure determination at 3.3 Å and 3.5 Å resolution, biochemical transport assays Nature High 30867591
2015 LAT1 (SLC7A5) is the sole transport-competent subunit of the LAT1/CD98 heterodimer; recombinant hLAT1 reconstituted in proteoliposomes catalyzes Na⁺-independent antiport of histidine and other large neutral amino acids, while reconstituted hCD98 alone shows no transport activity. Proteoliposome reconstitution with recombinant proteins, radiolabeled substrate transport assays, SDS-PAGE under reducing/non-reducing conditions The international journal of biochemistry & cell biology High 26256001
1998 The light chain of the CD98 complex (SLC7A5/LAT1) was identified as the TA1/E16 protein by mass spectrometric peptide sequencing, antibody cross-reactivity, and co-immunoprecipitation of hemagglutinin-tagged E16 with anti-CD98 heavy chain antibody. Mass spectrometry peptide sequencing, co-immunoprecipitation, immunoblotting The Journal of biological chemistry High 9837878
2016 LAT1 transport activity (not CD98 expression level) is the key growth-limiting step of the CD98/LAT1 complex; LAT1 knockout ablates Na⁺-independent leucine transport, triggers ATF4/GCN2 amino acid stress response, suppresses mTORC1 activity, and arrests tumor growth in vitro and in vivo, while CD98 knockout retaining 10% residual LAT1 activity shows normal growth. Gene knockout (CRISPR/TALEN) in six cancer cell lines, leucine transport assays, mTORC1 signaling assays, xenograft tumor models, JPH203 pharmacological inhibition Cancer research High 27302165
2012 HIF2α activates mTORC1 by transcriptionally upregulating SLC7A5 expression; HIF2α binds directly to the Slc7a5 proximal promoter, and SLC7A5-mediated amino acid import drives mTORC1 activity in VHL-deficient tumor cells and in liver and lung tissue under low oxygen. Chromatin immunoprecipitation (ChIP) at Slc7a5 promoter, HIF2α gain/loss-of-function, mTORC1 activity assays, cell-based amino acid transport assays Molecular cell High 23103253
2017 Cysteine residue C407 in hLAT1 is critical for inhibition by dithiazole/dithiazine compounds; these inhibitors form disulfide bonds with C407 causing mixed-type, prolonged inhibition of histidine antiport, and the C407A mutant shows impaired inhibition. Proteoliposome transport assays, dose-response kinetics, site-directed mutagenesis (C407A), molecular docking on hLAT1 homology model Biochemical pharmacology High 28709952
2020 Cholesterol stimulates hLAT1 transport activity by selectively increasing substrate affinity at the internal site, stabilizing the inward-open conformation; ATP synergistically enhances this effect only in the presence of cholesterol via interaction with Lys204, confirmed by K204Q mutagenesis abolishing ATP response. Proteoliposome transport assays with cholesterol/ATP, site-directed mutagenesis (K204Q), computational docking Scientific reports High 33028978
2017 Cellular cholesterol depletion reduces the Vmax (but not Km) of LAT1-mediated substrate uptake; a soluble cholesterol analogue is required for stable purification of the LAT1-CD98 complex while retaining substrate interaction capability. Cholesterol depletion assays in cells, L-DOPA uptake kinetics, protein purification with cholesterol analogue Scientific reports Medium 28272458
2019 PKC activation by PMA triggers ubiquitylation of LAT1 N-terminal tail lysines K19/K25/K30 by the Nedd4-2 E3 ubiquitin ligase, leading to endocytosis and lysosomal degradation of LAT1 in HeLa cells. PMA stimulation, systematic mutagenesis of cytosolic lysines, Nedd4-2 siRNA knockdown, endocytosis assays Scientific reports High 31728037
