Affinage

SLC7A8

Large neutral amino acids transporter small subunit 2 · UniProt Q9UHI5

Round 2 corrected Audit flag: wrong gene
Length
535 aa
Mass
58.4 kDa
Annotated
2026-04-28
98 papers in source corpus 38 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC7A8 (LAT2) is the catalytic light-chain subunit of a heterodimeric sodium-independent amino acid antiporter that, upon disulfide-linked heterodimerization with the heavy chain 4F2hc (SLC3A2), traffics to the plasma membrane and mediates obligatory 1:1 exchange of neutral amino acids with strongly asymmetric intra- and extracellular affinities (PMID:10391915, PMID:11847106). Localized to the basolateral membrane of renal proximal tubules, intestinal epithelia, choroid plexus, and lens epithelium, LAT2 drives reabsorption of neutral amino acids in functional cooperation with the aromatic amino acid uniporter TAT1 (SLC16A10), and its loss causes aminoaciduria, age-related hearing loss, and cataract in mice and humans (PMID:21726201, PMID:29610403, PMID:29355479, PMID:31231240). Beyond canonical amino acids, LAT2 transports thyroid hormone metabolites, L-DOPA, S-nitroso-L-cysteine, methylmercury-cysteine conjugates, and doxorubicin (PMID:15466357, PMID:12117417, PMID:15769744, PMID:26601072). In skeletal muscle, LAT2 ablation causes glutamine accumulation that constitutively activates lysosomal mTORC1 and suppresses fasting-induced proteolysis, while in CD4+ T cells LAT2 selectively supports Th2 metabolism, proliferation, and effector function via mTOR and c-Myc pathways (PMID:40546137, PMID:41269086).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1999 High

    The identity of LAT2 as a broad-specificity neutral amino acid transporter requiring 4F2hc for surface expression was established, resolving how a second L-type system with distinct substrate preference operates as a disulfide-linked heterodimer at renal and intestinal basolateral membranes.

    Evidence Xenopus oocyte co-expression with 4F2hc; subcellular localization; radiolabeled amino acid uptake kinetics; immunofluorescence on kidney/intestine sections

    PMID:10391915 PMID:10574970

    Open questions at the time
    • Exchange stoichiometry and asymmetric affinity not yet quantified
    • Structural basis of 4F2hc requirement for LAT2 trafficking unknown
    • In vivo physiological role not yet demonstrated by genetic loss-of-function
  2. 2002 High

    Quantitative demonstration that LAT2-4F2hc is an obligatory 1:1 antiporter with millimolar intracellular Km versus micromolar extracellular Km resolved the asymmetric affinity model that explains how intracellular amino acid pools drive net substrate exchange.

    Evidence Xenopus oocyte co-expression; simultaneous HPLC quantification of influx and efflux; intracellular substrate injection

    PMID:11847106

    Open questions at the time
    • Structural determinants of affinity asymmetry unknown
    • How 4F2hc contributes to asymmetric kinetics not addressed
  3. 2001 High

    The requirement for the 4F2hc extracellular domain in LAT2 surface trafficking—distinct from LAT1—established that the heavy chain plays a light-chain-specific chaperoning role beyond disulfide linkage.

    Evidence C-terminal truncation mutants of 4F2hc co-expressed with LAT2 in oocytes; surface biotinylation; transport assays

    PMID:11311135

    Open questions at the time
    • Whether 4F2hc ectodomain also modulates LAT2 substrate specificity was untested
    • No structural model of the ectodomain-LAT2 interface
  4. 2002 High

    Identification of methylmercury-cysteine as a LAT2 substrate acting as a methionine mimic expanded the transporter's known cargo beyond canonical amino acids to environmentally relevant toxicants.

    Evidence Xenopus oocyte expression; [14C]MeHg-L-cysteine uptake with Km/Vmax determination; trans-stimulation

    PMID:12117417

    Open questions at the time
    • In vivo relevance for mercury toxicity not tested
    • No structural basis for molecular mimicry
  5. 2004 High

    siRNA knockdown established LAT2 as the primary L-DOPA transporter in renal epithelial cells, extending its physiological substrate repertoire to catecholamine precursors.

