{"gene":"SLC7A5","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":2019,"finding":"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.","method":"Cryo-EM structure determination at 3.3 Å and 3.5 Å resolution, biochemical transport assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure with functional biochemical validation in a single rigorous study","pmids":["30867591"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Proteoliposome reconstitution with recombinant proteins, radiolabeled substrate transport assays, SDS-PAGE under reducing/non-reducing conditions","journal":"The international journal of biochemistry & cell biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with purified recombinant subunits tested separately, multiple orthogonal methods","pmids":["26256001"],"is_preprint":false},{"year":1998,"finding":"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.","method":"Mass spectrometry peptide sequencing, co-immunoprecipitation, immunoblotting","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (MS, reciprocal IP, genetic reconstitution) in a single study","pmids":["9837878"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Gene knockout (CRISPR/TALEN) in six cancer cell lines, leucine transport assays, mTORC1 signaling assays, xenograft tumor models, JPH203 pharmacological inhibition","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined mechanistic readouts replicated across six cell lines and in vivo","pmids":["27302165"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Chromatin immunoprecipitation (ChIP) at Slc7a5 promoter, HIF2α gain/loss-of-function, mTORC1 activity assays, cell-based amino acid transport assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — ChIP plus functional epistasis with multiple orthogonal approaches","pmids":["23103253"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Proteoliposome transport assays, dose-response kinetics, site-directed mutagenesis (C407A), molecular docking on hLAT1 homology model","journal":"Biochemical pharmacology","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution combined with mutagenesis confirming catalytic residue","pmids":["28709952"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Proteoliposome transport assays with cholesterol/ATP, site-directed mutagenesis (K204Q), computational docking","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 — reconstitution assay plus mutagenesis with computational support in a single study","pmids":["33028978"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Cholesterol depletion assays in cells, L-DOPA uptake kinetics, protein purification with cholesterol analogue","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — cell-based transport kinetics plus biochemical purification, single lab","pmids":["28272458"],"is_preprint":false},{"year":2019,"finding":"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.","method":"PMA stimulation, systematic mutagenesis of cytosolic lysines, Nedd4-2 siRNA knockdown, endocytosis assays","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — mutagenesis of specific residues combined with E3 ligase identification and functional endocytosis readout","pmids":["31728037"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Mass spectrometry of Kv1.2 multi-protein complexes, electrophysiology (whole-cell patch clamp), co-expression studies, disease mutant characterization","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — MS identification plus electrophysiological functional validation with multiple mutants","pmids":["30356053"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Radiolabeled gabapentin uptake in hCMEC/D3 and LAT1-transfected HEK293 cells, siRNA knockdown, pharmacological inhibition, kinetic analysis","journal":"Biochemical pharmacology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal approaches (overexpression, KD, kinetics) confirming substrate identity","pmids":["23567998"],"is_preprint":false},{"year":2018,"finding":"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%.","method":"LAT1/LAT2 overexpression in HEK293, LC-MS/MS uptake quantification, LAT1 siRNA knockdown, JPH203 inhibition in hCMEC/D3 cells","journal":"Pharmaceutical research","confidence":"High","confidence_rationale":"Tier 2 — overexpression and KD with quantitative transport assays, multiple methods","pmids":["30374619"],"is_preprint":false},{"year":2015,"finding":"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.","method":"LAT1/EZH2 shRNA knockdown, SAM metabolite measurement, gene expression analysis, tumor growth assays","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis and metabolite measurements, single lab","pmids":["25979827"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Conditional Slc7a5 knockout in mouse intestinal epithelium with Kras/Apc mutations, metabolic flux analysis, protein synthesis assays, tumor growth models","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic KO in vivo with mechanistic readouts (amino acid levels, protein synthesis, mTORC1) replicated across models","pmids":["33414552"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-immunoprecipitation of CD69 with LAT1-CD98, surface expression assays, L-Trp uptake measurements, AhR reporter assays, IL-22 secretion in CD69-deficient mice","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP plus functional in vivo rescue experiments","pmids":["27376471"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Covalent chemical cross-linking, mass spectrometric protein identification, co-immunoprecipitation, RNA