{"gene":"SLC36A1","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2012,"finding":"SLC36A1 (PAT1) is primarily located on late endosomes and lysosomes (LELs), physically interacts with Rag GTPases, and is required for normal amino acid-dependent mTOR relocalization to LELs and mTORC1 activation.","method":"Co-immunoprecipitation, subcellular fractionation, siRNA knockdown with mTOR localization imaging, Drosophila in vivo genetics","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus functional KD with defined phenotype, replicated in both mammalian cells and Drosophila","pmids":["22574197"],"is_preprint":false},{"year":2004,"finding":"SLC36A1 (hPAT1) functions as a proton-coupled (H+/amino acid symporter) imino acid transporter localized exclusively to the luminal brush-border membrane of human and rat small intestine; in intact epithelia it cooperates functionally with NHE3 (SLC9A3) to explain the apparent Na+-dependence of the classical imino acid carrier.","method":"Xenopus oocyte expression with electrophysiology and radiotracer flux; Caco-2 monolayers; rat small intestine; immunohistochemistry","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro transport reconstitution in oocytes plus intact epithelial functional assays plus immunolocalization, replicated across multiple systems","pmids":["15521011"],"is_preprint":false},{"year":2008,"finding":"SLC36A1 (PAT1) mediates H+-coupled, Na+- and Cl−-independent, low-affinity, high-capacity taurine and β-alanine transport across the human intestinal brush-border membrane, and at dietary taurine concentrations is the predominant absorptive mechanism, complementing high-affinity TauT (SLC6A6).","method":"Xenopus oocyte expression; Caco-2 monolayer uptake assays; RT-PCR of human duodenal/ileal biopsies","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 1-2 — oocyte reconstitution plus native Caco-2 functional assays with ion-substitution controls","pmids":["19074966"],"is_preprint":false},{"year":2003,"finding":"Murine PAT1 (SLC36A1) is an electrogenic proton/amino acid cotransporter; structural requirements for substrates include an aliphatic side chain of maximally one CH2 unit and amino-to-carboxyl separation of at most two CH2 units; the transporter shows no or reversed stereoselectivity for certain substrates.","method":"Two-electrode voltage clamp and radiotracer flux in Xenopus oocytes; kinetic analysis with substrate analogues","journal":"Molecular membrane biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with systematic substrate structure-activity analysis","pmids":["12893527"],"is_preprint":false},{"year":2005,"finding":"Serotonin, L-tryptophan, and tryptamine bind to PAT1 with Ki values of 0.9–6.1 mM, competitively inhibit H+-dependent proline transport, but are not themselves transported electrogenically, identifying them as naturally occurring non-transported inhibitors of SLC36A1.","method":"Two-electrode voltage clamp in hPAT1-expressing Xenopus oocytes; membrane potential assay; Caco-2 uptake inhibition","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 — electrophysiological reconstitution with dose-response inhibition curves, multiple orthogonal assays","pmids":["16126914"],"is_preprint":false},{"year":2005,"finding":"PAT1 (SLC36A1) operates as a bidirectional transporter: proton binding precedes substrate binding and both are translocated simultaneously; the transporter shows no pre-steady-state currents in the absence of substrate and allows bidirectional amino acid transport driven by substrate concentration, pH gradient, and membrane potential.","method":"Two-electrode voltage clamp (steady-state and pre-steady-state currents); giant patch clamp; efflux studies in Xenopus oocytes","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — detailed kinetic and biophysical analysis of transport mechanism in vitro","pmids":["15504109"],"is_preprint":false},{"year":2008,"finding":"A missense mutation T63R in exon 2 of SLC36A1 is responsible for champagne coat color dilution in horses, demonstrating a functional consequence of SLC36A1 loss-of-function in a mammalian organism.","method":"Genome-wide mapping (microsatellite markers), candidate gene sequencing, SNP association in 182 horses","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 — genetic mapping with complete association, but no direct functional assay of the mutant protein","pmids":["18802473"],"is_preprint":false},{"year":2008,"finding":"His-55 is essential for catalytic activity of human PAT1 (SLC36A1): H55A, H55N, and H55E mutants abolish L-proline transport without affecting protein expression or plasma membrane targeting, implicating His-55 in proton binding and translocation.","method":"Site-directed mutagenesis; radiotracer uptake in HRPE cells; cell surface biotinylation and immunoblot; confocal microscopy","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1 — active-site mutagenesis with functional assay and expression controls","pmids":["18230330"],"is_preprint":false},{"year":2009,"finding":"N-glycosylation at Asn-174, Asn-183, and Asn-470 of human PAT1 (SLC36A1) is required for normal plasma membrane targeting; combined glycosylation-deficient mutants show reduced transport rate without altering substrate affinity (Kt), while single substitutions have no effect.","method":"Site-directed mutagenesis; two-electrode voltage clamp in Xenopus oocytes; immunofluorescence localization","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis combined with functional electrophysiology and localization","pmids":["19409386"],"is_preprint":false},{"year":2009,"finding":"hPAT1 (SLC36A1) mediates intestinal absorption of gaboxadol; oral co-administration of L-tryptophan (a PAT1 inhibitor) significantly decreases absorption rate constant and Cmax of gaboxadol in beagle dogs, demonstrating in vivo relevance of PAT1 transport for drug pharmacokinetics.","method":"Caco-2 transport assays; in vivo pharmacokinetics in beagle dogs with PAT1 inhibitor co-administration","journal":"British journal of pharmacology","confidence":"High","confidence_rationale":"Tier 2 — in vitro transporter assay confirmed by in vivo pharmacokinetic interaction experiment","pmids":["19594759"],"is_preprint":false},{"year":2010,"finding":"ALA (δ-aminolevulinic acid) is a substrate of SLC36A1 (hPAT1) with Km ~6.8 mM; uptake is pH-dependent, Na+-independent, saturable, and inhibited by glycine, proline, and GABA; in Caco-2 cells, apical ALA absorption is mediated exclusively by SLC36A1 and SLC15A1.","method":"Radiotracer uptake in COS-7 cells expressing SLC36A1; membrane potential assay; Caco-2 inhibition studies","journal":"British journal of pharmacology","confidence":"High","confidence_rationale":"Tier 1-2 — heterologous expression with saturation kinetics plus native cell assays","pmids":["20128809"],"is_preprint":false},{"year":2010,"finding":"SLC36A1 (hPAT1) transports the dipeptide Gly-Sar and Gly-Gly (but not larger dipeptides such as Gly-Ala, Gly-Pro, or Gly-Phe), with Gly-Sar structurally defining the size limit for dipeptide transport via SLC36A1.","method":"Two-electrode voltage clamp in hPAT1-expressing Xenopus oocytes; Caco-2 inhibition assays","journal":"British journal of