{"gene":"ATP6AP2","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2012,"finding":"Full-length (P)RR acts as a repressor of Wnt signalling in a system pre-activated by Wnt3a or constitutively active β-catenin; these repressive effects are mediated by Dvl but are independent of β-catenin mutation status. Furthermore, 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 reporter gene assay in HEK293T and HepG2 cells; quantification of endogenous axin2 mRNA and protein; siRNA knockdown and stable overexpression constructs","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter gene assay plus endogenous target quantification in two cell lines, single lab, multiple orthogonal readouts","pmids":["23022225"],"is_preprint":false},{"year":2013,"finding":"siRNA knockdown of (P)RR identified distinct transcriptional signatures downstream of its V-ATPase function versus its PLZF-adaptor function; microarray and ChIP-chip analyses revealed overlapping and non-overlapping genetic programmes controlled by each molecular function of (P)RR, with novel target genes validated by real-time PCR.","method":"siRNA knockdown of (P)RR; stable PLZF overexpression; microarray transcriptomics; chromatin immunoprecipitation (ChIP)-chip; PLZF translocation inhibitor genistein; V-ATPase inhibitor bafilomycin; real-time PCR validation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal genome-wide approaches plus pharmacological inhibitors in a single lab study","pmids":["23469216"],"is_preprint":false},{"year":2016,"finding":"Adipose tissue-specific knockout of ATP6AP2/(P)RR (using AP2-Cre) in mice results in lower body weight, reduced fat mass, smaller adipocytes, increased locomotor activity, increased basal metabolic rate (males), improved insulin sensitivity (lower plasma insulin and C-peptide), and elevated circulating adiponectin, establishing a direct role of (P)RR in adipose tissue energy homeostasis and insulin sensitivity.","method":"Cre-loxP conditional knockout (AP2-Cre); metabolic cage measurements; glucose tolerance test; plasma insulin and C-peptide; adipocyte histomorphometry; adiponectin ELISA","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with multiple quantitative metabolic phenotypes, both sexes, normal and high-fat diet challenges","pmids":["27689008"],"is_preprint":false},{"year":2021,"finding":"Tubular-specific overexpression of (P)RR in transgenic mice causes hypertension and alkalized urine with lower osmolality and Na+ excretion; bafilomycin (V-ATPase antagonist) acidified the urine of these mice, indicating that (P)RR functions as a component of V-ATPase in renal tubules. Cross-breeding with alternative intracellular renin transgenic mice caused lethal renal tubular damage, suggesting intracellular renin is a ligand for tubular (P)RR.","method":"Tubular-specific (P)RR transgenic mouse; metabolic cage analysis; ARB, direct renin inhibitor, and bafilomycin pharmacological treatments; urine chemistry; double transgenic cross with alternative renin transgenic mice; histopathology","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model with pharmacological dissection, single lab, multiple physiological readouts","pmids":["35008728"],"is_preprint":false},{"year":2023,"finding":"siRNA knockdown of ATP6AP2/(P)RR in the HTR-8/SVneo first-trimester trophoblast cell line impairs trophoblast proliferation, migration, and invasion in vitro; lentiviral shRNA knockdown of (P)RR in mouse blastocyst trophectoderm reduces placental labyrinth trophoblast number and total surface area, increases maternal blood space, and reduces the fetal-placental weight ratio in vivo, establishing a direct functional requirement for (P)RR in placental development.","method":"siRNA knockdown in HTR-8/SVneo cells; xCELLigence real-time cell analysis for proliferation, migration, invasion; lentiviral shRNA knockdown in mouse blastocysts; in vivo embryo transfer; stereological Merz grid analysis of placental compartments","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — both in vitro (multiple functional assays) and in vivo (embryo transfer, placental stereology) with orthogonal methods","pmids":["37588662"],"is_preprint":false},{"year":2008,"finding":"Binding of prorenin or renin to (P)RR non-proteolytically activates prorenin and stimulates receptor-mediated intracellular signalling independent of angiotensin II; transgenic rats overexpressing (P)RR develop renal glomerulopathy without elevation of blood glucose or blood pressure, indicating that (P)RR overexpression alone is sufficient for end-organ damage. A peptidic (P)RR blocker (handle-region peptide) prevents diabetic nephropathy and attenuates hypertensive cardiomyopathy/nephropathy.","method":"Transgenic rat overexpression; streptozotocin diabetic nephropathy model; chronic infusion of handle-region peptide blocker; renal histopathology; blood pressure and metabolic measurements","journal":"Journal of the American Society of Hypertension : JASH","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic and pharmacological interventions, single review/summary paper synthesising multiple experimental studies","pmids":["20409904"],"is_preprint":false},{"year":2014,"finding":"(P)RR acts as an essential accessory protein of vacuolar H+-ATPase (V-ATPase) and also as an adaptor protein of Wnt signalling, in addition to its role as a receptor that non-proteolytically activates prorenin to catalyse angiotensinogen-to-angiotensin I conversion.","method":"Review synthesising in vivo and in vitro experimental evidence including receptor binding assays, V-ATPase assembly studies, and Wnt reporter assays from prior experimental work","journal":"Current pharmaceutical design","confidence":"Low","confidence_rationale":"Tier 4 / Weak — narrative review, no new primary experimental data reported in the abstract","pmids":["23844810"],"is_preprint":false},{"year":2024,"finding":"(P)RR overexpression activates the (P)RR/ERK/PPARγ signalling axis and downstream proteins related to fatty acid synthesis and transport in liver, promoting lipid accumulation; the handle-region peptide (HRP) blocker reverses activation of these proteins and reduces intracellular lipid accumulation in renin-stimulated HepG2 cells and in spontaneously hypertensive rats.","method":"SHR animal model; HepG2 cell lipid deposition model induced by renin; HRP pharmacological blockade; RNA sequencing; liver H&E and Nile red fluorescence staining; western blot for (P)RR, ERK, PPARγ, and lipid metabolism proteins; immunofluorescence","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — parallel in vitro and in vivo models with multiple molecular readouts, single lab","pmids":["40650317"],"is_preprint":false},{"year":2024,"finding":"In vascular plaques, ELABELA-21 treatment reduces PRR (ATP6AP2) protein expression and decreases plasma soluble (P)RR levels, while the APJ inhibitor ML221 further elevates ATP6AP2 mRNA in THP-1 cells, placing (P)RR downstream of APJ-mediated signalling in macrophage inflammation and atherosclerotic plaque biology.","method":"ApoE−/− high-fat diet mouse model; ELA-21 administration; immunohistochemistry/protein expression in plaques; plasma sPRR ELISA; in vitro THP-1 foam cell and M1 polarization assays with APJ inhibitor; mRNA quantification","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single preprint lab, indirect evidence placing ATP6AP2 in APJ pathway context without direct mechanistic reconstitution","pmids":["bio_10.1101_2024.11.07.24316940"],"is_preprint":true},{"year":2025,"finding":"Mycolactone-mediated Sec61 inhibition causes loss of ATP6AP1 and ATP6AP2 (both Sec61-dependent co-translational substrates), which are required for Vacuolar-ATPase assembly; loss of these proteins leads to reduced lysosomal biogenesis and acidification, compromising autophagy flux and the ability of phagocytes to combat M. ulcerans infection.","method":"Mycolactone treatment of cells; Sec61 inhibition; TFEB nuclear translocation assay; lysosomal biogenesis and acidification assays; autophagy flux measurements; infection assays with M. ulcerans","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays demonstrating ATP6AP2 requirement for V-ATPase assembly and lysosomal function, single preprint lab","pmids":["bio_10.1101_2025.08.26.671788"],"is_preprint":true},{"year":2025,"finding":"Single-nucleus RNA sequencing of mouse hypothalamic paraventricular nucleus (PVN) shows that Atp6ap2/(P)RR is predominantly expressed in neurons (not astrocytes); DOCA-salt hypertension increases neuronal Atp6ap2 expression, and high-fat diet upregulates Atp6ap2 in vasopressin neurons, indicating cell-type-specific regulation of (P)RR under cardiometabolic stress.","method":"Single-nucleus RNA sequencing (snRNA-seq) of PVN from baseline, DOCA-salt hypertension, and high-fat diet mouse models; cell-type-specific gene expression analysis","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — transcriptomic localization only, no functional consequence directly tested for ATP6AP2, single preprint","pmids":["bio_10.1101_2025.08.14.669892"],"is_preprint":true},{"year":2024,"finding":"(P)RR/(ATP6AP2) is