interference knockdown","journal":"Molecular & cellular proteomics","confidence":"High","confidence_rationale":"Tier 2 — cross-linking MS plus reciprocal co-IP and functional RNAi readouts","pmids":["15901826"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Comparative proteomics, co-immunoprecipitation of SLFN5 with ATF4, LAT1 expression rescue, amino acid measurements, mTORC1 signaling assays, in vivo xenograft","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP plus functional epistasis, single lab","pmids":["33985973"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Site-directed mutagenesis of N-glycosylation sites, biotinylation assay for membrane presence, brefeldin A trafficking assay, LAT1 transport activity measurement","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1-2 — systematic mutagenesis combined with trafficking and functional transport assays","pmids":["36028562"],"is_preprint":false},{"year":2018,"finding":"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.","method":"SLC7A5 siRNA knockdown, pharmacological inhibition, mTORC1 signaling assays, extracellular acidification rate measurement, cytokine measurement","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — KD with defined mechanistic pathway readouts, single lab","pmids":["29422900"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation of TRIM35 with SLC7A5, ubiquitination assays, fibroblast-specific Trim35 KO mice with TAC model, LC-MS/MS, RNA-Seq, mTORC1 signaling assays","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP plus ubiquitination assay and in vivo rescue, single lab","pmids":["39304904"],"is_preprint":false},{"year":2024,"finding":"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.","method":"MeRIP-qPCR, RNA immunoprecipitation, ChIP-qPCR, co-immunoprecipitation, ubiquitination assays, clonogenic survival assays, metabolite measurements, in vivo mouse models","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods establishing m6A-mediated SLC7A5 regulation, single lab","pmids":["38281999"],"is_preprint":false},{"year":2023,"finding":"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.","method":"T cell-specific SRC2 knockout mice, Slc7a5 overexpression rescue, proliferation and cytokine assays, EAE and colitis models","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with defined pathway epistasis and in vivo rescue confirming mechanistic role","pmids":["37094160"],"is_preprint":false},{"year":2024,"finding":"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.","method":"RNA sequencing, proteomics, immunofluorescence of Kv1.2 membrane localization, whole-cell electrophysiology, behavioral pain assays in HFD/STZ and db/db mouse models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway established with molecular and functional readouts in vivo, single lab","pmids":["38946582"],"is_preprint":false},{"year":2000,"finding":"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.","method":"Amino acid deprivation experiments in rat hepatic cell lines, mRNA quantification, amino acid transport activity assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — specific amino acid deprivation experiments distinguishing LAT1 from CD98hc responses, single lab","pmids":["10681508"],"is_preprint":false},{"year":2015,"finding":"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.","method":"MARCH overexpression, catalytically inactive MARCH mutant, ubiquitylation-resistant CD98 mutant, March1-null T cells, in vitro proliferation and in vivo clonal expansion assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis plus KO with functional proliferation readouts, single lab","pmids":["26493331"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Constitutively active Rab4A knockin, Rab4A T cell-specific knockout, stable isotope tracing of metabolic pathways, gene expression analysis, flow cytometry","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — gain/loss-of-function with stable isotope metabolic tracing, single lab","pmids":["38519468"],"is_preprint":false},{"year":2020,"finding":"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.","method":"ChIP-seq/microarray integration identifying MITF targets, siRNA knockdown of SLC7A5, pharmacological inhibition, melanin content assays, reconstructed human epidermis model","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP-seq target identification plus functional KD and pharmacological validation","pmids":["32240722"],"is_preprint":false},{"year":2019,"finding":"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.","method":"HIF-2α and HIF-1α shRNA knockdown in Neuro2A cells, ChIP at Slc7a5 promoter under hypoxia, qRT-PCR","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP demonstrating direct promoter binding combined with isoform-specific shRNA, single lab","pmids":["30761250"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Endothelial-specific Foxc1 knockout mice, retinal vascular growth assays, mTOR activity assays, mTOR agonist rescue experiment","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with epistasis rescue experiment establishing pathway position in vivo","pmids":["38755144"],"is_preprint":false},{"year":2023,"finding":"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.","method":"MeRIP/RIP assays, RNA pull-down, ChIP for JunD at SLC7A5 promoter, co-immunoprecipitation, in vivo tumor models","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods establishing transcriptional regulation axis, single