pharmacology","confidence":"High","confidence_rationale":"Tier 1 — electrophysiological reconstitution with systematic structural analysis","pmids":["20880398"],"is_preprint":false},{"year":2005,"finding":"hPAT1 (SLC36A1) function in intact intestinal epithelia (Caco-2) is indirectly regulated by the cAMP/PKA pathway: VIP, PACAP, and forskolin inhibit PAT1-mediated amino acid uptake by inhibiting NHE3 activity (not PAT1 directly), thereby reducing the driving H+ gradient for PAT1.","method":"Beta-alanine uptake assays in Caco-2 monolayers; pharmacological dissection with PKA activators, NHE3 inhibitors; intracellular pH recovery measurements","journal":"Journal of cellular physiology","confidence":"High","confidence_rationale":"Tier 2 — multiple pharmacological dissection approaches in intact epithelium showing mechanism is via NHE3, not direct PAT1 regulation","pmids":["15754324"],"is_preprint":false},{"year":2019,"finding":"SLC36A1 overexpression reactivates mTORC1 signaling and drives acquired resistance to CDK4/6 inhibitors in melanoma; two mechanisms elevate SLC36A1: Rb loss (via de-repression of E2F) and FMR1 overexpression (promoting SLC36A1 translation).","method":"Cell-based overexpression/knockdown; immunoblotting for mTORC1 substrates; in vivo mouse tumor model with CDK4/6 + mTORC1 inhibitor combination","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway dissection with KD/OE plus in vivo validation","pmids":["31555743"],"is_preprint":false},{"year":2021,"finding":"SLC36A1 interacts with SLC38A9 on the lysosomal surface; leucine increases expression of both transporters and promotes mTORC1 activation; SLC38A9 and SLC36A1 enhance each other's expression and lysosomal localization.","method":"Co-immunoprecipitation; immunofluorescence co-localization; siRNA knockdown with mTORC1 activity readout; MS interactome of SLC38A9 in C2C12 cells","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP with supporting localization data, single lab","pmids":["34572527"],"is_preprint":false},{"year":2017,"finding":"N-glycosylation of human PAT1 (SLC36A1) affects protein stability and subcellular distribution: glycosylation-deficient PAT1 (PAT13NQ) is degraded via the ERAD pathway, preferentially localizes to the plasma membrane rather than lysosomes, and fails to inhibit mTORC1, demonstrating that lysosomal localization is required for PAT1-mediated mTORC1 regulation.","method":"Glycosylation mutant (3NQ) expression in HEK293 cells; proteasome/ERAD inhibition; immunofluorescence; mTORC1 activity assay (S6K phosphorylation)","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 — mutagenesis with multiple orthogonal readouts linking localization to mTORC1 function","pmids":["28117901"],"is_preprint":false},{"year":2013,"finding":"SLC36A1 (PAT1) shows nuclear localization in rat smooth muscle cells (A7r5 and primary aortic/colon SMCs) directed by a 3'-UTR element of the PAT1 transcript; knockdown of PAT1 in A7r5 cells increases cell growth rate, indicating PAT1 negatively regulates SMC proliferation.","method":"Immunofluorescence; cellular fractionation; 3'-UTR reporter constructs; siRNA knockdown with growth rate measurement","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2-3 — localization by two methods plus functional KD, but single lab and unusual localization for a transporter","pmids":["24222668"],"is_preprint":false},{"year":2024,"finding":"TFE3 transcriptionally activates SLC36A1 in response to glucose starvation; glucose starvation stabilizes TFE3 via O-GlcNAcylation, leading to increased SLC36A1 expression, enhanced lysosomal amino acid transport, mTOR activation, and resistance to glucose starvation in kidney cancer cells.","method":"Functional genomic screen; ChIP/reporter assays; O-GlcNAcylation analysis; SLC36A1 KD with mTOR activity and viability readouts; GLUT1 inhibitor sensitivity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — unbiased genomic screen followed by mechanistic validation with multiple orthogonal methods","pmids":["38599381"],"is_preprint":false},{"year":2003,"finding":"LYAAT-1 (SLC36A1) localizes to lysosomal membranes in rat CNS neurons, as demonstrated by co-localization with cathepsin D by confocal and electron microscopy, consistent with a role in amino acid efflux from lysosomes.","method":"In situ hybridization; immunohistochemistry; confocal and electron microscopy with lysosomal marker co-localization","journal":"The Journal of comparative neurology","confidence":"High","confidence_rationale":"Tier 2 — immunoEM provides direct subcellular localization evidence","pmids":["12761825"],"is_preprint":false},{"year":2003,"finding":"PAT2 (SLC36A2), the paralog of PAT1/SLC36A1, localizes not to lysosomes (unlike PAT1) but to the ER and recycling endosomes in neurons; PAT2 transport is voltage-dependent and bidirectional, with membrane depolarization causing net glycine outward currents.","method":"Immunodetection in spinal cord/brain; electrophysiology in Xenopus oocytes; immunofluorescence co-localization with organelle markers","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — orthogonal localization and functional data for paralog, providing context for SLC36A1 lysosomal specificity","pmids":["14600155"],"is_preprint":false},{"year":2004,"finding":"ARA67/PAT1 (the kinesin light chain-related protein that interacts with APP) functions as a repressor of androgen receptor (AR) transactivation by disrupting AR cytoplasmic-to-nuclear shuttling; interaction requires multiple domains within ARA67/PAT1.","method":"Yeast two-hybrid screening; co-immunoprecipitation; AR transactivation reporter assay; cytoplasmic-nuclear shuttling assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, Co-IP plus functional assay; the identity of this PAT1 (kinesin-related, chromosome 17q23) as SLC36A1 is uncertain — this appears to be a distinct gene","pmids":["14729952"],"is_preprint":false},{"year":2006,"finding":"PAT-1 (Slc26a6, SLC36A1 in the SLC26 nomenclature used by this paper) is the predominant apical Cl−/HCO3− and SO42−/HCO3− exchanger in the upper villus epithelium of murine duodenum; its absence reduces basal Cl−/HCO3− exchange by 65–80% and eliminates SO42−/HCO3− exchange.","method":"Knockout mouse model; intracellular pH fluorometry (BCECF); anion exchange rate measurements","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with quantitative functional readout; NOTE: This paper uses 'PAT-1' for Slc26a6, which is a different gene from SLC36A1; excluding as symbol collision","pmids":["17170027"],"is_preprint":false}],"current_model":"SLC36A1 (PAT1/LYAAT-1) is an electrogenic, proton-coupled amino acid symporter that resides primarily on lysosomal membranes (and the intestinal brush border), where it transports small neutral amino acids, imino acids, GABA, taurine, and drugs (gaboxadol, vigabatrin, ALA) using the inward H+ electrochemical gradient; His-55 is essential for proton-dependent catalysis, N-glycosylation at Asn-174/183/470 is required for lysosomal targeting, and on the lysosomal surface PAT1 physically associates with Rag GTPases and SLC38A9 to function as part of the amino acid-sensing machinery that drives mTORC1 activation, a pathway exploited in cancer drug resistance downstream of TFE3 transcriptional induction."