{"gene":"SLC7A6","run_date":"2026-06-10T07:46:35","timeline":{"discoveries":[{"year":1999,"finding":"SLC7A6 (LAT-2) encodes a light chain subunit that must heterodimerize with 4F2hc (CD98/SLC3A2) to reach the plasma membrane and induce sodium-independent amino acid transport activity with broad specificity for small and large zwitterionic amino acids via an exchanger mechanism; expression of LAT-2 alone in Xenopus oocytes produced no transport activity and the protein remained intracellular, whereas co-expression with 4F2hc directed LAT-2 to the plasma membrane and reconstituted system L transport.","method":"Xenopus laevis oocyte expression system with co-expression of tagged N-myc-LAT-2 ± 4F2hc, amino acid uptake assays, trans-stimulation experiments, and subcellular localization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — functional reconstitution in oocytes with transport assays and subcellular localization, foundational paper with 342 citations and multiple orthogonal methods","pmids":["10391915"],"is_preprint":false},{"year":2003,"finding":"LAT-2 is the primary transporter responsible for basolateral system L amino acid exchange activity in the renal proximal tubule cell line OK; antisense-mediated reduction of LAT-2 expression decreased apical-to-basolateral transepithelial flux of cystine and elevated intracellular cysteine content, demonstrating a specific role for LAT-2 in net basolateral efflux of cysteine.","method":"Stable antisense transfection of LAT-2 in OK cells, amino acid uptake assays, transepithelial flux assays, intracellular amino acid content measurement","journal":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function (antisense knockdown) with specific transepithelial flux phenotype and intracellular metabolite readout, multiple orthogonal assays in single lab","pmids":["12660317"],"is_preprint":false},{"year":2002,"finding":"LAT-2 mediates Na+-independent L-DOPA uptake with broad specificity for small and large neutral amino acids in renal opossum kidney cells; LAT-2 transport is stimulated by acid pH and inhibited by BCH, and LAT-2 was found to be equally distributed at apical and basolateral membranes.","method":"Functional transport assays in OKLC and OKHC clonal renal cell lines, pharmacological inhibition with BCH, efflux stimulation assays, pH dependence experiments","journal":"The Journal of membrane biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological and functional characterization without genetic knockdown or structural validation; replicated across two clonal cell lines","pmids":["11944084"],"is_preprint":false},{"year":2003,"finding":"The CD98/LAT-2 heterodimer is expressed at the basolateral membrane of intestinal epithelia (Caco2-BBE) and forms a supramolecular complex with ICAM-1; CD98 ligation decreases Km and Vmax of LAT-2, while ICAM-1 ligation increases Km and Vmax, with both ligations inducing threonine phosphorylation of the ~160 kDa CD98/LAT-2–ICAM-1 complex.","method":"Co-immunoprecipitation, antibody cross-linking of CD98 and ICAM-1, amino acid transport kinetics (Km, Vmax), phosphorylation assays in Caco2-BBE polarized monolayers","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and functional kinetic assays in polarized cells, single lab with multiple orthogonal methods","pmids":["12716892"],"is_preprint":false},{"year":2005,"finding":"In Xenopus oocytes and mammalian cells, a dominant-negative SLC7A7 (y+LAT-1) mutant (E36del) interferes with y+LAT-2 (SLC7A6) transport activity, suggesting a multiheteromeric interaction between y+LAT-1 and y+LAT-2 within the same complex and explaining why increased SLC7A6 expression in LPI patient lymphoblasts does not fully compensate for SLC7A7 loss.","method":"Expression of SLC7A7 mutants (E36del, F152L) in Xenopus laevis oocytes and mammalian cells, amino acid transport activity assays, functional epistasis analysis","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reconstitution in oocytes with defined mutants establishing dominant-negative interference between y+LAT-1 and y+LAT-2, single lab","pmids":["15756301"],"is_preprint":false},{"year":2014,"finding":"SLC7A6 (y+LAT2) is the isoform responsible for betaine uptake in mouse cumulus-oocyte complexes (COCs); SLC7A6 transcript and protein are present in COCs but absent in isolated oocytes or eggs, and betaine accumulated by cumulus cells via SLC7A6 is transferred to the enclosed oocyte through gap junctions.","method":"Pharmacological inhibition profiling (methionine, leucine, lysine, arginine, proline), Na+/Cl- dependence assays, RT-PCR and western blot for SLC7A6 in COC fractions, gap junction inhibition experiments, betaine uptake assays","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — identified by expression profiling plus pharmacological transport characterization consistent with y+L system; no genetic knockdown of SLC7A6, but multiple orthogonal approaches converge on