{"gene":"ATP6AP2","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2002,"finding":"Expression cloning of the human (pro)renin receptor (ATP6AP2) identified a 350-amino acid single-transmembrane-domain protein with specific renin and prorenin binding. Receptor binding increased the catalytic efficiency of angiotensinogen conversion to angiotensin I by fourfold and induced intracellular signaling including phosphorylation of serine and tyrosine residues and activation of MAP kinases ERK1 and ERK2. Confocal microscopy localized the receptor to glomerular mesangium and subendothelium of coronary and kidney arteries, co-localizing with renin.","method":"Expression cloning, radioligand binding assay, stable transfection, in vitro angiotensinogen conversion assay, phosphorylation assay, ERK activation assay, confocal microscopy","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 — original cloning with multiple orthogonal functional assays (binding, enzymatic, signaling, localization) in a highly cited foundational paper","pmids":["12045255"],"is_preprint":false},{"year":1998,"finding":"A novel 9.2-kDa protein (M9.2, later identified as ATP6AP2) was identified as a component of the membrane sector of vacuolar proton-translocating ATPase (V-ATPase) isolated from bovine chromaffin granules by blue native PAGE. It showed sequence and structural similarity to yeast Vma21p, required for V-ATPase assembly.","method":"Blue native PAGE, biochemical fractionation of chromaffin granule membranes, amino-terminal protein sequencing, sequence analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct biochemical isolation and sequencing of protein from native V-ATPase complex, highly cited foundational paper","pmids":["9556572"],"is_preprint":false},{"year":2006,"finding":"The transcription factor promyelocytic zinc finger protein (PLZF) was identified as a direct protein interaction partner of the C-terminal domain of ATP6AP2/(pro)renin receptor via yeast two-hybrid screening and co-immunoprecipitation. Upon renin activation of the receptor, PLZF translocates to the nucleus, represses transcription of the receptor itself (negative feedback), and activates transcription of the PI3K p85α subunit. Renin stimulation of cardiomyoblasts increased cell number and decreased apoptosis via this PLZF/PI3K pathway. The receptor also homodimerizes.","method":"Yeast two-hybrid screening, co-immunoprecipitation, siRNA knockdown, chromatin immunoprecipitation, electrophoretic mobility-shift assay, site-directed mutagenesis, PLZF knockout mice","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (Y2H, co-IP, ChIP, EMSA, mutagenesis, KO mice) in a highly cited paper","pmids":["17082479"],"is_preprint":false},{"year":2006,"finding":"Renin acting through ATP6AP2/(pro)renin receptor on mesangial cells induces TGF-β1 and matrix proteins (PAI-1, fibronectin, collagen I) through a receptor-mediated, angiotensin II-independent mechanism. siRNA knockdown of the renin receptor mRNA abolished these effects, demonstrating the receptor is required for renin-induced TGF-β1 upregulation.","method":"siRNA knockdown, recombinant renin treatment, renin enzymatic inhibitor controls, angiotensin receptor antagonist controls, mRNA and protein quantification","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 2 — siRNA knockdown with specific inhibitor controls establishes receptor-mediated, Ang II-independent mechanism; highly cited","pmids":["16374430"],"is_preprint":false},{"year":2007,"finding":"Transgenic rats overexpressing human ATP6AP2/(pro)renin receptor developed proteinuria and glomerulosclerosis with MAPK activation and increased TGF-β1 expression in kidneys, independent of angiotensin II elevation and blood pressure changes. A (pro)renin receptor blocker peptide inhibited these effects, while ACE inhibition did not, establishing that the receptor directly drives Ang II-independent MAPK signaling and nephropathy.","method":"Transgenic rat generation, (pro)renin receptor blocker peptide infusion, ACE inhibitor treatment, MAPK activity assays, TGF-β1 expression analysis, histology, proteinuria measurement, cell culture receptor activation","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 2 — in vivo transgenic and pharmacological dissection with multiple endpoints; highly cited","pmids":["17494887"],"is_preprint":false},{"year":2010,"finding":"ATP6AP2/(pro)renin receptor (PRR) was identified as a component of the Wnt receptor complex, functioning as an adaptor between Wnt receptors (LRP6/Frizzled) and the vacuolar H+-ATPase (V-ATPase) complex in a renin-independent manner. PRR and V-ATPase activity (and hence endosomal acidification) were required for Wnt/β-catenin signal transmission and for antero-posterior patterning of Xenopus early central nervous system development.","method":"Co-immunoprecipitation, siRNA knockdown in HEK293 and other cell lines, Wnt reporter assays, Xenopus embryo microinjection and morpholino knockdown, epistasis analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical complex identification plus in vivo epistasis in Xenopus; published in Science, highly cited","pmids":["20093472"],"is_preprint":false},{"year":2012,"finding":"Full-length ATP6AP2/(P)RR acts as a repressor of Wnt signaling in a system pre-activated by Wnt3a or constitutively active β-catenin. The repressive effects are mediated through Dishevelled (Dvl) but are independent of β-catenin mutation status. The V-ATPase complex, but not PLZF translocation or renin enzymatic activity, is necessary for induction of Tcf/Lef-responsive genes by Wnt3a.","method":"Tcf/Lef luciferase reporter assays in HEK293T and HepG2 cells, endogenous Axin2 mRNA and protein quantification, Wnt3a stimulation, constitutively active β-catenin overexpression","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2-3 — reporter assays and endogenous target gene quantification; single lab but multiple cell lines and conditions","pmids":["23022225"],"is_preprint":false},{"year":2013,"finding":"Using siRNA against (P)RR, stable overexpression of PLZF, and specific inhibitors of V-ATPase (bafilomycin) and PLZF (genistein), distinct and overlapping transcriptional signatures downstream of ATP6AP2 were identified by microarray and ChIP-chip analyses. This revealed separate genetic programs controlled by the V-ATPase-associated function versus the PLZF-mediated signaling function of (P)RR, with novel target genes validated by real-time PCR.","method":"siRNA knockdown, stable PLZF overexpression, bafilomycin and genistein treatment, microarray transcriptomics, chromatin immunoprecipitation-chip (ChIP-chip), real-time PCR validation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal approaches dissecting distinct downstream pathways; single lab","pmids":["23469216"],"is_preprint":false},{"year":2016,"finding":"Adipose tissue-specific knockout of ATP6AP2/(P)RR (using AP2-Cre) in mice resulted in lower body weight, reduced fat mass, smaller adipocytes, increased locomotor activity, higher circulating adiponectin, and improved insulin sensitivity. These findings establish a role for adipose (P)RR in regulating fat mass, metabolic rate, and insulin sensitivity.","method":"Conditional knockout using Cre-loxP (AP2-Cre), metabolic cage analysis, glucose tolerance test, insulin/C-peptide measurements, adiponectin ELISA, body composition analysis","journal":"Molecular metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — clean conditional KO with defined metabolic phenotypes; single lab","pmids":["27689008"],"is_preprint":false},{"year":2020,"finding":"Cryo-electron microscopy of rat brain V-ATPase at near-atomic resolution revealed that ATP6AP2/PRR and ATP6AP1/Ac45 are transmembrane accessory subunits whose cleaved forms have their transmembrane anchors enclosed within the c-ring of the V-ATPase membrane sector (Vo), enabling assembly of the catalytic (V1) and membrane (Vo) regions of the enzyme. The structure defines an ATP:proton ratio of 3:10 for brain V-ATPase.","method":"Cryo-electron microscopy, SidK-based affinity purification of native brain V-ATPase, atomic model building","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure with atomic model from native brain tissue; published in Science","pmids":["32165585"],"is_preprint":false},{"year":2021,"finding":"Tubular epithelial-specific overexpression of ATP6AP2/(P)RR in transgenic mice caused hypertension and alkalized urine with lower osmolality and Na+ excretion. Bafilomycin (V-ATPase antagonist) acidized urine of (P)RR-TG mice, restoring the V-ATPase function phenotype. Double-transgenic mice co-expressing tubular (P)RR and intracellular alternative renin (ARen2) developed lethal renal tubular damage, suggesting intracellular renin acts as a ligand for (P)RR in tubules and that (P)RR functions as V-ATPase in renal tubules.","method":"Transgenic mouse generation, ARB/DRI/bafilomycin treatment, metabolic cage urine analysis, double-transgenic crossing, renal histopathology","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — transgenic overexpression with pharmacological dissection; single lab, multiple endpoints","pmids":["35008728"],"is_preprint":false},{"year":2023,"finding":"siRNA knockdown of ATP6AP2/(P)RR in HTR-8/SVneo trophoblast cells impaired proliferation, migration, and invasion. In vivo lentiviral knockdown of (P)RR specifically in the trophectoderm of mouse blastocysts reduced placental labyrinth trophoblast number, decreased total surface area available for exchange, increased maternal blood space, and reduced fetal-placental weight ratio, demonstrating (P)RR is necessary for appropriate placental development and function.","method":"siRNA knockdown, xCELLigence real-time cell analysis (proliferation, migration, invasion), lentiviral (P)RR shRNA knockdown in mouse blastocysts, embryo transfer to pseudopregnant mice, stereological morphometry of placentae at EA10 and EA18","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro siRNA plus in vivo lentiviral knockdown with quantitative morphometric readouts; single lab","pmids":["37588662"],"is_preprint":false},{"year":2025,"finding":"Sustained exposure of cells to mycolactone (a Sec61 inhibitor) caused loss of ATP6AP1 and ATP6AP2, which are Sec61-dependent substrates required for V-ATPase assembly, leading to reduced lysosomal biogenesis and acidification. This demonstrates that ATP6AP2 requires co-translational translocation via Sec61 into the ER for its biosynthesis and subsequent V-ATPase assembly.","method":"Mycolactone treatment, immunoblotting for ATP6AP2 and ATP6AP1, TFEB nuclear translocation assay, lysosomal acidification assay, autophagy flux assay","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic dissection of biosynthetic requirement; preprint, single lab","pmids":["bio_10.1101_2025.08.26.671788"],"is_preprint":true},{"year":2025,"finding":"In a model of spontaneous hypertension combined with MAFLD, hepatic (P)RR/ERK/PPARγ pathway and downstream fatty acid synthesis and transport proteins were upregulated. Blocking (P)RR with handle region peptide (HRP) reversed activation of ERK and PPARγ and reduced intracellular lipid accumulation in renin-activated HepG2 cells, identifying a (P)RR/ERK/PPARγ axis in hepatic lipid metabolism.","method":"SHR animal model, renin-activated HepG2 cell model, HRP pharmacological blockade, immunoblotting, Nile red fluorescence staining, immunofluorescence, RNA sequencing, liver histology","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 — in vivo and in vitro with pharmacological blockade and multiple readouts; single lab, novel pathway claim","pmids":["40650317"],"is_preprint":false},{"year":2025,"finding":"In a two-kidney one-clip mouse model, collecting duct-specific deletion of ATP6AP2/(pro)renin receptor (CD PRR KO) was identified as a key upstream regulator of intrarenal aldosterone biosynthesis. CD PRR KO reduced the hypertensive and fibrotic response to renovascular constriction, establishing (P)RR as a regulator of intrarenal renin-dependent aldosterone generation and ischemic nephropathy.","method":"Inducible renal tubule-specific C11B2 KO, collecting duct-specific PRR KO (CD PRR KO) and renin KO mice, 2K1C surgical model, blood pressure measurement, renal fibrosis/inflammation histology, aldosterone assays","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with defined physiological phenotypes; preprint, single lab","pmids":["bio_10.1101_2025.08.24.671658"],"is_preprint":true}],"current_model":"ATP6AP2 (PRR/(pro)renin receptor) is a single-pass transmembrane protein that functions as an accessory subunit of the vacuolar H+-ATPase (V-ATPase), with its cleaved transmembrane anchor embedded within the V-ATPase c-ring (established by cryo-EM structure); it binds renin and prorenin to enhance angiotensin I generation and activate ERK1/2 and MAP kinase signaling independent of angiotensin II; it interacts directly with PLZF to drive a nuclear signaling cascade activating PI3K-p85α; it serves as an essential adaptor between Wnt receptors and V-ATPase to enable endosomal acidification required for Wnt/β-catenin signal transduction; it also represses Wnt signaling through Dishevelled in a context-dependent manner; and it requires Sec61-mediated co-translational ER insertion for its biosynthesis and V-ATPase assembly, with tissue-specific roles established in kidney tubules, adipose tissue, placenta, and liver."},"narrative":{"teleology":[{"year":1998,"claim":"Identification of a novel 9.2-kDa protein (M9.2) as a membrane-sector component of V-ATPase established that ATP6AP2 is physically part of the proton pump, analogous to yeast Vma21p.","evidence":"Blue native PAGE and amino-terminal sequencing of bovine chromaffin granule V-ATPase","pmids":["9556572"],"confidence":"High","gaps":["Exact topology within the V-ATPase complex was unknown","Whether M9.2 had any function beyond V-ATPase assembly was not addressed"]},{"year":2002,"claim":"Expression cloning revealed that the same protein is a cell-surface receptor for renin and prorenin, answering how renin signals intracellularly independent of angiotensin II and establishing a dual identity for ATP6AP2.","evidence":"Expression cloning, radioligand binding, angiotensinogen conversion assay, ERK1/2 phosphorylation, and confocal microscopy in human cell lines and tissue sections","pmids":["12045255"],"confidence":"High","gaps":["Structural basis of dual function (receptor vs. V-ATPase subunit) unresolved","Downstream signaling beyond ERK1/2 was unknown"]},{"year":2006,"claim":"Discovery of PLZF as a direct cytoplasmic interaction partner and demonstration of renin-induced fibrogenic gene programs revealed distinct downstream signaling branches — a PLZF/PI3K-p85α nuclear pathway and an angiotensin II–independent TGF-β1/matrix protein axis.","evidence":"Yeast two-hybrid, co-IP, ChIP, EMSA, PLZF KO mice (PLZF pathway); siRNA knockdown with renin inhibitor and Ang II receptor antagonist controls in mesangial cells (TGF-β1 pathway)","pmids":["17082479","16374430"],"confidence":"High","gaps":["Whether PLZF and ERK pathways are independent or convergent was not resolved","In vivo disease relevance of PLZF axis remained untested"]},{"year":2007,"claim":"Transgenic overexpression in rats demonstrated that receptor-level activation is sufficient to cause nephropathy (proteinuria, glomerulosclerosis) with MAPK/TGF-β1 activation, establishing in vivo pathogenic relevance independent of angiotensin II.","evidence":"Transgenic rat model with PRR blocker peptide and ACE inhibitor controls, proteinuria and histology endpoints","pmids":["17494887"],"confidence":"High","gaps":["Whether the blocker peptide acts exclusively at PRR was debated","Mechanism linking receptor overexpression to V-ATPase function in vivo was not addressed"]},{"year":2010,"claim":"Identification of ATP6AP2 as an essential adaptor between Wnt receptors and V-ATPase for β-catenin signaling revealed a third, renin-independent function and explained how endosomal acidification is coupled to developmental signaling.","evidence":"Co-IP of PRR with LRP6 and V-ATPase subunits, Wnt reporter assays, Xenopus morpholino knockdown with epistasis analysis","pmids":["20093472"],"confidence":"High","gaps":["Structural basis for PRR bridging LRP6 to V-ATPase was unknown","Context-dependent repression vs. activation of Wnt signaling was not reconciled"]},{"year":2012,"claim":"The finding that full-length PRR can repress Wnt signaling through Dishevelled showed that its Wnt-modulatory role is context-dependent and bidirectional, separating V-ATPase-dependent Wnt activation from a Dvl-mediated repressive function.","evidence":"Tcf/Lef luciferase reporters and endogenous Axin2 quantification in HEK293T and HepG2 cells stimulated with Wnt3a or constitutively active β-catenin","pmids":["23022225"],"confidence":"Medium","gaps":["Molecular determinants distinguishing activating vs. repressive modes remain unidentified","In vivo relevance of Wnt-repressive function not tested"]},{"year":2013,"claim":"Genome-wide dissection of V-ATPase versus PLZF transcriptional programs downstream of PRR established that these two functions control distinct but partially overlapping gene networks.","evidence":"siRNA knockdown, stable PLZF overexpression, bafilomycin/genistein treatment, microarray and ChIP-chip in cell lines","pmids":["23469216"],"confidence":"Medium","gaps":["Physiological relevance of the identified target genes was not validated in vivo","Extent of overlap between V-ATPase and PLZF programs was not fully resolved"]},{"year":2016,"claim":"Adipose-specific knockout demonstrated that PRR regulates fat mass, metabolic rate, and insulin sensitivity, extending its physiological roles beyond the cardiovascular and renal systems.","evidence":"AP2-Cre conditional knockout mice with metabolic cage analysis, glucose tolerance tests, adiponectin measurements","pmids":["27689008"],"confidence":"Medium","gaps":["Whether the adipose phenotype is V-ATPase-dependent or renin-receptor-dependent was not determined","Downstream lipid-metabolic mechanism in adipocytes was not resolved"]},{"year":2020,"claim":"Near-atomic cryo-EM of brain V-ATPase resolved how ATP6AP2 integrates into the proton pump: its cleaved transmembrane domain is enclosed within the Vo c-ring, providing the first structural explanation for its dual identity as both a V-ATPase subunit and a receptor.","evidence":"Cryo-EM of SidK-affinity-purified rat brain V-ATPase at near-atomic resolution with atomic model building","pmids":["32165585"],"confidence":"High","gaps":["How uncleaved full-length PRR simultaneously presents the ectodomain for renin binding and integrates into V-ATPase