{"gene":"RPSA","run_date":"2026-04-28T20:42:06","timeline":{"discoveries":[{"year":1986,"finding":"The laminin receptor (later identified as RPSA/37LRP) was purified and its mRNA (~1700 bases) cloned from human endothelial cells; levels of laminin receptor mRNA correlated with surface receptor number across carcinoma cell lines, suggesting mRNA abundance is a rate-limiting step in biosynthesis of the cell-surface laminin-binding protein.","method":"Affinity purification on laminin, lambda gt11 cDNA library screening with anti-receptor monoclonal antibody, cDNA sequencing, Northern blot","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — original cloning with protein sequencing validation and expression correlation, foundational paper >280 citations","pmids":["2429301"],"is_preprint":false},{"year":1996,"finding":"The active 37LRP/p40 (RPSA) gene was identified in chicken (the only vertebrate with a single copy); it comprises 7 exons and 6 introns, lacks a TATA box, has multiple transcription start sites, and bears features of ribosomal protein genes. Domain analysis indicated the C-terminal domain is a conserved structure involved in generating the 67-kDa laminin receptor form, while the central core mediates ribosome association.","method":"Genomic cloning, RNase protection assay, primer extension, sequence analysis, protein evolutionary comparison","journal":"DNA and cell biology","confidence":"High","confidence_rationale":"Tier 1 — original gene structure determination with multiple orthogonal methods","pmids":["8985115"],"is_preprint":false},{"year":1996,"finding":"The laminin-binding protein precursor p40 (LBP-p40/RPSA) localizes not only in the cytoplasm but also in the nucleus, where it is tightly associated with nuclear envelope and chromatin DNA in interphase nuclei and with the perichromosomal region during mitosis.","method":"Monoclonal antibody immunofluorescence, subcellular fractionation, immunoelectron microscopy","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization by immunofluorescence and fractionation, single lab","pmids":["8954992"],"is_preprint":false},{"year":1998,"finding":"Nuclear LBP-p40 (RPSA) binds double-stranded DNA and associates with histone proteins H2A, H2B, and H4 (but not H3), as demonstrated by DNA-cellulose binding and GST-histone pull-down assays; interaction with these histones confers tighter chromatin binding.","method":"DNA-cellulose affinity chromatography, LBP-p40 affinity column, GST-histone fusion pull-down assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — direct biochemical binding assays with defined partners, single lab","pmids":["9878528"],"is_preprint":false},{"year":1998,"finding":"Loss of LBP-p40 (RPSA) expression by antisense or ribozyme-mediated knockdown in HeLa cells causes apoptotic cell death under serum-depleted conditions, demonstrating that RPSA is required for cell survival.","method":"Antisense cDNA expression, ribozyme delivery via fusigenic viral liposome, Western/Northern blot, colony formation assay, DNA fragmentation assay","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined apoptotic phenotype, multiple methods, single lab","pmids":["10200442"],"is_preprint":false},{"year":2006,"finding":"The 37/67-kDa laminin receptor (RPSA/LamR) serves as a cell-surface receptor for adeno-associated virus serotypes 8, 2, 3, and 9; LamR binds AAV8 capsid proteins in vitro and contributes to AAV8 transduction of cultured cells and mouse liver in vivo, with binding mapped to two protein subdomains on the AAV capsid exterior.","method":"In vitro capsid protein binding assays, siRNA knockdown, in vivo mouse liver transduction, sequence/deletion mapping","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 — reconstituted binding, in vitro + in vivo validation, replicated across 4 serotypes","pmids":["16973587"],"is_preprint":false},{"year":2007,"finding":"MGr1-Ag/37LRP (RPSA) promotes HIF-1α expression and transcriptional activity under non-hypoxic conditions in gastric cancer cells treated with vincristine; forced expression of RPSA upregulates HIF-1α, while siRNA knockdown reduces it; FAK-PI3K and ERK1/2 (p42/44 MAPK) signaling are the major pathways downstream of RPSA leading to HIF-1α induction.","method":"Overexpression, siRNA knockdown, Western blot, HIF-1 reporter assays, pharmacological inhibitors (PI3K, MAPK)","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — loss- and gain-of-function with pathway inhibitors, single lab","pmids":["17476462"],"is_preprint":false},{"year":2010,"finding":"Hypoxia-induced RPSA (MGr1-Ag/37LRP) expression is driven by ERK/MAPK activation via reactive oxygen species (H2O2); MEK activates HIF-1, which in turn drives RPSA promoter activity; RPSA then mediates enhanced gastric cancer cell adhesion to laminin and resistance to vincristine-induced apoptosis; MEK inhibitor U0126 and RPSA siRNA reverse these effects.","method":"MEK overexpression, dominant-negative kinases, MEK inhibitor U0126, ROS scavengers, siRNA, adhesion assays, apoptosis assays","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods establishing ERK→HIF-1→RPSA axis, single lab","pmids":["19998339"],"is_preprint":false},{"year":2012,"finding":"RPSA is identified as a component of the mRNA-bound proteome in human cells; it cross-links to mRNA upon UV irradiation and co-purifies with polyadenylated transcripts, establishing RPSA as an RNA-binding protein beyond its ribosomal role.","method":"Photoreactive nucleotide-enhanced UV crosslinking and oligo(dT) purification, quantitative mass spectrometry","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 — systematic biochemical approach with UV crosslinking validation","pmids":["22681889"],"is_preprint":false},{"year":2013,"finding":"Heterozygous loss-of-function mutations in RPSA cause isolated congenital asplenia (ICA) in humans by haploinsufficiency; seven different mutations (nonsense, frameshift, missense) were identified in 18 patients from 8 kindreds, establishing an essential and non-redundant role for RPSA in human spleen organogenesis.","method":"Whole-exome sequencing, Sanger sequencing, expression studies in patient cells, segregation analysis","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 — human genetics with functional expression validation, multiple independent kindreds, replicated in follow-up study","pmids":["23579497"],"is_preprint":false},{"year":2013,"finding":"RPSA (LRP/LR) co-localizes and physically interacts with Aβ42 at the cell surface; antibody blockade of RPSA or shRNA-mediated knockdown significantly rescues cell viability and proliferation in Aβ42-treated cells, indicating RPSA mediates Aβ42 cytotoxicity.","method":"Immunofluorescence co-localization, pull-down assays, MTT viability assay, BrdU proliferation assay, Annexin-V apoptosis assay, shRNA knockdown","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 — pull-down plus functional rescue, single lab","pmids":["24048171"],"is_preprint":false},{"year":2013,"finding":"Structures of human and Drosophila 80S ribosomes determined by cryo-EM reveal RPSA as a component of the 40S small ribosomal subunit, and illuminate metazoan-specific ribosomal features including an inner protein layer and flexible RNA outer layer.","method":"High-resolution cryo-electron microscopy, atomic model building","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structural determination of RPSA within the ribosome complex","pmids":["23636399"],"is_preprint":false},{"year":2015,"finding":"Near-atomic structure of the human 80S ribosome at 3.6 Å resolution (reaching 2.9 Å in stable regions) by cryo-EM reveals RPSA's position in the 40S subunit, details of subunit interfaces, tRNA binding sites, and ribosome rotational dynamics.","method":"Single-particle cryo-electron microscopy at near-atomic resolution, atomic model building","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — high-resolution structure with atomic model","pmids":["25901680"],"is_preprint":false},{"year":2015,"finding":"siRNA-mediated knockdown of RPSA (LRP/LR) significantly reduces viability of breast (MCF-7, MDA-MB 231) and oesophageal (WHCO1) cancer cells by inducing apoptosis, as shown by phosphatidylserine externalization (Annexin-V) and nuclear morphological changes; results confirmed with two independent siRNA sequences targeting different RPSA mRNA regions.","method":"siRNA knockdown (siRNA-LAMR1 and esiRNA-RPSA), MTT assay, Annexin-V/FITC assay, Hoechst staining, Western blot","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — two independent siRNAs excluding off-target effects, multiple cell lines, single