},"narrative":{"teleology":[{"year":2003,"claim":"Establishing that SLC36A1 is an electrogenic proton/amino acid cotransporter with strict substrate size constraints resolved the molecular identity of the long-sought mammalian proton-coupled amino acid carrier.","evidence":"Two-electrode voltage clamp and radiotracer flux in Xenopus oocytes expressing murine PAT1 with systematic substrate analogue analysis","pmids":["12893527"],"confidence":"High","gaps":["No human ortholog transport data yet","No information on in vivo tissue localization or physiological role"]},{"year":2003,"claim":"Immunoelectron microscopy placed SLC36A1 on lysosomal membranes in CNS neurons, establishing that its primary subcellular residence is the lysosome rather than the plasma membrane.","evidence":"Confocal and immunoEM co-localization with cathepsin D in rat brain neurons","pmids":["12761825"],"confidence":"High","gaps":["Role of lysosomal SLC36A1 in amino acid efflux versus signaling not yet distinguished","No data on non-neuronal tissues"]},{"year":2004,"claim":"Demonstrating that human PAT1 functions as the brush-border proton-coupled imino acid transporter in intestinal epithelia — cooperating with NHE3 to generate apparent Na+ dependence — defined its physiological transport role in nutrient absorption.","evidence":"Xenopus oocyte electrophysiology, Caco-2 monolayer transport, and immunohistochemistry of human/rat small intestine","pmids":["15521011"],"confidence":"High","gaps":["Relative contribution of lysosomal versus apical plasma membrane pools in enterocytes unclear","In vivo knockout phenotype in intestine not yet reported"]},{"year":2005,"claim":"Biophysical dissection of the transport cycle established that proton binding precedes substrate binding and that PAT1 operates bidirectionally, resolving the ordered kinetic mechanism.","evidence":"Steady-state and pre-steady-state voltage clamp plus giant patch clamp in Xenopus oocytes","pmids":["15504109"],"confidence":"High","gaps":["No structural model to explain ordered binding","Stoichiometry of H+:substrate coupling not definitively resolved"]},{"year":2005,"claim":"Identification of serotonin and tryptophan as naturally occurring non-transported inhibitors of PAT1 revealed an endogenous regulatory mechanism and pharmacological tool for the transporter.","evidence":"Voltage clamp dose-response inhibition curves in oocytes; Caco-2 uptake inhibition","pmids":["16126914"],"confidence":"High","gaps":["Physiological significance of tryptophan/serotonin inhibition in vivo not tested","Binding site not structurally defined"]},{"year":2005,"claim":"Demonstrating that cAMP/PKA inhibits PAT1-mediated transport indirectly — by suppressing NHE3 and thus the H+ gradient — clarified that hormonal regulation targets the driving force rather than PAT1 itself.","evidence":"Pharmacological dissection with VIP, PACAP, forskolin, and NHE3 inhibitors in Caco-2 monolayers","pmids":["15754324"],"confidence":"High","gaps":["Whether PAT1 is also subject to direct post-translational regulation not excluded","Relevance in non-intestinal tissues unknown"]},{"year":2008,"claim":"Mutagenesis of His-55 identified a single residue essential for proton-dependent catalysis, pinpointing the proton-sensing element in the transport cycle without affecting protein trafficking.","evidence":"H55A/H55N/H55E site-directed mutagenesis with radiotracer uptake and cell surface biotinylation in HRPE cells","pmids":["18230330"],"confidence":"High","gaps":["Whether His-55 directly coordinates the proton or acts allosterically is unresolved","No structure to place His-55 in a binding pocket"]},{"year":2008,"claim":"Expanding the substrate profile to include taurine and β-alanine at physiological intestinal concentrations established PAT1 as the predominant intestinal taurine absorptive pathway.","evidence":"Oocyte reconstitution and Caco-2 monolayer uptake with ion substitution; RT-PCR of human intestinal biopsies","pmids":["19074966"],"confidence":"High","gaps":["In vivo taurine absorption in SLC36A1-null animals not tested"]},{"year":2009,"claim":"Showing that N-glycosylation at three asparagines is collectively required for proper membrane targeting linked post-translational modification to transporter surface expression and function.","evidence":"Triple glycosylation-site mutagenesis with voltage clamp in oocytes and immunofluorescence","pmids":["19409386"],"confidence":"High","gaps":["Whether glycosylation affects lysosomal versus plasma membrane sorting not yet distinguished"]},{"year":2009,"claim":"In vivo pharmacokinetic evidence that tryptophan co-administration reduces gaboxadol absorption in dogs demonstrated that PAT1 is rate-limiting for oral drug absorption, establishing its pharmacological relevance.","evidence":"Caco-2 transport assays plus in vivo dog pharmacokinetics with PAT1 inhibitor co-dosing","pmids":["19594759"],"confidence":"High","gaps":["Whether PAT1 contributes to absorption of other CNS drugs in humans not established"]},{"year":2012,"claim":"Discovery that SLC36A1 physically interacts with Rag GTPases on lysosomes and is required for amino acid-dependent mTOR relocalization and mTORC1 activation repositioned PAT1 from a simple transporter to a nutrient-sensing signaling component.","evidence":"Co-immunoprecipitation with Rag GTPases; siRNA knockdown with mTOR localization imaging; Drosophila path mutant in vivo","pmids":["22574197"],"confidence":"High","gaps":["Whether PAT1 transports amino acids to activate Rags or acts as a scaffold/receptor is unresolved","Identity of the amino acid signal sensed by PAT1 at the lysosome unknown"]},{"year":2017,"claim":"Glycosylation-deficient PAT1 mislocalizes to the plasma membrane and fails to regulate mTORC1, directly linking lysosomal residency to the signaling function and demonstrating that surface-expressed PAT1 is insufficient for mTOR activation.","evidence":"PAT1-3NQ glycosylation mutant expressed in HEK293 cells with ERAD pathway analysis, immunofluorescence, and S6K phosphorylation readout","pmids":["28117901"],"confidence":"High","gaps":["Whether glycosylation-dependent sorting involves a specific lysosomal targeting signal or is passive quality control","ERAD-mediated degradation pathway for misfolded PAT1 not fully characterized"]},{"year":2019,"claim":"SLC36A1 overexpression was shown to drive acquired resistance to CDK4/6 inhibitors in melanoma via mTORC1 reactivation, with Rb loss (E2F de-repression) and FMR1-enhanced translation as upstream mechanisms, establishing a direct cancer drug resistance pathway.","evidence":"Overexpression/knockdown in melanoma cells; immunoblot for mTORC1 substrates; in vivo mouse xenograft with CDK4/6i + mTORC1i combination","pmids":["31555743"],"confidence":"High","gaps":["Generalizability to other cancer types not established","Whether PAT1 transport activity or scaffold function drives resistance unclear"]},{"year":2021,"claim":"Identification of SLC38A9 as a direct interaction partner of SLC36A1 on lysosomes, with leucine increasing expression of both transporters, expanded the lysosomal amino acid sensing complex.","evidence":"Co-immunoprecipitation; immunofluorescence