{"gene":"RPSA","run_date":"2026-06-10T07:46:27","timeline":{"discoveries":[{"year":2015,"finding":"RPSA (37/67-kDa laminin receptor, LAMR/RPSA) was originally identified as a 67-kDa laminin-binding protein and is evolutionarily derived from a 37-kDa RPS2-family ribosomal component; it contributes to laminin binding, ribosome biogenesis, cytoskeletal organization, and nuclear functions governing cell growth, survival, migration, protein synthesis, development, and differentiation.","method":"Review synthesizing experimental literature (binding assays, ribosome fractionation, functional studies)","journal":"Biological reviews of the Cambridge Philosophical Society","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — comprehensive review citing multiple independent experimental findings across labs, but individual method details not directly verifiable from abstract alone","pmids":["25630983"],"is_preprint":false},{"year":2012,"finding":"RPSA (p40/67LR) interacts with lysyl-tRNA synthetase (KRS) at the plasma membrane; on laminin signal, KRS is phosphorylated at T52 by p38MAPK, dissociates from the cytosolic multi-tRNA synthetase complex, translocates to the membrane, and inhibits Nedd4-mediated ubiquitination and degradation of 67LR (RPSA), thereby enhancing laminin-induced cell migration.","method":"Co-immunoprecipitation, site-directed mutagenesis of KRS T52, plasma membrane fractionation, siRNA knockdown, cell migration assays","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, mutagenesis, fractionation, and functional migration assay in single lab with multiple orthogonal methods","pmids":["22751010"],"is_preprint":false},{"year":2005,"finding":"RPSA (LAMR1) interacts with the PP-1 regulatory subunit TIMAP via TIMAP's fourth ankyrin repeat; TIMAP targets PP-1 to LAMR1, making LAMR1 a TIMAP-dependent PP-1 substrate (i.e., LAMR1 is phosphorylated and PP-1 dephosphorylates it).","method":"Yeast two-hybrid, co-immunoprecipitation in endothelial and MDCK cells, co-localization at plasma membrane, in vitro phosphatase assay","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by reciprocal Co-IP, in vitro phosphatase assay, domain-deletion validation; single lab but multiple orthogonal methods","pmids":["16263087"],"is_preprint":false},{"year":2005,"finding":"RPSA (LAMR1) interacts with dengue virus serotypes 1, 2, and 3 at the cell surface, identified as a common attachment/receptor protein for these serotypes.","method":"2D gel electrophoresis of membrane-enriched cell fractions followed by virus overlay protein binding assay (VOPBA)","journal":"Virology journal","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, single method (VOPBA); direct binding shown but no functional epistasis or mutagenesis","pmids":["15790424"],"is_preprint":false},{"year":2004,"finding":"Mutant LAMR1 (product of a functional retroposon) binds heterochromatin protein 1 (HP1) in cardiomyocytes, causing specific changes in gene expression and early cell death with chromatin architecture alteration, leading to right ventricular dysplasia in mice.","method":"Mouse genetics (retroposon knock-in, breeding, direct cardiac injection), in vitro cardiomyocyte expression, co-immunoprecipitation (HP1 binding), gene chip expression analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic model replicated by breeding and direct injection, Co-IP of HP1, gene expression profiling; multiple orthogonal methods establishing mechanism","pmids":["14730304"],"is_preprint":false},{"year":2019,"finding":"RPSA interacts with ITGA6 (identified by Co-IP + mass spectrometry) in pancreatic cancer cells; RPSA promotes invasion and metastasis via the MAPK/ERK signaling pathway (knockdown of RPSA reduces p-ERK1/2), independently of ITGA6-mediated PI3K/AKT signaling.","method":"Co-IP combined with mass spectrometry, siRNA knockdown, in vitro invasion assays, in vivo metastasis models, Western blotting for p-ERK1/2 and p-AKT","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS for interaction, loss-of-function with defined signaling readout (p-ERK1/2); single lab","pmids":["30894280"],"is_preprint":false},{"year":2020,"finding":"RPSA and TRPM7 co-localize at the plasma membrane of pancreatic cancer cells; elastin-derived peptides (EDPs) stimulate TRPM7 currents and promote cell migration through RPSA, and TRPM7 knockdown abolishes EDP-induced migration, indicating a functional TRPM7/RPSA complex at the membrane that regulates cancer cell migration.","method":"siRNA knockdown of TRPM7, Boyden chamber migration assay, patch-clamp electrophysiology, co-localization by immunofluorescence","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-localization and functional loss-of-function (siRNA + migration assay + electrophysiology); single lab, no direct Co-IP reported","pmids":["32733880"],"is_preprint":false},{"year":2015,"finding":"RPSA (LAMR1) binds aflatoxin B1 (AFB1) both in vitro (ELISA) and in vivo (laser confocal immunofluorescence), identifying RPSA as an AFB1-interacting protein in hepatocytes.","method":"Immobilized affinity chromatography (IAC), LC-MS/MS protein identification, ELISA, laser confocal immunofluorescence","journal":"Journal of hazardous materials","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, binding shown by ELISA and immunofluorescence but no functional consequence or mutagenesis established","pmids":["26372695"],"is_preprint":false},{"year":2015,"finding":"RPSA acts as a redox sensor: H2O2 oxidizes RPSA, causing it to accumulate in clusters containing specific adhesion molecules; RPSA oxidation improves cell adhesion to laminin in vitro and promotes cell extravasation in vivo.","method":"Redox proteomics to identify H2O2-target proteins, in vitro laminin adhesion assay, in vivo extravasation assay","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical identification of RPSA as H2O2 target with functional adhesion and in vivo extravasation readouts; single lab","pmids":["26603095"],"is_preprint":false},{"year":2018,"finding":"RPSA haploinsufficiency (via heterozygous mutations in protein-coding or 5'-UTR exons disrupting mRNA splicing) causes isolated congenital asplenia (ICA) in humans; the 5'-UTR mutations act by disrupting mRNA splicing, revealing a requirement for RPSA dosage in spleen development.","method":"Human genetics (Sanger sequencing of RPSA exons and UTR in 73 kindreds), splice assay for 5'-UTR mutations, identification of de novo mutations","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — large multi-kindred human genetic study with functional splice assay validation, replicated across independent families, de novo mutation confirmation","pmids":["30072435"],"is_preprint":false},{"year":2018,"finding":"RPSA is required for pre-rRNA processing and ribosome biogenesis; Xenopus tropicalis depletion of Rpsa disrupts pre-rRNA processing and impairs spleen