2018 SLC7A5 (LAT1) physically associates with and regulates surface expression and activity of the Kv1.2 voltage-gated potassium channel; co-expression with Slc7a5 reduces total Kv1.2 protein, hyperpolarizes voltage-dependence of activation by −47 mV, and accelerates inactivation. Slc3a2 co-expression attenuates these effects, and epilepsy-linked Slc7a5 mutations with localization defects show diminished Kv1.2 regulation. Mass spectrometry of Kv1.2 multi-protein complexes, electrophysiology (whole-cell patch clamp), co-expression studies, disease mutant characterization Nature communications High 30356053
2013 Gabapentin is a substrate for LAT1 (SLC7A5) in brain endothelial cells and LAT1-transfected HEK293 cells, with saturable kinetics (Km ~217–930 µM), demonstrated by radiolabeled uptake assays, siRNA knockdown of LAT1, and LAT1 overexpression. Radiolabeled gabapentin uptake in hCMEC/D3 and LAT1-transfected HEK293 cells, siRNA knockdown, pharmacological inhibition, kinetic analysis Biochemical pharmacology High 23567998
2018 Pregabalin is transported specifically by LAT1 (SLC7A5) but not LAT2 at the blood-brain barrier; overexpression of LAT1 in HEK293 cells increases pregabalin uptake (Km ~0.29 mM), and LAT1 siRNA knockdown reduces uptake in human brain endothelial cells by 75%. LAT1/LAT2 overexpression in HEK293, LC-MS/MS uptake quantification, LAT1 siRNA knockdown, JPH203 inhibition in hCMEC/D3 cells Pharmaceutical research High 30374619
2015 LAT1 (SLC7A5) imports methionine to support S-adenosylmethionine production, which sustains EZH2-dependent histone methylation; EZH2 knockdown de-represses RXRα which then reduces LAT1 transcription, establishing a LAT1-EZH2 positive feedback loop. Amino acid depletion or LAT1 knockdown reduces SAM levels and EZH2 activity. LAT1/EZH2 shRNA knockdown, SAM metabolite measurement, gene expression analysis, tumor growth assays The EMBO journal Medium 25979827
2021 SLC7A5 maintains intracellular amino acid levels following oncogenic KRAS activation to support bulk protein synthesis; Slc7a5 deletion in KRAS-mutant colorectal cancer mouse models abrogates tumorigenesis, and combining Slc7a5 deletion with mTORC1 inhibition eliminates established Kras-mutant tumors. Conditional Slc7a5 knockout in mouse intestinal epithelium with Kras/Apc mutations, metabolic flux analysis, protein synthesis assays, tumor growth models Nature genetics High 33414552
2016 CD69 physically associates with the LAT1-CD98 complex on γδ T cells, regulating surface expression of LAT1-CD98 and uptake of L-tryptophan, which controls intracellular levels of AhR activators and thereby AhR-dependent IL-22 secretion contributing to psoriasis pathogenesis. Co-immunoprecipitation of CD69 with LAT1-CD98, surface expression assays, L-Trp uptake measurements, AhR reporter assays, IL-22 secretion in CD69-deficient mice Nature immunology High 27376471
2005 CD147 selectively associates with the CD98 heavy chain–LAT1 complex (along with ASCT2 and monocarboxylate transporters) at the cell surface, forming a metabolic supercomplex; RNA interference knockdown of CD147 or CD98hc reduces cell proliferation and activates AMP-activated protein kinase. Covalent chemical cross-linking, mass spectrometric protein identification, co-immunoprecipitation, RNA interference knockdown Molecular & cellular proteomics High 15901826
2021 SLFN5 interacts with ATF4 and regulates LAT1 expression in castration-resistant prostate cancer; SLFN5 depletion decreases intracellular essential amino acids and impairs mTORC1 signaling in a LAT1-dependent manner, establishing SLFN5 as an upstream regulator of the LAT1-mTORC1 axis. Comparative proteomics, co-immunoprecipitation of SLFN5 with ATF4, LAT1 expression rescue, amino acid measurements, mTORC1 signaling assays, in vivo xenograft Cancer research Medium 33985973