    Evidence siRNA knockdown in LLC-PK1 cells; [14C]-L-DOPA uptake and efflux; qRT-PCR

    PMID:15466357

    Open questions at the time
    • Contribution relative to other transporters in vivo unknown
    • Relevance to L-DOPA pharmacokinetics not established
  6. 2007 High

    Demonstration that TAT1 and LAT2 functionally cooperate without physical interaction—TAT1 recycling aromatic amino acids to fuel LAT2-mediated net efflux—provided the mechanistic model for basolateral amino acid reabsorption in kidney.

    Evidence Xenopus oocyte co-expression; HPLC efflux quantification; functionally inactive surface mutants; negative co-IP and crosslinking

    PMID:17273864

    Open questions at the time
    • In vivo validation by double knockout not yet performed
    • Whether this cooperation operates in other epithelia unknown
  7. 2011 High

    Targeted Slc7a8 knockout in mice confirmed the in vivo requirement for LAT2 in renal neutral amino acid reabsorption (aminoaciduria phenotype) and revealed an unexpected role in neonatal cortical thyroid hormone supply via genetic epistasis with Mct8.

    Evidence Slc7a8−/− mice; urine amino acid analysis; Mct8/Lat2 double knockout; cerebral cortex T3 measurements and target gene expression

    PMID:21726201 PMID:24819605

    Open questions at the time
    • Intestinal and placental transport roles not confirmed by knockout
    • Mechanism of LAT2's thyroid hormone transport contribution limited to early postnatal window
  8. 2014 High

    Electron microscopy and biochemical reconstitution revealed the architecture of the 4F2hc-LAT2 heterodimer, showing the ectodomain covers LAT2's extracellular face and stabilizes it, establishing the structural framework for understanding heavy-chain modulation.

    Evidence Negative-stain TEM single-particle analysis; Pichia pastoris purification; proteoliposome reconstitution; crosslinking

    PMID:24516142

    Open questions at the time
    • Atomic-resolution structure not available
    • Substrate-bound conformational states not captured
  9. 2018 High

    LAT2 loss-of-function was linked to age-related hearing loss—both in Slc7a8−/− mice showing cochlear damage and in human patients carrying transport-defective SLC7A8 variants—establishing a Mendelian-type disease connection.

    Evidence Slc7a8−/− mice; ABR testing; cochlear histology; in vitro transport assays of human patient variants

    PMID:29355479

    Open questions at the time
    • Specific amino acid(s) whose deficiency drives ototoxicity unknown
    • Whether cochlear phenotype is cell-autonomous not determined
  10. 2018 High

    Double knockout of LAT2 and TAT1 in vivo confirmed their functional cooperation for renal amino acid reabsorption and revealed compensatory upregulation of y+LAT1, demonstrating transporter network plasticity at the basolateral membrane.

    Evidence LAT2/TAT1 double-knockout mice; urine amino acid analysis; Western blot for compensatory transporter expression

    PMID:29610403

    Open questions at the time
    • Molecular signals driving compensatory transporter upregulation unknown
    • Functional consequences in non-renal epithelia not assessed
  11. 2019 High

    LAT2 ablation caused cataract in mice with depleted lens amino acids, and a human homozygous SLC7A8 frameshift abolished transport and segregated with congenital cataract, establishing a second Mendelian phenotype.

    Evidence Slc7a8−/− and double Slc7a8/Slc16a10 KO mice; slit-lamp; lens amino acid HPLC; in vitro transport of human variants in HeLa cells

    PMID:31231240

    Open questions at the time
    • Which specific amino acid deficit is cataractogenic not pinpointed
    • Whether lens-specific rescue would prevent cataract untested
  12. 2020 High

    Multiple cryo-EM structures at improving resolution (sub-nanometer to 3.2 Å) defined the substrate binding pocket of LAT2 within the 4F2hc heterodimer and revealed that 4F2hc modulates LAT2 substrate affinity beyond its trafficking role, fundamentally redefining heavy-chain function.

    Evidence Cryo-EM at 3.2 Å with anticalin; molecular dynamics; Pichia pastoris expression of LAT2 alone vs. heterodimer with comparative kinetics

    PMID:33066406 PMID:33298890 PMID:36310334

    Open questions at the time
    • Outward-open conformation structure not captured
    • Substrate-bound structures at atomic resolution for multiple substrates lacking
    • Mechanism by which 4F2hc ectodomain allosterically tunes LAT2 selectivity not resolved
  13. 2022 High

    LAT2-mediated amino acid uptake was shown to activate mTORC1 and downstream c-Myc in osteosarcoma cells, linking transporter activity to immune evasion via CD47 upregulation, thereby placing LAT2 in the signaling interface between amino acid import and tumor immunity.