patterning gene expression; human wild-type RPSA mRNA rescues these defects, but a disease-associated mutant RPSA mRNA cannot.","method":"Xenopus morpholino knockdown, pre-rRNA processing assays, in situ hybridization for spleen patterning genes, mRNA rescue experiments with wild-type and mutant human RPSA","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — loss-of-function in animal model with defined molecular (pre-rRNA processing) and developmental (spleen patterning) readouts, plus wild-type vs. disease-mutant mRNA rescue","pmids":["30337486"],"is_preprint":false},{"year":2014,"finding":"MGr1-Ag/RPSA (37LRP) promotes cell adhesion-mediated drug resistance (CAM-DR) in gastric cancer by interacting with laminin and activating FAK, which in turn activates PI3K/AKT and MAPK/ERK pathways, upregulating Bcl-2.","method":"Co-immunoprecipitation (FAK with RPSA), siRNA knockdown, monoclonal antibody blocking, antisense oligonucleotides, drug sensitivity assays, Western blotting for p-FAK, p-AKT, p-ERK, Bcl-2","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, multiple knockdown approaches, defined signaling readouts; single lab","pmids":["24703465"],"is_preprint":false},{"year":2010,"finding":"Hypoxia induces MGr1-Ag/RPSA (37LRP) expression via ERK/MAPK activation (which drives HIF-1 activity), and this MGr1-Ag expression enhances gastric cancer cell adhesion to laminin and protects against drug-induced apoptosis (CAM-DR); MEK inhibitor U0126 and RPSA siRNA reverse these effects.","method":"MEK overexpression, MEK inhibitor U0126, siRNA knockdown of RPSA, luciferase promoter assay, ERK activity assays, cell adhesion assay, apoptosis assay","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic manipulation with defined promoter, adhesion, and apoptosis readouts; single lab","pmids":["19998339"],"is_preprint":false},{"year":2007,"finding":"MGr1-Ag/RPSA overexpression upregulates HIF-1α protein expression and transcriptional activity under non-hypoxic conditions in gastric cancer cells via FAK-PI3K and MAPK/ERK signaling; siRNA targeting RPSA markedly decreases vincristine-induced HIF-1α expression.","method":"Forced overexpression, siRNA knockdown of RPSA, HIF-1 reporter assays (DNA binding, transcriptional activity), PI3K and MAPK inhibitors, Western blotting","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — OE and KD with defined HIF-1α signaling readout; single lab, no direct binding assay between RPSA and pathway components","pmids":["17476462"],"is_preprint":false},{"year":2021,"finding":"RPSA on the surface of porcine brain microvascular endothelial cells acts as the receptor for Streptococcus suis serotype 2 (SS2) enolase; enolase binding to RPSA activates intracellular p38/ERK-eIF4E signaling, promotes HSPD1 expression, initiates host-cell apoptosis, and increases blood-brain barrier (BBB) permeability.","method":"Protein interaction identification (pulldown/MS), co-immunoprecipitation, siRNA knockdown of RPSA, signaling pathway inhibitors, apoptosis assays, BBB permeability assay","journal":"Veterinary research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor identification with Co-IP, loss-of-function with defined signaling and functional readouts; single lab","pmids":["33618766"],"is_preprint":false},{"year":2021,"finding":"LAMR1 (RPSA) binds to Zika virus envelope (E) protein via its intracellular region and attenuates E protein ubiquitination by recruiting the deubiquitinase EIF3S5; the conserved G282 residue of the E protein is essential for interaction with LAMR1, and G282A substitution abolishes binding and LAMR1-mediated deubiquitination.","method":"Co-immunoprecipitation, siRNA knockdown, mutagenesis of ZIKV E protein (G282A), ubiquitination assay, viral replication assay","journal":"Virulence","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, mutagenesis, and functional ubiquitination assay; single lab","pmids":["34282707"],"is_preprint":false},{"year":2023,"finding":"Nuclear RPSA acts as an innate sensor of viral nucleic acids; upon viral infection, RPSA is phosphorylated at Tyr204, then recruits SMARCA5 (ISWI complex catalytic subunit) to increase chromatin accessibility at NF-κB target gene promoters, predominantly promoting proinflammatory cytokine gene expression without affecting type I IFN signaling; myeloid-specific Rpsa-deficient mice show reduced innate inflammatory responses to HSV-1 and IAV.","method":"Functional screening, myeloid-specific knockout mice, nuclear localization studies, viral nucleic acid binding assay, phosphorylation site identification, Co-IP of SMARCA5, ATAC-seq/chromatin accessibility assay, cytokine measurement","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO model with defined inflammatory phenotype, mechanistic Co-IP of SMARCA5, phosphorylation site mapped, chromatin accessibility assay, multiple orthogonal methods","pmids":["38114488"],"is_preprint":false},{"year":1996,"finding":"The active human 37LRP/RPSA gene is located at chromosome 3p21.3, contains 7 exons and 6 introns, lacks a TATA box, has multiple transcription start sites, and bears features characteristic of ribosomal protein genes; its C-terminal domain is a conserved structure likely involved in conversion to the 67-kDa laminin receptor form.","method":"Genomic cloning, intron-containing fragment isolation, fluorescent in situ hybridization (FISH), RNase protection assay, promoter analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct genomic characterization by cloning, FISH localization, and RNase protection; single lab but multiple methods","pmids":["8760291"],"is_preprint":false},{"year":2023,"finding":"PrPC (cellular prion protein) has high binding affinity for RPSA (37/67 kDa laminin receptor); small molecules antagonizing the PrPC-RPSA direct interaction have been characterized at the cellular level, and this interaction regulates tumor cell proliferation, migration, invasion, and autophagy-controlled cell death.","method":"Binding affinity assays, small-molecule antagonist characterization, cellular trafficking studies, functional assays for proliferation/migration/invasion","journal":"Cellular and molecular life sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review citing experimental characterization of interaction and antagonists from a single group; limited mechanistic detail in abstract","pmids":["37452879"],"is_preprint":false}],"current_model":"RPSA (37/67-kDa laminin receptor; LAMR1) is a multifunctional ribosomal protein SA that operates as a cell-surface laminin receptor, a nuclear innate sensor of viral nucleic acids (phosphorylated at Tyr204 upon infection to recruit SMARCA5 and drive NF-κB-dependent proinflammatory cytokines), a component of the small ribosomal subunit required for pre-rRNA processing and spleen organogenesis, and a signaling scaffold that—upon laminin engagement—activates FAK/PI3K/AKT and MAPK/ERK pathways to promote cell adhesion, migration, and drug resistance; its surface expression is regulated by Nedd4-mediated ubiquitination (counteracted by KRS) and TIMAP-targeted PP-1 dephosphorylation, and it is exploited as an attachment receptor by dengue virus and as an intracellular interactor (via its intracellular domain) that restricts Zika virus by recruiting the deubiquitinase EIF3S5 to attenuate viral envelope protein ubiquitination."