2022 N-glycosylation of CD98 (SLC3A2) at residues N365, N381, N424, and N506 is required for its trafficking to the plasma membrane and protein stability; the unglycosylated quadruple mutant fails to reach the plasma membrane, correlating with reduced LAT1 presence at the membrane and decreased LAT1 transport activity. Site-directed mutagenesis of N-glycosylation sites, biotinylation assay for membrane presence, brefeldin A trafficking assay, LAT1 transport activity measurement Scientific reports High 36028562
2018 SLC7A5-mediated leucine influx promotes mTORC1 activation leading to glycolytic reprogramming and pro-inflammatory IL-1β production in human monocytes/macrophages; pharmacological blockade or siRNA silencing of SLC7A5 reduces mTORC1 activity and IL-1β levels. SLC7A5 siRNA knockdown, pharmacological inhibition, mTORC1 signaling assays, extracellular acidification rate measurement, cytokine measurement Frontiers in immunology Medium 29422900
2024 TRIM35 E3 ubiquitin ligase interacts with, ubiquitinates, and upregulates SLC7A5, thereby enhancing amino acid transport and activating mTORC1 signaling in cardiac fibroblasts to promote fibrosis and hypertrophy; SLC7A5 overexpression rescues the reduced fibrosis caused by TRIM35 conditional knockout. Co-immunoprecipitation of TRIM35 with SLC7A5, ubiquitination assays, fibroblast-specific Trim35 KO mice with TAC model, LC-MS/MS, RNA-Seq, mTORC1 signaling assays Cell communication and signaling Medium 39304904
2024 IGF2BP2 m6A reader enhances stability and translation of SLC7A5 mRNA through m6A modification, increasing SLC7A5-mediated methionine transport and SAM production, which feeds back to upregulate IGF2BP2 via H3K4me3; FBW7/GSK3β-mediated degradation of IGF2BP2 breaks this loop, and the IGF2BP2-SLC7A5 positive feedback promotes radioresistance via AKT/mTOR signaling. MeRIP-qPCR, RNA immunoprecipitation, ChIP-qPCR, co-immunoprecipitation, ubiquitination assays, clonogenic survival assays, metabolite measurements, in vivo mouse models Journal of experimental & clinical cancer research Medium 38281999
2023 SRC2 acts as a coactivator recruited by c-Myc to stimulate Slc7a5 transcription in CD4+ T cells; SRC2-deficient T cells fail to upregulate Slc7a5 upon activation, show defective proliferation and cytokine production, and forced Slc7a5 expression rescues these defects. T cell-specific SRC2 knockout mice, Slc7a5 overexpression rescue, proliferation and cytokine assays, EAE and colitis models Proceedings of the National Academy of Sciences High 37094160
2024 LAT1 (Slc7a5) upregulation in diabetic neuropathy (via ATF4 activation under BCAA deficiency) reduces Kv1.2 channel localization to the cell membrane, increases neuronal excitability, and causes neuropathic pain; LAT1 inhibition with BCH or intrathecal JPH203 alleviates allodynia in mouse DNP models. RNA sequencing, proteomics, immunofluorescence of Kv1.2 membrane localization, whole-cell electrophysiology, behavioral pain assays in HFD/STZ and db/db mouse models Advanced science Medium 38946582
2000 TA1/LAT-1 (SLC7A5) mRNA is specifically upregulated in response to arginine depletion in primary rat hepatocytes but not in response to glutamine deprivation, and this adaptive response is lost in gamma-glutamyl transpeptidase-positive transformed/tumorigenic hepatic cells; CD98 heavy chain does not respond to arginine levels. Amino acid deprivation experiments in rat hepatic cell lines, mRNA quantification, amino acid transport activity assays The Journal of biological chemistry Medium 10681508