is structurally unresolved","Tissue-specific regulation of cleavage and c-ring incorporation is unknown"]},{"year":2021,"claim":"Tubule-specific overexpression and double-transgenic studies showed that intracellular renin can act as a ligand for PRR within renal tubular epithelium, linking V-ATPase-dependent urinary acidification to intracrine renin signaling.","evidence":"Transgenic mouse overexpression, bafilomycin treatment, double-transgenic crossing with intracellular renin (ARen2), metabolic cage urine analysis and renal histopathology","pmids":["35008728"],"confidence":"Medium","gaps":["Direct binding of intracellular renin to PRR in tubular cells was not biochemically demonstrated","Mechanism of lethal tubular damage in double-transgenics was not resolved"]},{"year":2023,"claim":"In vivo trophoblast-specific knockdown established that PRR is required for placental labyrinth development and fetal-placental growth, expanding its developmental biology role beyond Xenopus axis patterning to mammalian organogenesis.","evidence":"siRNA in HTR-8/SVneo trophoblast cells plus lentiviral shRNA knockdown in mouse blastocyst trophectoderm with stereological placental morphometry","pmids":["37588662"],"confidence":"Medium","gaps":["Whether placental phenotype is Wnt-dependent, V-ATPase-dependent, or renin-signaling-dependent is unknown","Human placental disease relevance (e.g., pre-eclampsia) not established"]},{"year":2025,"claim":"Identification of a PRR/ERK/PPARγ axis in hepatic lipid metabolism and demonstration that collecting-duct PRR regulates intrarenal aldosterone biosynthesis extended the tissue-specific signaling repertoire to liver steatosis and renovascular hypertension.","evidence":"SHR animal model with renin-activated HepG2 cells and HRP blockade (liver); collecting-duct-specific PRR KO and 2K1C surgical model (kidney)","pmids":["40650317","bio_10.1101_2025.08.24.671658"],"confidence":"Medium","gaps":["PRR/ERK/PPARγ axis awaits independent replication","Direct PRR–aldosterone synthase regulatory mechanism is undefined","Both studies are from single laboratories"]},{"year":null,"claim":"It remains unknown how the full-length receptor simultaneously accommodates extracellular renin/prorenin binding and c-ring integration, how tissue-specific proteolytic processing is regulated, and what determines whether PRR activates or represses Wnt signaling in a given cellular context.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of full-length uncleaved PRR in complex with renin or prorenin exists","Protease(s) and regulation of PRR cleavage are incompletely defined","Context-dependent switch between Wnt activation and repression is mechanistically unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,3,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,6]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[5,9]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[9,12]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1,9]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,3,4,5,6,13]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[1,9,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,11]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[8,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,10]}],"complexes":["V-ATPase (Vo sector)","Wnt signalosome (LRP6/Frizzled/PRR/V-ATPase)"],"partners":["ATP6AP1","ZBTB16","LRP6","FZD8","REN","DVL2"],"other_free_text":[]},"mechanistic_narrative":"ATP6AP2 is a multifunctional single-pass transmembrane protein that serves both as an accessory subunit of the vacuolar H⁺-ATPase (V-ATPase) and as a cell-surface receptor for renin and prorenin, coupling extracellular renin-angiotensin signaling to intracellular proton pump function. As a V-ATPase component, its cleaved transmembrane anchor is enclosed within the Vo c-ring, where it is essential for V-ATPase assembly and endosomal/lysosomal acidification [PMID:32165585, PMID:9556572]; this acidification function is co-opted by the Wnt signaling pathway, in which ATP6AP2 acts as an adaptor bridging Wnt receptors (LRP6/Frizzled) to V-ATPase to enable β-catenin signal transduction [PMID:20093472]. As a renin/prorenin receptor, ligand binding enhances angiotensinogen-to-angiotensin I conversion and activates angiotensin II–independent intracellular signaling through ERK1/2 MAP kinases and, via the transcription factor PLZF, through PI3K-p85α, driving fibrogenic (TGF-β1, fibronectin, collagen I) and proliferative programs in kidney, heart, adipose tissue, placenta, and liver [PMID:12045255, PMID:17082479, PMID:16374430, PMID:27689008]. Transgenic overexpression of ATP6AP2 in renal tubules or glomeruli causes hypertension, proteinuria, and glomerulosclerosis independently of angiotensin II, establishing the receptor as a direct contributor to nephropathy [PMID:17494887, PMID:35008728]."},"prefetch_data":{"uniprot":{"accession":"O75787","full_name":"Renin receptor","aliases":["ATPase H(+)-transporting lysosomal accessory protein 2","ATPase H(+)-transporting lysosomal-interacting protein 2","ER-localized type I transmembrane adapter","Embryonic liver differentiation factor 10","N14F","Renin/prorenin receptor","Vacuolar ATP synthase membrane sector-associated protein M8-9","ATP6M8-9","V-ATPase M8.9 subunit"],"length_aa":350,"mass_kda":39.0,"function":"Multifunctional protein which functions as a renin, prorenin cellular receptor and is involved in the assembly of the lysosomal proton-transporting V-type ATPase (V-ATPase) and the acidification of the endo-lysosomal system (PubMed:12045255, PubMed:29127204, PubMed:30374053, PubMed:32276428). May mediate renin-dependent cellular responses by activating ERK1 and ERK2 (PubMed:12045255). By increasing the catalytic efficiency of renin in AGT/angiotensinogen conversion to angiotensin I, may also play a role in the renin-angiotensin system (RAS) (PubMed:12045255). Through its function in V-type ATPase (v-ATPase) assembly and acidification of the lysosome it regulates protein degradation and may control different signaling pathways important for proper brain development, synapse morphology and synaptic transmission (By similarity)","subcellular_location":"Endoplasmic reticulum membrane; Lysosome membrane; Cytoplasmic vesicle, autophagosome membrane; Cell projection, dendritic spine membrane; Cell projection, axon; Endosome membrane; Cytoplasmic vesicle, clathrin-coated vesicle membrane; Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane","url":"https://www.uniprot.org/uniprotkb/O75787/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ATP6AP2","classification":"Common Essential","n_dependent_lines":1089,"n_total_lines":1208,"dependency_fraction":0.9014900662251656},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000182220","cell_line_id":"CID001640","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"golgi","grade":2}],"interactors":[{"gene":"ATP6AP1","stoichiometry":10.0},{"gene":"ATP6V1G1","stoichiometry":10.0},{"gene":"TFRC","stoichiometry":10.0},{"gene":"ATP6V1A","stoichiometry":10.0},{"gene":"ATP6V1E1","stoichiometry":10.0},{"gene":"ATP6V0C","stoichiometry":10.0},{"gene":"ATP6V1B2","stoichiometry":10.0},{"gene":"ATP6V1D","stoichiometry":10.0},{"gene":"WBP11","stoichiometry":10.0},{"gene":"ATP6V0D1","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001640","total_profiled":1310},"omim":[{"mim_id":"616877","title":"TRANSMEMBRANE PROTEIN 9; TMEM9","url":"https://www.omim.org/entry/616877"},{"mim_id":"603931","title":"ATPase, H+ TRANSPORTING, LYSOSOMAL, 9-KD, V0 SUBUNIT E1; ATP6V0E1","url":"https://www.omim.org/entry/603931"},{"mim_id":"301045","title":"CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIr; CDG2R","url":"https://www.omim.org/entry/301045"},{"mim_id":"300915","title":"MICROPHTHALMIA, SYNDROMIC 13; MCOPS13","url":"https://www.omim.org/entry/300915"},{"mim_id":"300911","title":"PARKINSONISM WITH SPASTICITY, X-LINKED; XPDS","url":"https://www.omim.org/entry/300911"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"parathyroid gland","ntpm":719.4}],"url":"https://www.proteinatlas.org/search/ATP6AP2"},"hgnc":{"alias_symbol":["PRR","M8-9","RENR","(P)RR","APT6M8-9","ATP6M8-9"],"prev_symbol":["ATP6IP2"]},"alphafold":{"accession":"O75787","domains":[{"cath_id":"-","chopping":"15-267","consensus_level":"high","plddt":84.7245,"start":15,"end":267},{"cath_id":"1.20.5","chopping":"303-344","consensus_level":"high","plddt":85.3586,"start":303,"end":344}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75787","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75787-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75787-F1-predicted_aligned_error_v6.png","plddt_mean":79.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATP6AP2","jax_strain_url":"https://www.jax.org/strain/search?query=ATP6AP2"},"sequence":{"accession":"O75787","fasta_url":"https://rest.uniprot.org/uniprotkb/O75787.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75787/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75787"}},"corpus_meta":[{"pmid":"12767698","id":"PMC_12767698","title":"Comparative 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The V-ATPase complex, but not PLZF translocation or renin enzymatic activity, is necessary for induction of Tcf/Lef-responsive genes by Wnt3a.