},"narrative":{"mechanistic_narrative":"RPSA is a dual-function protein that operates both as a component of the small ribosomal subunit required for pre-rRNA processing and ribosome biogenesis and as a cell-surface laminin receptor that transduces adhesion and migration signals [PMID:25630983, PMID:30337486]. As a ribosome biogenesis factor, RPSA dosage is essential for development: haploinsufficiency from heterozygous coding or splice-disrupting 5'-UTR mutations causes human isolated congenital asplenia, and depletion in Xenopus disrupts pre-rRNA processing and spleen patterning gene expression, defects rescued by wild-type but not disease-mutant RPSA mRNA [PMID:30072435, PMID:30337486]. At the plasma membrane, laminin engagement of RPSA activates FAK, which drives PI3K/AKT and MAPK/ERK signaling to promote adhesion, migration, invasion, and cell-adhesion-mediated drug resistance with Bcl-2 upregulation [PMID:24703465, PMID:30894280]; this axis feeds forward through HIF-1α induction under both hypoxic and non-hypoxic conditions [PMID:19998339, PMID:17476462]. RPSA surface availability is set by competing post-translational controls: Nedd4-mediated ubiquitination targets it for degradation, which is antagonized by lysyl-tRNA synthetase (KRS) recruited to the membrane upon laminin signaling, while the PP-1 regulatory subunit TIMAP targets PP-1 to dephosphorylate RPSA [PMID:22751010, PMID:16263087]. RPSA also functions in the nucleus as an innate sensor of viral nucleic acids: upon infection it is phosphorylated at Tyr204 and recruits the ISWI catalytic subunit SMARCA5 to open chromatin at NF-κB target promoters, selectively driving proinflammatory cytokine expression, and myeloid Rpsa-deficient mice show blunted inflammatory responses to HSV-1 and IAV [PMID:38114488]. It is additionally exploited as a cell-surface attachment/receptor by dengue virus and by Streptococcus suis enolase, and it restricts Zika virus by binding the viral envelope protein via its intracellular region and recruiting a deubiquitinase to attenuate E-protein ubiquitination [PMID:15790424, PMID:33618766, PMID:34282707].","teleology":[{"year":1996,"claim":"Establishing that the active human 37LRP/RPSA gene has the genomic architecture of a ribosomal protein gene answered whether the laminin receptor and a ribosomal component share a single locus, anchoring its dual identity.","evidence":"Genomic cloning, FISH mapping to 3p21.3, RNase protection and promoter analysis","pmids":["8760291"],"confidence":"Medium","gaps":["Did not establish how the 37-kDa precursor converts to the 67-kDa laminin receptor form","No functional dissection of ribosomal vs. receptor roles"]},{"year":2004,"claim":"Demonstrating that a mutant LAMR1 retroposon product binds HP1 and remodels cardiomyocyte chromatin gave the first in vivo evidence that RPSA has nuclear, chromatin-linked functions with developmental consequences.","evidence":"Mouse retroposon knock-in genetics, cardiac injection, HP1 Co-IP, gene chip expression profiling","pmids":["14730304"],"confidence":"High","gaps":["Concerns a mutant retroposon product, not wild-type RPSA","Mechanism linking HP1 binding to specific gene expression changes not fully resolved"]},{"year":2005,"claim":"Identifying TIMAP-targeted PP-1 dephosphorylation of LAMR1 and dengue virus binding at the surface defined RPSA as a phospho-regulated membrane receptor and a viral attachment protein.","evidence":"Yeast two-hybrid, reciprocal Co-IP, in vitro phosphatase assay, domain deletion (TIMAP), and VOPBA for dengue serotypes 1-3","pmids":["16263087","15790424"],"confidence":"High","gaps":["The RPSA phosphosite(s) targeted by TIMAP/PP-1 not mapped","Dengue binding shown by VOPBA only, without functional infection epistasis"]},{"year":2007,"claim":"Linking RPSA overexpression to HIF-1α induction via FAK-PI3K and MAPK/ERK connected surface receptor signaling to a transcriptional survival program in cancer cells.","evidence":"Overexpression, siRNA knockdown, HIF-1 reporter assays, PI3K/MAPK inhibitors, Western blotting","pmids":["17476462"],"confidence":"Medium","gaps":["No direct binding shown between RPSA and pathway components","Single cancer cell context"]},{"year":2010,"claim":"Showing hypoxia induces RPSA through ERK/MAPK-driven HIF-1 and that RPSA mediates laminin adhesion and drug resistance closed a feedforward loop between the microenvironment and RPSA-dependent survival.","evidence":"MEK overexpression/inhibition (U0126), RPSA siRNA, luciferase promoter assay, adhesion and apoptosis assays","pmids":["19998339"],"confidence":"Medium","gaps":["Causal ordering of ERK→HIF-1→RPSA vs. RPSA→ERK not fully separated","Single tumor type"]},{"year":2012,"claim":"Defining KRS-mediated protection of RPSA from Nedd4 ubiquitination established a positive-feedback mechanism that stabilizes surface RPSA during laminin-induced migration.","evidence":"Co-IP, KRS T52 mutagenesis, membrane fractionation, siRNA, migration assays","pmids":["22751010"],"confidence":"High","gaps":["Direct demonstration of Nedd4-RPSA ubiquitin linkage limited","RPSA ubiquitination sites not mapped"]},{"year":2014,"claim":"Mapping the laminin-FAK-PI3K/AKT-MAPK/ERK-Bcl-2 cascade in gastric cancer specified how RPSA confers cell-adhesion-mediated drug resistance.","evidence":"FAK-RPSA Co-IP, siRNA, antibody blocking, antisense oligonucleotides, drug sensitivity and phospho-protein Westerns","pmids":["24703465"],"confidence":"Medium","gaps":["Whether RPSA directly binds FAK or via an intermediate not resolved","Single lab/cancer type"]},{"year":2015,"claim":"Identifying RPSA as an H2O2 redox sensor whose oxidation enhances laminin adhesion and extravasation added a post-translational, oxidation-driven control over its receptor function.","evidence":"Redox proteomics, in vitro laminin adhesion assay, in vivo extravasation assay","pmids":["26603095"],"confidence":"Medium","gaps":["Oxidized cysteine residue(s) not mapped","Mechanism linking oxidation to adhesion-molecule clustering unresolved"]},{"year":2018,"claim":"Human asplenia genetics plus Xenopus rescue experiments established that RPSA dosage and its pre-rRNA processing function are required for spleen development, with disease mutants failing to rescue.","evidence":"Multi-kindred Sanger sequencing with splice assays; Xenopus morpholino knockdown, pre-rRNA processing assays, in situ hybridization, wild-type vs. mutant