2015 MARCH1/MARCH8 E3 ubiquitin ligases ubiquitylate CD98 heavy chain (SLC3A2), leading to lysosomal degradation; blocking ubiquitylation via catalytically inactive MARCH or a ubiquitylation-resistant CD98 mutant prevents CD98 downregulation, and T cells expressing ubiquitylation-resistant CD98 show increased proliferation and clonal expansion in vivo. MARCH overexpression, catalytically inactive MARCH mutant, ubiquitylation-resistant CD98 mutant, March1-null T cells, in vitro proliferation and in vivo clonal expansion assays Journal of cell science Medium 26493331
2024 Rab4A-directed endosomal traffic controls CD98 receptor recycling; constitutively active Rab4AQ72L promotes CD98-dependent kynurenine production and mTOR activation, while Rab4A deletion in T cells restrains CD98 expression, mitochondrial metabolism, and T cell lineage skewing in lupus-prone mice. Constitutively active Rab4A knockin, Rab4A T cell-specific knockout, stable isotope tracing of metabolic pathways, gene expression analysis, flow cytometry Nature communications Medium 38519468
2020 MITF transcription factor directly regulates SLC7A5 expression; SLC7A5 knockdown or pharmacological inhibition (BCH, JPH203) decreases melanin synthesis in melanocytes and melanoma cells without affecting tyrosinase activity, acting through a distinct depigmenting pathway. ChIP-seq/microarray integration identifying MITF targets, siRNA knockdown of SLC7A5, pharmacological inhibition, melanin content assays, reconstructed human epidermis model The Journal of investigative dermatology Medium 32240722
2019 HIF-2α (but not HIF-1α) directly binds the proximal promoter of Slc7a5 in differentiated neuronal cells and drives hypoxia-induced Slc7a5 upregulation; shRNA-mediated knockdown of HIF-2α but not HIF-1α abolishes this response. HIF-2α and HIF-1α shRNA knockdown in Neuro2A cells, ChIP at Slc7a5 promoter under hypoxia, qRT-PCR FEBS open bio Medium 30761250
2024 FOXC1 transcription factor in endothelial cells directly regulates Slc7a5 (and Slc3a2) expression; endothelial-specific Foxc1 deletion impairs mTOR activity and retinal angiogenesis, which is rescued by the mTOR agonist MHY-1485, placing LAT1/4F2hc-mediated amino acid transport downstream of FOXC1 and upstream of mTOR in angiogenesis. Endothelial-specific Foxc1 knockout mice, retinal vascular growth assays, mTOR activity assays, mTOR agonist rescue experiment Nature communications High 38755144
2023 ALYREF m5C reader recognizes m5C sites in JunD mRNA and stabilizes it, leading to JunD-mediated transcriptional upregulation of SLC7A5; increased SLC7A5 then depletes amino acids in the tumor microenvironment restricting CD8+ T cell function, and ALYREF knockdown decreases SLC7A5 expression and inactivates mTORC1. MeRIP/RIP assays, RNA pull-down, ChIP for JunD at SLC7A5 promoter, co-immunoprecipitation, in vivo tumor models Cell death discovery Medium 38402198
2021 LAT1 mediates transport of methylmercury-L-cysteine conjugates (structural mimics of methionine) across the placental cell membrane; LAT1 knockdown reduces MeHg accumulation but increases susceptibility to MeHg toxicity due to reduced glutathione synthesis, demonstrating LAT1's essential role in cysteine-dependent antioxidant defense. siRNA knockdown of LAT1 in HTR-8/SVneo cells, MeHg accumulation assays, cell viability, apoptosis, oxidative stress assays, GSH measurement International journal of molecular sciences Medium 33567754
2023 LAT1 (SLC7A5) deficiency in murine CD4+ T cells impairs immune synapse formation with reduced recruitment of CD3ζ and phospho-tyrosine signaling molecules under inflammatory conditions, and reduces transcription of TCR/CD28 signaling genes including Akt1, Akt2, Nfatc2, Nfkb1 and Nfkb2. CD4+ T cell-specific LAT1 deletion, TIRF microscopy of immune synapse, RNA-sequencing, experimental arthritis models Journal of autoimmunity Medium 37229811