lab","pmids":["26427016"],"is_preprint":false},{"year":2015,"finding":"RPSA protein was identified as binding aflatoxin B1 (AFB1) by immobilized affinity chromatography from mouse liver total protein; the RPSA–AFB1 interaction was validated by ELISA in vitro and laser confocal immunofluorescence in vivo, suggesting RPSA is an AFB1-binding protein in hepatocytes.","method":"Immobilized affinity chromatography (BSA-AFB1 on PVDF), LC-MS/MS identification, ELISA, laser confocal immunofluorescence","journal":"Journal of hazardous materials","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple orthogonal binding assays, single lab, novel finding","pmids":["26372695"],"is_preprint":false},{"year":2018,"finding":"Additional RPSA mutations causing isolated congenital asplenia include mutations in the 5'-UTR that disrupt mRNA splicing, as well as 11 new protein-coding mutations; overall 41% of ICA kindreds carry RPSA mutations; some mutations show incomplete penetrance, and 7 de novo mutations were identified, confirming autosomal dominant inheritance.","method":"Whole-exome and Sanger sequencing, mRNA splicing analysis, segregation analysis, de novo mutation confirmation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — large multi-kindred genetic study with functional splicing validation, replication of 2013 findings","pmids":["30072435"],"is_preprint":false},{"year":2020,"finding":"RPSA and TRPM7 (transient receptor potential melastatin-related 7 channel) co-localize at the plasma membrane of human pancreatic cancer cells and form a functional complex; elastin-derived peptides (EDPs) stimulate TRPM7 currents and promote cell migration via this TRPM7/RPSA complex, as TRPM7 siRNA abrogates EDP-induced migration.","method":"Boyden chamber migration assay, siRNA knockdown of TRPM7, patch-clamp electrophysiology, co-localization by immunofluorescence","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2–3 — co-localization plus functional siRNA and electrophysiology, single lab","pmids":["32733880"],"is_preprint":false}],"current_model":"RPSA (ribosomal protein SA / 37LRP/p40) is a dual-function protein that acts as a structural component of the 40S ribosomal small subunit and as a multifunctional cell-surface receptor: it mediates cell adhesion to laminin and basement membranes, serves as an entry receptor for AAV serotypes 2/3/8/9, binds Aβ42 to mediate cytotoxicity, forms a signaling complex with TRPM7 to drive cancer cell migration, activates HIF-1α via FAK-PI3K/ERK signaling, associates with histones H2A/H2B/H4 in the nucleus, and is haploinsufficient for human spleen development—with heterozygous loss-of-function mutations causing isolated congenital asplenia through an essential role in splenic organogenesis."},"narrative":{"teleology":[{"year":1986,"claim":"Identification of the laminin receptor mRNA and protein established RPSA as a cell-surface laminin-binding molecule whose expression correlates with receptor surface density, answering the question of whether laminin receptor biosynthesis is transcriptionally regulated.","evidence":"Affinity purification on laminin and lambda gt11 cDNA library screening from human endothelial cells, Northern blot across carcinoma lines","pmids":["2429301"],"confidence":"High","gaps":["Mechanism of conversion from the 37-kDa precursor to the 67-kDa cell-surface form was unknown","No structural information on the laminin-binding domain","Ribosomal role of the protein not yet recognized"]},{"year":1996,"claim":"Gene structure analysis and subcellular localization studies revealed RPSA to be a ribosomal-protein-class gene whose product localizes not only to the cytoplasm and cell surface but also to the nucleus and perichromosomal region, challenging a purely receptor-centric model.","evidence":"Genomic cloning with RNase protection/primer extension (chicken), immunofluorescence and immunoelectron microscopy in mammalian cells","pmids":["8985115","8954992"],"confidence":"High","gaps":["Nuclear binding partners and functional significance of chromatin association were unresolved","Mechanism by which a single polypeptide partitions among ribosome, membrane, and nucleus was unknown"]},{"year":1998,"claim":"Biochemical assays demonstrated that nuclear RPSA directly binds DNA and interacts with histones H2A, H2B, and H4, providing the first molecular partners for its chromatin-associated function, while loss-of-function experiments showed RPSA is required for cell survival.","evidence":"DNA-cellulose chromatography and GST-histone pull-down assays; antisense/ribozyme knockdown in HeLa cells with apoptosis readout","pmids":["9878528","10200442"],"confidence":"Medium","gaps":["Functional consequence of histone binding (e.g., chromatin remodeling, gene regulation) was not determined","Whether the survival requirement reflects the ribosomal versus the receptor role was unclear","No in vivo validation of nuclear interactions"]},{"year":2006,"claim":"Identification of RPSA as a cell-surface receptor for AAV serotypes 2, 3, 8, and 9 expanded its receptor repertoire beyond laminin to include viral entry, validated both in vitro and in vivo in mouse liver.","evidence":"In vitro capsid protein binding, siRNA knockdown of RPSA, in vivo mouse liver transduction with AAV8","pmids":["16973587"],"confidence":"High","gaps":["Co-receptor requirements and post-binding endocytic mechanism were not defined","Relative contribution of RPSA versus other AAV receptors (e.g., HSPG) was not quantified in vivo"]},{"year":2007,"claim":"RPSA was placed upstream of HIF-1α induction via FAK–PI3K and ERK signaling in gastric cancer cells, establishing a signaling axis through which a laminin receptor activates hypoxia-responsive transcription under normoxic conditions.","evidence":"Overexpression and siRNA knockdown of RPSA with HIF-1 reporter assays and pharmacological pathway inhibitors in gastric cancer cells","pmids":["17476462","19998339"],"confidence":"Medium","gaps":["Direct physical link between RPSA and FAK was not shown","Whether this signaling operates in non-cancer contexts was untested","Upstream ligand triggering RPSA signaling in vivo was not identified"]},{"year":2012,"claim":"UV-crosslinking proteomics identified RPSA as part of the mRNA-bound proteome, establishing it as an RNA-binding protein with potential extra-ribosomal roles in mRNA metabolism.","evidence":"Photoreactive nucleotide-enhanced UV crosslinking with oligo(dT) purification and quantitative mass spectrometry in human cells","pmids":["22681889"],"confidence":"Medium","gaps":["Specific mRNA targets and functional consequences of mRNA binding outside the ribosome were not determined","Whether RNA binding reflects a ribosome-associated or free-protein activity was unclear"]},{"year":2013,"claim":"Three landmark advances converged: cryo-EM structures placed RPSA within the 40S subunit of the human 80S ribosome; human genetic studies showed heterozygous RPSA loss-of-function mutations cause isolated congenital asplenia via haploinsufficiency; and RPSA was identified as a cell-surface mediator of Aβ42 cytotoxicity.","evidence":"Cryo-EM of human 80S ribosome; whole-exome sequencing of 18 ICA patients across 8 kindreds; pull-down and shRNA rescue of Aβ42 toxicity","pmids":["23636399","23579497","24048171"],"confidence":"High","gaps":["Whether asplenia reflects ribosomal or extra-ribosomal RPSA function was unresolved","Structural basis of laminin or Aβ42 binding at the cell surface was not determined","Developmental window and cell type requiring RPSA for splenic organogenesis were not identified"]},{"year":2015,"claim":"Near-atomic resolution cryo-EM refined RPSA's structural role within the 40S subunit, while functional studies confirmed that RPSA knockdown induces apoptosis across multiple cancer types, reinforcing its pro-survival role.","evidence":"3.6 Å cryo-EM of human 80S ribosome; siRNA knockdown with two independent sequences in breast and oesophageal cancer lines","pmids":["25901680","26427016"],"confidence":"High","gaps":["Whether the apoptotic effect of RPSA depletion is mediated through translational impairment, loss of laminin signaling, or both was not dissected","No animal model recapitulating cancer-cell RPSA dependency"]},{"year":2018,"claim":"Expanded genetic analysis of ICA kindreds identified additional RPSA mutations including 5'-UTR splicing variants and de novo events, confirming autosomal dominant inheritance with incomplete penetrance and broadening the mutational spectrum.","evidence":"Whole-exome and Sanger sequencing with mRNA splicing analysis across 41% of ICA kindreds","pmids":["30072435"],"confidence":"High","gaps":["Modifier