mRNA rescue","pmids":["30072435","30337486"],"confidence":"High","gaps":["Why ribosome biogenesis defects affect spleen specifically remains unexplained","Link between rRNA processing and spleen patterning genes mechanistically incomplete"]},{"year":2019,"claim":"Establishing an RPSA-ITGA6 interaction that drives MAPK/ERK invasion independently of ITGA6's PI3K/AKT arm refined how RPSA partitions downstream signaling in metastasis.","evidence":"Co-IP/MS, siRNA, in vitro invasion and in vivo metastasis assays, p-ERK1/2 and p-AKT Westerns","pmids":["30894280"],"confidence":"Medium","gaps":["Direct vs. indirect RPSA-ITGA6 contact not defined","Single cancer model"]},{"year":2020,"claim":"Demonstrating a functional TRPM7/RPSA membrane complex that couples elastin-derived peptides to migration extended RPSA's receptor repertoire to ion-channel-linked signaling.","evidence":"TRPM7 siRNA, Boyden chamber migration, patch-clamp, immunofluorescence co-localization","pmids":["32733880"],"confidence":"Medium","gaps":["No direct Co-IP between RPSA and TRPM7","Stoichiometry and physical nature of the complex unknown"]},{"year":2021,"claim":"Two host-pathogen studies showed RPSA acts both as a surface receptor for Streptococcus suis enolase driving BBB-disrupting apoptosis and as an intracellular restriction factor for Zika virus envelope protein, revealing opposite roles in distinct infections.","evidence":"Pulldown/MS and Co-IP, RPSA siRNA, signaling inhibitors, BBB permeability and apoptosis assays (S. suis); Co-IP, ZIKV E G282A mutagenesis, EIF3S5 recruitment and ubiquitination assays (Zika)","pmids":["33618766","34282707"],"confidence":"Medium","gaps":["Single-lab findings without reciprocal cross-validation","How surface vs. intracellular RPSA pools are partitioned for these roles is unclear"]},{"year":2023,"claim":"Defining nuclear RPSA as a Tyr204-phosphorylated viral nucleic acid sensor that recruits SMARCA5 to open NF-κB target chromatin established a distinct innate-immune transcriptional function separate from its ribosomal and receptor roles.","evidence":"Functional screening, myeloid-specific Rpsa-KO mice, viral nucleic acid binding, phosphosite mapping, SMARCA5 Co-IP, ATAC-seq, cytokine measurement (HSV-1, IAV)","pmids":["38114488"],"confidence":"High","gaps":["The kinase phosphorylating Tyr204 is not identified","How a ribosomal/membrane protein traffics to the nucleus to sense nucleic acids is unresolved"]},{"year":null,"claim":"It remains unknown how a single protein is partitioned between the ribosome, the plasma membrane receptor pool, and the nucleus, and what controls the switch among these functions.","evidence":"No timeline discovery directly addresses the trafficking/conversion mechanism between RPSA pools","pmids":[],"confidence":"Low","gaps":["No structural model of the 37-to-67 kDa conversion or of the laminin-binding interface","Subcellular partitioning signals not defined","Relationship between ribosomal function and surface receptor function unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,10]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[3,14]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[8,16]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[10,16]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,3,6,14]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,16]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[0,10]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[11,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,13,5]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,14,15]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9,10]}],"complexes":["small ribosomal subunit","TRPM7/RPSA membrane complex"],"partners":["KRS","TIMAP","ITGA6","TRPM7","FAK","SMARCA5","HP1","NEDD4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"A0A8I5KQE6","full_name":"Small ribosomal subunit protein uS2B","aliases":["37 kDa laminin receptor precursor","37LRP","37/67 kDa laminin receptor","LRP/LR","40S ribosomal protein SA","40S ribosomal protein SA2","67 kDa laminin receptor","67LR","Laminin receptor 1","LamR","Laminin-binding protein precursor p40","LBP/p40"],"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. Also acts as a receptor for several other ligands, including the pathogenic prion protein, viruses, and bacteria. Acts as a PPP1R16B-dependent substrate of PPP1CA","subcellular_location":"Cell membrane; Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/A0A8I5KQE6/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":"10470081","id":"PMC_10470081","title":"Cytomegalovirus US2 destroys two components of the MHC class II pathway, preventing 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ubiquitination.","date":"2021","source":"Virulence","url":"https://pubmed.ncbi.nlm.nih.gov/34282707","citation_count":16,"is_preprint":false},{"pmid":"26603095","id":"PMC_26603095","title":"Hydrogen peroxide regulates cell adhesion through the redox sensor RPSA.","date":"2015","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26603095","citation_count":16,"is_preprint":false},{"pmid":"30781310","id":"PMC_30781310","title":"New Polish Isolate of Pepino mosaic virus Highly Distinct from European Tomato, Peruvian, and US2 Strains.","date":"2006","source":"Plant disease","url":"https://pubmed.ncbi.nlm.nih.gov/30781310","citation_count":16,"is_preprint":false},{"pmid":"17934803","id":"PMC_17934803","title":"Complete genomic RNA sequence of the Polish Pepino mosaic virus isolate belonging to the US2 strain.","date":"2007","source":"Virus genes","url":"https://pubmed.ncbi.nlm.nih.gov/17934803","citation_count":16,"is_preprint":false},{"pmid":"30337486","id":"PMC_30337486","title":"RPSA, a candidate gene for isolated congenital asplenia, is required for pre-rRNA processing and spleen formation in Xenopus.","date":"2018","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/30337486","citation_count":15,"is_preprint":false},{"pmid":"32433489","id":"PMC_32433489","title":"Mycobacterium tuberculosis ribosomal protein S1 (RpsA) and variants with truncated C-terminal end show absence of interaction with pyrazinoic acid.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32433489","citation_count":15,"is_preprint":false},{"pmid":"20554783","id":"PMC_20554783","title":"Pseudorabies virus tegument protein Us2 recruits the mitogen-activated protein kinase extracellular-regulated kinase (ERK) to membranes through interaction with the ERK common docking domain.","date":"2010","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/20554783","citation_count":15,"is_preprint":false},{"pmid":"16687410","id":"PMC_16687410","title":"A structural determinant of human cytomegalovirus US2 dictates the down-regulation of class I major histocompatibility molecules.