SLC7A6","pmids":["24599290"],"is_preprint":false},{"year":2022,"finding":"CDYL2 represses SLC7A6 expression by decreasing H3K4me3 enrichment at the SLC7A6 promoter; reduced SLC7A6 expression suppresses amino acid transport and inhibits mTORC1/S6K signaling in hepatocellular carcinoma cells, placing SLC7A6 downstream of a STAT5A→CDYL2→SLC7A6→mTORC1 axis.","method":"Gain- and loss-of-function experiments for CDYL2, chromatin immunoprecipitation (ChIP) for H3K4me3 at SLC7A6 promoter, western blotting for mTORC1/S6K pathway components, in vitro and in vivo tumor assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishes epigenetic mechanism of SLC7A6 regulation with functional pathway readout; single lab, multiple orthogonal methods","pmids":["35314791"],"is_preprint":false},{"year":2024,"finding":"Knockdown of the intronic retention (RI) isoform of SLC7A6 (SLC7A6-RI) enhances colon cancer cell proliferation in vitro and tumor growth in vivo by activating the PI3K-Akt-mTOR signaling pathway, as evidenced by increased p-mTOR and PCNA levels.","method":"siRNA knockdown of SLC7A6-RI isoform, in vivo xenograft experiments, western blotting for p-mTOR and PCNA, bioinformatics analysis of TCGA COAD data","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular pathway readout in vitro and in vivo, single lab","pmids":["39403788"],"is_preprint":false},{"year":2025,"finding":"AlphaFold3 structural modeling predicted an interaction between SLC7A6 and oxidized glutathione (GSSG); biochemical assays following SLC7A6 knockdown showed altered intracellular levels of GSSG, GSH, and nitric oxide, suggesting SLC7A6 participates in redox homeostasis and ferroptosis regulation through GSSG transport.","method":"AlphaFold3 structural prediction, SLC7A6 knockdown, biochemical assays for GSSG/GSH/NO, CCK-8 and Transwell functional assays","journal":"International journal of biological macromolecules","confidence":"Low","confidence_rationale":"Tier 4 / Weak — structural prediction only (AlphaFold3, no experimental structure validation), indirect biochemical readout without direct transport reconstitution","pmids":["41043754"],"is_preprint":false}],"current_model":"SLC7A6 (y+LAT-2) is a light-chain subunit of a heteromeric amino acid transporter that obligatorily associates with the heavy chain 4F2hc (CD98/SLC3A2) to traffic to the plasma membrane, where it mediates sodium-independent, exchanger-mode transport of a broad range of zwitterionic amino acids (system L/y+L activity); at the basolateral membrane of renal proximal tubule and intestinal epithelial cells it drives net efflux of cysteine and dibasic amino acids, its transport kinetics are acutely regulated by ICAM-1 interactions via a supramolecular complex, and its expression is transcriptionally controlled by a STAT5A→CDYL2→H3K4me3 epigenetic axis that feeds into mTORC1/S6K signaling."},"narrative":{"mechanistic_narrative":"SLC7A6 (y+LAT-2/LAT-2) is the light-chain subunit of a heteromeric amino acid transporter that must obligatorily heterodimerize with the heavy chain 4F2hc (CD98/SLC3A2) to traffic to the plasma membrane and reconstitute sodium-independent, exchanger-mode transport of small and large zwitterionic amino acids (system L/y+L activity); expressed alone it remains intracellular and transport-inactive [PMID:10391915]. In polarized epithelia it operates at the basolateral membrane: in renal proximal tubule cells it drives net efflux of cysteine, with loss of function reducing transepithelial cystine flux and raising intracellular cysteine [PMID:12660317], and in renal opossum kidney cells it mediates broad Na+-independent uptake of neutral amino acids including L-DOPA, stimulated by acid pH and inhibited by BCH [PMID:11944084]. Within the CD98/LAT-2 complex at the intestinal basolateral membrane, SLC7A6 transport kinetics are acutely tuned by a supramolecular assembly with ICAM-1, where CD98 versus ICAM-1 ligation reciprocally shift Km and Vmax and induce threonine phosphorylation of the complex [PMID:12716892]. SLC7A6 transporter function feeds amino-acid-dependent mTORC1/S6K signaling, and its expression is restrained by a STAT5A→CDYL2 axis that lowers H3K4me3 at the SLC7A6 promoter [PMID:35314791]. Tissue-specific roles include betaine uptake by cumulus cells for delivery to the oocyte via gap junctions [PMID:24599290].","teleology":[{"year":1999,"claim":"Established that SLC7A6 is not an autonomous transporter but a light chain requiring 4F2hc to reach the surface and confer system L exchange activity, defining its molecular architecture.","evidence":"Xenopus oocyte co-expression of tagged LAT-2 ± 4F2hc with uptake, trans-stimulation, and localization assays","pmids":["10391915"],"confidence":"High","gaps":["No structural model of the heterodimer","Stoichiometry and substrate translocation mechanism not resolved"]},{"year":2002,"claim":"Characterized the substrate range and regulatory properties of SLC7A6 transport, showing broad neutral amino acid (including L-DOPA) handling