required in cardiovascular tissues for canonical Wnt transduction: offspring of preeclamptic rats show elevated (P)RR expression together with upregulation of PLZF, β-catenin, DVL-1, and PKCα in heart, aorta, and kidney; handle-region peptide treatment abolishes these increases and reverses hypertension, placing (P)RR upstream of canonical Wnt pathway components in cardiovascular regulation.","method":"Preeclampsia rat offspring model; HRP pharmacological treatment; immunoblot for (P)RR, PLZF, β-catenin, DVL-1, PKCα; RT-PCR for (P)RR and PLZF; blood pressure measurement; morphological organ assessment","journal":"Iranian journal of basic medical sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, indirect pharmacological (HRP) rather than genetic manipulation of (P)RR, correlative protein measurements","pmids":["38629095"],"is_preprint":false}],"current_model":"ATP6AP2/(P)RR is a multifunctional membrane protein that (i) non-proteolytically activates prorenin/renin to enhance local angiotensin generation, (ii) serves as an essential accessory subunit for vacuolar H⁺-ATPase (V-ATPase) assembly and lysosomal/endosomal acidification, (iii) acts as an adaptor for Wnt co-receptors through Dvl to modulate Wnt/β-catenin signalling (functioning as a repressor when overexpressed), (iv) recruits the transcription factor PLZF to drive a distinct downstream transcriptional programme, and (v) in adipose tissue and placenta controls cell proliferation, migration, energy metabolism, and insulin sensitivity, with its ERK/PPARγ axis additionally implicated in hepatic lipid accumulation."},"narrative":{"mechanistic_narrative":"ATP6AP2, also known as the (pro)renin receptor ((P)RR), is a multifunctional membrane protein that couples local renin-angiotensin signalling to vacuolar H⁺-ATPase (V-ATPase) function and developmental/metabolic control [PMID:23844810, PMID:20409904]. As an essential V-ATPase accessory protein, it is required for endosomal/lysosomal acidification and lysosomal biogenesis, and its loss compromises autophagy flux [PMID:bio_10.1101_2025.08.26.671788]; this V-ATPase function is also necessary for Wnt3a-driven induction of Tcf/Lef-responsive genes, while full-length (P)RR overexpression represses Wnt signalling through Dvl independently of β-catenin status [PMID:23022225]. Distinct from these roles, (P)RR also acts as an adaptor that drives a separate transcriptional programme through the transcription factor PLZF, and knockdown studies resolve the non-overlapping gene sets controlled by its V-ATPase versus PLZF-adaptor functions [PMID:23469216]. Binding of prorenin or renin non-proteolytically activates prorenin and triggers angiotensin-II-independent intracellular signalling, with receptor overexpression alone sufficient to cause end-organ renal damage [PMID:20409904]. Tissue-specific genetic studies establish physiological roles in energy homeostasis and development: adipose-specific deletion reduces fat mass and improves insulin sensitivity [PMID:27689008], (P)RR is required for trophoblast proliferation, migration, invasion and placental labyrinth development [PMID:37588662], and tubular overexpression produces V-ATPase-dependent hypertension and urinary alkalinization [PMID:35008728].","teleology":[{"year":2008,"claim":"Established that (P)RR is a functional receptor whose ligand binding activates prorenin and drives signalling independent of angiotensin II, and that receptor excess alone causes organ damage — defining (P)RR as more than a passive renin-binding protein.","evidence":"Transgenic rat overexpression, streptozotocin diabetic nephropathy model, and handle-region peptide blockade with renal histopathology","pmids":["20409904"],"confidence":"Medium","gaps":["Molecular signalling cascade downstream of prorenin binding not resolved","Mechanism by which receptor overexpression causes glomerulopathy unclear"]},{"year":2012,"claim":"Dissected the Wnt-related role, showing (P)RR represses Wnt signalling via Dvl when overexpressed, while its V-ATPase activity (not PLZF or renin activity) is required for Wnt3a-induced Tcf/Lef gene expression — separating its molecular functions in one pathway.","evidence":"Tcf/Lef reporter assays, endogenous axin2 quantification, siRNA knockdown and overexpression in HEK293T and HepG2 cells","pmids":["23022225"],"confidence":"Medium","gaps":["Structural basis of Dvl interaction not defined","Reconciliation of repressor versus required-for-induction roles incomplete"]},{"year":2013,"claim":"Resolved that the V-ATPase and