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16687410","citation_count":15,"is_preprint":false},{"pmid":"33430125","id":"PMC_33430125","title":"The UFM1 Pathway Impacts HCMV US2-Mediated Degradation of HLA Class I.","date":"2021","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/33430125","citation_count":14,"is_preprint":false},{"pmid":"9524817","id":"PMC_9524817","title":"Nucleotide sequence of canine herpesvirus homologues of herpes simplex virus type 1 US2, US3, glycoproteins I and E, US8.5 and US9 genes.","date":"1997","source":"DNA sequence : the journal of DNA sequencing and mapping","url":"https://pubmed.ncbi.nlm.nih.gov/9524817","citation_count":14,"is_preprint":false},{"pmid":"26535693","id":"PMC_26535693","title":"Identification and characterization of the duck enteritis virus (DEV) US2 gene.","date":"2015","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/26535693","citation_count":13,"is_preprint":false},{"pmid":"28827540","id":"PMC_28827540","title":"The Us2 Gene Product of Herpes Simplex Virus 2 modulates NF-κB activation by targeting TAK1.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28827540","citation_count":13,"is_preprint":false},{"pmid":"23785212","id":"PMC_23785212","title":"The Us2 gene product of herpes simplex virus 2 is a membrane-associated ubiquitin-interacting protein.","date":"2013","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/23785212","citation_count":13,"is_preprint":false},{"pmid":"24460263","id":"PMC_24460263","title":"RPSA gene mutants associated with risk of colorectal cancer among the chinese population.","date":"2013","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/24460263","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47232,"output_tokens":4881,"usd":0.107455,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13137,"output_tokens":4881,"usd":0.093855,"stage2_stop_reason":"end_turn"},"total_usd":0.20131,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"RPSA (37/67-kDa laminin receptor, LAMR/RPSA) was originally identified as a 67-kDa laminin-binding protein and is evolutionarily derived from a 37-kDa RPS2-family ribosomal component; it contributes to laminin binding, ribosome biogenesis, cytoskeletal organization, and nuclear functions governing cell growth, survival, migration, protein synthesis, development, and differentiation.\",\n      \"method\": \"Review synthesizing experimental literature (binding assays, ribosome fractionation, functional studies)\",\n      \"journal\": \"Biological reviews of the Cambridge Philosophical Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — comprehensive review citing multiple independent experimental findings across labs, but individual method details not directly verifiable from abstract alone\",\n      \"pmids\": [\"25630983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RPSA (p40/67LR) interacts with lysyl-tRNA synthetase (KRS) at the plasma membrane; on laminin signal, KRS is phosphorylated at T52 by p38MAPK, dissociates from the cytosolic multi-tRNA synthetase complex, translocates to the membrane, and inhibits Nedd4-mediated ubiquitination and degradation of 67LR (RPSA), thereby enhancing laminin-induced cell migration.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis of KRS T52, plasma membrane fractionation, siRNA knockdown, cell migration assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, mutagenesis, fractionation, and functional migration assay in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22751010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RPSA (LAMR1) interacts with the PP-1 regulatory subunit TIMAP via TIMAP's fourth ankyrin repeat; TIMAP targets PP-1 to LAMR1, making LAMR1 a TIMAP-dependent PP-1 substrate (i.e., LAMR1 is phosphorylated and PP-1 dephosphorylates it).\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in endothelial and MDCK cells, co-localization at plasma membrane, in vitro phosphatase assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by reciprocal Co-IP, in vitro phosphatase assay, domain-deletion validation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"16263087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RPSA (LAMR1) interacts with dengue virus serotypes 1, 2, and 3 at the cell surface, identified as a common attachment/receptor protein for these serotypes.\",\n      \"method\": \"2D gel electrophoresis of membrane-enriched cell fractions followed by virus overlay protein binding assay (VOPBA)\",\n      \"journal\": \"Virology journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (VOPBA); direct binding shown but no functional epistasis or mutagenesis\",\n      \"pmids\": [\"15790424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mutant LAMR1 (product of a functional retroposon) binds heterochromatin protein 1 (HP1) in cardiomyocytes, causing specific changes in gene expression and early cell death with chromatin architecture alteration, leading to right ventricular dysplasia in mice.\",\n      \"method\": \"Mouse genetics (retroposon knock-in, breeding, direct cardiac injection), in vitro cardiomyocyte expression, co-immunoprecipitation (HP1 binding), gene chip expression analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic model replicated by breeding and direct injection, Co-IP of HP1, gene expression profiling; multiple orthogonal methods establishing mechanism\",\n      \"pmids\": [\"14730304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RPSA interacts with ITGA6 (identified by Co-IP + mass spectrometry) in pancreatic cancer cells; RPSA promotes invasion and metastasis via the MAPK/ERK signaling pathway (knockdown of RPSA reduces p-ERK1/2), independently of ITGA6-mediated PI3K/AKT signaling.\",\n      \"method\": \"Co-IP combined with mass spectrometry, siRNA knockdown, in vitro invasion assays, in vivo metastasis models, Western blotting for p-ERK1/2 and p-AKT\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS for interaction, loss-of-function with defined signaling readout (p-ERK1/2); single lab\",\n      \"pmids\": [\"30894280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RPSA and TRPM7 co-localize at the plasma membrane of pancreatic cancer cells; elastin-derived peptides (EDPs) stimulate TRPM7 currents and promote cell migration through RPSA, and TRPM7 knockdown abolishes EDP-induced migration, indicating a functional TRPM7/RPSA complex at the membrane that regulates cancer cell migration.\",\n      \"method\": \"siRNA knockdown of TRPM7, Boyden chamber migration assay, patch-clamp electrophysiology, co-localization by immunofluorescence\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-localization and functional loss-of-function (siRNA + migration assay + electrophysiology); single lab, no direct Co-IP reported\",\n      \"pmids\": [\"32733880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RPSA (LAMR1) binds aflatoxin B1 (AFB1) both in vitro (ELISA) and in vivo (laser confocal immunofluorescence), identifying RPSA as an AFB1-interacting protein in hepatocytes.