2024 YAP/TAZ activation in KRAS inhibitor-resistant cancer cells reverses KRAS inhibitor-induced proliferation arrest by transcriptionally activating SLC7A5, which in turn restores mTORC1 activity; this YAP/TAZ-SLC7A5-mTORC1 axis is an acquired resistance mechanism to KRAS G12C and G12D inhibitors. Transcriptomic analysis of resistant cells, YAP/TAZ/TEAD knockdown, SLC7A5 expression assays, mTORC1 signaling assays, pharmacological rescue JCI insight Medium 39704172

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Amino acid transporters ASCT2 and LAT1 in cancer: partners in crime? Seminars in cancer biology 591 15916903
2019 Structure of the human LAT1-4F2hc heteromeric amino acid transporter complex. Nature 270 30867591
2018 The Human SLC7A5 (LAT1): The Intriguing Histidine/Large Neutral Amino Acid Transporter and Its Relevance to Human Health. Frontiers in chemistry 230 29988369
2021 The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer. Nature genetics 204 33414552
2021 Amino acid transporter LAT1 (SLC7A5) as a molecular target for cancer diagnosis and therapeutics. Pharmacology & therapeutics 193 34390745
2019 The L-Type Amino Acid Transporter LAT1-An Emerging Target in Cancer. International journal of molecular sciences 183 31100853
2012 HIF2α acts as an mTORC1 activator through the amino acid carrier SLC7A5. Molecular cell 174 23103253
2012 CD98 at the crossroads of adaptive immunity and cancer. Journal of cell science 165 22499670
2016 Genetic Disruption of the Multifunctional CD98/LAT1 Complex Demonstrates the Key Role of Essential Amino Acid Transport in the Control of mTORC1 and Tumor Growth. Cancer research 150 27302165
2018 The glutamine transporter ASCT2 (SLC1A5) promotes tumor growth independently of the amino acid transporter LAT1 (SLC7A5). The Journal of biological chemistry 146 29326164
2005 Metabolic activation-related CD147-CD98 complex. Molecular & cellular proteomics : MCP 139 15901826
2021 Targeting SLC1A5 and SLC3A2/SLC7A5 as a Potential Strategy to Strengthen Anti-Tumor Immunity in the Tumor Microenvironment. Frontiers in immunology 132 33953707
2015 LAT1 is the transport competent unit of the LAT1/CD98 heterodimeric amino acid transporter. The international journal of biochemistry & cell biology 119 26256001
2013 Transport of gabapentin by LAT1 (SLC7A5). Biochemical pharmacology 108 23567998
2018 Role of SLC7A5 in Metabolic Reprogramming of Human Monocyte/Macrophage Immune Responses. Frontiers in immunology 107 29422900
2011 CD98 expression modulates intestinal homeostasis, inflammation, and colitis-associated cancer in mice. The Journal of clinical investigation 103 21490400
2016 CD69 controls the uptake of L-tryptophan through LAT1-CD98 and AhR-dependent secretion of IL-22 in psoriasis. Nature immunology 101 27376471
2009 MicroRNA-7 modulates CD98 expression during intestinal epithelial cell differentiation. The Journal of biological chemistry 97 19892711
2012 Relation of LAT1/4F2hc expression with pathological grade, proliferation and angiogenesis in human gliomas. BMC clinical pathology 87 22373026
2013 Targeting intestinal inflammation with CD98 siRNA/PEI-loaded nanoparticles. Molecular therapy : the journal of the American Society of Gene Therapy 86 24025751
2020 Review of the Correlation of LAT1 With Diseases: Mechanism and Treatment. Frontiers in chemistry 74 33195053
2018 The Regulation and Function of the L-Type Amino Acid Transporter 1 (LAT1) in Cancer. International journal of molecular sciences 70 30103560
2007 Expression of LAT1 predicts risk of progression of transitional cell carcinoma of the upper urinary tract. Virchows Archiv : an international journal of pathology 68 17622555