    Evidence siRNA/shRNA LAT2 depletion; mTORC1/c-Myc ChIP; CD47 expression; macrophage phagocytosis assay; xenograft model

    PMID:36274066

    Open questions at the time
    • Whether LAT2's signaling role is cell-type specific or generalizable unknown
    • Direct LAT2-mTORC1 signaling mechanism (sensing vs. substrate supply) not dissected
  14. 2025 High

    Two independent studies revealed tissue-specific metabolic consequences of LAT2 loss: in skeletal muscle, glutamine accumulation constitutively activates lysosomal mTORC1 and blocks fasting-induced proteolysis; in CD4+ T cells, LAT2 selectively supports Th2 metabolism and effector function via mTOR/c-Myc.

    Evidence Slc7a8−/− mice; intramuscular amino acid metabolomics; mTORC1-Lamp1 colocalization; rapamycin rescue; Th2 differentiation assays; helminth and allergen models

    PMID:40546137 PMID:41269086

    Open questions at the time
    • Whether glutamine is the sole mTORC1-activating metabolite in LAT2-deficient muscle not proven
    • Mechanism of Th2-selective LAT2 dependence vs. other T helper lineages not resolved
    • Translational relevance of LAT2 as a therapeutic target in muscle wasting or allergy unexplored

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for the outward-open conformation and full substrate translocation cycle, the precise mechanism by which LAT2-imported amino acids activate mTORC1 across different tissues, and whether pharmacological modulation of LAT2 can be exploited therapeutically for hearing loss, cataract, or immune disorders.
  • No outward-open or occluded-state structure available
  • Direct sensing mechanism linking LAT2 transport to lysosomal mTORC1 recruitment not identified
  • No selective LAT2 inhibitor or activator tool compounds reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 16
Localization
GO:0005886 plasma membrane 7
Pathway
R-HSA-382551 Transport of small molecules 11 R-HSA-1430728 Metabolism 5 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 1
Partners
SLC16A10SLC3A2
Complex memberships
4F2hc-LAT2 (SLC3A2-SLC7A8) heterodimer