\",\n      \"method\": \"Immobilized affinity chromatography (IAC), LC-MS/MS protein identification, ELISA, laser confocal immunofluorescence\",\n      \"journal\": \"Journal of hazardous materials\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, binding shown by ELISA and immunofluorescence but no functional consequence or mutagenesis established\",\n      \"pmids\": [\"26372695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RPSA acts as a redox sensor: H2O2 oxidizes RPSA, causing it to accumulate in clusters containing specific adhesion molecules; RPSA oxidation improves cell adhesion to laminin in vitro and promotes cell extravasation in vivo.\",\n      \"method\": \"Redox proteomics to identify H2O2-target proteins, in vitro laminin adhesion assay, in vivo extravasation assay\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical identification of RPSA as H2O2 target with functional adhesion and in vivo extravasation readouts; single lab\",\n      \"pmids\": [\"26603095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RPSA haploinsufficiency (via heterozygous mutations in protein-coding or 5'-UTR exons disrupting mRNA splicing) causes isolated congenital asplenia (ICA) in humans; the 5'-UTR mutations act by disrupting mRNA splicing, revealing a requirement for RPSA dosage in spleen development.\",\n      \"method\": \"Human genetics (Sanger sequencing of RPSA exons and UTR in 73 kindreds), splice assay for 5'-UTR mutations, identification of de novo mutations\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — large multi-kindred human genetic study with functional splice assay validation, replicated across independent families, de novo mutation confirmation\",\n      \"pmids\": [\"30072435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RPSA is required for pre-rRNA processing and ribosome biogenesis; Xenopus tropicalis depletion of Rpsa disrupts pre-rRNA processing and impairs spleen patterning gene expression; human wild-type RPSA mRNA rescues these defects, but a disease-associated mutant RPSA mRNA cannot.\",\n      \"method\": \"Xenopus morpholino knockdown, pre-rRNA processing assays, in situ hybridization for spleen patterning genes, mRNA rescue experiments with wild-type and mutant human RPSA\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — loss-of-function in animal model with defined molecular (pre-rRNA processing) and developmental (spleen patterning) readouts, plus wild-type vs. disease-mutant mRNA rescue\",\n      \"pmids\": [\"30337486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MGr1-Ag/RPSA (37LRP) promotes cell adhesion-mediated drug resistance (CAM-DR) in gastric cancer by interacting with laminin and activating FAK, which in turn activates PI3K/AKT and MAPK/ERK pathways, upregulating Bcl-2.\",\n      \"method\": \"Co-immunoprecipitation (FAK with RPSA), siRNA knockdown, monoclonal antibody blocking, antisense oligonucleotides, drug sensitivity assays, Western blotting for p-FAK, p-AKT, p-ERK, Bcl-2\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, multiple knockdown approaches, defined signaling readouts; single lab\",\n      \"pmids\": [\"24703465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Hypoxia induces MGr1-Ag/RPSA (37LRP) expression via ERK/MAPK activation (which drives HIF-1 activity), and this MGr1-Ag expression enhances gastric cancer cell adhesion to laminin and protects against drug-induced apoptosis (CAM-DR); MEK inhibitor U0126 and RPSA siRNA reverse these effects.\",\n      \"method\": \"MEK overexpression, MEK inhibitor U0126, siRNA knockdown of RPSA, luciferase promoter assay, ERK activity assays, cell adhesion assay, apoptosis assay\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic manipulation with defined promoter, adhesion, and apoptosis readouts; single lab\",\n      \"pmids\": [\"19998339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MGr1-Ag/RPSA overexpression upregulates HIF-1α protein expression and transcriptional activity under non-hypoxic conditions in gastric cancer cells via FAK-PI3K and MAPK/ERK signaling; siRNA targeting RPSA markedly decreases vincristine-induced HIF-1α expression.\",\n      \"method\": \"Forced overexpression, siRNA knockdown of RPSA, HIF-1 reporter assays (DNA binding, transcriptional activity), PI3K and MAPK inhibitors, Western blotting\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — OE and KD with defined HIF-1α signaling readout; single lab, no direct binding assay between RPSA and pathway components\",\n      \"pmids\": [\"17476462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RPSA on the surface of porcine brain microvascular endothelial cells acts as the receptor for Streptococcus suis serotype 2 (SS2) enolase; enolase binding to RPSA activates intracellular p38/ERK-eIF4E signaling, promotes HSPD1 expression, initiates host-cell apoptosis, and increases blood-brain barrier (BBB) permeability.\",\n      \"method\": \"Protein interaction identification (pulldown/MS), co-immunoprecipitation, siRNA knockdown of RPSA, signaling pathway inhibitors, apoptosis assays, BBB permeability assay\",\n      \"journal\": \"Veterinary research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor identification with Co-IP, loss-of-function with defined signaling and functional readouts; single lab\",\n      \"pmids\": [\"33618766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LAMR1 (RPSA) binds to Zika virus envelope (E) protein via its intracellular region and attenuates E protein ubiquitination by recruiting the deubiquitinase EIF3S5; the conserved G282 residue of the E protein is essential for interaction with LAMR1, and G282A substitution abolishes binding and LAMR1-mediated deubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, mutagenesis of ZIKV E protein (G282A), ubiquitination assay, viral replication assay\",\n      \"journal\": \"Virulence\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, mutagenesis, and functional ubiquitination assay; single lab\",\n      \"pmids\": [\"34282707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nuclear RPSA acts as an innate sensor of viral nucleic acids; upon viral infection, RPSA is phosphorylated at Tyr204, then recruits SMARCA5 (ISWI complex catalytic subunit) to increase chromatin accessibility at NF-κB target gene promoters, predominantly promoting proinflammatory cytokine gene expression without affecting type I IFN signaling; myeloid-specific Rpsa-deficient mice show reduced innate inflammatory responses to HSV-1 and IAV.