lab","pmids":["38402198"],"is_preprint":false},{"year":2021,"finding":"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.","method":"siRNA knockdown of LAT1 in HTR-8/SVneo cells, MeHg accumulation assays, cell viability, apoptosis, oxidative stress assays, GSH measurement","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — KD with mechanistic readouts linking LAT1 transport to GSH synthesis, single lab","pmids":["33567754"],"is_preprint":false},{"year":2023,"finding":"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.","method":"CD4+ T cell-specific LAT1 deletion, TIRF microscopy of immune synapse, RNA-sequencing, experimental arthritis models","journal":"Journal of autoimmunity","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with mechanistic imaging and transcriptomic readouts, single lab","pmids":["37229811"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Transcriptomic analysis of resistant cells, YAP/TAZ/TEAD knockdown, SLC7A5 expression assays, mTORC1 signaling assays, pharmacological rescue","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 — genetic and pharmacological epistasis with mechanistic pathway placement, single lab","pmids":["39704172"],"is_preprint":false}],"current_model":"SLC7A5 (LAT1) functions as the sole transport-competent subunit of a heterodimeric antiporter complex with 4F2hc/CD98 (SLC3A2), mediating Na⁺- and pH-independent exchange of large neutral amino acids (preferred substrate: histidine/leucine), thyroid hormones, and drugs (gabapentin, pregabalin, L-DOPA) across the plasma membrane in an inward-open conformation stabilized by cholesterol and ATP; transport activity is regulated by Nedd4-2-mediated ubiquitylation of N-terminal lysines causing endocytosis, and by TRIM35-mediated ubiquitylation increasing transporter levels; as the primary route for essential amino acid import, LAT1 activates mTORC1 signaling—a function exploited downstream of HIF-2α, FOXC1, YAP/TAZ, SLFN5, and oncogenic KRAS—and additionally modulates Kv1.2 potassium channel gating by direct interaction, placing it at the nexus of nutrient sensing, immune activation, tumor metabolism, and neuropathic pain."},"narrative":{"teleology":[{"year":1998,"claim":"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","pmids":["9837878"],"confidence":"High","gaps":["Functional contribution of each subunit to transport not yet resolved","Stoichiometry of the complex unknown"]},{"year":2000,"claim":"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","pmids":["10681508"],"confidence":"Medium","gaps":["Transcription factor mediating arginine-responsive induction not identified","Mechanism of lost regulation in transformed cells unknown"]},{"year":2005,"claim":"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","pmids":["15901826"],"confidence":"High","gaps":["Whether CD147 directly modulates LAT1 transport kinetics not tested","Structural basis of the supercomplex unknown"]},{"year":2012,"claim":"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","pmids":["23103253"],"confidence":"High","gaps":["Other HIF-2α-independent transcriptional regulators of Slc7a5 not fully mapped","Whether HIF-2α regulation is tissue-specific not resolved"]},{"year":2013,"claim":"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","pmids":["23567998"],"confidence":"High","gaps":["In vivo contribution of LAT1 vs. other routes for gabapentin CNS entry not quantified"]},{"year":2015,"claim":"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","pmids":["26256001"],"confidence":"High","gaps":["Role of CD98 in trafficking vs. allosteric modulation of LAT1 not fully distinguished"]},{"year":2015,"claim":"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","pmids":["25979827"],"confidence":"Medium","gaps":["Whether this feedback operates in non-tumor cells unknown","Quantitative contribution of LAT1 vs. other methionine transporters to SAM pools not established"]},{"year":2016,"claim":"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","pmids":["27302165"],"confidence":"High","gaps":["Compensatory upregulation of other amino acid transporters not systematically assessed"]},{"year":2016,"claim":"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","pmids":["27376471"],"confidence":"High","gaps":["Whether CD69–LAT1 interaction is direct or mediated by CD98 not resolved","Structural basis of the trimolecular complex unknown"]},{"year":2017,"claim":"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","pmids":["28709952"],"confidence":"High","gaps":["Role of C407 in normal catalytic cycle (not just inhibitor binding) unclear"]},{"year":2017,"claim":"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)","pmids":["28272458","33028978"],"confidence":"High","gaps":["Structural basis of cholesterol binding site on LAT1 not resolved","Physiological relevance of ATP–K204 interaction in vivo unknown"]},{"year":2018,"claim":"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","pmids":["30356053"],"confidence":"High","gaps":["Whether transport activity is required for Kv1.2 regulation not determined","In vivo neuronal relevance confirmed only later in diabetic neuropathy models"]},{"year":2018,"claim":"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","pmids":["29422900"],"confidence":"Medium","gaps":["Contribution of LAT1 vs. other leucine transporters in macrophage activation not quantified"]},{"year":2019,"claim":"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","pmids":["30867591"],"confidence":"High","gaps":["Outward-open conformation not captured","Substrate-bound transition states not