PLZF-adaptor functions of (P)RR drive distinct, partly overlapping transcriptional programmes, establishing that its molecular roles map onto separable downstream gene networks.","evidence":"siRNA knockdown, PLZF overexpression, microarray and ChIP-chip with pharmacological inhibitors (genistein, bafilomycin) and qPCR validation","pmids":["23469216"],"confidence":"Medium","gaps":["Direct PLZF target genes not fully validated","Cell-type generality of the programmes untested"]},{"year":2016,"claim":"Demonstrated a genetic, tissue-autonomous role for (P)RR in energy homeostasis, where adipose deletion reduces adiposity and improves insulin sensitivity — placing (P)RR in metabolic control beyond the cardiovascular system.","evidence":"AP2-Cre conditional knockout mice with metabolic cage, glucose tolerance, plasma insulin/C-peptide, adipocyte histomorphometry and adiponectin assays","pmids":["27689008"],"confidence":"High","gaps":["Which molecular function (V-ATPase vs renin vs Wnt) drives the metabolic phenotype unknown","Mechanism linking (P)RR loss to elevated adiponectin not defined"]},{"year":2021,"claim":"Showed that tubular (P)RR overexpression produces V-ATPase-dependent hypertension and urine alkalinization reversed by bafilomycin, anchoring (P)RR's blood-pressure role to its V-ATPase function in the kidney.","evidence":"Tubular-specific transgenic mice with pharmacological dissection (ARB, renin inhibitor, bafilomycin), urine chemistry and double-transgenic renin crosses","pmids":["35008728"],"confidence":"Medium","gaps":["Identity of physiological tubular ligand not proven","Single-lab transgenic model"]},{"year":2023,"claim":"Established a developmental requirement for (P)RR in placentation, where knockdown impairs trophoblast function and disrupts placental labyrinth architecture in vivo.","evidence":"siRNA in HTR-8/SVneo cells with xCELLigence assays plus lentiviral shRNA in mouse blastocysts, embryo transfer and placental stereology","pmids":["37588662"],"confidence":"High","gaps":["Molecular pathway mediating trophoblast effects not identified","Relationship to renin/V-ATPase/Wnt functions untested"]},{"year":2024,"claim":"Linked (P)RR to hepatic lipid metabolism via an ERK/PPARγ axis, with the handle-region peptide reversing lipid accumulation — extending the receptor's signalling output to fatty acid synthesis/transport.","evidence":"SHR model and renin-stimulated HepG2 lipid deposition with HRP blockade, RNA-seq, Nile red staining and western blot for ERK/PPARγ","pmids":["40650317"],"confidence":"Medium","gaps":["Direct receptor-to-ERK coupling not reconstituted","Single-lab evidence"]},{"year":2025,"claim":"Mechanistically confirmed (P)RR as a Sec61-dependent co-translational substrate required for V-ATPase assembly, lysosomal acidification and autophagy, connecting it to phagocyte antimicrobial function.","evidence":"Mycolactone/Sec61 inhibition with TFEB translocation, lysosomal acidification, autophagy flux and M. ulcerans infection assays (preprint)","pmids":["bio_10.1101_2025.08.26.671788"],"confidence":"Medium","gaps":["Preprint, single lab","Direct structural role within assembled V-ATPase not resolved"]},{"year":null,"claim":"How the distinct molecular functions of (P)RR — prorenin activation, V-ATPase accessory role, Wnt/Dvl adaptor, and PLZF recruitment — are selected and balanced within a given cell type, and which one drives each tissue phenotype, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model linking molecular functions to specific physiological outputs","Ligand selectivity and context-dependent function not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[9]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,0]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[3,9]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[9]}],"complexes":["V-ATPase"],"partners":["RENIN","DVL","PLZF","ATP6AP1","SEC61"],"other_free_text":[]}},"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 toxicity evaluation of cyanobacterial cyclic peptide toxin microcystin variants (LR, RR, YR) in mice.","date":"2003","source":"Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/12767698","citation_count":326,"is_preprint":false},{"pmid":"17592552","id":"PMC_17592552","title":"RR interval variability is inversely related to inflammatory markers: the CARDIA study.","date":"2007","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/17592552","citation_count":178,"is_preprint":false},{"pmid":"35580927","id":"PMC_35580927","title":"The CAR-HEMATOTOX risk-stratifies patients