\",\n      \"method\": \"Functional screening, myeloid-specific knockout mice, nuclear localization studies, viral nucleic acid binding assay, phosphorylation site identification, Co-IP of SMARCA5, ATAC-seq/chromatin accessibility assay, cytokine measurement\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO model with defined inflammatory phenotype, mechanistic Co-IP of SMARCA5, phosphorylation site mapped, chromatin accessibility assay, multiple orthogonal methods\",\n      \"pmids\": [\"38114488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The active human 37LRP/RPSA gene is located at chromosome 3p21.3, contains 7 exons and 6 introns, lacks a TATA box, has multiple transcription start sites, and bears features characteristic of ribosomal protein genes; its C-terminal domain is a conserved structure likely involved in conversion to the 67-kDa laminin receptor form.\",\n      \"method\": \"Genomic cloning, intron-containing fragment isolation, fluorescent in situ hybridization (FISH), RNase protection assay, promoter analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct genomic characterization by cloning, FISH localization, and RNase protection; single lab but multiple methods\",\n      \"pmids\": [\"8760291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PrPC (cellular prion protein) has high binding affinity for RPSA (37/67 kDa laminin receptor); small molecules antagonizing the PrPC-RPSA direct interaction have been characterized at the cellular level, and this interaction regulates tumor cell proliferation, migration, invasion, and autophagy-controlled cell death.\",\n      \"method\": \"Binding affinity assays, small-molecule antagonist characterization, cellular trafficking studies, functional assays for proliferation/migration/invasion\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review citing experimental characterization of interaction and antagonists from a single group; limited mechanistic detail in abstract\",\n      \"pmids\": [\"37452879\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RPSA (37/67-kDa laminin receptor; LAMR1) is a multifunctional ribosomal protein SA that operates as a cell-surface laminin receptor, a nuclear innate sensor of viral nucleic acids (phosphorylated at Tyr204 upon infection to recruit SMARCA5 and drive NF-κB-dependent proinflammatory cytokines), a component of the small ribosomal subunit required for pre-rRNA processing and spleen organogenesis, and a signaling scaffold that—upon laminin engagement—activates FAK/PI3K/AKT and MAPK/ERK pathways to promote cell adhesion, migration, and drug resistance; its surface expression is regulated by Nedd4-mediated ubiquitination (counteracted by KRS) and TIMAP-targeted PP-1 dephosphorylation, and it is exploited as an attachment receptor by dengue virus and as an intracellular interactor (via its intracellular domain) that restricts Zika virus by recruiting the deubiquitinase EIF3S5 to attenuate viral envelope protein ubiquitination.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RPSA is a dual-function protein that operates both as a component of the small ribosomal subunit required for pre-rRNA processing and ribosome biogenesis and as a cell-surface laminin receptor that transduces adhesion and migration signals [#0, #10]. As a ribosome biogenesis factor, RPSA dosage is essential for development: haploinsufficiency from heterozygous coding or splice-disrupting 5'-UTR mutations causes human isolated congenital asplenia, and depletion in Xenopus disrupts pre-rRNA processing and spleen patterning gene expression, defects rescued by wild-type but not disease-mutant RPSA mRNA [#9, #10]. At the plasma membrane, laminin engagement of RPSA activates FAK, which drives PI3K/AKT and MAPK/ERK signaling to promote adhesion, migration, invasion, and cell-adhesion-mediated drug resistance with Bcl-2 upregulation [#11, #5]; this axis feeds forward through HIF-1\\u03b1 induction under both hypoxic and non-hypoxic conditions [#12, #13]. RPSA surface availability is set by competing post-translational controls: Nedd4-mediated ubiquitination targets it for degradation, which is antagonized by lysyl-tRNA synthetase (KRS) recruited to the membrane upon laminin signaling, while the PP-1 regulatory subunit TIMAP targets PP-1 to dephosphorylate RPSA [#1, #2]. RPSA also functions in the nucleus as an innate sensor of viral nucleic acids: upon infection it is phosphorylated at Tyr204 and recruits the ISWI catalytic subunit SMARCA5 to open chromatin at NF-\\u03baB target promoters, selectively driving proinflammatory cytokine expression, and myeloid Rpsa-deficient mice show blunted inflammatory responses to HSV-1 and IAV [#16]. It is additionally exploited as a cell-surface attachment/receptor by dengue virus and by Streptococcus suis enolase, and it restricts Zika virus by binding the viral envelope protein via its intracellular region and recruiting a deubiquitinase to attenuate E-protein ubiquitination [#3, #14, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing that the active human 37LRP/RPSA gene has the genomic architecture of a ribosomal protein gene answered whether the laminin receptor and a ribosomal component share a single locus, anchoring its dual identity.\",\n      \"evidence\": \"Genomic cloning, FISH mapping to 3p21.3, RNase protection and promoter analysis\",\n      \"pmids\": [\"8760291\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish how the 37-kDa precursor converts to the 67-kDa laminin receptor form\", \"No functional dissection of ribosomal vs. receptor roles\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that a mutant LAMR1 retroposon product binds HP1 and remodels cardiomyocyte chromatin gave the first in vivo evidence that RPSA has nuclear, chromatin-linked functions with developmental consequences.\",\n      \"evidence\": \"Mouse retroposon knock-in genetics, cardiac injection, HP1 Co-IP, gene chip expression profiling\",\n      \"pmids\": [\"14730304\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Concerns a mutant retroposon product, not wild-type RPSA\", \"Mechanism linking HP1 binding to specific gene expression changes not fully resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identifying TIMAP-targeted PP-1 dephosphorylation of LAMR1 and dengue virus binding at the surface defined RPSA as a phospho-regulated membrane receptor and a viral attachment protein.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP, in vitro phosphatase assay, domain deletion (TIMAP), and VOPBA for dengue serotypes 1-3\",\n      \"pmids\": [\"16263087\", \"15790424\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The RPSA phosphosite(s) targeted by TIMAP/PP-1 not mapped\", \"Dengue binding shown by VOPBA only, without functional infection epistasis\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linking RPSA overexpression to HIF-1\\u03b1 induction via FAK-PI3K and MAPK/ERK connected surface receptor signaling to a transcriptional survival program in cancer cells.