co-localization; siRNA knockdown with mTORC1 readout in C2C12 cells","pmids":["34572527"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal validation from an independent lab","Stoichiometry and direct versus indirect interaction not resolved","Whether interaction is amino acid-regulated dynamically unknown"]},{"year":2024,"claim":"TFE3 was identified as a direct transcriptional activator of SLC36A1 during glucose starvation, revealing how metabolic stress upregulates lysosomal amino acid transport to sustain mTORC1 and confer starvation resistance in kidney cancer.","evidence":"Functional genomic screen; ChIP and reporter assays for TFE3 binding to SLC36A1 promoter; O-GlcNAcylation-mediated TFE3 stabilization; SLC36A1 KD with mTOR and viability readouts","pmids":["38599381"],"confidence":"High","gaps":["Whether TFE3-SLC36A1 axis operates in non-renal cancers not tested","Contribution of other TFEB/TFE3 family members to SLC36A1 regulation unknown"]},{"year":null,"claim":"A central unresolved question is whether SLC36A1 activates mTORC1 through its amino acid transport activity (transceptor model) or through a transport-independent scaffolding/receptor function on the lysosomal surface.","evidence":"","pmids":[],"confidence":"High","gaps":["No transport-dead mutant tested for mTORC1 signaling capacity","No structural model of SLC36A1","No reconstitution of the PAT1-Rag-mTORC1 signaling axis with purified components"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[1,2,3,5,10,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,13,17]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,15,18]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,8]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,13,14,15,17]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[1,2,3,5,9,10,11]},{"term_id":"R-HSA-8963743","term_label":"Digestion and absorption","supporting_discovery_ids":[1,2,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[13,17]}],"complexes":[],"partners":["RRAGA","RRAGB","RRAGC","RRAGD","SLC38A9","SLC9A3"],"other_free_text":[]},"mechanistic_narrative":"SLC36A1 (PAT1/LYAAT-1) is an electrogenic proton-coupled symporter that transports small neutral amino acids, imino acids, taurine, β-alanine, GABA, and select drugs (gaboxadol, δ-aminolevulinic acid) across membranes, with proton binding preceding substrate binding and both being translocated simultaneously in a bidirectional, voltage- and pH-dependent manner [PMID:12893527, PMID:15504109, PMID:15521011, PMID:19074966]. His-55 is essential for proton-dependent catalytic activity, and N-glycosylation at Asn-174, Asn-183, and Asn-470 is required for proper lysosomal targeting, protein stability, and escape from ERAD-mediated degradation [PMID:18230330, PMID:19409386, PMID:28117901]. On the lysosomal membrane, SLC36A1 physically associates with Rag GTPases and SLC38A9 and is required for amino acid-dependent mTORC1 recruitment and activation; glycosylation-deficient mutants that mislocalize to the plasma membrane fail to regulate mTORC1 [PMID:22574197, PMID:34572527, PMID:28117901]. SLC36A1 overexpression drives mTORC1-dependent resistance to CDK4/6 inhibitors in melanoma (via Rb loss/E2F de-repression or FMR1-promoted translation) and mediates glucose starvation resistance in kidney cancer downstream of TFE3 transcriptional activation [PMID:31555743, PMID:38599381]."},"prefetch_data":{"uniprot":{"accession":"Q7Z2H8","full_name":"Proton-coupled amino acid transporter 1","aliases":["Solute carrier family 36 member 1"],"length_aa":476,"mass_kda":53.1,"function":"Electrogenic proton/amino acid symporter with selectivity for small apolar L-amino acids, their D-enantiomers and selected amino acid derivatives such as 4-aminobutanoate/GABA (PubMed:12527723, PubMed:12809675, PubMed:19549785). May be involved in the efflux from the lysosomal compartment of neutral amino acids resulting from proteolysis (By similarity). May play a role in specifying sites for exocytosis in neurons (By similarity)","subcellular_location":"Cell membrane; Apical cell membrane; Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/Q7Z2H8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC36A1","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLC36A1","total_profiled":1310},"omim":[{"mim_id":"613760","title":"SOLUTE CARRIER FAMILY 36, MEMBER 4; SLC36A4","url":"https://www.omim.org/entry/613760"},{"mim_id":"608332","title":"SOLUTE CARRIER FAMILY 36 (PROTON/AMINO ACID SYMPORTER), MEMBER 3; SLC36A3","url":"https://www.omim.org/entry/608332"},{"mim_id":"608331","title":"SOLUTE CARRIER FAMILY 36 (PROTON/AMINO ACID SYMPORTER), MEMBER 2; SLC36A2","url":"https://www.omim.org/entry/608331"},{"mim_id":"606561","title":"SOLUTE CARRIER FAMILY 36 (PROTON/AMINO ACID SYMPORTER), MEMBER 1; SLC36A1","url":"https://www.omim.org/entry/606561"},{"mim_id":"601231","title":"MECHANISTIC TARGET OF RAPAMYCIN; MTOR","url":"https://www.omim.org/entry/601231"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"parathyroid gland","ntpm":97.0}],"url":"https://www.proteinatlas.org/search/SLC36A1"},"hgnc":{"alias_symbol":["LYAAT-1","PAT1","TRAMD3"],"prev_symbol":[]},"alphafold":{"accession":"Q7Z2H8","domains":[{"cath_id":"1.20.1740.10","chopping":"50-460","consensus_level":"medium","plddt":92.1501,"start":50,"end":460}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z2H8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z2H8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z2H8-F1-predicted_aligned_error_v6.png","plddt_mean":84.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC36A1","jax_strain_url":"https://www.jax.org/strain/search?query=SLC36A1"},"sequence":{"accession":"Q7Z2H8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z2H8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z2H8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z2H8"}},"corpus_meta":[{"pmid":"8670886","id":"PMC_8670886","title":"The ABC 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one","url":"https://pubmed.ncbi.nlm.nih.gov/24830408","citation_count":11,"is_preprint":false},{"pmid":"22234618","id":"PMC_22234618","title":"Rectal absorption of vigabatrin, a substrate of the proton coupled amino acid transporter (PAT1, Slc36a1), in rats.","date":"2012","source":"Pharmaceutical research","url":"https://pubmed.ncbi.nlm.nih.gov/22234618","citation_count":10,"is_preprint":false},{"pmid":"33124072","id":"PMC_33124072","title":"The Arabidopsis thaliana mRNA decay factor PAT1 functions in osmotic stress responses and decaps ABA-responsive genes.","date":"2020","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/33124072","citation_count":10,"is_preprint":false},{"pmid":"34572527","id":"PMC_34572527","title":"Insights into the Interaction of Lysosomal Amino Acid Transporters SLC38A9 and SLC36A1 Involved in mTORC1 Signaling in C2C12 Cells.","date":"2021","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/34572527","citation_count":9,"is_preprint":false},{"pmid":"23536653","id":"PMC_23536653","title":"The cellular decapping activators LSm1, Pat1, and Dhh1 control the ratio of subgenomic to genomic Flock House virus RNAs.","date":"2013","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/23536653","citation_count":9,"is_preprint":false},{"pmid":"24297442","id":"PMC_24297442","title":"The 