\",\n      \"method\": \"Tcf/Lef reporter gene systems in HEK293T and HepG2 cells; quantification of endogenous axin2 mRNA and protein levels; siRNA and overexpression constructs; V-ATPase inhibitor (bafilomycin) and PLZF inhibitor (genistein)\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in a single study (reporter assay, endogenous target, pharmacological inhibitors), but from a single lab\",\n      \"pmids\": [\"23022225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Downstream signal transduction of (P)RR/ATP6AP2 involves two distinct pathways: (1) V-ATPase-dependent transcriptional regulation and (2) PLZF-dependent transcriptional regulation. Microarray and ChIP-chip analyses identified distinct and overlapping gene signatures for each pathway, establishing that the transmembrane/intracellular part of (P)RR acts as a V-ATPase accessory protein with separate signalling from its PLZF adaptor function.\",\n      \"method\": \"Microarray gene expression profiling; ChIP-chip; siRNA knockdown of (P)RR; stable PLZF overexpression; PLZF translocation inhibitor (genistein); V-ATPase inhibitor (bafilomycin); qRT-PCR validation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal genomic and pharmacological methods in a single lab\",\n      \"pmids\": [\"23469216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Adipose-tissue-specific knockout of ATP6AP2/(P)RR in mice reduces body weight and fat mass, increases locomotor activity and basal metabolic rate (in males), lowers plasma insulin and C-peptide indicating improved insulin sensitivity, and raises circulating adiponectin, demonstrating a functional role for (P)RR in adipose tissue energy homeostasis and insulin sensitivity.\",\n      \"method\": \"Cre-loxP adipose-specific knockout (AP2-Cre); metabolic cage analyses; glucose tolerance test; plasma hormone measurements; body composition assessment\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean tissue-specific KO with multiple defined metabolic phenotypic readouts in a single lab\",\n      \"pmids\": [\"27689008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Tubular-specific overexpression of (P)RR/ATP6AP2 in transgenic mice causes hypertension with alkalized urine and lower urinary Na⁺ excretion. The V-ATPase antagonist bafilomycin acidized urine of transgenic mice (restoring normal phenotype), while ARB and DRI (but not bafilomycin) reduced blood pressure, indicating that (P)RR functions as a V-ATPase component in renal tubules. Double transgenic mice co-expressing tubular (P)RR and intracellular alternative renin exhibited lethal renal tubular damage, suggesting intracellular renin acts as a (P)RR ligand.\",\n      \"method\": \"Tubular epithelial (P)RR transgenic mice; double transgenic cross with alternative renin mice; metabolic cage analyses; pharmacological treatment with ARB, DRI, and bafilomycin; urine chemistry\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transgenic animal model with pharmacological dissection and multiple readouts in a single lab\",\n      \"pmids\": [\"35008728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"siRNA knockdown of ATP6AP2/(P)RR in the first-trimester extravillous trophoblast cell line HTR-8/SVneo impairs trophoblast proliferation, migration, and invasion (measured by real-time cell analysis). In vivo lentiviral knockdown of (P)RR in mouse blastocyst trophectoderm reduces placental labyrinth trophoblast number, decreases total surface area available for exchange, increases maternal blood space, and reduces the fetal-placental weight ratio, establishing a direct functional role for (P)RR in placental development.\",\n      \"method\": \"siRNA knockdown; xCELLigence real-time cell analysis (proliferation, migration, invasion); lentiviral trophectoderm-specific knockdown in vivo; stereological placental morphometry; fetal-placental weight ratio\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — both in vitro and in vivo loss-of-function with defined cellular phenotypes, single lab\",\n      \"pmids\": [\"37588662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The (pro)renin receptor (P)RR/ATP6AP2, upon binding renin or prorenin, nonproteolytically activates prorenin, enabling catalytic conversion of angiotensinogen to angiotensin I, and also transduces intracellular signals to the nucleus. Chronic infusion of the peptidic (P)RR blocker (handle-region peptide) prevented streptozotocin-induced diabetic nephropathy and attenuated hypertensive cardiomyopathy and nephropathy in vivo.\",\n      \"method\": \"In vivo chronic infusion of handle-region peptide receptor blocker in diabetic and hypertensive rat models; transgenic rat overexpression model; measurement of end-organ damage\",\n      \"journal\": \"Journal of the American Society of Hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo pharmacological blockade and transgenic overexpression with defined organ damage readouts; review-level synthesis of multiple experiments\",\n      \"pmids\": [\"20409904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"(P)RR/ATP6AP2 serves a dual role: (1) as an essential accessory protein of vacuolar H⁺-ATPase (V-ATPase) and (2) as an adaptor protein of Wnt signalling, with distinct intracellular signalling pathways activated ligand-independently through its transmembrane and intracellular domains.\",\n      \"method\": \"Review synthesizing siRNA knockdown, pharmacological V-ATPase inhibition, PLZF translocation assays, and reporter gene studies from prior publications\",\n      \"journal\": \"Current pharmaceutical design\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — review synthesis of multiple prior experiments, consistent with primary data in other papers in corpus\",\n      \"pmids\": [\"23844810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Sustained Sec61 inhibition by mycolactone leads to loss of ATP6AP1 and ATP6AP2 (both Sec61-dependent substrates required for V-ATPase assembly), resulting in reduced lysosomal biogenesis and acidification, impaired late-stage autophagy, and nuclear translocation of the lysosomal stress marker TFEB. This establishes ATP6AP2 as a Sec61 substrate whose co-translational import into the ER is required for V-ATPase assembly and lysosomal function.\",\n      \"method\": \"Mycolactone treatment of cells; immunoblot for ATP6AP2 and ATP6AP1; lysosomal acidification assays; TFEB localization; autophagy flux assays; comparison with Sec61 substrate controls\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays in a single preprint demonstrating mechanistic link between ATP6AP2 ER import and V-ATPase/lysosome function\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In a mouse model of ischemia-induced hypertension (2K1C), collecting duct (P)RR (ATP6AP2) and collecting duct renin are identified as key upstream regulators of intrarenal aldosterone biosynthesis; collecting duct-specific (P)RR knockout attenuates 2K1C-induced intrarenal aldosterone generation, renal fibrosis, and inflammation.\",\n      \"method\": \"Collecting duct-specific conditional (P)RR KO mice (CD PRR KO); 2K1C surgical model; intrarenal and circulating aldosterone measurement; renal fibrosis and inflammation histology\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KO with defined pathway placement and multiple phenotypic readouts, single preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In atherosclerotic ApoE⁻/⁻ mice, ELABELA-21 treatment reduced PRR/(P)RR/ATP6AP2 protein expression in aortic root plaques and decreased plasma soluble PRR levels, while modulating macrophage M1/M2 balance. In vitro in THP-1 cells, APJ inhibitor ML221 further enhanced anti-inflammatory effects of ELA-21 with elevated ATP6AP2 mRNA, suggesting ATP6AP2 participates in macrophage inflammatory signalling downstream of the apelin receptor system.\",\n      \"method\": \"ApoE⁻/⁻ mouse atherosclerosis model; immunoblot/immunofluorescence for PRR in plaques; ELISA for soluble PRR; in vitro macrophage polarization assay; qPCR for ATP6AP2 mRNA\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — mechanistic placement is indirect, single preprint, ATP6AP2 measured as downstream readout rather than directly manipulated\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In the mouse hypothalamic paraventricular nucleus (PVN), ATP6AP2/(pro)renin receptor is predominantly expressed in neurons (not astrocytes). DOCA-salt hypertension increases neuronal Atp6ap2 expression, while HFD-induced obesity upregulates Atp6ap2 specifically in vasopressin neurons, indicating cell-type-specific regulation of ATP6AP2 under cardiometabolic stress.\",\n      \"method\": \"Single-nucleus RNA sequencing of PVN; DOCA-salt and high-fat diet mouse models; cell-type deconvolution and differential expression analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — transcriptomic localization without direct functional manipulation of ATP6AP2; single preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Offspring of preeclamptic rats show elevated (P)RR/ATP6AP2 expression in cardiovascular and renal tissues alongside activation of PLZF and canonical Wnt pathway molecules (β-catenin, DVL-1, PKCα). Treatment with the handle region peptide (HRP) abolished increased (P)RR, PLZF, and Wnt signalling and reduced hypertension, establishing that (P)RR mediates offspring hypertension via the canonical Wnt pathway.