resolved"]},{"year":2019,"claim":"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","pmids":["31728037"],"confidence":"High","gaps":["Whether Nedd4-2-mediated regulation operates in all LAT1-expressing tissues unknown","Deubiquitinase(s) that counteract this modification not identified"]},{"year":2021,"claim":"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","pmids":["33414552"],"confidence":"High","gaps":["Whether LAT1 dependency generalizes to all KRAS-driven cancers not tested"]},{"year":2022,"claim":"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","pmids":["36028562"],"confidence":"High","gaps":["Whether partial glycosylation retains function not fully characterized"]},{"year":2023,"claim":"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","pmids":["37094160"],"confidence":"High","gaps":["Direct ChIP evidence for SRC2 at the Slc7a5 promoter not shown in this study"]},{"year":2023,"claim":"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","pmids":["37229811"],"confidence":"Medium","gaps":["Whether synapse defect is secondary to amino acid deprivation vs. direct scaffolding not distinguished","Mechanism linking LAT1 to CD3ζ recruitment not identified"]},{"year":2024,"claim":"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)","pmids":["38755144","39704172","38281999","39304904"],"confidence":"Medium","gaps":["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"]},{"year":2024,"claim":"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","pmids":["38946582"],"confidence":"Medium","gaps":["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"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["Outward-open and occluded structures not captured","Transport-dependent vs. -independent Kv1.2 regulation not mechanistically separated","Deubiquitinase for LAT1 not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,3,5,6,10,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,22]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,8,15,17]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[8,25]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4,13,18,28,32]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,1,5,6,10,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,13,32]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14,18,21,31]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[8,19,24]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[8,17,25]}],"complexes":["LAT1-CD98/4F2hc heterodimer","CD147-CD98-LAT1 metabolic supercomplex"],"partners":["SLC3A2","BSG","KCNB1","NEDD4L","CD69","TRIM35","IGF2BP2"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"Q01650","full_name":"Large neutral amino acids transporter small subunit 1","aliases":["4F2 light chain","4F2 LC","4F2LC","CD98 light chain","Integral membrane protein E16","E16","L-type amino acid transporter 1","hLAT1","Solute carrier family 7 member 5","y+ system cationic amino acid transporter"],"length_aa":507,"mass_kda":55.0,"function":"The heterodimer with SLC3A2 functions as a sodium-independent, high-affinity transporter that mediates uptake of large neutral amino acids such as phenylalanine, tyrosine, leucine, histidine, methionine, tryptophan, valine, isoleucine and alanine (PubMed:10049700, PubMed:10574970, PubMed:11557028, PubMed:11564694, PubMed:12117417, PubMed:12225859, PubMed:15769744, PubMed:18262359, PubMed:25998567, PubMed:30867591, PubMed:9751058). The heterodimer with SLC3A2 mediates the uptake of L-DOPA (By similarity). Functions as an amino acid exchanger (PubMed:11557028, PubMed:12117417, PubMed:12225859, PubMed:30867591). May play a role in the transport of L-DOPA across the blood-brain barrier (By similarity). May act as the major transporter of tyrosine in fibroblasts (Probable). May mediate blood-to-retina L-leucine transport across the inner blood-retinal barrier (By similarity). Can mediate the transport of thyroid hormones diiodothyronine (T2), triiodothyronine (T3) and thyroxine (T4) across the cell membrane (PubMed:11564694). When associated with LAPTM4B, the heterodimer formed by SLC3A2 and SLC7A5 is recruited to lysosomes to promote leucine uptake into these organelles, and thereby mediates mTORC1 activation (PubMed:25998567). Involved in the uptake of toxic methylmercury (MeHg) when administered as the L-cysteine or D,L-homocysteine complexes (PubMed:12117417). Involved in the cellular activity of small molecular weight nitrosothiols, via the stereoselective transport of L-nitrosocysteine (L-CNSO) across the membrane (PubMed:15769744) (Microbial infection) In case of hepatitis C virus/HCV infection, the complex formed by SLC3A2 and SLC7A5/LAT1 plays a role in HCV propagation by facilitating viral entry into host cell and increasing L-leucine uptake-mediated mTORC1 signaling activation, thereby contributing to HCV-mediated pathogenesis","subcellular_location":"Apical cell membrane; Cell membrane; Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/Q01650/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC7A5","classification":"Not Classified","n_dependent_lines":322,"n_total_lines":1208,"dependency_fraction":0.26655629139072845},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000103257","cell_line_id":"CID001373","localizations":[{"compartment":"membrane","grade":3},{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"NDRG1","stoichiometry":10.0},{"gene":"NEFM","stoichiometry":10.0},{"gene":"ATP1B3","stoichiometry":0.2},{"gene":"SLC3A2","stoichiometry":0.2},{"gene":"ATP1A1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001373","total_profiled":1310},"omim":[{"mim_id":"618483","title":"LLGL