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 SLC7A8 (LAT2) encodes a sodium-independent L-type amino acid transporter that requires heterodimerization with 4F2hc (CD98 heavy chain) for plasma membrane localization and transport activity. Expressed alone in Xenopus oocytes, LAT2 localizes intracellularly and is non-functional; co-expression with 4F2hc traffics it to the plasma membrane and induces broad-specificity transport of small and large zwitterionic amino acids. The transport is highly trans-stimulated, indicating an obligatory exchanger mechanism. Xenopus oocyte expression system; N-myc-tagged protein; subcellular localization assay; radiolabeled amino acid uptake; trans-stimulation assays The Journal of biological chemistry High 10391915
1999 LAT2/SLC7A8 forms a disulfide-linked heterodimer with 4F2hc and mediates L-type amino acid uptake with higher affinity for L-phenylalanine and transport of L-alanine at physiological concentrations compared to LAT1-4F2hc. LAT2-4F2hc also mediates amino acid efflux in the presence of an external substrate, consistent with obligatory exchange. LAT2 colocalizes with 4F2hc at the basolateral membrane of kidney proximal tubules and small intestine epithelia, implicating it in epithelial amino acid (re)absorption. Xenopus oocyte co-injection of mouse LAT2 and human 4F2hc cRNAs; SDS-PAGE under non-reducing conditions (disulfide); L-[3H]phenylalanine and L-[3H]alanine uptake kinetics; immunofluorescence of kidney and intestine sections The Journal of biological chemistry High 10574970
1999 SLC7A8 maps to chromosome 14q11.2 within the lysinuric protein intolerance (LPI) critical region, is highly expressed in skeletal muscle, intestine, kidney, and placenta, and encodes a predicted 535-amino-acid protein homologous to CD98 light chain amino acid permeases. Mutational analysis excluded SLC7A8 from direct causation of LPI. Bioinformatic cloning; Northern blot; RNA in situ hybridization on mouse embryos; Sanger sequencing for mutation analysis Genomics Medium 10610726
2000 The LAT2-4F2hc heterodimer functions as an obligatory antiporter: only preloaded intracellular amino acids can be released in exchange for extracellular substrates, confirming an exchanger rather than uniporter mechanism for this transporter complex. Xenopus oocyte expression; radiolabeled amino acid efflux under various loading conditions; competitive inhibition assays The Biochemical journal Medium 10903140
2001 The extracellular domain of 4F2hc is specifically required for plasma membrane trafficking of LAT2 (and y+LAT2) but not LAT1. C-terminal truncations of 4F2hc that retain only the transmembrane helix are sufficient for LAT1 surface expression but almost completely abolish LAT2 surface expression, revealing that LAT2 requires interaction with the extracellular domain of 4F2hc for correct trafficking. Xenopus oocyte expression of C-terminally truncated 4F2hc mutants co-expressed with LAT1, LAT2, or y+LAT2; surface biotinylation; radiolabeled amino acid transport assays The Biochemical journal High 11311135
2002 LAT2-4F2hc functions as an obligatory amino acid exchanger with 1:1 stoichiometry. Intracellular substrates strongly trans-stimulate influx, and LAT2-4F2hc has much lower apparent affinity for intracellular substrates (Km in millimolar range) compared to extracellular substrates, creating strongly asymmetric affinity that allows the intracellular amino acid concentration to control transporter activity. Xenopus oocyte expression; HPLC quantification of simultaneous amino acid influx and efflux; intracellular substrate injection; kinetic analysis The EMBO journal High 11847106
2002 LAT2-4F2hc transports methylmercury when complexed with L-cysteine (MeHg-L-cysteine), acting as a molecular mimic of methionine. Both cis- and trans-substrate properties were confirmed: MeHg-L-cysteine uptake by LAT2 has Km ~64 µM with Vmax higher than methionine, and methionine efflux is trans-stimulated by external leucine and phenylalanine even against an inward methionine gradient. Xenopus oocyte expression of LAT2-4F2hc; [14C]MeHg-L-cysteine uptake; [3H]methionine trans-stimulation; kinetic analysis (Km, Vmax) The Biochemical journal High 12117417
2003 LAT2 at the basolateral membrane of renal proximal tubule cells plays a major specific role in basolateral efflux of cysteine/cystine. Antisense-mediated partial knockdown of LAT2 in OK cells reduced basolateral system L amino acid exchange activity, decreased apical-to-basolateral transepithelial flux of cystine, and caused a 2-3 fold increase in intracellular cysteine, identifying LAT2 as a key transporter mediating cystine reabsorption across the basolateral membrane. Stable transfection with LAT2 antisense construct in OK cells; radiolabeled amino acid transport; transepithelial flux assay; intracellular amino acid content measurement Journal of the American Society of Nephrology High 12660317