with pH and BCH sensitivity.","evidence":"Functional transport assays in OKLC/OKHC renal clonal lines with pharmacological inhibition and efflux/pH dependence","pmids":["11944084"],"confidence":"Medium","gaps":["No genetic loss-of-function","Apical vs basolateral distribution differed from later epithelial findings"]},{"year":2003,"claim":"Defined the physiological epithelial role of SLC7A6 as the basolateral system L exchanger driving net cysteine efflux in renal proximal tubule.","evidence":"Antisense knockdown in OK cells with transepithelial cystine flux and intracellular metabolite measurement","pmids":["12660317"],"confidence":"High","gaps":["Effect shown in one cell line, not in vivo kidney","Contribution relative to other system L carriers not quantified"]},{"year":2003,"claim":"Revealed that SLC7A6 transport kinetics are acutely regulated through a supramolecular CD98/LAT-2–ICAM-1 complex rather than being constitutive.","evidence":"Reciprocal co-IP, antibody cross-linking, kinetic and phosphorylation assays in polarized Caco2-BBE monolayers","pmids":["12716892"],"confidence":"Medium","gaps":["Signaling kinase mediating threonine phosphorylation not identified","Physiological trigger for ICAM-1 ligation in vivo unknown"]},{"year":2005,"claim":"Showed SLC7A6 functionally interacts with SLC7A7 (y+LAT-1) in a multiheteromeric arrangement, explaining incomplete compensation in lysinuric protein intolerance.","evidence":"Dominant-negative SLC7A7 mutant expression in oocytes and mammalian cells with transport epistasis analysis","pmids":["15756301"],"confidence":"Medium","gaps":["Direct physical evidence for a shared complex limited","Composition of the multiheteromer not defined"]},{"year":2014,"claim":"Identified a tissue-specific transport role for SLC7A6 in cumulus cell betaine uptake delivered to the oocyte, extending its substrate physiology beyond renal epithelia.","evidence":"Expression profiling, pharmacological transport characterization, and gap-junction inhibition in mouse cumulus-oocyte complexes","pmids":["24599290"],"confidence":"Medium","gaps":["No genetic knockdown of SLC7A6 in this context","Identity established by inference from y+L profile"]},{"year":2022,"claim":"Placed SLC7A6 downstream of an epigenetic regulatory axis and upstream of amino-acid-driven growth signaling, linking its expression to mTORC1/S6K output.","evidence":"CDYL2 gain/loss-of-function, ChIP for H3K4me3 at the SLC7A6 promoter, and mTORC1/S6K readouts in hepatocellular carcinoma models","pmids":["35314791"],"confidence":"Medium","gaps":["Direct demonstration that transporter activity (not protein level) drives mTORC1 not isolated","Single tumor type"]},{"year":2024,"claim":"Distinguished an intron-retention isoform of SLC7A6 with a tumor-suppressive effect on colon cancer growth via PI3K-Akt-mTOR signaling.","evidence":"siRNA knockdown of SLC7A6-RI, xenografts, p-mTOR/PCNA western blots, and TCGA COAD analysis","pmids":["39403788"],"confidence":"Medium","gaps":["Mechanism linking the RI isoform to mTOR not resolved","Relationship between RI isoform and canonical transporter function unclear"]},{"year":2025,"claim":"Proposed a redox-related substrate (oxidized glutathione) for SLC7A6 linking it to ferroptosis regulation.","evidence":"AlphaFold3 prediction of SLC7A6–GSSG interaction with biochemical GSSG/GSH/NO assays after knockdown","pmids":["41043754"],"confidence":"Low","gaps":["Structural prediction only, no experimental structure","No direct transport reconstitution of GSSG"]},{"year":null,"claim":"How SLC7A6 transport activity is mechanistically coupled to mTORC1 signaling and whether GSSG is a genuine transported substrate remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No experimental structure of the SLC7A6/4F2hc heterodimer","Direct substrate-flux link to mTORC1 not established","GSSG transport not demonstrated in a reconstituted system"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,3]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,1,2]}],"complexes":["CD98/4F2hc-LAT-2 heteromeric amino acid transporter","CD98/LAT-2–ICAM-1 supramolecular complex"],"partners":["SLC3A2","ICAM1","SLC7A7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92536","full_name":"Y+L amino acid transporter 2","aliases":["Cationic amino acid transporter, y+ system","Solute carrier family 7 member 6","y(+)L-type amino acid transporter 2","Y+LAT2","y+LAT-2"],"length_aa":515,"mass_kda":56.8,"function":"Heterodimer with SLC3A2, that functions as an antiporter which operates as an efflux route by exporting cationic amino acids such as L-arginine from inside the cells in exchange with neutral amino acids like L-leucine, L-glutamine and isoleucine, plus sodium ions and may participate in nitric oxide synthesis (PubMed:10903140, PubMed:11311135, PubMed:14603368, PubMed:15756301, PubMed:16785209, PubMed:17329401, PubMed:19562367, PubMed:31705628, PubMed:9829974). Also exchanges L-arginine with L-lysine in a