SCRIBBLE CELL POLARITY COMPLEX COMPONENT 2; LLGL2","url":"https://www.omim.org/entry/618483"},{"mim_id":"617256","title":"SOLUTE CARRIER FAMILY 7, MEMBER 13; SLC7A13","url":"https://www.omim.org/entry/617256"},{"mim_id":"614923","title":"BRANCHED-CHAIN KETO ACID DEHYDROGENASE KINASE DEFICIENCY; BCKDKD","url":"https://www.omim.org/entry/614923"},{"mim_id":"612525","title":"PYLORIC STENOSIS, INFANTILE HYPERTROPHIC, 5; IHPS5","url":"https://www.omim.org/entry/612525"},{"mim_id":"604735","title":"UBIQUITIN-SPECIFIC PROTEASE 16; USP16","url":"https://www.omim.org/entry/604735"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":104.4},{"tissue":"esophagus","ntpm":96.2}],"url":"https://www.proteinatlas.org/search/SLC7A5"},"hgnc":{"alias_symbol":["LAT1","E16","D16S469E","MPE16","CD98"],"prev_symbol":[]},"alphafold":{"accession":"Q01650","domains":[{"cath_id":"1.20.1740.10","chopping":"53-501","consensus_level":"medium","plddt":89.7222,"start":53,"end":501}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01650","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q01650-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q01650-F1-predicted_aligned_error_v6.png","plddt_mean":85.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC7A5","jax_strain_url":"https://www.jax.org/strain/search?query=SLC7A5"},"sequence":{"accession":"Q01650","fasta_url":"https://rest.uniprot.org/uniprotkb/Q01650.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q01650/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01650"}},"corpus_meta":[{"pmid":"15916903","id":"PMC_15916903","title":"Amino 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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.\",\n      \"method\": \"Proteoliposome reconstitution with recombinant proteins, radiolabeled substrate transport assays, SDS-PAGE under reducing/non-reducing conditions\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with purified recombinant subunits tested separately, multiple orthogonal methods\",\n      \"pmids\": [\"26256001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry peptide sequencing, co-immunoprecipitation, immunoblotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (MS, reciprocal IP, genetic reconstitution) in a single study\",\n      \"pmids\": [\"9837878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Gene knockout (CRISPR/TALEN) in six cancer cell lines, leucine transport assays, mTORC1 signaling assays, xenograft tumor models, JPH203 pharmacological inhibition\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined mechanistic readouts replicated across six cell lines and in vivo\",\n      \"pmids\": [\"27302165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) at Slc7a5 promoter, HIF2α gain/loss-of-function, mTORC1 activity assays, cell-based amino acid transport assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus functional epistasis with multiple orthogonal approaches\",\n      \"pmids\": [\"23103253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Proteoliposome transport assays, dose-response kinetics, site-directed mutagenesis (C407A), molecular docking on hLAT1 homology model\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution combined with mutagenesis confirming catalytic residue\",\n      \"pmids\": [\"28709952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Proteoliposome transport assays with cholesterol/ATP, site-directed mutagenesis (K204Q), computational docking\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution assay plus mutagenesis with computational support in a single study\",\n      \"pmids\": [\"33028978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Cholesterol depletion assays in cells, L-DOPA uptake kinetics, protein purification with cholesterol analogue\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-based transport kinetics plus biochemical purification, single lab\",\n      \"pmids\": [\"28272458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"PMA stimulation, systematic mutagenesis of cytosolic lysines, Nedd4-2 siRNA knockdown, endocytosis assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis of specific residues combined with E3 ligase identification and functional endocytosis readout\",\n      \"pmids\": [\"31728037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry of Kv1.2 multi-protein complexes, electrophysiology (whole-cell patch clamp), co-expression studies, disease mutant characterization\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS identification plus electrophysiological functional validation with multiple mutants\",\n      \"pmids\": [\"30356053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Radiolabeled gabapentin uptake in hCMEC/D3 and LAT1-transfected HEK293 cells, siRNA knockdown, pharmacological inhibition, kinetic analysis\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches (overexpression, KD, kinetics) confirming substrate identity\",\n      \"pmids\": [\"23567998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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%.