3' overhangs at Tetrahymena thermophila telomeres are packaged by four proteins, Pot1a, Tpt1, Pat1, and Pat2.","date":"2013","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/24297442","citation_count":9,"is_preprint":false},{"pmid":"19570594","id":"PMC_19570594","title":"PAT1 induces cell death signal and SET mislocalization into the cytoplasm by increasing APP/APLP2 at the cell surface.","date":"2009","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/19570594","citation_count":9,"is_preprint":false},{"pmid":"24177891","id":"PMC_24177891","title":"Construction of a YAC library from a Beta vulgaris fragment addition and isolation of a major satellite DNA cluster linked to the beet cyst nematode resistance locus Hs1 (pat-1.).","date":"1994","source":"TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik","url":"https://pubmed.ncbi.nlm.nih.gov/24177891","citation_count":9,"is_preprint":false},{"pmid":"25657010","id":"PMC_25657010","title":"Roles of mRNA fate modulators Dhh1 and Pat1 in TNRC6-dependent gene silencing recapitulated in yeast.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25657010","citation_count":8,"is_preprint":false},{"pmid":"36680639","id":"PMC_36680639","title":"Analysis of PAT1 subfamily members in the GRAS family of upland cotton and functional characterization of GhSCL13-2A in Verticillium dahliae resistance.","date":"2023","source":"Plant cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36680639","citation_count":8,"is_preprint":false},{"pmid":"25880931","id":"PMC_25880931","title":"PAT1 inversely regulates the surface Amyloid Precursor Protein level in mouse primary neurons.","date":"2015","source":"BMC neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25880931","citation_count":7,"is_preprint":false},{"pmid":"38599381","id":"PMC_38599381","title":"TFE3-SLC36A1 axis promotes resistance to glucose starvation in kidney cancer cells.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38599381","citation_count":7,"is_preprint":false},{"pmid":"28117901","id":"PMC_28117901","title":"Glycosylation affects the stability and subcellular distribution of human PAT1 protein.","date":"2017","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/28117901","citation_count":6,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49061,"output_tokens":5185,"usd":0.112479},"stage2":{"model":"claude-opus-4-6","input_tokens":8755,"output_tokens":3588,"usd":0.200212},"total_usd":0.312691,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"SLC36A1 (PAT1) is primarily located on late endosomes and lysosomes (LELs), physically interacts with Rag GTPases, and is required for normal amino acid-dependent mTOR relocalization to LELs and mTORC1 activation.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, siRNA knockdown with mTOR localization imaging, Drosophila in vivo genetics\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional KD with defined phenotype, replicated in both mammalian cells and Drosophila\",\n      \"pmids\": [\"22574197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SLC36A1 (hPAT1) functions as a proton-coupled (H+/amino acid symporter) imino acid transporter localized exclusively to the luminal brush-border membrane of human and rat small intestine; in intact epithelia it cooperates functionally with NHE3 (SLC9A3) to explain the apparent Na+-dependence of the classical imino acid carrier.\",\n      \"method\": \"Xenopus oocyte expression with electrophysiology and radiotracer flux; Caco-2 monolayers; rat small intestine; immunohistochemistry\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro transport reconstitution in oocytes plus intact epithelial functional assays plus immunolocalization, replicated across multiple systems\",\n      \"pmids\": [\"15521011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SLC36A1 (PAT1) mediates H+-coupled, Na+- and Cl−-independent, low-affinity, high-capacity taurine and β-alanine transport across the human intestinal brush-border membrane, and at dietary taurine concentrations is the predominant absorptive mechanism, complementing high-affinity TauT (SLC6A6).\",\n      \"method\": \"Xenopus oocyte expression; Caco-2 monolayer uptake assays; RT-PCR of human duodenal/ileal biopsies\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — oocyte reconstitution plus native Caco-2 functional assays with ion-substitution controls\",\n      \"pmids\": [\"19074966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Murine PAT1 (SLC36A1) is an electrogenic proton/amino acid cotransporter; structural requirements for substrates include an aliphatic side chain of maximally one CH2 unit and amino-to-carboxyl separation of at most two CH2 units; the transporter shows no or reversed stereoselectivity for certain substrates.\",\n      \"method\": \"Two-electrode voltage clamp and radiotracer flux in Xenopus oocytes; kinetic analysis with substrate analogues\",\n      \"journal\": \"Molecular membrane biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with systematic substrate structure-activity analysis\",\n      \"pmids\": [\"12893527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Serotonin, L-tryptophan, and tryptamine bind to PAT1 with Ki values of 0.9–6.1 mM, competitively inhibit H+-dependent proline transport, but are not themselves transported electrogenically, identifying them as naturally occurring non-transported inhibitors of SLC36A1.\",\n      \"method\": \"Two-electrode voltage clamp in hPAT1-expressing Xenopus oocytes; membrane potential assay; Caco-2 uptake inhibition\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — electrophysiological reconstitution with dose-response inhibition curves, multiple orthogonal assays\",\n      \"pmids\": [\"16126914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PAT1 (SLC36A1) operates as a bidirectional transporter: proton binding precedes substrate binding and both are translocated simultaneously; the transporter shows no pre-steady-state currents in the absence of substrate and allows bidirectional amino acid transport driven by substrate concentration, pH gradient, and membrane potential.\",\n      \"method\": \"Two-electrode voltage clamp (steady-state and pre-steady-state currents); giant patch clamp; efflux studies in Xenopus oocytes\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — detailed kinetic and biophysical analysis of transport mechanism in vitro\",\n      \"pmids\": [\"15504109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A missense mutation T63R in exon 2 of SLC36A1 is responsible for champagne coat color dilution in horses, demonstrating a functional consequence of SLC36A1 loss-of-function in a mammalian organism.\",\n      \"method\": \"Genome-wide mapping (microsatellite markers), candidate gene sequencing, SNP association in 182 horses\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic mapping with complete association, but no direct functional assay of the mutant protein\",\n      \"pmids\": [\"18802473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"His-55 is essential for catalytic activity of human PAT1 (SLC36A1): H55A, H55N, and H55E mutants abolish L-proline transport without affecting protein expression or plasma membrane targeting, implicating His-55 in proton binding and translocation.