sodium-independent manner (PubMed:10903140). The transport mechanism is electroneutral and operates with a stoichiometry of 1:1 (PubMed:10903140). Contributes to ammonia-induced increase of L-arginine uptake in cerebral cortical astrocytes leading to ammonia-dependent increase of nitric oxide (NO) production via inducible nitric oxide synthase (iNOS) induction, and protein nitration (By similarity). May mediate transport of ornithine in retinal pigment epithelial (RPE) cells (PubMed:17197568). May also transport glycine betaine in a sodium dependent manner from the cumulus granulosa into the enclosed oocyte (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q92536/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC7A6","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000103064","cell_line_id":"CID001374","localizations":[{"compartment":"membrane","grade":3},{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"CIAPIN1","stoichiometry":10.0},{"gene":"RNF169","stoichiometry":10.0},{"gene":"ANAPC11","stoichiometry":10.0},{"gene":"DDX46","stoichiometry":10.0},{"gene":"SLC3A2","stoichiometry":10.0},{"gene":"TCERG1","stoichiometry":10.0},{"gene":"PSIP1","stoichiometry":4.0},{"gene":"CALM2","stoichiometry":0.2},{"gene":"UHRF1BP1","stoichiometry":0.2},{"gene":"CNN3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001374","total_profiled":1310},"omim":[{"mim_id":"619192","title":"SOLUTE CARRIER FAMILY 7, MEMBER 6 OPPOSITE STRAND; SLC7A6OS","url":"https://www.omim.org/entry/619192"},{"mim_id":"605641","title":"SOLUTE CARRIER FAMILY 7 (CATIONIC AMINO ACID TRANSPORTER, y+ SYSTEM), MEMBER 6; SLC7A6","url":"https://www.omim.org/entry/605641"},{"mim_id":"604235","title":"SOLUTE CARRIER FAMILY 7 (CATIONIC AMINO ACID TRANSPORTER, y+ SYSTEM), MEMBER 8; SLC7A8","url":"https://www.omim.org/entry/604235"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":67.0}],"url":"https://www.proteinatlas.org/search/SLC7A6"},"hgnc":{"alias_symbol":["y+LAT-2","KIAA0245","LAT3","LAT-2"],"prev_symbol":[]},"alphafold":{"accession":"Q92536","domains":[{"cath_id":"1.20.1740.10","chopping":"54-501","consensus_level":"high","plddt":88.6757,"start":54,"end":501}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92536","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92536-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92536-F1-predicted_aligned_error_v6.png","plddt_mean":83.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC7A6","jax_strain_url":"https://www.jax.org/strain/search?query=SLC7A6"},"sequence":{"accession":"Q92536","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92536.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92536/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92536"}},"corpus_meta":[{"pmid":"10391915","id":"PMC_10391915","title":"Identification of a membrane protein, LAT-2, that Co-expresses with 4F2 heavy chain, an L-type amino acid transport activity with broad specificity for small and large zwitterionic amino acids.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10391915","citation_count":342,"is_preprint":false},{"pmid":"8807075","id":"PMC_8807075","title":"Transferable cefoxitin resistance in enterobacteria from Greek hospitals and characterization of a plasmid-mediated group 1 beta-lactamase (LAT-2).","date":"1996","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/8807075","citation_count":61,"is_preprint":false},{"pmid":"9818739","id":"PMC_9818739","title":"Transferable class C beta-lactamases in Escherichia coli strains isolated in Greek hospitals and characterization of two enzyme variants (LAT-3 and LAT-4) closely related to Citrobacter freundii AmpC beta-lactamase.","date":"1998","source":"The Journal of antimicrobial chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/9818739","citation_count":39,"is_preprint":false},{"pmid":"19443642","id":"PMC_19443642","title":"Amino acid transporter LAT3 is required for podocyte development and function.","date":"2009","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/19443642","citation_count":37,"is_preprint":false},{"pmid":"12660317","id":"PMC_12660317","title":"Basolateral LAT-2 has a major role in the transepithelial flux of L-cystine in the renal proximal tubule cell line OK.","date":"2003","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/12660317","citation_count":32,"is_preprint":false},{"pmid":"11944084","id":"PMC_11944084","title":"Na+-independent transporters, LAT-2 and b0,+, exchange L-DOPA with neutral and basic amino acids in two clonal renal cell lines.","date":"2002","source":"The Journal of membrane biology","url":"https://pubmed.ncbi.nlm.nih.gov/11944084","citation_count":31,"is_preprint":false},{"pmid":"24762008","id":"PMC_24762008","title":"Monoterpene glycoside ESK246 from Pittosporum targets LAT3 amino acid transport and prostate cancer cell growth.","date":"2014","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/24762008","citation_count":30,"is_preprint":false},{"pmid":"12716892","id":"PMC_12716892","title":"CD98 and intracellular adhesion molecule I regulate the activity of amino acid transporter LAT-2 in polarized intestinal epithelia.