2003 CD98 (4F2hc) ligation at the basolateral membrane of intestinal Caco-2 epithelial cells decreases the Km and Vmax of LAT2-mediated transport, while ICAM-1 ligation increases both Km and Vmax, demonstrating that LAT2 transport activity is regulated by co-receptor signaling. ICAM-1 selectively co-immunoprecipitates with CD98/LAT2 at the basolateral membrane, and cross-linking of either receptor induces threonine phosphorylation of an ~160 kDa CD98/LAT2-ICAM-1 complex. Co-immunoprecipitation; antibody-mediated receptor cross-linking; amino acid transport kinetics (Km, Vmax) in Caco-2 monolayers; phosphorylation assay The Journal of biological chemistry Medium 12716892
2004 LAT2 mediates Na+-independent, pH-sensitive L-DOPA transport in renal LLC-PK1 epithelial cells. siRNA silencing of LAT2 reduced [14C]-L-DOPA accumulation by ~85% and outward transport by ~90%, confirming LAT2 as the primary L-DOPA transporter; the LAT2-mediated mechanism supports both influx and efflux of L-DOPA, consistent with heteroexchange. siRNA knockdown of LAT2 in LLC-PK1 cells; real-time quantitative RT-PCR; [14C]-L-DOPA uptake and efflux assays; competitive inhibition FASEB journal High 15466357
2004 rBAT (apical) and LAT2 (basolateral) can each mediate L-DOPA uptake into renal proximal tubule cells, with distinct kinetics: rBAT shows micromolar Km while LAT2 shows millimolar Km for L-DOPA. Antisense oligonucleotides to LAT2 inhibited LAT2 cRNA-induced L-DOPA transport and partially blocked cortical poly-A+ RNA-induced transport. Xenopus oocyte expression; kinetic analysis; sequence-specific antisense oligonucleotides; [14C]-L-DOPA uptake American journal of physiology. Renal physiology Medium 15180924
2005 LAT2 (co-expressed with 4F2hc) stereoselectively transports S-nitroso-L-cysteine (L-CSNO) but not D-CSNO or other nitrosothiols, identifying LAT2 as a transporter for this nitric oxide donor. L-CSNO transport by LAT2 is Na+-independent, inhibited by leucine and BCH, and the transport mechanism involves direct cellular uptake of intact L-CSNO. Xenopus oocyte expression of LAT2-4F2hc; [14C]-L-CSNO uptake; stereoselectivity assays; competitive inhibition; overexpression and siRNA knockdown in mammalian cells The Journal of biological chemistry High 15769744
2005 LAT2 and TAT1 (SLC16A10) colocalize in the basolateral membrane of human renal proximal tubules and together mediate renal reabsorption of neutral amino acids. LAT2 transports all neutral amino acids while TAT1 is specific for aromatic amino acids, and their basolateral colocalization supports a two-transporter model for basolateral exit of reabsorbed amino acids. Immunohistochemistry on human kidney sections; Northern blot; functional characterization in Xenopus oocytes Archives of pharmacal research Medium 15918515
2007 TAT1 (SLC16A10) and LAT2-4F2hc functionally cooperate to drive net amino acid efflux: TAT1 recycles aromatic amino acids (influx substrates of LAT2) by facilitated diffusion, enabling LAT2-4F2hc to continuously release glutamine and other neutral amino acids from cells. This cooperation requires the transport activity of both proteins but not their physical interaction, as coimmunoprecipitation and crosslinking were negative. Xenopus oocyte co-expression; HPLC analysis of amino acid efflux; functionally inactive surface-expressed mutants; co-immunoprecipitation; crosslinking experiments; immunofluorescence colocalization in kidney Pflugers Archiv High 17273864
2011 Targeted inactivation of Slc7a8 in mice causes increased urinary loss of small neutral amino acids (aminoaciduria), demonstrating that LAT2 is required for renal reabsorption of neutral amino acids in vivo. Motor coordination is mildly impaired in Slc7a8-/- mice. Circulating thyroid hormones and TSH remain normal in knockout mice, suggesting functional compensation by MCT8 for thyroid hormone transport. Targeted gene knockout (Slc7a8-/- mice); urine amino acid analysis; behavioral testing (motor coordination); thyroid hormone and TSH measurements; thyroid hormone-responsive gene expression The Biochemical journal High 21726201