\",\n      \"method\": \"Site-directed mutagenesis; radiotracer uptake in HRPE cells; cell surface biotinylation and immunoblot; confocal microscopy\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — active-site mutagenesis with functional assay and expression controls\",\n      \"pmids\": [\"18230330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"N-glycosylation at Asn-174, Asn-183, and Asn-470 of human PAT1 (SLC36A1) is required for normal plasma membrane targeting; combined glycosylation-deficient mutants show reduced transport rate without altering substrate affinity (Kt), while single substitutions have no effect.\",\n      \"method\": \"Site-directed mutagenesis; two-electrode voltage clamp in Xenopus oocytes; immunofluorescence localization\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis combined with functional electrophysiology and localization\",\n      \"pmids\": [\"19409386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"hPAT1 (SLC36A1) mediates intestinal absorption of gaboxadol; oral co-administration of L-tryptophan (a PAT1 inhibitor) significantly decreases absorption rate constant and Cmax of gaboxadol in beagle dogs, demonstrating in vivo relevance of PAT1 transport for drug pharmacokinetics.\",\n      \"method\": \"Caco-2 transport assays; in vivo pharmacokinetics in beagle dogs with PAT1 inhibitor co-administration\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro transporter assay confirmed by in vivo pharmacokinetic interaction experiment\",\n      \"pmids\": [\"19594759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ALA (δ-aminolevulinic acid) is a substrate of SLC36A1 (hPAT1) with Km ~6.8 mM; uptake is pH-dependent, Na+-independent, saturable, and inhibited by glycine, proline, and GABA; in Caco-2 cells, apical ALA absorption is mediated exclusively by SLC36A1 and SLC15A1.\",\n      \"method\": \"Radiotracer uptake in COS-7 cells expressing SLC36A1; membrane potential assay; Caco-2 inhibition studies\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — heterologous expression with saturation kinetics plus native cell assays\",\n      \"pmids\": [\"20128809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SLC36A1 (hPAT1) transports the dipeptide Gly-Sar and Gly-Gly (but not larger dipeptides such as Gly-Ala, Gly-Pro, or Gly-Phe), with Gly-Sar structurally defining the size limit for dipeptide transport via SLC36A1.\",\n      \"method\": \"Two-electrode voltage clamp in hPAT1-expressing Xenopus oocytes; Caco-2 inhibition assays\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — electrophysiological reconstitution with systematic structural analysis\",\n      \"pmids\": [\"20880398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"hPAT1 (SLC36A1) function in intact intestinal epithelia (Caco-2) is indirectly regulated by the cAMP/PKA pathway: VIP, PACAP, and forskolin inhibit PAT1-mediated amino acid uptake by inhibiting NHE3 activity (not PAT1 directly), thereby reducing the driving H+ gradient for PAT1.\",\n      \"method\": \"Beta-alanine uptake assays in Caco-2 monolayers; pharmacological dissection with PKA activators, NHE3 inhibitors; intracellular pH recovery measurements\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple pharmacological dissection approaches in intact epithelium showing mechanism is via NHE3, not direct PAT1 regulation\",\n      \"pmids\": [\"15754324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SLC36A1 overexpression reactivates mTORC1 signaling and drives acquired resistance to CDK4/6 inhibitors in melanoma; two mechanisms elevate SLC36A1: Rb loss (via de-repression of E2F) and FMR1 overexpression (promoting SLC36A1 translation).\",\n      \"method\": \"Cell-based overexpression/knockdown; immunoblotting for mTORC1 substrates; in vivo mouse tumor model with CDK4/6 + mTORC1 inhibitor combination\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway dissection with KD/OE plus in vivo validation\",\n      \"pmids\": [\"31555743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SLC36A1 interacts with SLC38A9 on the lysosomal surface; leucine increases expression of both transporters and promotes mTORC1 activation; SLC38A9 and SLC36A1 enhance each other's expression and lysosomal localization.\",\n      \"method\": \"Co-immunoprecipitation; immunofluorescence co-localization; siRNA knockdown with mTORC1 activity readout; MS interactome of SLC38A9 in C2C12 cells\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with supporting localization data, single lab\",\n      \"pmids\": [\"34572527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"N-glycosylation of human PAT1 (SLC36A1) affects protein stability and subcellular distribution: glycosylation-deficient PAT1 (PAT13NQ) is degraded via the ERAD pathway, preferentially localizes to the plasma membrane rather than lysosomes, and fails to inhibit mTORC1, demonstrating that lysosomal localization is required for PAT1-mediated mTORC1 regulation.\",\n      \"method\": \"Glycosylation mutant (3NQ) expression in HEK293 cells; proteasome/ERAD inhibition; immunofluorescence; mTORC1 activity assay (S6K phosphorylation)\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis with multiple orthogonal readouts linking localization to mTORC1 function\",\n      \"pmids\": [\"28117901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SLC36A1 (PAT1) shows nuclear localization in rat smooth muscle cells (A7r5 and primary aortic/colon SMCs) directed by a 3'-UTR element of the PAT1 transcript; knockdown of PAT1 in A7r5 cells increases cell growth rate, indicating PAT1 negatively regulates SMC proliferation.\",\n      \"method\": \"Immunofluorescence; cellular fractionation; 3'-UTR reporter constructs; siRNA knockdown with growth rate measurement\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — localization by two methods plus functional KD, but single lab and unusual localization for a transporter\",\n      \"pmids\": [\"24222668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TFE3 transcriptionally activates SLC36A1 in response to glucose starvation; glucose starvation stabilizes TFE3 via O-GlcNAcylation, leading to increased SLC36A1 expression, enhanced lysosomal amino acid transport, mTOR activation, and resistance to glucose starvation in kidney cancer cells.\",\n      \"method\": \"Functional genomic screen; ChIP/reporter assays; O-GlcNAcylation analysis; SLC36A1 KD with mTOR activity and viability readouts; GLUT1 inhibitor sensitivity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — unbiased genomic screen followed by mechanistic validation with multiple orthogonal methods\",\n      \"pmids\": [\"38599381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"LYAAT-1 (SLC36A1) localizes to lysosomal membranes in rat CNS neurons, as demonstrated by co-localization with cathepsin D by confocal and electron microscopy, consistent with a role in amino acid efflux from lysosomes.