\",\n      \"method\": \"LAT1/LAT2 overexpression in HEK293, LC-MS/MS uptake quantification, LAT1 siRNA knockdown, JPH203 inhibition in hCMEC/D3 cells\",\n      \"journal\": \"Pharmaceutical research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — overexpression and KD with quantitative transport assays, multiple methods\",\n      \"pmids\": [\"30374619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"LAT1/EZH2 shRNA knockdown, SAM metabolite measurement, gene expression analysis, tumor growth assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis and metabolite measurements, single lab\",\n      \"pmids\": [\"25979827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional Slc7a5 knockout in mouse intestinal epithelium with Kras/Apc mutations, metabolic flux analysis, protein synthesis assays, tumor growth models\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO in vivo with mechanistic readouts (amino acid levels, protein synthesis, mTORC1) replicated across models\",\n      \"pmids\": [\"33414552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation of CD69 with LAT1-CD98, surface expression assays, L-Trp uptake measurements, AhR reporter assays, IL-22 secretion in CD69-deficient mice\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus functional in vivo rescue experiments\",\n      \"pmids\": [\"27376471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Covalent chemical cross-linking, mass spectrometric protein identification, co-immunoprecipitation, RNA interference knockdown\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cross-linking MS plus reciprocal co-IP and functional RNAi readouts\",\n      \"pmids\": [\"15901826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Comparative proteomics, co-immunoprecipitation of SLFN5 with ATF4, LAT1 expression rescue, amino acid measurements, mTORC1 signaling assays, in vivo xenograft\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus functional epistasis, single lab\",\n      \"pmids\": [\"33985973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Site-directed mutagenesis of N-glycosylation sites, biotinylation assay for membrane presence, brefeldin A trafficking assay, LAT1 transport activity measurement\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — systematic mutagenesis combined with trafficking and functional transport assays\",\n      \"pmids\": [\"36028562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"SLC7A5 siRNA knockdown, pharmacological inhibition, mTORC1 signaling assays, extracellular acidification rate measurement, cytokine measurement\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with defined mechanistic pathway readouts, single lab\",\n      \"pmids\": [\"29422900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation of TRIM35 with SLC7A5, ubiquitination assays, fibroblast-specific Trim35 KO mice with TAC model, LC-MS/MS, RNA-Seq, mTORC1 signaling assays\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus ubiquitination assay and in vivo rescue, single lab\",\n      \"pmids\": [\"39304904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"MeRIP-qPCR, RNA immunoprecipitation, ChIP-qPCR, co-immunoprecipitation, ubiquitination assays, clonogenic survival assays, metabolite measurements, in vivo mouse models\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods establishing m6A-mediated SLC7A5 regulation, single lab\",\n      \"pmids\": [\"38281999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"T cell-specific SRC2 knockout mice, Slc7a5 overexpression rescue, proliferation and cytokine assays, EAE and colitis models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined pathway epistasis and in vivo rescue confirming mechanistic role\",\n      \"pmids\": [\"37094160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"RNA sequencing, proteomics, immunofluorescence of Kv1.2 membrane localization, whole-cell electrophysiology, behavioral pain assays in HFD/STZ and db/db mouse models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway established with molecular and functional readouts in vivo, single lab\",\n      \"pmids\": [\"38946582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Amino acid deprivation experiments in rat hepatic cell lines, mRNA quantification, amino acid transport activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — specific amino acid deprivation experiments distinguishing LAT1 from CD98hc responses, single lab\",\n      \"pmids\": [\"10681508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"MARCH overexpression, catalytically inactive MARCH mutant, ubiquitylation-resistant CD98 mutant, March1-null T cells, in vitro proliferation and in vivo clonal expansion assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis plus KO with functional proliferation readouts, single lab\",\n      \"pmids\": [\"26493331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Constitutively active Rab4A knockin, Rab4A T cell-specific knockout, stable isotope tracing of metabolic pathways, gene expression analysis, flow cytometry\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain/loss-of-function with stable isotope metabolic tracing, single lab\",\n      \"pmids\": [\"38519468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP-seq/microarray integration identifying MITF targets, siRNA knockdown of SLC7A5, pharmacological inhibition, melanin content assays, reconstructed human epidermis model\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq target identification plus functional KD and pharmacological validation\",\n      \"pmids\": [\"32240722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"HIF-2α and HIF-1α shRNA knockdown in Neuro2A cells, ChIP at Slc7a5 promoter under hypoxia, qRT-PCR\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrating direct promoter binding combined with isoform-specific shRNA, single lab\",\n      \"pmids\": [\"30761250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Endothelial-specific Foxc1 knockout mice, retinal vascular growth