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12716892","citation_count":29,"is_preprint":false},{"pmid":"31345230","id":"PMC_31345230","title":"EGF-activated PI3K/Akt signalling coordinates leucine uptake by regulating LAT3 expression in prostate cancer.","date":"2019","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/31345230","citation_count":25,"is_preprint":false},{"pmid":"24599290","id":"PMC_24599290","title":"Uptake of betaine into mouse cumulus-oocyte complexes via the SLC7A6 isoform of y+L transporter.","date":"2014","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/24599290","citation_count":23,"is_preprint":false},{"pmid":"34050700","id":"PMC_34050700","title":"Functional analysis of LAT3 in prostate cancer: Its downstream target and relationship with androgen receptor.","date":"2021","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/34050700","citation_count":22,"is_preprint":false},{"pmid":"32794418","id":"PMC_32794418","title":"Circular RNA circ-SLC7A6 acts as a tumor suppressor in non-small cell lung cancer through abundantly sponging miR-21.","date":"2020","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/32794418","citation_count":21,"is_preprint":false},{"pmid":"15756301","id":"PMC_15756301","title":"A y(+)LAT-1 mutant protein interferes with y(+)LAT-2 activity: implications for the molecular pathogenesis of lysinuric protein intolerance.","date":"2005","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/15756301","citation_count":19,"is_preprint":false},{"pmid":"35314791","id":"PMC_35314791","title":"STAT5A modulates CDYL2/SLC7A6 pathway to inhibit the proliferation and invasion of hepatocellular carcinoma by targeting to mTORC1.","date":"2022","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/35314791","citation_count":17,"is_preprint":false},{"pmid":"39403788","id":"PMC_39403788","title":"Analysis of SLC genes alternative splicing identifies the SLC7A6 RI isoform as a therapeutic target for colorectal cancer.","date":"2024","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/39403788","citation_count":8,"is_preprint":false},{"pmid":"33977919","id":"PMC_33977919","title":"Optoproteomics elucidates the interactome of L-type amino acid transporter 3 (LAT3).","date":"2021","source":"Chemical communications (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/33977919","citation_count":5,"is_preprint":false},{"pmid":"24142711","id":"PMC_24142711","title":"Suppression of amino acid transporter LAT3 expression on proliferation of K562 cells.","date":"2013","source":"Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban","url":"https://pubmed.ncbi.nlm.nih.gov/24142711","citation_count":4,"is_preprint":false},{"pmid":"41043754","id":"PMC_41043754","title":"Structural characterization and functional role of SLC7A6 in GSSG transport and Ferroptosis regulation.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/41043754","citation_count":0,"is_preprint":false},{"pmid":"40568133","id":"PMC_40568133","title":"A whole genomic CRISPR-Cas9 screen identifies the amino acid transporter SLC43A1 (LAT3) as a major determinant of oxaliplatin sensitivity in colorectal cancer cells.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40568133","citation_count":0,"is_preprint":false},{"pmid":"42227585","id":"PMC_42227585","title":"A whole genomic CRISPR-Cas9 screen identifies the amino acid transporter SLC43A1 (LAT3) as a major determinant of oxaliplatin sensitivity in colorectal cancer cells.","date":"2026","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/42227585","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.21.649594","title":"A whole genomic CRISPR-Cas9 screen identifies the amino acid transporter  <i>SLC43A1</i>  (LAT3) as a major determinant of oxaliplatin sensitivity in colorectal cancer cells","date":"2025-04-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.21.649594","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12745,"output_tokens":2998,"usd":0.041603,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9877,"output_tokens":3016,"usd":0.062392,"stage2_stop_reason":"end_turn"},"total_usd":0.103995,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the papers, I need to carefully distinguish:\n\n1. **SLC7A6** (y+LAT-2, LAT-2) - the query gene, a heteromeric amino acid transporter light chain\n2. **LAT3/SLC43A1** - a different gene (L-type amino acid transporter 3), which appears in many papers\n3. **LAT-2/LAT-3** as bacterial beta-lactamases (papers [2], [3]) - symbol collision, exclude\n4. **circ-SLC7A6** (paper [12]) - non-protein locus product, exclude\n\nPapers [4], [7], [9], [11], [13 partial], [16], [17], [19], [20], [21] describe LAT3/SLC43A1, NOT SLC7A6. I must exclude those as a different gene.