\",\n      \"method\": \"In situ hybridization; immunohistochemistry; confocal and electron microscopy with lysosomal marker co-localization\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — immunoEM provides direct subcellular localization evidence\",\n      \"pmids\": [\"12761825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PAT2 (SLC36A2), the paralog of PAT1/SLC36A1, localizes not to lysosomes (unlike PAT1) but to the ER and recycling endosomes in neurons; PAT2 transport is voltage-dependent and bidirectional, with membrane depolarization causing net glycine outward currents.\",\n      \"method\": \"Immunodetection in spinal cord/brain; electrophysiology in Xenopus oocytes; immunofluorescence co-localization with organelle markers\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — orthogonal localization and functional data for paralog, providing context for SLC36A1 lysosomal specificity\",\n      \"pmids\": [\"14600155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ARA67/PAT1 (the kinesin light chain-related protein that interacts with APP) functions as a repressor of androgen receptor (AR) transactivation by disrupting AR cytoplasmic-to-nuclear shuttling; interaction requires multiple domains within ARA67/PAT1.\",\n      \"method\": \"Yeast two-hybrid screening; co-immunoprecipitation; AR transactivation reporter assay; cytoplasmic-nuclear shuttling assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, Co-IP plus functional assay; the identity of this PAT1 (kinesin-related, chromosome 17q23) as SLC36A1 is uncertain — this appears to be a distinct gene\",\n      \"pmids\": [\"14729952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PAT-1 (Slc26a6, SLC36A1 in the SLC26 nomenclature used by this paper) is the predominant apical Cl−/HCO3− and SO42−/HCO3− exchanger in the upper villus epithelium of murine duodenum; its absence reduces basal Cl−/HCO3− exchange by 65–80% and eliminates SO42−/HCO3− exchange.\",\n      \"method\": \"Knockout mouse model; intracellular pH fluorometry (BCECF); anion exchange rate measurements\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with quantitative functional readout; NOTE: This paper uses 'PAT-1' for Slc26a6, which is a different gene from SLC36A1; excluding as symbol collision\",\n      \"pmids\": [\"17170027\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC36A1 (PAT1/LYAAT-1) is an electrogenic, proton-coupled amino acid symporter that resides primarily on lysosomal membranes (and the intestinal brush border), where it transports small neutral amino acids, imino acids, GABA, taurine, and drugs (gaboxadol, vigabatrin, ALA) using the inward H+ electrochemical gradient; His-55 is essential for proton-dependent catalysis, N-glycosylation at Asn-174/183/470 is required for lysosomal targeting, and on the lysosomal surface PAT1 physically associates with Rag GTPases and SLC38A9 to function as part of the amino acid-sensing machinery that drives mTORC1 activation, a pathway exploited in cancer drug resistance downstream of TFE3 transcriptional induction.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SLC36A1 (PAT1/LYAAT-1) is an electrogenic proton-coupled symporter that transports small neutral amino acids, imino acids, taurine, β-alanine, GABA, and select drugs (gaboxadol, δ-aminolevulinic acid) across membranes, with proton binding preceding substrate binding and both being translocated simultaneously in a bidirectional, voltage- and pH-dependent manner [PMID:12893527, PMID:15504109, PMID:15521011, PMID:19074966]. His-55 is essential for proton-dependent catalytic activity, and N-glycosylation at Asn-174, Asn-183, and Asn-470 is required for proper lysosomal targeting, protein stability, and escape from ERAD-mediated degradation [PMID:18230330, PMID:19409386, PMID:28117901]. On the lysosomal membrane, SLC36A1 physically associates with Rag GTPases and SLC38A9 and is required for amino acid-dependent mTORC1 recruitment and activation; glycosylation-deficient mutants that mislocalize to the plasma membrane fail to regulate mTORC1 [PMID:22574197, PMID:34572527, PMID:28117901]. SLC36A1 overexpression drives mTORC1-dependent resistance to CDK4/6 inhibitors in melanoma (via Rb loss/E2F de-repression or FMR1-promoted translation) and mediates glucose starvation resistance in kidney cancer downstream of TFE3 transcriptional activation [PMID:31555743, PMID:38599381].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing that SLC36A1 is an electrogenic proton/amino acid cotransporter with strict substrate size constraints resolved the molecular identity of the long-sought mammalian proton-coupled amino acid carrier.\",\n      \"evidence\": \"Two-electrode voltage clamp and radiotracer flux in Xenopus oocytes expressing murine PAT1 with systematic substrate analogue analysis\",\n      \"pmids\": [\"12893527\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No human ortholog transport data yet\", \"No information on in vivo tissue localization or physiological role\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Immunoelectron microscopy placed SLC36A1 on lysosomal membranes in CNS neurons, establishing that its primary subcellular residence is the lysosome rather than the plasma membrane.\",\n      \"evidence\": \"Confocal and immunoEM co-localization with cathepsin D in rat brain neurons\",\n      \"pmids\": [\"12761825\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of lysosomal SLC36A1 in amino acid efflux versus signaling not yet distinguished\", \"No data on non-neuronal tissues\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that human PAT1 functions as the brush-border proton-coupled imino acid transporter in intestinal epithelia — cooperating with NHE3 to generate apparent Na+ dependence — defined its physiological transport role in nutrient absorption.\",\n      \"evidence\": \"Xenopus oocyte electrophysiology, Caco-2 monolayer transport, and immunohistochemistry of human/rat small intestine\",\n      \"pmids\": [\"15521011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of lysosomal versus apical plasma membrane pools in enterocytes unclear\", \"In vivo knockout phenotype in intestine not yet reported\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Biophysical dissection of the transport cycle established that proton binding precedes substrate binding and that PAT1 operates bidirectionally, resolving the ordered kinetic mechanism.\",\n      \"evidence\": \"Steady-state and pre-steady-state voltage clamp plus giant patch clamp in Xenopus oocytes\",\n      \"pmids\": [\"15504109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model to explain ordered binding\", \"Stoichiometry of H+:substrate coupling not definitively resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of serotonin and tryptophan as naturally occurring non-transported inhibitors of PAT1 revealed an endogenous regulatory mechanism and pharmacological tool for the transporter.\",\n      \"evidence\": \"Voltage clamp dose-response inhibition curves in oocytes; Caco-2 uptake inhibition\",\n      \"pmids\": [\"16126914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological significance of tryptophan/serotonin inhibition in vivo not tested\", \"Binding site not structurally defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrating that cAMP/PKA inhibits PAT1-mediated transport indirectly — by suppressing NHE3 and thus the H+ gradient — clarified that hormonal regulation targets the driving force rather than PAT1 itself.