\",\n      \"method\": \"Preeclampsia rat model; immunoblot for (P)RR, PLZF, β-catenin, DVL-1, PKCα; RT-PCR; HRP pharmacological blockade; blood pressure measurement\",\n      \"journal\": \"Iranian journal of basic medical sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — pharmacological blockade with pathway markers, single lab, no direct genetic manipulation of ATP6AP2\",\n      \"pmids\": [\"38629095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"(P)RR/ATP6AP2 overexpression in spontaneously hypertensive rats and renin-stimulated HepG2 cells activates the (P)RR/ERK/PPARγ axis, upregulating downstream proteins related to fatty acid synthesis and transport, promoting hepatic lipid accumulation. Blocking (P)RR with handle region peptide (HRP) reversed activation of these proteins and reduced intracellular lipid accumulation, identifying a novel (P)RR/ERK/PPARγ signalling axis in metabolic liver disease.\",\n      \"method\": \"SHR animal model; renin-stimulated HepG2 cell lipid deposition model; HRP treatment; immunoblot for (P)RR, ERK, PPARγ and downstream lipid metabolism proteins; Nile red fluorescence staining; RNA sequencing\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — both in vivo and in vitro models with pharmacological rescue and multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"40650317\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATP6AP2/(P)RR is a multifunctional membrane protein that (1) binds renin/prorenin to nonproteolytically activate them and locally generate angiotensin I, (2) serves as an essential accessory subunit for vacuolar H⁺-ATPase (V-ATPase) assembly and lysosomal acidification via Sec61-dependent ER translocation, (3) transduces ligand-independent intracellular signals through PLZF (as an adaptor) and V-ATPase-dependent pathways to regulate distinct transcriptional programmes, (4) modulates Wnt/β-catenin signalling via Dishevelled in a V-ATPase-dependent manner, (5) activates ERK/PPARγ signalling to promote hepatic lipid metabolism, and (6) is required in trophoblasts for placental development and in adipose tissue for normal energy homeostasis and insulin sensitivity.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper, then extract discoveries only from KEPT papers about ATP6AP2 (the pro-renin receptor, also known as PRR or (P)RR).\n\n**Classification:**\n\nFrom the retrieved 100 papers: The vast majority are clearly EXCLUDE — they describe RR intervals (cardiology), MC-RR (microcystin variants), R/R (relapsed/refractory) oncology trials, RR-TB (rifampicin-resistant tuberculosis), R-r (maize gene complex), or other unrelated \"RR\" topics. Papers about ATP6AP2/(P)RR that are KEEP:\n- Paper [24]: (P)RR as repressor of Wnt signaling — KEEP\n- Paper [58]: Distinct signal transduction pathways downstream of (P)RR — KEEP\n- Paper [19]: Adipose tissue (P)RR knockout — KEEP\n- Paper [53]: Tubular (P)RR transgenic mice — KEEP\n- Paper [62]: Placental (P)RR deficiency — KEEP\n- Paper [65]: (P)RR in end-organ damage — KEEP\n- Paper [66]: (P)RR and s(P)RR in pregnancy — KEEP (review, limited mechanistic)\n- Paper [71]: (P)RR review cardiovascular — KEEP (review)\n- Paper [82]: (P)RR overexpression, hypertension, MAFLD — KEEP\n- Paper [86]: Cardiovascular effect of preeclampsia, (P)RR — KEEP\n- Paper [92]: Preprint, RAS in PVN, Atp6ap2 expression — KEEP (preprint, expression-level)\n- Paper [93]: ELABELA/atherosclerosis, ATP6AP2 mentioned — marginal, expression only — EXCLUDE\n- Paper [94]: Mycolactone/Sec61/V-ATPase, ATP6AP1 and ATP6AP2 loss — KEEP\n- Paper [100]: CD PRR KO, intrarenal aldosterone — KEEP\n\nFrom gene2pubmed curated papers:\n- [5] PMID:12045255: Original cloning of renin receptor, binding, ERK signaling — KEEP\n- [14] PMID:20093472: PRR as Wnt receptor complex component, V-ATPase — KEEP\n- [19] PMID:16374430: Renin receptor mediates TGF-beta via siRNA — KEEP\n- [23] PMID:9556572: M9.2/ATP6AP2 identified in V-ATPase membrane sector — KEEP\n- [24] PMID:17082479: PLZF interaction, signal transduction — KEEP\n- [27] PMID:17494887: (P)RR-transgenic rats, MAPK activation — KEEP\n- [30] PMID:32165585: Cryo-EM structure of V-ATPase with ATP6AP2/PRR — KEEP\n- [1] PMID:22658674: mRNA interactome, ATP6AP2 identified as RBP — KEEP (if ATP6AP2 specifically identified)\n- [3] PMID:19615732: DUB interactome — may include ATP6AP2 as interactor — marginal\n- [4] PMID:26186194: BioPlex, ATP6AP2 as interactor — interaction data only\n- [6] PMID:28514442: BioPlex 2.0 — interaction data\n- [7] PMID:26496610: HeLa interactome\n- [8] PMID:32296183: HuRI\n- [9] PMID:33961781: BioPlex 3.0\n- [11] PMID:19056867: Urinary exosomes, ATP6AP2 identified\n- [13] PMID:33060197: Coronavirus interactome\n- [21] PMID:27342126: ZIKV/DENV dependency — ATP6AP2 may be identified\n- [22] PMID:31006538: ER-phagy\n- [28] PMID:29568061: MAC-tag AP-MS/BioID\n\nFor the large interactome/proteomics papers, ATP6AP2 appears as a detected protein but no specific mechanistic finding about ATP6AP2 function is described in the abstracts. I'll only extract if the abstract specifically describes a finding about ATP6AP2's mechanism.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"Expression cloning of the human (pro)renin receptor (ATP6AP2) identified a 350-amino acid single-transmembrane-domain protein with specific renin and prorenin binding. Receptor binding increased the catalytic efficiency of angiotensinogen conversion to angiotensin I by fourfold and induced intracellular signaling including phosphorylation of serine and tyrosine residues and activation of MAP kinases ERK1 and ERK2. Confocal microscopy localized the receptor to glomerular mesangium and subendothelium of coronary and kidney arteries, co-localizing with renin.\",\n      \"method\": \"Expression cloning, radioligand binding assay, stable transfection, in vitro angiotensinogen conversion assay, phosphorylation assay, ERK activation assay, confocal microscopy\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — original cloning with multiple orthogonal functional assays (binding, enzymatic, signaling, localization) in a highly cited foundational paper\",\n      \"pmids\": [\"12045255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"A novel 9.2-kDa protein (M9.2, later identified as ATP6AP2) was identified as a component of the membrane sector of vacuolar proton-translocating ATPase (V-ATPase) isolated from bovine chromaffin granules by blue native PAGE. It showed sequence and structural similarity to yeast Vma21p, required for V-ATPase assembly.\",\n      \"method\": \"Blue native PAGE, biochemical fractionation of chromaffin granule membranes, amino-terminal protein sequencing, sequence analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct biochemical isolation and sequencing of protein from native V-ATPase complex, highly cited foundational paper\",\n      \"pmids\": [\"9556572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The transcription factor promyelocytic zinc finger protein (PLZF) was identified as a direct protein interaction partner of the C-terminal domain of ATP6AP2/(pro)renin receptor via yeast two-hybrid screening and co-immunoprecipitation. Upon renin activation of the receptor, PLZF translocates to the nucleus, represses transcription of the receptor itself (negative feedback), and activates transcription of the PI3K p85α subunit. Renin stimulation of cardiomyoblasts increased cell number and decreased apoptosis via this PLZF/PI3K pathway. The receptor also homodimerizes.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, siRNA knockdown, chromatin immunoprecipitation, electrophoretic mobility-shift assay, site-directed mutagenesis, PLZF knockout mice\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (Y2H, co-IP, ChIP, EMSA, mutagenesis, KO mice) in a highly cited paper\",\n      \"pmids\": [\"17082479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Renin acting through ATP6AP2/(pro)renin receptor on mesangial cells induces TGF-β1 and matrix proteins (PAI-1, fibronectin, collagen I) through a receptor-mediated, angiotensin II-independent mechanism. siRNA knockdown of the renin receptor mRNA abolished these effects, demonstrating the receptor is required for renin-induced TGF-β1 upregulation.\",\n      \"method\": \"siRNA knockdown, recombinant renin treatment, renin enzymatic inhibitor controls, angiotensin receptor antagonist controls, mRNA and protein quantification\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — siRNA knockdown with specific inhibitor controls establishes receptor-mediated, Ang II-independent mechanism; highly cited\",\n      \"pmids\": [\"16374430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Transgenic rats overexpressing human ATP6AP2/(pro)renin receptor developed proteinuria and glomerulosclerosis with MAPK activation and increased TGF-β1 expression in kidneys, independent of angiotensin II elevation and blood pressure changes. A (pro)renin receptor blocker peptide inhibited these effects, while ACE inhibition did not, establishing that the receptor directly drives Ang II-independent MAPK signaling and nephropathy.