2009 Abnormal expression of myelination genes and alterations in white matter fractional anisotropy following prenatal viral influenza infection at E16 in mice. Schizophrenia research 66 19487109
1998 The light chain of CD98 is identified as E16/TA1 protein. The Journal of biological chemistry 66 9837878
2017 Modulation of LAT1 (SLC7A5) transporter activity and stability by membrane cholesterol. Scientific reports 65 28272458
2024 Rab4A-directed endosome traffic shapes pro-inflammatory mitochondrial metabolism in T cells via mitophagy, CD98 expression, and kynurenine-sensitive mTOR activation. Nature communications 64 38519468
2017 Potent inhibitors of human LAT1 (SLC7A5) transporter based on dithiazole and dithiazine compounds for development of anticancer drugs. Biochemical pharmacology 61 28709952
2017 Long non-coding RNA PVT1-5 promotes cell proliferation by regulating miR-126/SLC7A5 axis in lung cancer. Biochemical and biophysical research communications 58 29277611
2015 Antitumor activity of an anti-CD98 antibody. International journal of cancer 55 25556716
2014 Expression of amino acid transporters (LAT1, ASCT2 and xCT) as clinical significance in hepatocellular carcinoma. Hepatology research : the official journal of the Japan Society of Hepatology 54 25297701
2015 Reciprocal regulation of amino acid import and epigenetic state through Lat1 and EZH2. The EMBO journal 52 25979827
2000 TA1/LAT-1/CD98 light chain and system L activity, but not 4F2/CD98 heavy chain, respond to arginine availability in rat hepatic cells. Loss Of response in tumor cells. The Journal of biological chemistry 50 10681508
2016 Direct Sensing of Nutrients via a LAT1-like Transporter in Drosophila Insulin-Producing Cells. Cell reports 46 27681427
2021 ASCT2 and LAT1 Contribution to the Hallmarks of Cancer: From a Molecular Perspective to Clinical Translation. Cancers 45 33429909
2017 Relationship between LAT1 expression and resistance to chemotherapy in pancreatic ductal adenocarcinoma. Cancer chemotherapy and pharmacology 44 29149426
2008 Intestinal epithelial CD98: an oligomeric and multifunctional protein. Biochimica et biophysica acta 44 18625289
2018 Transport of Pregabalin Via L-Type Amino Acid Transporter 1 (SLC7A5) in Human Brain Capillary Endothelial Cell Line. Pharmaceutical research 42 30374619
2016 CD98 regulates vascular smooth muscle cell proliferation in atherosclerosis. Atherosclerosis 42 28012647
2014 Glycoprotein CD98 as a receptor for colitis-targeted delivery of nanoparticle. Journal of materials chemistry. B 41 24729869
2022 Endocytosis-Independent and Cancer-Selective Cytosolic Protein Delivery via Reversible Tagging with LAT1 substrate. Advanced materials (Deerfield Beach, Fla.) 39 35789055
2019 The Role of Large Neutral Amino Acid Transporter (LAT1) in Cancer. Current cancer drug targets 38 31376820
2020 Co-Expression Effect of SLC7A5/SLC3A2 to Predict Response to Endocrine Therapy in Oestrogen-Receptor-Positive Breast Cancer. International journal of molecular sciences 36 32093034
2015 Basigin-mediated redistribution of CD98 promotes cell spreading and tumorigenicity in hepatocellular carcinoma. Journal of experimental & clinical cancer research : CR 36 26437640
2023 Correlation between the expression of LAT1 in cancer cells and the potential efficacy of boron neutron capture therapy. Journal of radiation research 35 36371738
2021 Novel strategies to improve tumour therapy by targeting the proteins MCT1, MCT4 and LAT1. European journal of medicinal chemistry 35 34517305
2012 Homeostatic and innate immune responses: role of the transmembrane glycoprotein CD98. Cellular and molecular life sciences : CMLS 35 22460579
2023 Targeting glutamine metabolic reprogramming of SLC7A5 enhances the efficacy of anti-PD-1 in triple-negative breast cancer. Frontiers in immunology 32 37731509