\n\nPapers about SLC7A6: [1], [5], [6], [8], [10], [13], [14], [15], [18]\n\nPaper [13] discusses both y+LAT-1 (SLC7A7) and y+LAT-2 (SLC7A6) - include SLC7A6 findings only.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"SLC7A6 (LAT-2) encodes a light chain subunit that must heterodimerize with 4F2hc (CD98/SLC3A2) to reach the plasma membrane and induce sodium-independent amino acid transport activity with broad specificity for small and large zwitterionic amino acids via an exchanger mechanism; expression of LAT-2 alone in Xenopus oocytes produced no transport activity and the protein remained intracellular, whereas co-expression with 4F2hc directed LAT-2 to the plasma membrane and reconstituted system L transport.\",\n      \"method\": \"Xenopus laevis oocyte expression system with co-expression of tagged N-myc-LAT-2 ± 4F2hc, amino acid uptake assays, trans-stimulation experiments, and subcellular localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — functional reconstitution in oocytes with transport assays and subcellular localization, foundational paper with 342 citations and multiple orthogonal methods\",\n      \"pmids\": [\"10391915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"LAT-2 is the primary transporter responsible for basolateral system L amino acid exchange activity in the renal proximal tubule cell line OK; antisense-mediated reduction of LAT-2 expression decreased apical-to-basolateral transepithelial flux of cystine and elevated intracellular cysteine content, demonstrating a specific role for LAT-2 in net basolateral efflux of cysteine.\",\n      \"method\": \"Stable antisense transfection of LAT-2 in OK cells, amino acid uptake assays, transepithelial flux assays, intracellular amino acid content measurement\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function (antisense knockdown) with specific transepithelial flux phenotype and intracellular metabolite readout, multiple orthogonal assays in single lab\",\n      \"pmids\": [\"12660317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"LAT-2 mediates Na+-independent L-DOPA uptake with broad specificity for small and large neutral amino acids in renal opossum kidney cells; LAT-2 transport is stimulated by acid pH and inhibited by BCH, and LAT-2 was found to be equally distributed at apical and basolateral membranes.\",\n      \"method\": \"Functional transport assays in OKLC and OKHC clonal renal cell lines, pharmacological inhibition with BCH, efflux stimulation assays, pH dependence experiments\",\n      \"journal\": \"The Journal of membrane biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological and functional characterization without genetic knockdown or structural validation; replicated across two clonal cell lines\",\n      \"pmids\": [\"11944084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The CD98/LAT-2 heterodimer is expressed at the basolateral membrane of intestinal epithelia (Caco2-BBE) and forms a supramolecular complex with ICAM-1; CD98 ligation decreases Km and Vmax of LAT-2, while ICAM-1 ligation increases Km and Vmax, with both ligations inducing threonine phosphorylation of the ~160 kDa CD98/LAT-2–ICAM-1 complex.\",\n      \"method\": \"Co-immunoprecipitation, antibody cross-linking of CD98 and ICAM-1, amino acid transport kinetics (Km, Vmax), phosphorylation assays in Caco2-BBE polarized monolayers\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and functional kinetic assays in polarized cells, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"12716892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In Xenopus oocytes and mammalian cells, a dominant-negative SLC7A7 (y+LAT-1) mutant (E36del) interferes with y+LAT-2 (SLC7A6) transport activity, suggesting a multiheteromeric interaction between y+LAT-1 and y+LAT-2 within the same complex and explaining why increased SLC7A6 expression in LPI patient lymphoblasts does not fully compensate for SLC7A7 loss.\",\n      \"method\": \"Expression of SLC7A7 mutants (E36del, F152L) in Xenopus laevis oocytes and mammalian cells, amino acid transport activity assays, functional epistasis analysis\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reconstitution in oocytes with defined mutants establishing dominant-negative interference between y+LAT-1 and y+LAT-2, single lab\",\n      \"pmids\": [\"15756301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SLC7A6 (y+LAT2) is the isoform responsible for betaine uptake in mouse cumulus-oocyte complexes (COCs); SLC7A6 transcript and protein are present in COCs but absent in isolated oocytes or eggs, and betaine accumulated by cumulus cells via SLC7A6 is transferred to the enclosed oocyte through gap junctions.