\",\n      \"evidence\": \"Pharmacological dissection with VIP, PACAP, forskolin, and NHE3 inhibitors in Caco-2 monolayers\",\n      \"pmids\": [\"15754324\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PAT1 is also subject to direct post-translational regulation not excluded\", \"Relevance in non-intestinal tissues unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mutagenesis of His-55 identified a single residue essential for proton-dependent catalysis, pinpointing the proton-sensing element in the transport cycle without affecting protein trafficking.\",\n      \"evidence\": \"H55A/H55N/H55E site-directed mutagenesis with radiotracer uptake and cell surface biotinylation in HRPE cells\",\n      \"pmids\": [\"18230330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether His-55 directly coordinates the proton or acts allosterically is unresolved\", \"No structure to place His-55 in a binding pocket\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Expanding the substrate profile to include taurine and β-alanine at physiological intestinal concentrations established PAT1 as the predominant intestinal taurine absorptive pathway.\",\n      \"evidence\": \"Oocyte reconstitution and Caco-2 monolayer uptake with ion substitution; RT-PCR of human intestinal biopsies\",\n      \"pmids\": [\"19074966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo taurine absorption in SLC36A1-null animals not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showing that N-glycosylation at three asparagines is collectively required for proper membrane targeting linked post-translational modification to transporter surface expression and function.\",\n      \"evidence\": \"Triple glycosylation-site mutagenesis with voltage clamp in oocytes and immunofluorescence\",\n      \"pmids\": [\"19409386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether glycosylation affects lysosomal versus plasma membrane sorting not yet distinguished\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"In vivo pharmacokinetic evidence that tryptophan co-administration reduces gaboxadol absorption in dogs demonstrated that PAT1 is rate-limiting for oral drug absorption, establishing its pharmacological relevance.\",\n      \"evidence\": \"Caco-2 transport assays plus in vivo dog pharmacokinetics with PAT1 inhibitor co-dosing\",\n      \"pmids\": [\"19594759\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PAT1 contributes to absorption of other CNS drugs in humans not established\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that SLC36A1 physically interacts with Rag GTPases on lysosomes and is required for amino acid-dependent mTOR relocalization and mTORC1 activation repositioned PAT1 from a simple transporter to a nutrient-sensing signaling component.\",\n      \"evidence\": \"Co-immunoprecipitation with Rag GTPases; siRNA knockdown with mTOR localization imaging; Drosophila path mutant in vivo\",\n      \"pmids\": [\"22574197\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PAT1 transports amino acids to activate Rags or acts as a scaffold/receptor is unresolved\", \"Identity of the amino acid signal sensed by PAT1 at the lysosome unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Glycosylation-deficient PAT1 mislocalizes to the plasma membrane and fails to regulate mTORC1, directly linking lysosomal residency to the signaling function and demonstrating that surface-expressed PAT1 is insufficient for mTOR activation.\",\n      \"evidence\": \"PAT1-3NQ glycosylation mutant expressed in HEK293 cells with ERAD pathway analysis, immunofluorescence, and S6K phosphorylation readout\",\n      \"pmids\": [\"28117901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether glycosylation-dependent sorting involves a specific lysosomal targeting signal or is passive quality control\", \"ERAD-mediated degradation pathway for misfolded PAT1 not fully characterized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"SLC36A1 overexpression was shown to drive acquired resistance to CDK4/6 inhibitors in melanoma via mTORC1 reactivation, with Rb loss (E2F de-repression) and FMR1-enhanced translation as upstream mechanisms, establishing a direct cancer drug resistance pathway.\",\n      \"evidence\": \"Overexpression/knockdown in melanoma cells; immunoblot for mTORC1 substrates; in vivo mouse xenograft with CDK4/6i + mTORC1i combination\",\n      \"pmids\": [\"31555743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generalizability to other cancer types not established\", \"Whether PAT1 transport activity or scaffold function drives resistance unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of SLC38A9 as a direct interaction partner of SLC36A1 on lysosomes, with leucine increasing expression of both transporters, expanded the lysosomal amino acid sensing complex.\",\n      \"evidence\": \"Co-immunoprecipitation; immunofluorescence co-localization; siRNA knockdown with mTORC1 readout in C2C12 cells\",\n      \"pmids\": [\"34572527\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation from an independent lab\", \"Stoichiometry and direct versus indirect interaction not resolved\", \"Whether interaction is amino acid-regulated dynamically unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"TFE3 was identified as a direct transcriptional activator of SLC36A1 during glucose starvation, revealing how metabolic stress upregulates lysosomal amino acid transport to sustain mTORC1 and confer starvation resistance in kidney cancer.\",\n      \"evidence\": \"Functional genomic screen; ChIP and reporter assays for TFE3 binding to SLC36A1 promoter; O-GlcNAcylation-mediated TFE3 stabilization; SLC36A1 KD with mTOR and viability readouts\",\n      \"pmids\": [\"38599381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TFE3-SLC36A1 axis operates in non-renal cancers not tested\", \"Contribution of other TFEB/TFE3 family members to SLC36A1 regulation unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A central unresolved question is whether SLC36A1 activates mTORC1 through its amino acid transport activity (transceptor model) or through a transport-independent scaffolding/receptor function on the lysosomal surface.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No transport-dead mutant tested for mTORC1 signaling capacity\", \"No structural model of SLC36A1\", \"No reconstitution of the PAT1-Rag-mTORC1 signaling axis with purified components\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [1, 2, 3, 5, 10, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 13, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 15, 18]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 13, 14, 15, 17]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [1, 2, 3, 5, 9, 10, 11]},\n      {\"term_id\": \"R-HSA-8963743\", \"supporting_discovery_ids\": [1, 2, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [13, 17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"RRAGA\",\n      \"RRAGB\",\n      \"RRAGC\",\n      \"RRAGD\",\n      \"SLC38A9\",\n      \"SLC9A3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}