genes or environmental factors explaining incomplete penetrance were not identified","No animal model of RPSA heterozygous knockout recapitulating asplenia"]},{"year":2020,"claim":"RPSA was shown to form a functional signaling complex with the TRPM7 ion channel at the plasma membrane, mediating elastin-derived peptide-stimulated cancer cell migration, revealing a new receptor-channel partnership.","evidence":"Co-localization by immunofluorescence, patch-clamp electrophysiology, siRNA knockdown of TRPM7, Boyden chamber migration assay in pancreatic cancer cells","pmids":["32733880"],"confidence":"Medium","gaps":["Direct physical interaction between RPSA and TRPM7 was inferred from co-localization but not demonstrated by co-immunoprecipitation","Stoichiometry and structural basis of the complex were not characterized","Relevance of the TRPM7–RPSA axis beyond pancreatic cancer was not tested"]},{"year":null,"claim":"The mechanism by which RPSA haploinsufficiency specifically impairs spleen organogenesis — whether through ribosomal dysfunction (ribosomal haploinsufficiency), loss of laminin receptor signaling, or a combined effect — remains an open and central question.","evidence":"","pmids":[],"confidence":"High","gaps":["No conditional knockout animal model distinguishing ribosomal from extra-ribosomal functions in splenic development","Structural basis of RPSA's laminin and Aβ42 binding at the cell surface is unknown","Mechanism of 37-kDa to 67-kDa conversion remains unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,11,12]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[8,11]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[5]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,6,10,16]}],"localization":[{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[1,11,12]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5,10,16]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,11,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,7,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,15]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4,13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5]}],"complexes":["40S ribosomal small subunit","80S ribosome"],"partners":["TRPM7","H2AFX","H2B","HIST1H4A"],"other_free_text":[]},"mechanistic_narrative":"RPSA is a dual-function protein that serves as a structural component of the 40S small ribosomal subunit and as a cell-surface laminin receptor with roles in cell adhesion, viral entry, and signal transduction. Cryo-EM structures of the human 80S ribosome position RPSA within the small subunit, while its cell-surface form mediates laminin binding, acts as an entry receptor for adeno-associated virus serotypes 2/3/8/9, and engages amyloid-β42 to promote cytotoxicity [PMID:25901680, PMID:16973587, PMID:24048171]. Beyond translation and adhesion, RPSA localizes to the nucleus where it associates with histones H2A, H2B, and H4 and with chromatin DNA, cross-links to polyadenylated mRNA as an RNA-binding protein, and activates HIF-1α through FAK–PI3K and ERK signaling in cancer cells [PMID:9878528, PMID:22681889, PMID:17476462]. Heterozygous loss-of-function mutations in RPSA cause isolated congenital asplenia by haploinsufficiency, establishing a non-redundant requirement for this gene in human spleen organogenesis [PMID:23579497, PMID:30072435]."},"prefetch_data":{"uniprot":{"accession":"P08865","full_name":"Small ribosomal subunit protein uS2","aliases":["37 kDa laminin receptor precursor","37LRP","37/67 kDa laminin receptor","LRP/LR","40S ribosomal protein SA","67 kDa laminin receptor","67LR","Colon carcinoma laminin-binding protein","Laminin receptor 1","LamR","Laminin-binding protein precursor p40","LBP/p40","Multidrug resistance-associated protein MGr1-Ag","NEM/1CHD4"],"length_aa":295,"mass_kda":32.9,"function":"Required for the assembly and/or stability of the 40S ribosomal subunit. Required for the processing of the 20S rRNA-precursor to mature 18S rRNA in a late step of the maturation of 40S ribosomal subunits. Also functions as a cell surface receptor for laminin. Plays a role in cell adhesion to the basement membrane and in the consequent activation of signaling transduction pathways. May play a role in cell fate determination and tissue morphogenesis. Acts as a PPP1R16B-dependent substrate of PPP1CA (Microbial infection) Acts as a receptor for the Adeno-associated viruses 2,3,8 and 9 (Microbial infection) Acts as a receptor for the Dengue virus (Microbial infection) Acts as a receptor for the Sindbis virus (Microbial infection) Acts as a receptor for the Venezuelan equine encephalitis virus (Microbial infection) Acts as a receptor for the pathogenic prion protein (Microbial infection) Acts as a receptor for bacteria","subcellular_location":"Cell membrane; Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/P08865/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RPSA","classification":"Common Essential","n_dependent_lines":320,"n_total_lines":320,"dependency_fraction":1.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ENY2","stoichiometry":10.0},{"gene":"RACK1","stoichiometry":10.0},{"gene":"RBM8A","stoichiometry":10.0},{"gene":"RPL11","stoichiometry":10.0},{"gene":"RPL4","stoichiometry":10.0},{"gene":"RPL5","stoichiometry":10.0},{"gene":"RPS16","stoichiometry":10.0},{"gene":"SRP9","stoichiometry":10.0},{"gene":"CAPRIN1","stoichiometry":4.0},{"gene":"DRG1","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/RPSA","total_profiled":1310},"omim":[{"mim_id":"600584","title":"NK2 HOMEOBOX 5; NKX2-5","url":"https://www.omim.org/entry/600584"},{"mim_id":"271400","title":"ASPLENIA, ISOLATED CONGENITAL; ICAS","url":"https://www.omim.org/entry/271400"},{"mim_id":"150370","title":"RIBOSOMAL PROTEIN SA; RPSA","url":"https://www.omim.org/entry/150370"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RPSA"},"hgnc":{"alias_symbol":["LRP","37LRP","p40","SA","uS2"],"prev_symbol":["LAMR1"]},"alphafold":{"accession":"A0A8I5KQE6","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A0A8I5KQE6","model_url":"https://alphafold.ebi.ac.uk/files/AF-A0A8I5KQE6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A0A8I5KQE6-F1-predicted_aligned_error_v6.png","plddt_mean":78.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RPSA","jax_strain_url":"https://www.jax.org/strain/search?query=RPSA"},"sequence":{"accession":"A0A8I5KQE6","fasta_url":"https://rest.uniprot.org/uniprotkb/A0A8I5KQE6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A0A8I5KQE6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A0A8I5KQE6"}},"corpus_meta":[{"pmid":"12690199","id":"PMC_12690199","title":"LRP: role in vascular wall integrity and protection from atherosclerosis.","date":"2003","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/12690199","citation_count":483,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10066607","id":"PMC_10066607","title":"SA, JA, ethylene, and disease resistance in plants.","date":"1998","source":"Current opinion in plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/10066607","citation_count":410,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9449704","id":"PMC_9449704","title":"Inducible inactivation of hepatic LRP gene by cre-mediated recombination confirms role of LRP in clearance of chylomicron remnants.","date":"1998","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/9449704","citation_count":398,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30243088","id":"PMC_30243088","title":"Syringic acid (SA) ‒ A Review of Its Occurrence, Biosynthesis, Pharmacological and Industrial Importance.","date":"2018","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/30243088","citation_count":313,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8103745","id":"PMC_8103745","title":"The interleukin-12 subunit p40 specifically inhibits effects of the interleukin-12 heterodimer.","date":"1993","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8103745","citation_count":275,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10632583","id":"PMC_10632583","title":"Role of tissue plasminogen activator receptor LRP in hippocampal long-term potentiation.","date":"2000","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/10632583","citation_count":235,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19098903","id":"PMC_19098903","title":"SRF and myocardin regulate LRP-mediated amyloid-beta clearance in brain vascular cells.","date":"2008","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19098903","citation_count":226,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15749709","id":"PMC_15749709","title":"The low density lipoprotein receptor-related protein (LRP) is a novel beta-secretase (BACE1) substrate.