\",\n      \"method\": \"Pharmacological inhibition profiling (methionine, leucine, lysine, arginine, proline), Na+/Cl- dependence assays, RT-PCR and western blot for SLC7A6 in COC fractions, gap junction inhibition experiments, betaine uptake assays\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — identified by expression profiling plus pharmacological transport characterization consistent with y+L system; no genetic knockdown of SLC7A6, but multiple orthogonal approaches converge on SLC7A6\",\n      \"pmids\": [\"24599290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CDYL2 represses SLC7A6 expression by decreasing H3K4me3 enrichment at the SLC7A6 promoter; reduced SLC7A6 expression suppresses amino acid transport and inhibits mTORC1/S6K signaling in hepatocellular carcinoma cells, placing SLC7A6 downstream of a STAT5A→CDYL2→SLC7A6→mTORC1 axis.\",\n      \"method\": \"Gain- and loss-of-function experiments for CDYL2, chromatin immunoprecipitation (ChIP) for H3K4me3 at SLC7A6 promoter, western blotting for mTORC1/S6K pathway components, in vitro and in vivo tumor assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishes epigenetic mechanism of SLC7A6 regulation with functional pathway readout; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35314791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Knockdown of the intronic retention (RI) isoform of SLC7A6 (SLC7A6-RI) enhances colon cancer cell proliferation in vitro and tumor growth in vivo by activating the PI3K-Akt-mTOR signaling pathway, as evidenced by increased p-mTOR and PCNA levels.\",\n      \"method\": \"siRNA knockdown of SLC7A6-RI isoform, in vivo xenograft experiments, western blotting for p-mTOR and PCNA, bioinformatics analysis of TCGA COAD data\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular pathway readout in vitro and in vivo, single lab\",\n      \"pmids\": [\"39403788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AlphaFold3 structural modeling predicted an interaction between SLC7A6 and oxidized glutathione (GSSG); biochemical assays following SLC7A6 knockdown showed altered intracellular levels of GSSG, GSH, and nitric oxide, suggesting SLC7A6 participates in redox homeostasis and ferroptosis regulation through GSSG transport.\",\n      \"method\": \"AlphaFold3 structural prediction, SLC7A6 knockdown, biochemical assays for GSSG/GSH/NO, CCK-8 and Transwell functional assays\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — structural prediction only (AlphaFold3, no experimental structure validation), indirect biochemical readout without direct transport reconstitution\",\n      \"pmids\": [\"41043754\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC7A6 (y+LAT-2) is a light-chain subunit of a heteromeric amino acid transporter that obligatorily associates with the heavy chain 4F2hc (CD98/SLC3A2) to traffic to the plasma membrane, where it mediates sodium-independent, exchanger-mode transport of a broad range of zwitterionic amino acids (system L/y+L activity); at the basolateral membrane of renal proximal tubule and intestinal epithelial cells it drives net efflux of cysteine and dibasic amino acids, its transport kinetics are acutely regulated by ICAM-1 interactions via a supramolecular complex, and its expression is transcriptionally controlled by a STAT5A→CDYL2→H3K4me3 epigenetic axis that feeds into mTORC1/S6K signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC7A6 (y+LAT-2/LAT-2) is the light-chain subunit of a heteromeric amino acid transporter that must obligatorily heterodimerize with the heavy chain 4F2hc (CD98/SLC3A2) to traffic to the plasma membrane and reconstitute sodium-independent, exchanger-mode transport of small and large zwitterionic amino acids (system L/y+L activity); expressed alone it remains intracellular and transport-inactive [#0]. In polarized epithelia it operates at the basolateral membrane: in renal proximal tubule cells it drives net efflux of cysteine, with loss of function reducing transepithelial cystine flux and raising intracellular cysteine [#1], and in renal opossum kidney cells it mediates broad Na+-independent uptake of neutral amino acids including L-DOPA, stimulated by acid pH and inhibited by BCH [#2]. Within the CD98/LAT-2 complex at the intestinal basolateral membrane, SLC7A6 transport kinetics are acutely tuned by a supramolecular assembly with ICAM-1, where CD98 versus ICAM-1 ligation reciprocally shift Km and Vmax and induce threonine phosphorylation of the complex [#3]. SLC7A6 transporter function feeds amino-acid-dependent mTORC1/S6K signaling, and its expression is restrained by a STAT5A\\u2192CDYL2 axis that lowers H3K4me3 at the SLC7A6 promoter [#6]. Tissue-specific roles include betaine uptake by cumulus cells for delivery to the oocyte via gap junctions [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that SLC7A6 is not an autonomous transporter but a light chain requiring 4F2hc to reach the surface and confer system L exchange activity, defining its molecular architecture.