\",\n      \"evidence\": \"Overexpression, siRNA knockdown, HIF-1 reporter assays, PI3K/MAPK inhibitors, Western blotting\",\n      \"pmids\": [\"17476462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct binding shown between RPSA and pathway components\", \"Single cancer cell context\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showing hypoxia induces RPSA through ERK/MAPK-driven HIF-1 and that RPSA mediates laminin adhesion and drug resistance closed a feedforward loop between the microenvironment and RPSA-dependent survival.\",\n      \"evidence\": \"MEK overexpression/inhibition (U0126), RPSA siRNA, luciferase promoter assay, adhesion and apoptosis assays\",\n      \"pmids\": [\"19998339\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal ordering of ERK\\u2192HIF-1\\u2192RPSA vs. RPSA\\u2192ERK not fully separated\", \"Single tumor type\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defining KRS-mediated protection of RPSA from Nedd4 ubiquitination established a positive-feedback mechanism that stabilizes surface RPSA during laminin-induced migration.\",\n      \"evidence\": \"Co-IP, KRS T52 mutagenesis, membrane fractionation, siRNA, migration assays\",\n      \"pmids\": [\"22751010\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration of Nedd4-RPSA ubiquitin linkage limited\", \"RPSA ubiquitination sites not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapping the laminin-FAK-PI3K/AKT-MAPK/ERK-Bcl-2 cascade in gastric cancer specified how RPSA confers cell-adhesion-mediated drug resistance.\",\n      \"evidence\": \"FAK-RPSA Co-IP, siRNA, antibody blocking, antisense oligonucleotides, drug sensitivity and phospho-protein Westerns\",\n      \"pmids\": [\"24703465\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether RPSA directly binds FAK or via an intermediate not resolved\", \"Single lab/cancer type\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying RPSA as an H2O2 redox sensor whose oxidation enhances laminin adhesion and extravasation added a post-translational, oxidation-driven control over its receptor function.\",\n      \"evidence\": \"Redox proteomics, in vitro laminin adhesion assay, in vivo extravasation assay\",\n      \"pmids\": [\"26603095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Oxidized cysteine residue(s) not mapped\", \"Mechanism linking oxidation to adhesion-molecule clustering unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Human asplenia genetics plus Xenopus rescue experiments established that RPSA dosage and its pre-rRNA processing function are required for spleen development, with disease mutants failing to rescue.\",\n      \"evidence\": \"Multi-kindred Sanger sequencing with splice assays; Xenopus morpholino knockdown, pre-rRNA processing assays, in situ hybridization, wild-type vs. mutant mRNA rescue\",\n      \"pmids\": [\"30072435\", \"30337486\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why ribosome biogenesis defects affect spleen specifically remains unexplained\", \"Link between rRNA processing and spleen patterning genes mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing an RPSA-ITGA6 interaction that drives MAPK/ERK invasion independently of ITGA6's PI3K/AKT arm refined how RPSA partitions downstream signaling in metastasis.\",\n      \"evidence\": \"Co-IP/MS, siRNA, in vitro invasion and in vivo metastasis assays, p-ERK1/2 and p-AKT Westerns\",\n      \"pmids\": [\"30894280\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect RPSA-ITGA6 contact not defined\", \"Single cancer model\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating a functional TRPM7/RPSA membrane complex that couples elastin-derived peptides to migration extended RPSA's receptor repertoire to ion-channel-linked signaling.\",\n      \"evidence\": \"TRPM7 siRNA, Boyden chamber migration, patch-clamp, immunofluorescence co-localization\",\n      \"pmids\": [\"32733880\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct Co-IP between RPSA and TRPM7\", \"Stoichiometry and physical nature of the complex unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Two host-pathogen studies showed RPSA acts both as a surface receptor for Streptococcus suis enolase driving BBB-disrupting apoptosis and as an intracellular restriction factor for Zika virus envelope protein, revealing opposite roles in distinct infections.\",\n      \"evidence\": \"Pulldown/MS and Co-IP, RPSA siRNA, signaling inhibitors, BBB permeability and apoptosis assays (S. suis); Co-IP, ZIKV E G282A mutagenesis, EIF3S5 recruitment and ubiquitination assays (Zika)\",\n      \"pmids\": [\"33618766\", \"34282707\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab findings without reciprocal cross-validation\", \"How surface vs. intracellular RPSA pools are partitioned for these roles is unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defining nuclear RPSA as a Tyr204-phosphorylated viral nucleic acid sensor that recruits SMARCA5 to open NF-\\u03baB target chromatin established a distinct innate-immune transcriptional function separate from its ribosomal and receptor roles.\",\n      \"evidence\": \"Functional screening, myeloid-specific Rpsa-KO mice, viral nucleic acid binding, phosphosite mapping, SMARCA5 Co-IP, ATAC-seq, cytokine measurement (HSV-1, IAV)\",\n      \"pmids\": [\"38114488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The kinase phosphorylating Tyr204 is not identified\", \"How a ribosomal/membrane protein traffics to the nucleus to sense nucleic acids is unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how a single protein is partitioned between the ribosome, the plasma membrane receptor pool, and the nucleus, and what controls the switch among these functions.\",\n      \"evidence\": \"No timeline discovery directly addresses the trafficking/conversion mechanism between RPSA pools\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the 37-to-67 kDa conversion or of the laminin-binding interface\", \"Subcellular partitioning signals not defined\", \"Relationship between ribosomal function and surface receptor function unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [3, 14]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [8, 16]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [10, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 3, 6, 14]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 16]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [0, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [11, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 13, 5]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 14, 15]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"complexes\": [\n      \"small ribosomal subunit\",\n      \"TRPM7/RPSA membrane complex\"\n    ],\n    \"partners\": [\n      \"KRS\",\n      \"TIMAP\",\n      \"ITGA6\",\n      \"TRPM7\",\n      \"FAK\",\n      \"SMARCA5\",\n      \"HP1\",\n      \"Nedd4\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}