assays, mTOR activity assays, mTOR agonist rescue experiment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with epistasis rescue experiment establishing pathway position in vivo\",\n      \"pmids\": [\"38755144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"MeRIP/RIP assays, RNA pull-down, ChIP for JunD at SLC7A5 promoter, co-immunoprecipitation, in vivo tumor models\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods establishing transcriptional regulation axis, single lab\",\n      \"pmids\": [\"38402198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown of LAT1 in HTR-8/SVneo cells, MeHg accumulation assays, cell viability, apoptosis, oxidative stress assays, GSH measurement\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with mechanistic readouts linking LAT1 transport to GSH synthesis, single lab\",\n      \"pmids\": [\"33567754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"CD4+ T cell-specific LAT1 deletion, TIRF microscopy of immune synapse, RNA-sequencing, experimental arthritis models\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with mechanistic imaging and transcriptomic readouts, single lab\",\n      \"pmids\": [\"37229811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Transcriptomic analysis of resistant cells, YAP/TAZ/TEAD knockdown, SLC7A5 expression assays, mTORC1 signaling assays, pharmacological rescue\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological epistasis with mechanistic pathway placement, single lab\",\n      \"pmids\": [\"39704172\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC7A5 (LAT1) functions as the sole transport-competent subunit of a heterodimeric antiporter complex with 4F2hc/CD98 (SLC3A2), mediating Na⁺- and pH-independent exchange of large neutral amino acids (preferred substrate: histidine/leucine), thyroid hormones, and drugs (gabapentin, pregabalin, L-DOPA) across the plasma membrane in an inward-open conformation stabilized by cholesterol and ATP; transport activity is regulated by Nedd4-2-mediated ubiquitylation of N-terminal lysines causing endocytosis, and by TRIM35-mediated ubiquitylation increasing transporter levels; as the primary route for essential amino acid import, LAT1 activates mTORC1 signaling—a function exploited downstream of HIF-2α, FOXC1, YAP/TAZ, SLFN5, and oncogenic KRAS—and additionally modulates Kv1.2 potassium channel gating by direct interaction, placing it at the nexus of nutrient sensing, immune activation, tumor metabolism, and neuropathic pain.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Identifying the molecular identity of the CD98 light chain as SLC7A5/LAT1 established the subunit composition of the heterodimeric amino acid transporter.\",\n      \"evidence\": \"Mass spectrometry peptide sequencing plus reciprocal co-immunoprecipitation of tagged E16 with anti-CD98hc antibody\",\n      \"pmids\": [\"9837878\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional contribution of each subunit to transport not yet resolved\", \"Stoichiometry of the complex unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"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.\",\n      \"evidence\": \"Amino acid deprivation experiments in primary rat hepatocytes and transformed hepatic cell lines with mRNA quantification\",\n      \"pmids\": [\"10681508\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factor mediating arginine-responsive induction not identified\", \"Mechanism of lost regulation in transformed cells unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"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.\",\n      \"evidence\": \"Chemical cross-linking/mass spectrometry and reciprocal co-IP, with RNAi of CD147/CD98hc reducing proliferation and activating AMPK\",\n      \"pmids\": [\"15901826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD147 directly modulates LAT1 transport kinetics not tested\", \"Structural basis of the supercomplex unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"ChIP at Slc7a5 promoter, HIF-2α gain/loss-of-function, mTORC1 and amino acid transport assays in VHL-deficient cells and hypoxic tissues\",\n      \"pmids\": [\"23103253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other HIF-2α-independent transcriptional regulators of Slc7a5 not fully mapped\", \"Whether HIF-2α regulation is tissue-specific not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"Radiolabeled gabapentin uptake in brain endothelial cells and LAT1-transfected HEK293, plus siRNA knockdown and pharmacological inhibition\",\n      \"pmids\": [\"23567998\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo contribution of LAT1 vs. other routes for gabapentin CNS entry not quantified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Proteoliposome reconstitution of recombinant hLAT1 and hCD98 tested separately with radiolabeled substrates\",\n      \"pmids\": [\"26256001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of CD98 in trafficking vs. allosteric modulation of LAT1 not fully distinguished\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"LAT1/EZH2 shRNA knockdown, SAM metabolite measurement, and demonstration that EZH2 loss de-represses RXRα which then reduces LAT1 transcription\",\n      \"pmids\": [\"25979827\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this feedback operates in non-tumor cells unknown\", \"Quantitative contribution of LAT1 vs. other methionine transporters to SAM pools not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"LAT1 and CD98 knockout in six cell lines, leucine