2011 LAT2 plasma membrane expression in glomerular parietal epithelial cells (PECs) and podocytes activates the mTORC1 signaling pathway, preceding crescent formation in crescentic glomerulonephritis (CGN). LAT2 is specifically upregulated in these cells before crescent formation; in cell culture, plasma membrane LAT2 markedly stimulates mTORC1 signaling that is abrogated by a LAT inhibitor; and LAT inhibitor significantly reduced crescent formation in vivo. Immunohistochemistry and Western blot of isolated rat glomeruli; cell culture with LAT inhibitor; mTORC1 pathway analysis (p-S6K1); in vivo LAT inhibitor treatment of CGN model Laboratory investigation Medium 21403644
2011 Dihydrotestosterone (DHT) acutely increases expression of LAT2 protein and amino acid uptake in fast-twitch skeletal muscle fibers through a non-genomic mechanism requiring EGFR transactivation and ERK1/2 (MEK) signaling, but not androgen receptor or PI3K/Akt. This effect is also dependent on mTOR and involves increased protein synthesis. [14C]-labelled amino acid uptake in isolated mouse muscle fiber bundles; pharmacological inhibition of EGFR, MEK, mTOR, androgen receptor; Western blot for LAT2, p-EGFR, p-ERK1/2, p-RSK1/2; protein incorporation assay The Journal of physiology Medium 21606113
2012 Human LAT2 expressed stably in HEK293 cells (as heterodimer with endogenous 4F2hc) transports L-alanine as a preferred substrate with reliable kinetics. α-Alkyl amino acids (α-methyl-alanine, α-ethyl-L-alanine) interfere with LAT2 interaction, defining a steric constraint at the α-carbon of substrates that distinguishes LAT2 from LAT1. Stable HEK293 cell lines; [14C]-L-alanine transport assays; kinetic analysis; α-alkyl amino acid inhibition studies Journal of pharmacological sciences Medium 22850614
2014 The extracellular domain of 4F2hc interacts directly with LAT2, almost completely covering the extracellular face of the transporter as revealed by transmission electron microscopy and single-particle analysis. 4F2hc increases the stability of LAT2 in detergent-solubilized membranes and enables functional reconstitution of the heterodimer into proteoliposomes; the extracellular domain of 4F2hc alone is sufficient to stabilize solubilized LAT2. Transmission electron microscopy (negative stain); single-particle analysis; purification of recombinant 4F2hc-LAT2 from Pichia pastoris; crosslinking experiments; docking analysis; functional reconstitution into proteoliposomes Proceedings of the National Academy of Sciences of the United States of America High 24516142
2014 Cerebral cortex hyperthyroidism in neonatal Mct8-deficient mice is prevented by simultaneous ablation of Lat2, demonstrating that Lat2 is responsible for the increased thyroid hormone supply to the neonatal cerebral cortex in the absence of Mct8. This Lat2 effect is transient (absent from postnatal day 5 onward), and Lat2 expression in neurons and choroid plexus is consistent with a role in early postnatal thyroid hormone supply to the cortex. Double knockout mice (Mct8-/-/Lat2-/-); T3 concentration measurements in cerebral cortex; thyroid hormone target gene expression (Hr); comparison across postnatal development time points PloS one High 24819605
2014 Stabilization of purified 4F2hc-LAT2 with a combination of DDM, lauryl maltose neopentyl glycol, and cholesteryl hemisuccinate enables measurement of substrate binding by scintillation proximity assay and improves the 3D EM map, confirming that LAT2 is the substrate-transporting subunit of the heterodimer. Detergent screening; negative-stain TEM; scintillation proximity assay for substrate binding; 3D map reconstruction PloS one Medium 25299125
2015 LAT2 (co-expressed with CD98) transports 3,3'-diiodo-L-thyronine (3,3'-T2) with a low micromolar Km comparable to MCT8, and to a lesser extent T3. Various iodothyronine derivatives competitively inhibit 3,3'-T2 uptake, revealing that LAT2 preferentially transports 3,3'-T2 among thyroid hormone metabolites, suggesting a role in cellular availability of this deiodinase product. Xenopus oocyte co-injection of Lat2 and CD98 cRNAs; [125I]-3,3'-T2 and [125I]-T3 uptake; competitive inhibition with iodothyronine derivatives; Km determination European thyroid journal Medium 26601072
2015 BPA (boronophenylalanine), a boron neutron capture therapy agent, is a substrate for LAT2 (as well as ATB0,+ and LAT1), with a Km of 88.3 µM for LAT2-mediated transport in Xenopus oocytes. In cancer cell lines, LAT1 is the predominant BPA transporter at low concentrations, with LAT2 contributing at higher concentrations. Xenopus oocyte expression; HPLC-based BPA uptake quantification; kinetic analysis; siRNA knockdown in MCF-7 cells Cancer science Medium 25580517