\",\n      \"method\": \"Transgenic rat generation, (pro)renin receptor blocker peptide infusion, ACE inhibitor treatment, MAPK activity assays, TGF-β1 expression analysis, histology, proteinuria measurement, cell culture receptor activation\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo transgenic and pharmacological dissection with multiple endpoints; highly cited\",\n      \"pmids\": [\"17494887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ATP6AP2/(pro)renin receptor (PRR) was identified as a component of the Wnt receptor complex, functioning as an adaptor between Wnt receptors (LRP6/Frizzled) and the vacuolar H+-ATPase (V-ATPase) complex in a renin-independent manner. PRR and V-ATPase activity (and hence endosomal acidification) were required for Wnt/β-catenin signal transmission and for antero-posterior patterning of Xenopus early central nervous system development.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown in HEK293 and other cell lines, Wnt reporter assays, Xenopus embryo microinjection and morpholino knockdown, epistasis analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical complex identification plus in vivo epistasis in Xenopus; published in Science, highly cited\",\n      \"pmids\": [\"20093472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Full-length ATP6AP2/(P)RR acts as a repressor of Wnt signaling in a system pre-activated by Wnt3a or constitutively active β-catenin. The repressive effects are mediated through Dishevelled (Dvl) but are independent of β-catenin mutation status. The V-ATPase complex, but not PLZF translocation or renin enzymatic activity, is necessary for induction of Tcf/Lef-responsive genes by Wnt3a.\",\n      \"method\": \"Tcf/Lef luciferase reporter assays in HEK293T and HepG2 cells, endogenous Axin2 mRNA and protein quantification, Wnt3a stimulation, constitutively active β-catenin overexpression\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reporter assays and endogenous target gene quantification; single lab but multiple cell lines and conditions\",\n      \"pmids\": [\"23022225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Using siRNA against (P)RR, stable overexpression of PLZF, and specific inhibitors of V-ATPase (bafilomycin) and PLZF (genistein), distinct and overlapping transcriptional signatures downstream of ATP6AP2 were identified by microarray and ChIP-chip analyses. This revealed separate genetic programs controlled by the V-ATPase-associated function versus the PLZF-mediated signaling function of (P)RR, with novel target genes validated by real-time PCR.\",\n      \"method\": \"siRNA knockdown, stable PLZF overexpression, bafilomycin and genistein treatment, microarray transcriptomics, chromatin immunoprecipitation-chip (ChIP-chip), real-time PCR validation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches dissecting distinct downstream pathways; single lab\",\n      \"pmids\": [\"23469216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Adipose tissue-specific knockout of ATP6AP2/(P)RR (using AP2-Cre) in mice resulted in lower body weight, reduced fat mass, smaller adipocytes, increased locomotor activity, higher circulating adiponectin, and improved insulin sensitivity. These findings establish a role for adipose (P)RR in regulating fat mass, metabolic rate, and insulin sensitivity.\",\n      \"method\": \"Conditional knockout using Cre-loxP (AP2-Cre), metabolic cage analysis, glucose tolerance test, insulin/C-peptide measurements, adiponectin ELISA, body composition analysis\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with defined metabolic phenotypes; single lab\",\n      \"pmids\": [\"27689008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cryo-electron microscopy of rat brain V-ATPase at near-atomic resolution revealed that ATP6AP2/PRR and ATP6AP1/Ac45 are transmembrane accessory subunits whose cleaved forms have their transmembrane anchors enclosed within the c-ring of the V-ATPase membrane sector (Vo), enabling assembly of the catalytic (V1) and membrane (Vo) regions of the enzyme. The structure defines an ATP:proton ratio of 3:10 for brain V-ATPase.\",\n      \"method\": \"Cryo-electron microscopy, SidK-based affinity purification of native brain V-ATPase, atomic model building\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure with atomic model from native brain tissue; published in Science\",\n      \"pmids\": [\"32165585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Tubular epithelial-specific overexpression of ATP6AP2/(P)RR in transgenic mice caused hypertension and alkalized urine with lower osmolality and Na+ excretion. Bafilomycin (V-ATPase antagonist) acidized urine of (P)RR-TG mice, restoring the V-ATPase function phenotype. Double-transgenic mice co-expressing tubular (P)RR and intracellular alternative renin (ARen2) developed lethal renal tubular damage, suggesting intracellular renin acts as a ligand for (P)RR in tubules and that (P)RR functions as V-ATPase in renal tubules.\",\n      \"method\": \"Transgenic mouse generation, ARB/DRI/bafilomycin treatment, metabolic cage urine analysis, double-transgenic crossing, renal histopathology\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transgenic overexpression with pharmacological dissection; single lab, multiple endpoints\",\n      \"pmids\": [\"35008728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"siRNA knockdown of ATP6AP2/(P)RR in HTR-8/SVneo trophoblast cells impaired proliferation, migration, and invasion. In vivo lentiviral knockdown of (P)RR specifically in the trophectoderm of mouse blastocysts reduced placental labyrinth trophoblast number, decreased total surface area available for exchange, increased maternal blood space, and reduced fetal-placental weight ratio, demonstrating (P)RR is necessary for appropriate placental development and function.\",\n      \"method\": \"siRNA knockdown, xCELLigence real-time cell analysis (proliferation, migration, invasion), lentiviral (P)RR shRNA knockdown in mouse blastocysts, embryo transfer to pseudopregnant mice, stereological morphometry of placentae at EA10 and EA18\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro siRNA plus in vivo lentiviral knockdown with quantitative morphometric readouts; single lab\",\n      \"pmids\": [\"37588662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Sustained exposure of cells to mycolactone (a Sec61 inhibitor) caused loss of ATP6AP1 and ATP6AP2, which are Sec61-dependent substrates required for V-ATPase assembly, leading to reduced lysosomal biogenesis and acidification. This demonstrates that ATP6AP2 requires co-translational translocation via Sec61 into the ER for its biosynthesis and subsequent V-ATPase assembly.\",\n      \"method\": \"Mycolactone treatment, immunoblotting for ATP6AP2 and ATP6AP1, TFEB nuclear translocation assay, lysosomal acidification assay, autophagy flux assay\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection of biosynthetic requirement; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.08.26.671788\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In a model of spontaneous hypertension combined with MAFLD, hepatic (P)RR/ERK/PPARγ pathway and downstream fatty acid synthesis and transport proteins were upregulated. Blocking (P)RR with handle region peptide (HRP) reversed activation of ERK and PPARγ and reduced intracellular lipid accumulation in renin-activated HepG2 cells, identifying a (P)RR/ERK/PPARγ axis in hepatic lipid metabolism.\",\n      \"method\": \"SHR animal model, renin-activated HepG2 cell model, HRP pharmacological blockade, immunoblotting, Nile red fluorescence staining, immunofluorescence, RNA sequencing, liver histology\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — in vivo and in vitro with pharmacological blockade and multiple readouts; single lab, novel pathway claim\",\n      \"pmids\": [\"40650317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In a two-kidney one-clip mouse model, collecting duct-specific deletion of ATP6AP2/(pro)renin receptor (CD PRR KO) was identified as a key upstream regulator of intrarenal aldosterone biosynthesis. CD PRR KO reduced the hypertensive and fibrotic response to renovascular constriction, establishing (P)RR as a regulator of intrarenal renin-dependent aldosterone generation and ischemic nephropathy.\",\n      \"method\": \"Inducible renal tubule-specific C11B2 KO, collecting duct-specific PRR KO (CD PRR KO) and renin KO mice, 2K1C surgical model, blood pressure measurement, renal fibrosis/inflammation histology, aldosterone assays\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined physiological phenotypes; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.08.24.671658\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ATP6AP2 (PRR/(pro)renin receptor) is a single-pass transmembrane protein that functions as an accessory subunit of the vacuolar H+-ATPase (V-ATPase), with its cleaved transmembrane anchor embedded within the V-ATPase c-ring (established by cryo-EM structure); it binds renin and prorenin to enhance angiotensin I generation and activate ERK1/2 and MAP kinase signaling independent of angiotensin II; it interacts directly with PLZF to drive a nuclear signaling cascade activating PI3K-p85α; it serves as an essential adaptor between Wnt receptors and V-ATPase to enable endosomal acidification required for Wnt/β-catenin signal transduction; it also represses Wnt signaling through Dishevelled in a context-dependent manner; and it requires Sec61-mediated co-translational ER insertion for its biosynthesis and V-ATPase assembly, with tissue-specific roles established in kidney tubules, adipose tissue, placenta, and liver.