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15749709","citation_count":210,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10470081","id":"PMC_10470081","title":"Cytomegalovirus US2 destroys two components of the MHC class II pathway, preventing recognition by CD4+ T cells.","date":"1999","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/10470081","citation_count":207,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17457719","id":"PMC_17457719","title":"The LDL receptor-related protein (LRP) family: an old family of proteins with 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complexes.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22939629","citation_count":689,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28302793","id":"PMC_28302793","title":"Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15.","date":"2017","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/28302793","citation_count":533,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23636399","id":"PMC_23636399","title":"Structures of the human and Drosophila 80S 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technique","url":"https://pubmed.ncbi.nlm.nih.gov/11054877","citation_count":278,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46833,"output_tokens":2774,"usd":0.091054},"stage2":{"model":"claude-opus-4-6","input_tokens":6148,"output_tokens":2369,"usd":0.134947},"total_usd":0.533511,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":58322,"output_tokens":5511,"usd":0.128815},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":7666,"output_tokens":3232,"usd":0.178695}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"Heterozygous loss-of-function mutations in RPSA (encoding ribosomal protein SA) cause isolated congenital asplenia (ICA) by haploinsufficiency, establishing an essential role for RPSA in human spleen development.\",\n      \"method\": \"Whole-exome sequencing of ICA patients identifying heterozygous RPSA mutations (nonsense, frameshift, missense); expression studies confirming haploinsufficiency mechanism\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (exome sequencing + expression studies) across 18 patients from 8 kindreds, replicated in subsequent study\",\n      \"pmids\": [\"23579497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RPSA mutations in both translated and untranslated exons (including 5'-UTR splice-disrupting mutations) cause ICA with either complete or incomplete penetrance, confirming RPSA haploinsufficiency as the mechanism and identifying a hotspot/founder effect for recurrent mutations.\",\n      \"method\": \"Sequencing of RPSA coding and UTR regions in 73 ICA patients across 56 kindreds; functional validation of 5'-UTR mutations disrupting mRNA splicing; de novo mutation analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — large cohort with orthogonal genetic and functional methods, replicating and extending prior findings\",\n      \"pmids\": [\"30072435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"LBP-p40 (RPSA) localizes to the nucleus in addition to the cytoplasm, where it is tightly associated with both the nuclear envelope and chromatin DNA in interphase nuclei, and localizes to the perichromosomal region during mitosis.\",\n      \"method\": \"Monoclonal antibody (M108) immunofluorescence; biochemical fractionation; microsequencing of isolated p40 protein\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with fractionation and immunofluorescence, single lab\",\n      \"pmids\": [\"8954992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"LBP-p40 (RPSA) binds double-stranded DNA through associations with histones H2A, H2B, and H4 (but not H3), explaining its tight association with chromatin in the nucleus.\",\n      \"method\": \"DNA cellulose column binding; LBP-p40 affinity column pulldown from nuclear extract; GST-fusion recombinant histone binding assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro reconstitution with recombinant proteins and affinity chromatography, single lab\",\n      \"pmids\": [\"9878528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Loss of LBP-p40 (RPSA) expression in HeLa cells induces apoptosis under serum-depleted conditions, indicating RPSA is required for maintenance of cell viability.\",\n      \"method\": \"Antisense cDNA expression under inducible LacSwitch system; Western/Northern blotting to confirm knockdown; DNA fragmentation assay to confirm apoptosis; rescue by p40 cDNA re-expression; hammerhead ribozyme knockdown\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with multiple readouts and rescue experiment, single lab\",\n      \"pmids\": [\"10200442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RPSA (LRP/LR) knockdown by siRNA induces apoptosis in breast (MCF-7, MDA-MB-231) and oesophageal (WHCO1) cancer cells, demonstrating that RPSA is required for cancer cell viability.\",\n      \"method\": \"siRNA-LAMR1 and esiRNA-RPSA knockdown; Western blot to confirm LRP/LR downregulation; MTT viability assay; Annexin-V/FITC apoptosis assay; Hoechst nuclear morphology staining\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with two independent siRNAs and multiple orthogonal apoptosis readouts, single lab\",\n      \"pmids\": [\"26427016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RPSA and TRPM7 channel form a complex at the plasma membrane of pancreatic cancer cells and cooperatively regulate cancer cell migration in response to elastin-derived peptides (EDPs).\",\n      \"method\": \"Boyden chamber migration assay; siRNA knockdown of TRPM7; patch-clamp electrophysiology showing EDP-stimulated TRPM7 currents; colocalization of TRPM7 and RPSA at plasma membrane by immunofluorescence\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — colocalization plus functional knockdown linking complex to migration phenotype, single lab\",\n      \"pmids\": [\"32733880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RPSA (LRP/LR) interacts with amyloid-beta (Aβ42) at the cell surface, and this interaction mediates Aβ42-induced cytotoxicity; antibody blockade (IgG1-iS18) or shRNA knockdown of RPSA rescues cells from Aβ42-induced cell death.\",\n      \"method\": \"Immunofluorescence co-localization; pull-down assay; MTT viability and BrdU proliferation assays with anti-LRP/LR antibody blockade and shRNA knockdown\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — pulldown plus functional rescue with two independent perturbation methods, single lab\",\n      \"pmids\": [\"24048171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RPSA (LRP/LR) binds aflatoxin B1 (AFB1) in vitro and in vivo, as identified by immobilized affinity chromatography and confirmed by ELISA and laser confocal immunofluorescence, suggesting RPSA may mediate AFB1 entry into hepatocytes.\",\n      \"method\": \"Immobilized affinity chromatography (IAC) with BSA-AFB1; LC-MS/MS identification; ELISA binding assay; immunofluorescence co-localization in cells\",\n      \"journal\": \"Journal of hazardous materials\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, ligand-binding identification without mechanistic follow-up\",\n      \"pmids\": [\"26372695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The 37LRP/p40 (RPSA) active gene in chicken (single-copy vertebrate) consists of 7 exons and 6 introns with features characteristic of a ribosomal protein gene; protein structure analysis suggests the C-terminal domain is involved in generating the 67-kDa laminin receptor, while the central core mediates ribosome association.\",\n      \"method\": \"Gene structure determination; RNase protection assay; primer extension; evolutionary protein domain analysis\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3–4 — gene structure and evolutionary analysis without direct functional reconstitution of domain activities\",\n      \"pmids\": [\"8985115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Hypoxia-induced HIF-1α upregulation in gastric cancer cells depends on MGr1-Ag/37LRP (RPSA), with RPSA promoting HIF-1α transcriptional activity through FAK-PI3K and ERK1/2 signaling pathways; siRNA knockdown of RPSA markedly decreased vincristine-induced HIF-1α expression.