2022 The human LAT1-4F2hc (SLC7A5-SLC3A2) transporter complex: Physiological and pathophysiological implications. Basic & clinical pharmacology & toxicology 31 36460306
2018 Slc7a5 regulates Kv1.2 channels and modifies functional outcomes of epilepsy-linked channel mutations. Nature communications 31 30356053
2014 CD147 and CD98 complex-mediated homotypic aggregation attenuates the CypA-induced chemotactic effect on Jurkat T cells. Molecular immunology 30 25089027
2018 Expression of amino acid transporter (LAT1 and 4F2hc) in pulmonary pleomorphic carcinoma. Human pathology 28 30300664
2015 Ubiquitylation of CD98 limits cell proliferation and clonal expansion. Journal of cell science 28 26493331
2003 Physical association and functional interaction between beta1 integrin and CD98 on human T lymphocytes. Molecular immunology 28 12531285
2024 FBW7/GSK3β mediated degradation of IGF2BP2 inhibits IGF2BP2-SLC7A5 positive feedback loop and radioresistance in lung cancer. Journal of experimental & clinical cancer research : CR 27 38281999
2021 SLFN5 Regulates LAT1-Mediated mTOR Activation in Castration-Resistant Prostate Cancer. Cancer research 27 33985973
2020 Prolactin regulates LAT1 expression via STAT5 (signal transducer and activator of transcription 5) signaling in mammary epithelial cells of dairy cows. Journal of dairy science 27 32389479
2020 ATP modulates SLC7A5 (LAT1) synergistically with cholesterol. Scientific reports 27 33028978
2019 Hypoxia affects Slc7a5 expression through HIF-2α in differentiated neuronal cells. FEBS open bio 25 30761250
2019 Ubiquitylation and endocytosis of the human LAT1/SLC7A5 amino acid transporter. Scientific reports 24 31728037
2023 The proliferation of human mucosal-associated invariant T cells requires a MYC-SLC7A5-glycolysis metabolic axis. Science signaling 23 37071733
2011 Expression of 4F2hc (CD98) in pulmonary neuroendocrine tumors. Oncology reports 23 21750865
2024 ALYREF-JunD-SLC7A5 axis promotes pancreatic ductal adenocarcinoma progression through epitranscriptome-metabolism reprogramming and immune evasion. Cell death discovery 22 38402198
2021 Amino Acid Transporter LAT1 (SLC7A5) Mediates MeHg-Induced Oxidative Stress Defense in the Human Placental Cell Line HTR-8/SVneo. International journal of molecular sciences 22 33567754
2020 Intervening upregulated SLC7A5 could mitigate inflammatory mediator by mTOR-P70S6K signal in rheumatoid arthritis synoviocytes. Arthritis research & therapy 22 32867828
2022 N-glycosylation is crucial for trafficking and stability of SLC3A2 (CD98). Scientific reports 21 36028562
2021 Circular RNA circ-FAM158A promotes retinoblastoma progression by regulating miR-138-5p/SLC7A5 axis. Experimental eye research 20 34102206
2002 The role of CD98 in astrocytic neoplasms. Human cell 20 12126061
2024 YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis. JCI insight 18 39704172
2022 Galectin-3 enhances atrial remodelling and arrhythmogenesis through CD98 signalling. Acta physiologica (Oxford, England) 18 34995420
2021 CD98-induced CD147 signaling stabilizes the Foxp3 protein to maintain tissue homeostasis. Cellular & molecular immunology 18 34759371
2015 MicroRNA-126 inhibits cell proliferation in gastric cancer by targeting LAT-1. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 18 26054677
2009 LAT-1 expression in pre- and post-implantation embryos and placenta. Placenta 18 19193433
2008 Ecto-phosphorylation of CD98 regulates cell-cell interactions. PloS one 18 19065266
2023 SRC2 controls CD4+ T cell activation via stimulating c-Myc-mediated upregulation of amino acid transporter Slc7a5. Proceedings of the National Academy of Sciences of the United States of America 17 37094160