2017 LAT2-4F2hc mediates methylmercury (as MeHg-L-cysteine complex) uptake at the apical membrane of BeWo placental trophoblast cells. siRNA knockdown of LAT2 or 4F2hc significantly reduced leucine, methionine, and methylmercury uptake, establishing LAT2-4F2hc as a key pathway for placental methylmercury transport. siRNA knockdown of LAT2 and 4F2hc in BeWo cells; Transwell transport assay; [3H]leucine, [3H]methionine, and methylmercury uptake measurements International journal of molecular sciences Medium 28786956
2018 LAT2/SLC7A8 is expressed in the mouse inner ear, and its ablation (Slc7a8-/- mice) causes age-related hearing loss (ARHL) with damage to cochlear structures. Human SLC7A8 variants (p.Val302Ile, p.Arg418His, p.Thr402Met, p.Val460Glu) found in ARHL patients show significant decreases in transport activity when functionally expressed in vitro, supporting a causative role for SLC7A8 loss-of-function in ARHL. Slc7a8-/- mouse model; auditory brainstem response testing; cochlear histology; in vitro functional transport assays of patient variants in heterologous cells eLife High 29355479
2018 LAT2 promotes glutamine-dependent mTOR activation in pancreatic cancer cells, driving glycolysis and chemoresistance. LAT2 regulates two glutamine-dependent positive feedback loops: the LAT2/p-mTORSer2448 loop and the glutamine/p-mTORSer2448/glutamine synthetase loop. mTOR inhibitor (RAD001) reverses the LAT2-mediated decrease in gemcitabine sensitivity. LAT2 overexpression and knockdown in pancreatic cancer cells; mTOR pathway analysis (p-mTORSer2448); glycolysis assays; glutamine metabolism measurement; xenograft mouse model; drug sensitivity assays Journal of experimental & clinical cancer research Medium 30419950
2018 LAT2/CD98hc (SLC7A8/SLC3A2) and TAT1 (SLC16A10) functionally cooperate in vivo for renal reabsorption of neutral amino acids. Double-knockout (LAT2/TAT1) mice show greater urinary loss of aromatic and other neutral amino acids than single knockouts, and also display decreased reabsorption of cationic amino acids with compensatory upregulation of y+LAT1/CD98hc, demonstrating functional cooperation and compensation among basolateral amino acid transporters. Double-knockout mouse model (LAT2-TAT1 dKO); urine amino acid analysis; Western blot for transporter expression; comparison with single knockouts Journal of the American Society of Nephrology High 29610403
2019 Loss of LAT2 (Slc7a8 deletion) in mice causes cataract, particularly in older females, associated with a dramatic decrease in lens essential amino acid levels. A homozygous SLC7A8 single nucleotide deletion found in a human family with congenital cataract abolishes amino acid transport when expressed in HeLa cells. Heterozygous LAT2 variants from cataract patients also show reduced transport function. Simultaneous TAT1 deletion synergizes with LAT2 loss to increase cataract incidence. Slc7a8-/- and double Slc7a8/Slc16a10 knockout mice; slit-lamp examination; lens amino acid HPLC; in vitro transport assays of human variants in HeLa cells; immunofluorescence of LAT2 in ciliary and lens epithelium Frontiers in physiology High 31231240
2019 Cryo-EM 3D map of human 4F2hc-LAT2 at ~13 Å resolution reveals two prominent densities: the 4F2hc ectodomain (fitted using the available X-ray structure) and the LAT2 transmembrane domain, defining the relative positions of the two subunits with respect to each other and the membrane plane. Cryo-EM with direct electron detector and Volta phase plate; 3D map reconstruction; fitting of 4F2hc ectodomain X-ray structure International journal of molecular sciences Medium 30795505
2020 Sub-nanometer cryo-EM density map of 4F2hc-LAT2 reveals the inward-open conformation of LAT2 via homology modeling fitted into the map. Disease-causing point mutations in LAT2 are mapped to the substrate binding site and transmembrane helices, providing structural context for their functional effects. Cryo-EM; homology model generation of 4F2hc-LAT2 in inward-open conformation; fitting and analysis; disease mutation mapping International journal of molecular sciences Medium 32993041
2020 4F2hc modulates the substrate affinity and specificity of LAT2 (and LAT1): when LAT2 is expressed alone in Pichia pastoris (without 4F2hc), it localizes to the plasma membrane and is transport-competent, but shows different substrate affinity and specificity compared to the 4F2hc-LAT2 heterodimer. This demonstrates a novel function of the heavy chain beyond trafficking, namely modulation of light chain transport properties. Pichia pastoris expression of LAT2 alone and 4F2hc-LAT2; [3H]L-leucine radiolabel transport assay; substrate competition assays; kinetic analysis International journal of molecular sciences Medium 33066406