\",\n      \"method\": \"Forced overexpression and siRNA knockdown of MGr1-Ag/37LRP; reporter assays for HIF-1α transcriptional activity; pharmacological inhibition of FAK, PI3K, MAPK\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, pathway placement by pharmacological inhibitors without direct biochemical interaction evidence\",\n      \"pmids\": [\"17476462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Hypoxia-induced RPSA (MGr1-Ag/37LRP) expression is mediated by HIF-1 downstream of ERK/MAPK activation (triggered by ROS/H2O2), and RPSA promotes cancer cell adhesion to laminin and resistance to vincristine-induced apoptosis; siRNA targeting RPSA reversed hypoxia-enhanced adhesion.\",\n      \"method\": \"MEK overexpression and U0126 inhibitor; ROS scavengers; siRNA knockdown of RPSA; adhesion assay; apoptosis assay\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — pharmacological and siRNA approaches, single lab, no direct interaction data\",\n      \"pmids\": [\"19998339\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RPSA encodes ribosomal protein SA, a component of the 40S ribosomal small subunit that also functions at the cell surface as a laminin receptor precursor (37LRP/67LR); it is essential for human spleen development (haploinsufficiency causes isolated congenital asplenia), localizes to the nucleus where it associates with chromatin via histones H2A/H2B/H4, is required for cancer cell viability through apoptosis evasion, and at the plasma membrane forms a complex with TRPM7 to regulate cell migration and interacts with Aβ42 to mediate cytotoxicity.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\nThe target gene is human RPSA (ribosomal protein SA, also known as 37LRP/p40, laminin receptor precursor, 67LR precursor).\n\n**KEEP papers** (describe canonical RPSA protein function):\n- Corpus[15]: RPSA haploinsufficiency → congenital asplenia (Science 2013) ✓\n- Corpus[60]: LBP-p40 binds DNA/histones H2A, H2B, H4 ✓\n- Corpus[65]: Nuclear localization of LBP/p40 ✓\n- Corpus[75]: Active gene structure of 37LRP/p40 ✓\n- Corpus[78]: KD of LRP/LR induces apoptosis in cancer cells ✓\n- Corpus[80]: Loss of LBP-p40 induces apoptosis in HeLa cells ✓\n- Corpus[82]: RPSA mutations → ICA with incomplete penetrance ✓\n- Corpus[85]: MGr1-Ag/37LRP → HIF-1α induction via FAK-PI3K/MAPK ✓\n- Corpus[90]: Patented therapeutic approaches targeting LRP/LR ✓\n- Corpus[92]: LRP/LR interacts with Aβ42, mediates cytotoxicity ✓\n- Corpus[95]: RPSA binds AFB1 ✓\n- Corpus[54]: MGr1-Ag/37LRP expression via ERK/HIF-1 in gastric cancer ✓\n- Corpus[70]: TRPM7/RPSA complex regulates pancreatic cancer cell migration ✓\n- Gene2pubmed[26]: AAV8 receptor = 37/67 kDa laminin receptor (RPSA) ✓\n- Gene2pubmed[29]: Laminin receptor cloned as integrin (actually different protein - EXCLUDE, this is integrin not RPSA)\n- Gene2pubmed[27]: Laminin receptor as integrin member — EXCLUDE (describes integrin, not RPSA)\n- Gene2pubmed[25]: Structure of human 80S ribosome — RPSA is a component ✓\n- Gene2pubmed[18]: Structures of human and Drosophila 80S ribosome ✓\n- Gene2pubmed[29]: cDNA cloning of laminin receptor ✓ (PMID 2429301 — this clones the laminin receptor mRNA ~1700 bases, correlating with surface receptor levels)\n- Gene2pubmed[7]: mRNA-bound proteome identifies RPSA as RNA-binding protein ✓\n- Gene2pubmed[8]: Nucleolar proteome — RPSA detected ✓\n\n**EXCLUDE** (LRP1, LRP2, Lrp bacterial, SA=salicylic acid, IL-12 p40, US2 CMV, PSA prostate, etc.):\n- Corpus[1,3,6,7,8,10,13,16,19,20,23,24,29,30,35,38,44,47,49,53,55,56,63,67,68,72,73,79,98]: LRP1/LRP2 family\n- Corpus[2,4,11,12,32,41,64,84,81]: SA = salicylic acid (plants)\n- Corpus[5,9,12,26,57]: IL-12 p40/p75\n- Corpus[14,18,21,22,25,36,42,46,50,52,58,66,69,71,83,86,94]: Lrp = bacterial leucine-responsive regulatory protein\n- Corpus[17,33,48,59,74,77,89,91]: US2 = CMV protein\n- Corpus[31,39,51,61,93,96]: rpsA = Mycobacterium tuberculosis RpsA (pyrazinamide resistance) — EXCLUDE (bacterial, incompatible context)\n- Corpus[27,34,87,99]: LRP = lung resistance protein/vault protein\n- Corpus[28]: LRP/RAGE in Alzheimer's\n- Corpus[37]: LRP-1 cancer invasion\n- Corpus[40]: MRP1/LRP drug resistance\n- Corpus[43]: Duocarmycin SA (chemical)\n- Corpus[45]: LRP promoter (LRP1)\n- Corpus[62]: p40 = L1 retroelement ORF1 product\n- Corpus[76]: RpsA = fish Nocardia vaccine — EXCLUDE (bacterial antigen)\n- Corpus[97]: SA.FAPi (chelator compound)\n- Corpus[100]: rPSA = prostate-specific antigen — EXCLUDE (alias collision)\n\nGene2pubmed classifications:\n- [1,2,4,5,6,10,14,15]: large interactome screens — KEEP only if RPSA specifically mentioned as interactor (these are general screens; RPSA appears as a component but no specific mechanism extracted)\n- [3,13,19,22]: cDNA sequencing projects — KEEP for RPSA sequence identification\n- [7]: mRNA-bound proteome — KEEP (RPSA identified as RNA-binding)\n- [8,12]: Nucleolar proteomics — KEEP (RPSA in nucleolus)\n- [9]: Phosphotyrosine profiling — marginal\n- [11]: m6A methylation (VIRMA) — EXCLUDE\n- [16]: GO annotations — EXCLUDE\n- [17]: Sulfonamide/RBM39 — EXCLUDE\n- [18,25]: Ribosome structures — KEEP\n- [20]: OpenCell localization — KEEP\n- [21]: TDP-43 interactors — marginal KEEP if RPSA mentioned\n- [23]: Metazoan complexes — KEEP (ribosome)\n- [24]: Eukaryotic translation review — KEEP\n- [26]: AAV8 receptor = LamR (RPSA) — KEEP\n- [27]: Laminin receptor as integrin — EXCLUDE (different protein)\n- [28]: CRL ubiquitin ligase — EXCLUDE\n- [29]: Laminin receptor cDNA cloning — KEEP (PMID 2429301)\n- [30]: Integrins as laminin receptors — EXCLUDE\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1986,\n      \"finding\": \"The laminin receptor (later identified as RPSA/37LRP) was purified and its mRNA (~1700 bases) cloned from human endothelial cells; levels of laminin receptor mRNA correlated with surface receptor number across carcinoma cell lines, suggesting mRNA abundance is a rate-limiting step in biosynthesis of the cell-surface laminin-binding protein.\",\n      \"method\": \"Affinity purification on laminin, lambda gt11 cDNA library screening with anti-receptor monoclonal antibody, cDNA sequencing, Northern blot\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original cloning with protein sequencing validation and expression correlation, foundational paper >280 citations\",\n      \"pmids\": [\"2429301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The active 37LRP/p40 (RPSA) gene was identified in chicken (the only vertebrate with a single copy); it comprises 7 exons and 6 introns, lacks a TATA box, has multiple transcription start sites, and bears features of ribosomal protein genes. Domain analysis indicated the C-terminal domain is a conserved structure involved in generating the 67-kDa laminin receptor form, while the central core mediates ribosome association.\",\n      \"method\": \"Genomic cloning, RNase protection assay, primer extension, sequence analysis, protein evolutionary comparison\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original gene structure determination with multiple orthogonal methods\",\n      \"pmids\": [\"8985115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The laminin-binding protein precursor p40 (LBP-p40/RPSA) localizes not only in the cytoplasm but also in the nucleus, where it is tightly associated with nuclear envelope and chromatin DNA in interphase nuclei and with the perichromosomal region during mitosis.\",\n      \"method\": \"Monoclonal antibody immunofluorescence, subcellular fractionation, immunoelectron microscopy\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by immunofluorescence and fractionation, single lab\",\n      \"pmids\": [\"8954992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Nuclear LBP-p40 (RPSA) binds double-stranded DNA and associates with histone proteins H2A, H2B, and H4 (but not H3), as demonstrated by DNA-cellulose binding and GST-histone pull-down assays; interaction with these histones confers tighter chromatin binding.\",\n      \"method\": \"DNA-cellulose affinity chromatography, LBP-p40 affinity column, GST-histone fusion pull-down assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct biochemical binding assays with defined partners, single lab\",\n      \"pmids\": [\"9878528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Loss of LBP-p40 (RPSA) expression by antisense or ribozyme-mediated knockdown in HeLa cells causes apoptotic cell death under serum-depleted conditions, demonstrating that RPSA is required for cell survival.\",\n      \"method\": \"Antisense cDNA expression, ribozyme delivery via fusigenic viral liposome, Western/Northern blot, colony formation assay, DNA fragmentation assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined apoptotic phenotype, multiple methods, single lab\",\n      \"pmids\": [\"10200442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The 37/67-kDa laminin receptor (RPSA/LamR) serves as a cell-surface receptor for adeno-associated virus serotypes 8, 2, 3, and 9; LamR binds AAV8 capsid proteins in vitro and contributes to AAV8 transduction of cultured cells and mouse liver in vivo, with binding mapped to two protein subdomains on the AAV capsid exterior.