2020 Regulation of Melanogenesis by the Amino Acid Transporter SLC7A5. The Journal of investigative dermatology 17 32240722
2015 Aryl hydrocarbon receptor-dependent up-regulation of the heterodimeric amino acid transporter LAT1 (SLC7A5)/CD98hc (SLC3A2) by diesel exhaust particle extract in human bronchial epithelial cells. Toxicology and applied pharmacology 17 26621329
2012 CD98 increases renal epithelial cell proliferation by activating MAPKs. PloS one 17 22768207
2024 FOXC1 regulates endothelial CD98 (LAT1/4F2hc) expression in retinal angiogenesis and blood-retina barrier formation. Nature communications 16 38755144
2023 LAT1 enables T cell activation under inflammatory conditions. Journal of autoimmunity 16 37229811
2022 Structural Features Affecting the Interactions and Transportability of LAT1-Targeted Phenylalanine Drug Conjugates. Molecular pharmaceutics 16 36394563
2023 Insights into the Transport Cycle of LAT1 and Interaction with the Inhibitor JPH203. International journal of molecular sciences 15 36835453
2021 Metabolic adaptations to hypoxia in the neonatal mouse forebrain can occur independently of the transporters SLC7A5 and SLC3A2. Scientific reports 15 33907288
2022 Neuronal allodynic mechanisms of Slc7a5 (LAT1) in the spared nerve injury rodent model of neuropathic pain. Pflugers Archiv : European journal of physiology 14 35048187
2022 The role of L-type amino acid transporter 1 (Slc7a5) during in vitro myogenesis. American journal of physiology. Cell physiology 14 35848618
2016 Endothelial Cells Require CD98 for Efficient Angiogenesis-Brief Report. Arteriosclerosis, thrombosis, and vascular biology 14 27687603
2021 OIP5-AS1 contributes to the development in endometrial carcinoma cells by targeting miR-152-3p to up-regulate SLC7A5. Cancer cell international 13 34419049
2024 Maintenance of the branched-chain amino acid transporter LAT1 counteracts myotube atrophy following chemotherapy. American journal of physiology. Cell physiology 12 38284122
2021 Molecular characteristics supporting l-Type amino acid transporter 1 (LAT1)-mediated translocation. Bioorganic chemistry 12 33933805
2020 Putative roles of SLC7A5 (LAT1) transporter in pain. Neurobiology of pain (Cambridge, Mass.) 12 32715162
2018 LAT1-like transporters regulate dopaminergic transmission and sleep in Drosophila. Sleep 12 30016498
2017 Methionine Induces LAT1 Expression in Dairy Cow Mammary Gland by Activating the mTORC1 Signaling Pathway. DNA and cell biology 12 29040000
2014 Overview of the glucansucrase equipment of Leuconostoc citreum LBAE-E16 and LBAE-C11, two strains isolated from sourdough. FEMS microbiology letters 12 25790502
2024 Branched-Chain Amino Acids Deficiency Promotes Diabetic Neuropathic Pain Through Upregulating LAT1 and Inhibiting Kv1.2 Channel. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 11 38946582
2024 TRIM35 triggers cardiac remodeling by regulating SLC7A5-mediated amino acid transport and mTORC1 activation in fibroblasts. Cell communication and signaling : CCS 11 39304904
2021 The rs113883650 variant of SLC7A5 (LAT1) gene may alter brain phenylalanine content in PKU. Molecular genetics and metabolism reports 11 33868932
2020 Role of CD98 in liver disease. Annals of hepatology 11 32057700
2016 Molecular association of CD98, CD29, and CD147 critically mediates monocytic U937 cell adhesion. The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology 11 27610038
2016 The effects of prenatal H1N1 infection at E16 on FMRP, glutamate, GABA, and reelin signaling systems in developing murine cerebellum. Journal of neuroscience research 11 27735078
2012 Canine Lat1: molecular structure, distribution and its expression in cancer samples. The Journal of veterinary medical science 11 22322188