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ATP6AP2, also known as the (pro)renin receptor [(P)RR], is a multifunctional transmembrane protein that serves as both an essential accessory subunit of the vacuolar H⁺-ATPase (V-ATPase) required for lysosomal acidification and as a signalling receptor that transduces distinct intracellular programmes through V-ATPase-dependent, PLZF-dependent, and Wnt/β-catenin pathways [PMID:23469216, PMID:23022225]. As a renin/prorenin receptor, ATP6AP2 nonproteolytically activates prorenin to generate angiotensin I locally and triggers intracellular signalling cascades including ERK/PPARγ-mediated hepatic lipid metabolism [PMID:20409904, PMID:40650317]. Its co-translational insertion into the ER via Sec61 is required for V-ATPase assembly and downstream lysosomal biogenesis and autophagy flux [PMID:23844810]. Tissue-specific loss-of-function studies demonstrate essential roles for ATP6AP2 in adipose energy homeostasis and insulin sensitivity, renal tubular acid–base regulation, and placental trophoblast development [PMID:27689008, PMID:35008728, PMID:37588662].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing that ATP6AP2 functions as a cell-surface receptor for renin and prorenin, nonproteolytically activating prorenin and transducing intracellular signals — this defined the gene's identity beyond a V-ATPase accessory protein.\",\n      \"evidence\": \"Chronic infusion of handle-region peptide blocker in diabetic and hypertensive rat models; transgenic overexpression\",\n      \"pmids\": [\"20409904\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of prorenin activation by ATP6AP2 undefined\", \"Downstream signalling intermediates not yet mapped\", \"No crystal structure of the receptor–ligand complex\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved whether ATP6AP2 activates or represses Wnt signalling: full-length (P)RR acts as a Wnt repressor via Dishevelled, while V-ATPase activity (not PLZF or renin catalysis) is required for Wnt3a-induced Tcf/Lef gene activation, separating V-ATPase-dependent from ligand-dependent functions.\",\n      \"evidence\": \"Tcf/Lef reporter assays in HEK293T/HepG2; bafilomycin and genistein pharmacological dissection; endogenous Axin2 quantification\",\n      \"pmids\": [\"23022225\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which full-length (P)RR overexpression represses Wnt is unclear\", \"Endogenous stoichiometry between (P)RR and V-ATPase at the plasma membrane not established\", \"In vivo Wnt phenotype not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Genome-wide profiling demonstrated that the V-ATPase-dependent and PLZF-dependent transcriptional programmes downstream of ATP6AP2 are largely distinct, establishing that the transmembrane/cytoplasmic domain mediates dual independent signalling outputs.\",\n      \"evidence\": \"Microarray and ChIP-chip in cells with siRNA knockdown of (P)RR, PLZF overexpression, bafilomycin, and genistein\",\n      \"pmids\": [\"23469216\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical mechanism coupling V-ATPase activity to transcription not identified\", \"Overlap gene set not functionally characterized\", \"PLZF binding targets not validated by orthogonal ChIP-seq\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Synthesis of primary evidence consolidated the dual-function model: ATP6AP2 is simultaneously an essential V-ATPase accessory subunit and a Wnt signalling adaptor, with ligand-independent intracellular signalling distinct from its renin-binding activity.\",\n      \"evidence\": \"Review integrating siRNA, pharmacological inhibition, and reporter data from multiple studies\",\n      \"pmids\": [\"23844810\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstitution of V-ATPase assembly with purified ATP6AP2\", \"Stoichiometry of ATP6AP2 in the V-ATPase holoenzyme not determined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Adipose-specific deletion revealed that ATP6AP2 is required for normal fat mass, energy expenditure, and insulin sensitivity in vivo, extending the gene's functional reach beyond renin–angiotensin signalling to systemic metabolism.\",\n      \"evidence\": \"AP2-Cre conditional knockout mice; metabolic cage analyses; glucose tolerance and plasma hormone measurements\",\n      \"pmids\": [\"27689008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether metabolic phenotype is V-ATPase-dependent or renin-dependent not dissected\", \"Downstream adipocyte signalling pathway not identified\", \"Sexual dimorphism mechanism unexplained\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Tubular-specific overexpression showed that ATP6AP2 regulates renal acid–base handling through its V-ATPase function, while its blood pressure effects are renin–angiotensin dependent, pharmacologically dissecting the two functions in vivo.\",\n      \"evidence\": \"Tubular (P)RR transgenic mice; double transgenic with alternative renin; bafilomycin, ARB, and DRI treatments; urine chemistry\",\n      \"pmids\": [\"35008728\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the endogenous renal ligand for (P)RR uncertain\", \"Mechanism of lethal tubular damage in double transgenics not characterized at the molecular level\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Loss-of-function in trophoblasts demonstrated that ATP6AP2 is required for trophoblast proliferation, migration, and invasion in vitro and for normal placental labyrinth development in vivo, establishing a developmental role.\",\n      \"evidence\": \"siRNA in HTR-8/SVneo cells with real-time cell analysis; lentiviral trophectoderm-specific knockdown; stereological placental morphometry\",\n      \"pmids\": [\"37588662\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which downstream pathway (V-ATPase, Wnt, or RAS) mediates trophoblast phenotype is unknown\", \"Human placental relevance not directly tested beyond cell line\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of a (P)RR/ERK/PPARγ signalling axis in hepatocytes linked ATP6AP2 to hepatic lipid accumulation, extending the metabolic functions beyond adipose tissue to liver steatosis.\",\n      \"evidence\": \"SHR in vivo and renin-stimulated HepG2 in vitro models; handle-region peptide rescue; immunoblot and Nile red staining; RNA-seq\",\n      \"pmids\": [\"40650317\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ERK activation is direct or secondary to angiotensin generation not resolved\", \"Single lab finding awaiting independent replication\", \"No genetic loss-of-function in hepatocytes\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major open questions include: (1) the structural basis of ATP6AP2 integration into the V-ATPase holoenzyme, (2) the mechanism by which V-ATPase activity is transduced to transcriptional outputs, (3) which ATP6AP2 function (V-ATPase, Wnt, or RAS) predominates in each tissue context, and (4) whether ATP6AP2 mutations cause human Mendelian disease through loss of specific signalling branches.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of ATP6AP2 in V-ATPase complex\", \"No human genetic disease link established in this timeline\", \"Relative contribution of each signalling branch in vivo remains undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [5, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 3]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 5, 11, 12]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"complexes\": [\"V-ATPase\"],\n    \"partners\": [\"PLZF\", \"DVL1\", \"ATP6AP1\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"ATP6AP2 is a multifunctional single-pass transmembrane protein that serves both as an accessory subunit of the vacuolar H⁺-ATPase (V-ATPase) and as a cell-surface receptor for renin and prorenin, coupling extracellular renin-angiotensin signaling to intracellular proton pump function. As a V-ATPase component, its cleaved transmembrane anchor is enclosed within the Vo c-ring, where it is essential for V-ATPase assembly and endosomal/lysosomal acidification [PMID:32165585, PMID:9556572]; this acidification function is co-opted by the Wnt signaling pathway, in which ATP6AP2 acts as an adaptor bridging Wnt receptors (LRP6/Frizzled) to V-ATPase to enable β-catenin signal transduction [PMID:20093472]. As a renin/prorenin receptor, ligand binding enhances angiotensinogen-to-angiotensin I conversion and activates angiotensin II–independent intracellular signaling through ERK1/2 MAP kinases and, via the transcription factor PLZF, through PI3K-p85α, driving fibrogenic (TGF-β1, fibronectin, collagen I) and proliferative programs in kidney, heart, adipose tissue, placenta, and liver [PMID:12045255, PMID:17082479, PMID:16374430, PMID:27689008]. Transgenic overexpression of ATP6AP2 in renal tubules or glomeruli causes hypertension, proteinuria, and glomerulosclerosis independently of angiotensin II, establishing the receptor as a direct contributor to nephropathy [PMID:17494887, PMID:35008728].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of a novel 9.2-kDa protein (M9.2) as a membrane-sector component of V-ATPase established that ATP6AP2 is physically part of the proton pump, analogous to yeast Vma21p.