\",\n      \"method\": \"In vitro capsid protein binding assays, siRNA knockdown, in vivo mouse liver transduction, sequence/deletion mapping\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstituted binding, in vitro + in vivo validation, replicated across 4 serotypes\",\n      \"pmids\": [\"16973587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MGr1-Ag/37LRP (RPSA) promotes HIF-1α expression and transcriptional activity under non-hypoxic conditions in gastric cancer cells treated with vincristine; forced expression of RPSA upregulates HIF-1α, while siRNA knockdown reduces it; FAK-PI3K and ERK1/2 (p42/44 MAPK) signaling are the major pathways downstream of RPSA leading to HIF-1α induction.\",\n      \"method\": \"Overexpression, siRNA knockdown, Western blot, HIF-1 reporter assays, pharmacological inhibitors (PI3K, MAPK)\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss- and gain-of-function with pathway inhibitors, single lab\",\n      \"pmids\": [\"17476462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Hypoxia-induced RPSA (MGr1-Ag/37LRP) expression is driven by ERK/MAPK activation via reactive oxygen species (H2O2); MEK activates HIF-1, which in turn drives RPSA promoter activity; RPSA then mediates enhanced gastric cancer cell adhesion to laminin and resistance to vincristine-induced apoptosis; MEK inhibitor U0126 and RPSA siRNA reverse these effects.\",\n      \"method\": \"MEK overexpression, dominant-negative kinases, MEK inhibitor U0126, ROS scavengers, siRNA, adhesion assays, apoptosis assays\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods establishing ERK→HIF-1→RPSA axis, single lab\",\n      \"pmids\": [\"19998339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RPSA is identified as a component of the mRNA-bound proteome in human cells; it cross-links to mRNA upon UV irradiation and co-purifies with polyadenylated transcripts, establishing RPSA as an RNA-binding protein beyond its ribosomal role.\",\n      \"method\": \"Photoreactive nucleotide-enhanced UV crosslinking and oligo(dT) purification, quantitative mass spectrometry\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic biochemical approach with UV crosslinking validation\",\n      \"pmids\": [\"22681889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Heterozygous loss-of-function mutations in RPSA cause isolated congenital asplenia (ICA) in humans by haploinsufficiency; seven different mutations (nonsense, frameshift, missense) were identified in 18 patients from 8 kindreds, establishing an essential and non-redundant role for RPSA in human spleen organogenesis.\",\n      \"method\": \"Whole-exome sequencing, Sanger sequencing, expression studies in patient cells, segregation analysis\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human genetics with functional expression validation, multiple independent kindreds, replicated in follow-up study\",\n      \"pmids\": [\"23579497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RPSA (LRP/LR) co-localizes and physically interacts with Aβ42 at the cell surface; antibody blockade of RPSA or shRNA-mediated knockdown significantly rescues cell viability and proliferation in Aβ42-treated cells, indicating RPSA mediates Aβ42 cytotoxicity.\",\n      \"method\": \"Immunofluorescence co-localization, pull-down assays, MTT viability assay, BrdU proliferation assay, Annexin-V apoptosis assay, shRNA knockdown\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — pull-down plus functional rescue, single lab\",\n      \"pmids\": [\"24048171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Structures of human and Drosophila 80S ribosomes determined by cryo-EM reveal RPSA as a component of the 40S small ribosomal subunit, and illuminate metazoan-specific ribosomal features including an inner protein layer and flexible RNA outer layer.\",\n      \"method\": \"High-resolution cryo-electron microscopy, atomic model building\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structural determination of RPSA within the ribosome complex\",\n      \"pmids\": [\"23636399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Near-atomic structure of the human 80S ribosome at 3.6 Å resolution (reaching 2.9 Å in stable regions) by cryo-EM reveals RPSA's position in the 40S subunit, details of subunit interfaces, tRNA binding sites, and ribosome rotational dynamics.\",\n      \"method\": \"Single-particle cryo-electron microscopy at near-atomic resolution, atomic model building\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution structure with atomic model\",\n      \"pmids\": [\"25901680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"siRNA-mediated knockdown of RPSA (LRP/LR) significantly reduces viability of breast (MCF-7, MDA-MB 231) and oesophageal (WHCO1) cancer cells by inducing apoptosis, as shown by phosphatidylserine externalization (Annexin-V) and nuclear morphological changes; results confirmed with two independent siRNA sequences targeting different RPSA mRNA regions.\",\n      \"method\": \"siRNA knockdown (siRNA-LAMR1 and esiRNA-RPSA), MTT assay, Annexin-V/FITC assay, Hoechst staining, Western blot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — two independent siRNAs excluding off-target effects, multiple cell lines, single lab\",\n      \"pmids\": [\"26427016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RPSA protein was identified as binding aflatoxin B1 (AFB1) by immobilized affinity chromatography from mouse liver total protein; the RPSA–AFB1 interaction was validated by ELISA in vitro and laser confocal immunofluorescence in vivo, suggesting RPSA is an AFB1-binding protein in hepatocytes.\",\n      \"method\": \"Immobilized affinity chromatography (BSA-AFB1 on PVDF), LC-MS/MS identification, ELISA, laser confocal immunofluorescence\",\n      \"journal\": \"Journal of hazardous materials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple orthogonal binding assays, single lab, novel finding\",\n      \"pmids\": [\"26372695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Additional RPSA mutations causing isolated congenital asplenia include mutations in the 5'-UTR that disrupt mRNA splicing, as well as 11 new protein-coding mutations; overall 41% of ICA kindreds carry RPSA mutations; some mutations show incomplete penetrance, and 7 de novo mutations were identified, confirming autosomal dominant inheritance.\",\n      \"method\": \"Whole-exome and Sanger sequencing, mRNA splicing analysis, segregation analysis, de novo mutation confirmation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — large multi-kindred genetic study with functional splicing validation, replication of 2013 findings\",\n      \"pmids\": [\"30072435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RPSA and TRPM7 (transient receptor potential melastatin-related 7 channel) co-localize at the plasma membrane of human pancreatic cancer cells and form a functional complex; elastin-derived peptides (EDPs) stimulate TRPM7 currents and promote cell migration via this TRPM7/RPSA complex, as TRPM7 siRNA abrogates EDP-induced migration.\",\n      \"method\": \"Boyden chamber migration assay, siRNA knockdown of TRPM7, patch-clamp electrophysiology, co-localization by immunofluorescence\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — co-localization plus functional siRNA and electrophysiology, single lab\",\n      \"pmids\": [\"32733880\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RPSA (ribosomal protein SA / 37LRP/p40) is a dual-function protein that acts as a structural component of the 40S ribosomal small subunit and as a multifunctional cell-surface receptor: it mediates cell adhesion to laminin and basement membranes, serves as an entry receptor for AAV serotypes 2/3/8/9, binds Aβ42 to mediate cytotoxicity, forms a signaling complex with TRPM7 to drive cancer cell migration, activates HIF-1α via FAK-PI3K/ERK signaling, associates with histones H2A/H2B/H4 in the nucleus, and is haploinsufficient for human spleen development—with heterozygous loss-of-function mutations causing isolated congenital asplenia through an essential role in splenic organogenesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RPSA encodes a multifunctional protein that serves as a component of the 40S ribosomal subunit and as a laminin receptor precursor (37LRP/67LR) at the cell surface, with essential roles in human spleen development, chromatin association, cell viability, and cell migration. Heterozygous loss-of-function mutations in RPSA cause isolated congenital asplenia (ICA) through haploinsufficiency, with mutations in both coding and 5'-UTR regions confirmed across large patient cohorts [PMID:23579497, PMID:30072435]. In the nucleus, RPSA associates with chromatin through direct binding to histones H2A, H2B, and H4, and its loss induces apoptosis in both normal and cancer cell lines [PMID:9878528, PMID:10200442, PMID:26427016]. At the plasma membrane, RPSA functions as a receptor mediating amyloid-beta (Aβ42) cytotoxicity and forms a complex with the TRPM7 channel to regulate cancer cell migration [PMID:24048171, PMID:32733880].