transport, mTORC1 signaling, xenograft tumors, JPH203 pharmacological inhibition\",\n      \"pmids\": [\"27302165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Compensatory upregulation of other amino acid transporters not systematically assessed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP of CD69 with LAT1–CD98, L-Trp uptake measurements, AhR reporter, IL-22 in CD69-deficient mice\",\n      \"pmids\": [\"27376471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD69–LAT1 interaction is direct or mediated by CD98 not resolved\", \"Structural basis of the trimolecular complex unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"C407A mutagenesis in proteoliposome transport assays with kinetic analysis and molecular docking\",\n      \"pmids\": [\"28709952\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of C407 in normal catalytic cycle (not just inhibitor binding) unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cell-based cholesterol depletion with L-DOPA uptake kinetics (2017); proteoliposome assays with cholesterol/ATP and K204Q mutagenesis (2020)\",\n      \"pmids\": [\"28272458\", \"33028978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of cholesterol binding site on LAT1 not resolved\", \"Physiological relevance of ATP–K204 interaction in vivo unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"Mass spectrometry of Kv1.2 complexes, whole-cell patch clamp in co-expression system, epilepsy mutant characterization\",\n      \"pmids\": [\"30356053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether transport activity is required for Kv1.2 regulation not determined\", \"In vivo neuronal relevance confirmed only later in diabetic neuropathy models\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"SLC7A5 siRNA and pharmacological inhibition in human monocytes/macrophages with mTORC1 and cytokine readouts\",\n      \"pmids\": [\"29422900\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Contribution of LAT1 vs. other leucine transporters in macrophage activation not quantified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cryo-EM at 3.3/3.5 Å with and without inhibitor BCH, combined with transport assays\",\n      \"pmids\": [\"30867591\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Outward-open conformation not captured\", \"Substrate-bound transition states not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"Systematic mutagenesis of cytosolic lysines, Nedd4-2 siRNA, endocytosis assays in HeLa cells\",\n      \"pmids\": [\"31728037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Nedd4-2-mediated regulation operates in all LAT1-expressing tissues unknown\", \"Deubiquitinase(s) that counteract this modification not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Conditional Slc7a5 knockout in Kras/Apc-mutant mouse intestinal epithelium, metabolic flux analysis, protein synthesis assays, tumor growth\",\n      \"pmids\": [\"33414552\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LAT1 dependency generalizes to all KRAS-driven cancers not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"Quadruple N-glycosylation mutant of CD98 with biotinylation, trafficking, and transport assays\",\n      \"pmids\": [\"36028562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether partial glycosylation retains function not fully characterized\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"T cell-specific SRC2 KO mice, Slc7a5 rescue, proliferation/cytokine assays, EAE and colitis models\",\n      \"pmids\": [\"37094160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ChIP evidence for SRC2 at the Slc7a5 promoter not shown in this study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"T cell-specific LAT1 deletion, TIRF microscopy of immune synapse, RNA-seq, arthritis models\",\n      \"pmids\": [\"37229811\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether synapse defect is secondary to amino acid deprivation vs. direct scaffolding not distinguished\", \"Mechanism linking LAT1 to CD3ζ recruitment not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"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)\",\n      \"pmids\": [\"38755144\", \"39704172\", \"38281999\", \"39304904\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"RNA-seq, proteomics, Kv1.2 immunofluorescence, electrophysiology, behavioral pain assays in HFD/STZ and db/db mice treated with JPH203\",\n      \"pmids\": [\"38946582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Outward-open and occluded structures not captured\", \"Transport-dependent vs. -independent Kv1.2 regulation not mechanistically separated\", \"Deubiquitinase for LAT1 not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 3, 5, 6, 10, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 8, 15, 17]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [8, 25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4, 13, 18, 28, 32]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 1, 5, 6, 10, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 13, 32]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14, 18, 21, 31]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [8, 19, 24]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [8, 17, 25]}\n    ],\n    \"complexes\": [\n      \"LAT1-CD98/4F2hc heterodimer\",\n      \"CD147-CD98-LAT1 metabolic supercomplex\"\n    ],\n    \"partners\": [\n      \"SLC3A2\",\n      \"BSG\",\n      \"KCNB1\",\n      \"NEDD4L\",\n      \"CD69\",\n      \"TRIM35\",\n      \"IGF2BP2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}