\",\n      \"evidence\": \"Blue native PAGE and amino-terminal sequencing of bovine chromaffin granule V-ATPase\",\n      \"pmids\": [\"9556572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Exact topology within the V-ATPase complex was unknown\",\n        \"Whether M9.2 had any function beyond V-ATPase assembly was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Expression cloning revealed that the same protein is a cell-surface receptor for renin and prorenin, answering how renin signals intracellularly independent of angiotensin II and establishing a dual identity for ATP6AP2.\",\n      \"evidence\": \"Expression cloning, radioligand binding, angiotensinogen conversion assay, ERK1/2 phosphorylation, and confocal microscopy in human cell lines and tissue sections\",\n      \"pmids\": [\"12045255\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of dual function (receptor vs. V-ATPase subunit) unresolved\",\n        \"Downstream signaling beyond ERK1/2 was unknown\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Discovery of PLZF as a direct cytoplasmic interaction partner and demonstration of renin-induced fibrogenic gene programs revealed distinct downstream signaling branches — a PLZF/PI3K-p85α nuclear pathway and an angiotensin II–independent TGF-β1/matrix protein axis.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, ChIP, EMSA, PLZF KO mice (PLZF pathway); siRNA knockdown with renin inhibitor and Ang II receptor antagonist controls in mesangial cells (TGF-β1 pathway)\",\n      \"pmids\": [\"17082479\", \"16374430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether PLZF and ERK pathways are independent or convergent was not resolved\",\n        \"In vivo disease relevance of PLZF axis remained untested\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Transgenic overexpression in rats demonstrated that receptor-level activation is sufficient to cause nephropathy (proteinuria, glomerulosclerosis) with MAPK/TGF-β1 activation, establishing in vivo pathogenic relevance independent of angiotensin II.\",\n      \"evidence\": \"Transgenic rat model with PRR blocker peptide and ACE inhibitor controls, proteinuria and histology endpoints\",\n      \"pmids\": [\"17494887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the blocker peptide acts exclusively at PRR was debated\",\n        \"Mechanism linking receptor overexpression to V-ATPase function in vivo was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of ATP6AP2 as an essential adaptor between Wnt receptors and V-ATPase for β-catenin signaling revealed a third, renin-independent function and explained how endosomal acidification is coupled to developmental signaling.\",\n      \"evidence\": \"Co-IP of PRR with LRP6 and V-ATPase subunits, Wnt reporter assays, Xenopus morpholino knockdown with epistasis analysis\",\n      \"pmids\": [\"20093472\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for PRR bridging LRP6 to V-ATPase was unknown\",\n        \"Context-dependent repression vs. activation of Wnt signaling was not reconciled\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The finding that full-length PRR can repress Wnt signaling through Dishevelled showed that its Wnt-modulatory role is context-dependent and bidirectional, separating V-ATPase-dependent Wnt activation from a Dvl-mediated repressive function.\",\n      \"evidence\": \"Tcf/Lef luciferase reporters and endogenous Axin2 quantification in HEK293T and HepG2 cells stimulated with Wnt3a or constitutively active β-catenin\",\n      \"pmids\": [\"23022225\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular determinants distinguishing activating vs. repressive modes remain unidentified\",\n        \"In vivo relevance of Wnt-repressive function not tested\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Genome-wide dissection of V-ATPase versus PLZF transcriptional programs downstream of PRR established that these two functions control distinct but partially overlapping gene networks.\",\n      \"evidence\": \"siRNA knockdown, stable PLZF overexpression, bafilomycin/genistein treatment, microarray and ChIP-chip in cell lines\",\n      \"pmids\": [\"23469216\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Physiological relevance of the identified target genes was not validated in vivo\",\n        \"Extent of overlap between V-ATPase and PLZF programs was not fully resolved\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Adipose-specific knockout demonstrated that PRR regulates fat mass, metabolic rate, and insulin sensitivity, extending its physiological roles beyond the cardiovascular and renal systems.\",\n      \"evidence\": \"AP2-Cre conditional knockout mice with metabolic cage analysis, glucose tolerance tests, adiponectin measurements\",\n      \"pmids\": [\"27689008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether the adipose phenotype is V-ATPase-dependent or renin-receptor-dependent was not determined\",\n        \"Downstream lipid-metabolic mechanism in adipocytes was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Near-atomic cryo-EM of brain V-ATPase resolved how ATP6AP2 integrates into the proton pump: its cleaved transmembrane domain is enclosed within the Vo c-ring, providing the first structural explanation for its dual identity as both a V-ATPase subunit and a receptor.\",\n      \"evidence\": \"Cryo-EM of SidK-affinity-purified rat brain V-ATPase at near-atomic resolution with atomic model building\",\n      \"pmids\": [\"32165585\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How uncleaved full-length PRR simultaneously presents the ectodomain for renin binding and integrates into V-ATPase is structurally unresolved\",\n        \"Tissue-specific regulation of cleavage and c-ring incorporation is unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Tubule-specific overexpression and double-transgenic studies showed that intracellular renin can act as a ligand for PRR within renal tubular epithelium, linking V-ATPase-dependent urinary acidification to intracrine renin signaling.\",\n      \"evidence\": \"Transgenic mouse overexpression, bafilomycin treatment, double-transgenic crossing with intracellular renin (ARen2), metabolic cage urine analysis and renal histopathology\",\n      \"pmids\": [\"35008728\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding of intracellular renin to PRR in tubular cells was not biochemically demonstrated\",\n        \"Mechanism of lethal tubular damage in double-transgenics was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"In vivo trophoblast-specific knockdown established that PRR is required for placental labyrinth development and fetal-placental growth, expanding its developmental biology role beyond Xenopus axis patterning to mammalian organogenesis.\",\n      \"evidence\": \"siRNA in HTR-8/SVneo trophoblast cells plus lentiviral shRNA knockdown in mouse blastocyst trophectoderm with stereological placental morphometry\",\n      \"pmids\": [\"37588662\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether placental phenotype is Wnt-dependent, V-ATPase-dependent, or renin-signaling-dependent is unknown\",\n        \"Human placental disease relevance (e.g., pre-eclampsia) not established\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of a PRR/ERK/PPARγ axis in hepatic lipid metabolism and demonstration that collecting-duct PRR regulates intrarenal aldosterone biosynthesis extended the tissue-specific signaling repertoire to liver steatosis and renovascular hypertension.\",\n      \"evidence\": \"SHR animal model with renin-activated HepG2 cells and HRP blockade (liver); collecting-duct-specific PRR KO and 2K1C surgical model (kidney)\",\n      \"pmids\": [\"40650317\", \"bio_10.1101_2025.08.24.671658\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"PRR/ERK/PPARγ axis awaits independent replication\",\n        \"Direct PRR–aldosterone synthase regulatory mechanism is undefined\",\n        \"Both studies are from single laboratories\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how the full-length receptor simultaneously accommodates extracellular renin/prorenin binding and c-ring integration, how tissue-specific proteolytic processing is regulated, and what determines whether PRR activates or represses Wnt signaling in a given cellular context.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structure of full-length uncleaved PRR in complex with renin or prorenin exists\",\n        \"Protease(s) and regulation of PRR cleavage are incompletely defined\",\n        \"Context-dependent switch between Wnt activation and repression is mechanistically unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 3, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [9, 12]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 3, 4, 5, 6, 13]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [1, 9, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 11]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [8, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 10]}\n    ],\n    \"complexes\": [\n      \"V-ATPase (Vo sector)\",\n      \"Wnt signalosome (LRP6/Frizzled/PRR/V-ATPase)\"\n    ],\n    \"partners\": [\n      \"ATP6AP1\",\n      \"ZBTB16\",\n      \"LRP6\",\n      \"FZD8\",\n      \"REN\",\n      \"DVL2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}