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing that RPSA is not solely cytoplasmic but localizes to the nucleus — associated with chromatin and the nuclear envelope in interphase and with perichromosomal regions during mitosis — raised the question of what nuclear functions this ribosomal/laminin receptor protein serves.\",\n      \"evidence\": \"Monoclonal antibody immunofluorescence and biochemical fractionation in mammalian cells\",\n      \"pmids\": [\"8954992\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of nuclear localization was not determined\",\n        \"Mechanism of nuclear import was not identified\",\n        \"Whether nuclear and ribosomal pools are independently regulated was unknown\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"The molecular basis of RPSA's chromatin association was resolved: RPSA binds DNA indirectly through specific interactions with histones H2A, H2B, and H4 but not H3, providing a mechanistic explanation for its tight nuclear/chromatin association.\",\n      \"evidence\": \"DNA cellulose binding, affinity chromatography from nuclear extracts, and GST-fusion recombinant histone binding assays\",\n      \"pmids\": [\"9878528\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional role of histone binding (e.g., chromatin remodeling, ribosome biogenesis) was not established\",\n        \"Whether histone binding is required for RPSA's pro-survival function was untested\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Loss-of-function experiments established that RPSA is essential for cell viability: antisense-mediated knockdown of RPSA in HeLa cells induced apoptosis under serum-depleted conditions, rescued by re-expression, demonstrating a pro-survival function beyond its ribosomal role.\",\n      \"evidence\": \"Inducible antisense and ribozyme knockdown in HeLa cells with DNA fragmentation assay and cDNA rescue\",\n      \"pmids\": [\"10200442\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether the pro-survival function depends on ribosomal, nuclear, or cell-surface activity was not dissected\",\n        \"Downstream anti-apoptotic signaling pathway was not identified\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Two key roles of RPSA at the cell surface were defined: it serves as a receptor for Aβ42 mediating amyloid cytotoxicity (blockable by anti-LRP antibodies or shRNA knockdown), and — through human genetic studies — heterozygous loss-of-function mutations were shown to cause isolated congenital asplenia, establishing RPSA as essential and non-redundant for human spleen development.\",\n      \"evidence\": \"Pull-down and co-localization of RPSA-Aβ42 with functional rescue by antibody blockade and shRNA; whole-exome sequencing of 18 ICA patients from 8 kindreds with expression studies\",\n      \"pmids\": [\"24048171\", \"23579497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Why RPSA haploinsufficiency specifically affects spleen rather than other organs was unexplained\",\n        \"Whether Aβ42 binding occurs through the laminin-binding domain was not mapped\",\n        \"Whether the disease mechanism involves ribosomal or extra-ribosomal functions of RPSA was unknown\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The pro-survival role of RPSA was generalized to multiple cancer types: siRNA knockdown induced apoptosis in breast and oesophageal cancer cells, establishing RPSA as broadly required for cancer cell viability.\",\n      \"evidence\": \"Two independent siRNAs with MTT viability, Annexin-V apoptosis, and Hoechst staining in MCF-7, MDA-MB-231, and WHCO1 cells\",\n      \"pmids\": [\"26427016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether RPSA's anti-apoptotic role is mediated through laminin signaling, ribosomal function, or a separate mechanism was not resolved\",\n        \"In vivo relevance in tumor models was not tested\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The genetic basis of RPSA-associated asplenia was extended: mutations in both coding and untranslated exons (including 5'-UTR splice-disrupting variants) cause ICA, with recurrent mutations showing founder effects, firmly establishing haploinsufficiency across a broad mutational spectrum.\",\n      \"evidence\": \"Sequencing of 73 ICA patients across 56 kindreds with functional validation of 5'-UTR splice mutations\",\n      \"pmids\": [\"30072435\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Developmental mechanism by which reduced RPSA dosage impairs spleen organogenesis was not elucidated\",\n        \"No animal model recapitulating the asplenia phenotype was reported\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A new plasma membrane function was established: RPSA forms a complex with the TRPM7 ion channel and together they regulate elastin-derived peptide–stimulated pancreatic cancer cell migration, linking RPSA's receptor role to ion channel-mediated motility signaling.\",\n      \"evidence\": \"Colocalization by immunofluorescence, siRNA knockdown of TRPM7, patch-clamp electrophysiology, and Boyden chamber migration assay in pancreatic cancer cells\",\n      \"pmids\": [\"32733880\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct biochemical interaction between RPSA and TRPM7 (e.g., co-immunoprecipitation) was not shown\",\n        \"Whether the RPSA-TRPM7 complex forms in non-cancer contexts was untested\",\n        \"Stoichiometry and binding interface were not defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The central unresolved question is how RPSA's distinct functions — ribosomal subunit component, chromatin-associated histone binder, cell-surface laminin/Aβ42 receptor, and TRPM7 partner — are partitioned across subcellular pools, and which of these activities underlies its essential role in spleen development versus its pro-survival function in cancer cells.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No separation-of-function mutants distinguishing ribosomal from extra-ribosomal roles\",\n        \"No structural basis for the 37 kDa to 67 kDa conversion\",\n        \"No in vivo model recapitulating the asplenia phenotype to test developmental mechanism\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\n      \"40S ribosomal subunit\"\n    ],\n    \"partners\": [\n      \"TRPM7\",\n      \"H2AFX\",\n      \"H2BC1\",\n      \"H4C1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"RPSA is a dual-function protein that serves as a structural component of the 40S small ribosomal subunit and as a cell-surface laminin receptor with roles in cell adhesion, viral entry, and signal transduction. Cryo-EM structures of the human 80S ribosome position RPSA within the small subunit, while its cell-surface form mediates laminin binding, acts as an entry receptor for adeno-associated virus serotypes 2/3/8/9, and engages amyloid-β42 to promote cytotoxicity [PMID:25901680, PMID:16973587, PMID:24048171]. Beyond translation and adhesion, RPSA localizes to the nucleus where it associates with histones H2A, H2B, and H4 and with chromatin DNA, cross-links to polyadenylated mRNA as an RNA-binding protein, and activates HIF-1α through FAK–PI3K and ERK signaling in cancer cells [PMID:9878528, PMID:22681889, PMID:17476462]. Heterozygous loss-of-function mutations in RPSA cause isolated congenital asplenia by haploinsufficiency, establishing a non-redundant requirement for this gene in human spleen organogenesis [PMID:23579497, PMID:30072435].\",\n  \"teleology\": [\n    {\n      \"year\": 1986,\n      \"claim\": \"Identification of the laminin receptor mRNA and protein established RPSA as a cell-surface laminin-binding molecule whose expression correlates with receptor surface density, answering the question of whether laminin receptor biosynthesis is transcriptionally regulated.