2020 The structural insight into substrate recognition of LAT2-4F2hc was determined: the cryo-EM/crystal structure of the complex reveals the substrate binding pocket architecture in LAT2, with the 4F2hc ectodomain positioned above the LAT2 transporter domain. Structural basis for substrate selectivity of LAT2 within the heterodimeric complex was elucidated. Cryo-EM structure determination of LAT2-4F2hc; substrate binding pocket analysis Cell discovery High 33298890
2020 LAT2 (Slc7a8) localizes to the CSF-facing luminal membrane of choroid plexus epithelium. Deletion of Slc7a8 in mice increases CSF levels of LAT2 substrates (leucine, valine, tryptophan) and other amino acids, demonstrating that LAT2 normally reuptakes these amino acids from CSF back into the choroid plexus, thereby participating in maintenance of the amino acid concentration gradient between plasma and CSF. qRT-PCR on isolated choroid plexus; immunofluorescence localization; LAT2 knockout mice; CSF amino acid HPLC analysis Fluids and barriers of the CNS High 32046769
2022 Chemotherapy-induced macrophage secretion of IL-18 upregulates LAT2 expression in osteosarcoma tumor cells, leading to enhanced leucine and glutamine uptake, mTORC1 activation, and c-Myc-mediated CD47 transcription, resulting in tumor immune evasion. LAT2 depletion or LAT inhibitor treatment downregulates CD47, increases macrophage phagocytosis of tumor cells, and sensitizes tumors to doxorubicin. IL-18 stimulation; LAT2 depletion (siRNA/shRNA); amino acid uptake assays; mTORC1 activation (p-S6K); c-Myc ChIP; CD47 expression; macrophage phagocytosis assay; xenograft mouse model Nature communications High 36274066
2022 The cryo-EM structure of 4F2hc-LAT2 in complex with anticalin D11vs at 3.2 Å resolution reveals fixed water molecules in the LAT2 substrate binding site that may stabilize the binding region. Molecular dynamics simulations and local map resolution of 2.8-3.0 Å in the binding site provide mechanistic insight into substrate binding and selectivity of LAT2. Cryo-EM single-particle analysis at 3.2 Å; anticalin binding protein for particle alignment; molecular dynamics simulations; local resolution analysis Scientific reports High 36310334
2022 LAT2 (encoded by SLC7A8) transports doxorubicin as a substrate. HEK293 cells overexpressing LAT2 show significantly increased doxorubicin uptake compared to controls, while cisplatin and methotrexate are not transported. This identifies LAT2 as a novel doxorubicin uptake transporter with potential relevance to osteosarcoma treatment response. HEK293 overexpression of LAT2; in vitro doxorubicin transport assay; comparison with cisplatin and methotrexate Frontiers in pharmacology Medium 36438828
2025 LAT2 (SLC7A8) is a Th2-specific amino acid transporter in the CD4 T helper compartment. Slc7a8 deficiency impairs Th2 cell proliferation and cytokine production, disrupts Th2 metabolism with reduced mTOR activation, diminished mitochondrial function, and impaired c-Myc pathway, inducing cellular stress. LAT2-deficient mice show impaired type 2 immune responses to helminth infection and allergen-induced lung inflammation. Slc7a8-/- mice; Th1/Th2/Th17/Treg differentiation assays; proliferation and cytokine assays; metabolic profiling; mTOR and c-Myc pathway analysis; helminth infection and allergen challenge models The Journal of experimental medicine High 41269086
2025 LAT2 ablation in skeletal muscle causes glutamine (Gln) accumulation (6.3-fold increase) intramuscularly and inhibits fasting-induced proteolysis, primarily through reduced proteasomal and autophagic activity. This is mediated by mTORC1 recruitment to the lysosome (Lamp1 colocalization), as rapamycin treatment recovers proteolysis in LAT2KO muscle. Chronic Gln accumulation and decreased proteolysis in young LAT2KO mice produce an age-related muscle phenotype. LAT2 knockout mice; metabolomics (intramuscular amino acid HPLC); proteasomal and autophagic activity assays; mTORC1 colocalization (Lamp1); rapamycin rescue; aging, cachexia, and diabetes models Journal of cachexia, sarcopenia and muscle High 40546137

Source papers

Stage 0 corpus · 98 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Blood-Brain Barrier: From Physiology to Disease and Back. Physiological reviews 1645 30280653
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2008 Amino acid transport across mammalian intestinal and renal epithelia. Physiological reviews 657 18195088
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