\",\n      \"evidence\": \"Xenopus oocyte co-expression of tagged LAT-2 \\u00b1 4F2hc with uptake, trans-stimulation, and localization assays\",\n      \"pmids\": [\"10391915\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the heterodimer\", \"Stoichiometry and substrate translocation mechanism not resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Characterized the substrate range and regulatory properties of SLC7A6 transport, showing broad neutral amino acid (including L-DOPA) handling with pH and BCH sensitivity.\",\n      \"evidence\": \"Functional transport assays in OKLC/OKHC renal clonal lines with pharmacological inhibition and efflux/pH dependence\",\n      \"pmids\": [\"11944084\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No genetic loss-of-function\", \"Apical vs basolateral distribution differed from later epithelial findings\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined the physiological epithelial role of SLC7A6 as the basolateral system L exchanger driving net cysteine efflux in renal proximal tubule.\",\n      \"evidence\": \"Antisense knockdown in OK cells with transepithelial cystine flux and intracellular metabolite measurement\",\n      \"pmids\": [\"12660317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effect shown in one cell line, not in vivo kidney\", \"Contribution relative to other system L carriers not quantified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Revealed that SLC7A6 transport kinetics are acutely regulated through a supramolecular CD98/LAT-2\\u2013ICAM-1 complex rather than being constitutive.\",\n      \"evidence\": \"Reciprocal co-IP, antibody cross-linking, kinetic and phosphorylation assays in polarized Caco2-BBE monolayers\",\n      \"pmids\": [\"12716892\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling kinase mediating threonine phosphorylation not identified\", \"Physiological trigger for ICAM-1 ligation in vivo unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed SLC7A6 functionally interacts with SLC7A7 (y+LAT-1) in a multiheteromeric arrangement, explaining incomplete compensation in lysinuric protein intolerance.\",\n      \"evidence\": \"Dominant-negative SLC7A7 mutant expression in oocytes and mammalian cells with transport epistasis analysis\",\n      \"pmids\": [\"15756301\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical evidence for a shared complex limited\", \"Composition of the multiheteromer not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified a tissue-specific transport role for SLC7A6 in cumulus cell betaine uptake delivered to the oocyte, extending its substrate physiology beyond renal epithelia.\",\n      \"evidence\": \"Expression profiling, pharmacological transport characterization, and gap-junction inhibition in mouse cumulus-oocyte complexes\",\n      \"pmids\": [\"24599290\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No genetic knockdown of SLC7A6 in this context\", \"Identity established by inference from y+L profile\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed SLC7A6 downstream of an epigenetic regulatory axis and upstream of amino-acid-driven growth signaling, linking its expression to mTORC1/S6K output.\",\n      \"evidence\": \"CDYL2 gain/loss-of-function, ChIP for H3K4me3 at the SLC7A6 promoter, and mTORC1/S6K readouts in hepatocellular carcinoma models\",\n      \"pmids\": [\"35314791\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration that transporter activity (not protein level) drives mTORC1 not isolated\", \"Single tumor type\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Distinguished an intron-retention isoform of SLC7A6 with a tumor-suppressive effect on colon cancer growth via PI3K-Akt-mTOR signaling.\",\n      \"evidence\": \"siRNA knockdown of SLC7A6-RI, xenografts, p-mTOR/PCNA western blots, and TCGA COAD analysis\",\n      \"pmids\": [\"39403788\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking the RI isoform to mTOR not resolved\", \"Relationship between RI isoform and canonical transporter function unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed a redox-related substrate (oxidized glutathione) for SLC7A6 linking it to ferroptosis regulation.\",\n      \"evidence\": \"AlphaFold3 prediction of SLC7A6\\u2013GSSG interaction with biochemical GSSG/GSH/NO assays after knockdown\",\n      \"pmids\": [\"41043754\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Structural prediction only, no experimental structure\", \"No direct transport reconstitution of GSSG\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SLC7A6 transport activity is mechanistically coupled to mTORC1 signaling and whether GSSG is a genuine transported substrate remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No experimental structure of the SLC7A6/4F2hc heterodimer\", \"Direct substrate-flux link to mTORC1 not established\", \"GSSG transport not demonstrated in a reconstituted system\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [\"CD98/4F2hc-LAT-2 heteromeric amino acid transporter\", \"CD98/LAT-2\\u2013ICAM-1 supramolecular complex\"],\n    \"partners\": [\"SLC3A2\", \"ICAM1\", \"SLC7A7\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}