\",\n      \"evidence\": \"Affinity purification on laminin and lambda gt11 cDNA library screening from human endothelial cells, Northern blot across carcinoma lines\",\n      \"pmids\": [\"2429301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism of conversion from the 37-kDa precursor to the 67-kDa cell-surface form was unknown\",\n        \"No structural information on the laminin-binding domain\",\n        \"Ribosomal role of the protein not yet recognized\"\n      ]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Gene structure analysis and subcellular localization studies revealed RPSA to be a ribosomal-protein-class gene whose product localizes not only to the cytoplasm and cell surface but also to the nucleus and perichromosomal region, challenging a purely receptor-centric model.\",\n      \"evidence\": \"Genomic cloning with RNase protection/primer extension (chicken), immunofluorescence and immunoelectron microscopy in mammalian cells\",\n      \"pmids\": [\"8985115\", \"8954992\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Nuclear binding partners and functional significance of chromatin association were unresolved\",\n        \"Mechanism by which a single polypeptide partitions among ribosome, membrane, and nucleus was unknown\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Biochemical assays demonstrated that nuclear RPSA directly binds DNA and interacts with histones H2A, H2B, and H4, providing the first molecular partners for its chromatin-associated function, while loss-of-function experiments showed RPSA is required for cell survival.\",\n      \"evidence\": \"DNA-cellulose chromatography and GST-histone pull-down assays; antisense/ribozyme knockdown in HeLa cells with apoptosis readout\",\n      \"pmids\": [\"9878528\", \"10200442\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of histone binding (e.g., chromatin remodeling, gene regulation) was not determined\",\n        \"Whether the survival requirement reflects the ribosomal versus the receptor role was unclear\",\n        \"No in vivo validation of nuclear interactions\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of RPSA as a cell-surface receptor for AAV serotypes 2, 3, 8, and 9 expanded its receptor repertoire beyond laminin to include viral entry, validated both in vitro and in vivo in mouse liver.\",\n      \"evidence\": \"In vitro capsid protein binding, siRNA knockdown of RPSA, in vivo mouse liver transduction with AAV8\",\n      \"pmids\": [\"16973587\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Co-receptor requirements and post-binding endocytic mechanism were not defined\",\n        \"Relative contribution of RPSA versus other AAV receptors (e.g., HSPG) was not quantified in vivo\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"RPSA was placed upstream of HIF-1α induction via FAK–PI3K and ERK signaling in gastric cancer cells, establishing a signaling axis through which a laminin receptor activates hypoxia-responsive transcription under normoxic conditions.\",\n      \"evidence\": \"Overexpression and siRNA knockdown of RPSA with HIF-1 reporter assays and pharmacological pathway inhibitors in gastric cancer cells\",\n      \"pmids\": [\"17476462\", \"19998339\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct physical link between RPSA and FAK was not shown\",\n        \"Whether this signaling operates in non-cancer contexts was untested\",\n        \"Upstream ligand triggering RPSA signaling in vivo was not identified\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"UV-crosslinking proteomics identified RPSA as part of the mRNA-bound proteome, establishing it as an RNA-binding protein with potential extra-ribosomal roles in mRNA metabolism.\",\n      \"evidence\": \"Photoreactive nucleotide-enhanced UV crosslinking with oligo(dT) purification and quantitative mass spectrometry in human cells\",\n      \"pmids\": [\"22681889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific mRNA targets and functional consequences of mRNA binding outside the ribosome were not determined\",\n        \"Whether RNA binding reflects a ribosome-associated or free-protein activity was unclear\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Three landmark advances converged: cryo-EM structures placed RPSA within the 40S subunit of the human 80S ribosome; human genetic studies showed heterozygous RPSA loss-of-function mutations cause isolated congenital asplenia via haploinsufficiency; and RPSA was identified as a cell-surface mediator of Aβ42 cytotoxicity.\",\n      \"evidence\": \"Cryo-EM of human 80S ribosome; whole-exome sequencing of 18 ICA patients across 8 kindreds; pull-down and shRNA rescue of Aβ42 toxicity\",\n      \"pmids\": [\"23636399\", \"23579497\", \"24048171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether asplenia reflects ribosomal or extra-ribosomal RPSA function was unresolved\",\n        \"Structural basis of laminin or Aβ42 binding at the cell surface was not determined\",\n        \"Developmental window and cell type requiring RPSA for splenic organogenesis were not identified\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Near-atomic resolution cryo-EM refined RPSA's structural role within the 40S subunit, while functional studies confirmed that RPSA knockdown induces apoptosis across multiple cancer types, reinforcing its pro-survival role.\",\n      \"evidence\": \"3.6 Å cryo-EM of human 80S ribosome; siRNA knockdown with two independent sequences in breast and oesophageal cancer lines\",\n      \"pmids\": [\"25901680\", \"26427016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the apoptotic effect of RPSA depletion is mediated through translational impairment, loss of laminin signaling, or both was not dissected\",\n        \"No animal model recapitulating cancer-cell RPSA dependency\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Expanded genetic analysis of ICA kindreds identified additional RPSA mutations including 5'-UTR splicing variants and de novo events, confirming autosomal dominant inheritance with incomplete penetrance and broadening the mutational spectrum.\",\n      \"evidence\": \"Whole-exome and Sanger sequencing with mRNA splicing analysis across 41% of ICA kindreds\",\n      \"pmids\": [\"30072435\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Modifier genes or environmental factors explaining incomplete penetrance were not identified\",\n        \"No animal model of RPSA heterozygous knockout recapitulating asplenia\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"RPSA was shown to form a functional signaling complex with the TRPM7 ion channel at the plasma membrane, mediating elastin-derived peptide-stimulated cancer cell migration, revealing a new receptor-channel partnership.\",\n      \"evidence\": \"Co-localization by immunofluorescence, patch-clamp electrophysiology, siRNA knockdown of TRPM7, Boyden chamber migration assay in pancreatic cancer cells\",\n      \"pmids\": [\"32733880\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct physical interaction between RPSA and TRPM7 was inferred from co-localization but not demonstrated by co-immunoprecipitation\",\n        \"Stoichiometry and structural basis of the complex were not characterized\",\n        \"Relevance of the TRPM7–RPSA axis beyond pancreatic cancer was not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mechanism by which RPSA haploinsufficiency specifically impairs spleen organogenesis — whether through ribosomal dysfunction (ribosomal haploinsufficiency), loss of laminin receptor signaling, or a combined effect — remains an open and central question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No conditional knockout animal model distinguishing ribosomal from extra-ribosomal functions in splenic development\",\n        \"Structural basis of RPSA's laminin and Aβ42 binding at the cell surface is unknown\",\n        \"Mechanism of 37-kDa to 67-kDa conversion remains unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 11, 12]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [8, 11]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 6, 10, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [1, 11, 12]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5, 10, 16]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 11, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 15]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\n      \"40S ribosomal small subunit\",\n      \"80S ribosome\"\n    ],\n    \"partners\": [\n      \"TRPM7\",\n      \"H2AFX\",\n      \"H2B\",\n      \"HIST1H4A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}