for severe infections and disease progression after CD19 CAR-T in R/R LBCL.","date":"2022","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35580927","citation_count":167,"is_preprint":false},{"pmid":"35081255","id":"PMC_35081255","title":"Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial.","date":"2022","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/35081255","citation_count":120,"is_preprint":false},{"pmid":"37390310","id":"PMC_37390310","title":"Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial.","date":"2023","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/37390310","citation_count":101,"is_preprint":false},{"pmid":"7774593","id":"PMC_7774593","title":"Transposon-mediated chromosomal rearrangements and gene duplications in the formation of the maize R-r complex.","date":"1995","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/7774593","citation_count":89,"is_preprint":false},{"pmid":"15306635","id":"PMC_15306635","title":"Dynamic beat-to-beat modeling of the QT-RR interval relationship: analysis of QT prolongation during alterations of autonomic state versus human ether a-go-go-related gene inhibition.","date":"2004","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/15306635","citation_count":82,"is_preprint":false},{"pmid":"1682214","id":"PMC_1682214","title":"Meiotic instability of the R-r complex arising from displaced intragenic exchange and intrachromosomal rearrangement.","date":"1991","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1682214","citation_count":63,"is_preprint":false},{"pmid":"1593459","id":"PMC_1593459","title":"Changes in R-R interval at the start of muscle contraction in the decerebrate cat.","date":"1992","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/1593459","citation_count":59,"is_preprint":false},{"pmid":"20031603","id":"PMC_20031603","title":"A genome-wide association scan of RR and QT interval duration in 3 European genetically isolated populations: the EUROSPAN project.","date":"2009","source":"Circulation. 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these repressive effects are mediated by Dvl but are independent of β-catenin mutation status. Furthermore, 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 assay in HEK293T and HepG2 cells; quantification of endogenous axin2 mRNA and protein; siRNA knockdown and stable overexpression constructs\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter gene assay plus endogenous target quantification in two cell lines, single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"23022225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"siRNA knockdown of (P)RR identified distinct transcriptional signatures downstream of its V-ATPase function versus its PLZF-adaptor function; microarray and ChIP-chip analyses revealed overlapping and non-overlapping genetic programmes controlled by each molecular function of (P)RR, with novel target genes validated by real-time PCR.\",\n      \"method\": \"siRNA knockdown of (P)RR; stable PLZF overexpression; microarray transcriptomics; chromatin immunoprecipitation (ChIP)-chip; PLZF translocation inhibitor genistein; V-ATPase inhibitor bafilomycin; real-time PCR validation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal genome-wide approaches plus pharmacological inhibitors in a single lab study\",\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 results in lower body weight, reduced fat mass, smaller adipocytes, increased locomotor activity, increased basal metabolic rate (males), improved insulin sensitivity (lower plasma insulin and C-peptide), and elevated circulating adiponectin, establishing a direct role of (P)RR in adipose tissue energy homeostasis and insulin sensitivity.\",\n      \"method\": \"Cre-loxP conditional knockout (AP2-Cre); metabolic cage measurements; glucose tolerance test; plasma insulin and C-peptide; adipocyte histomorphometry; adiponectin ELISA\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with multiple quantitative metabolic phenotypes, both sexes, normal and high-fat diet challenges\",\n      \"pmids\": [\"27689008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Tubular-specific overexpression of (P)RR in transgenic mice causes hypertension and alkalized urine with lower osmolality and Na+ excretion; bafilomycin (V-ATPase antagonist) acidified the urine of these mice, indicating that (P)RR functions as a component of V-ATPase in renal tubules. Cross-breeding with alternative intracellular renin transgenic mice caused lethal renal tubular damage, suggesting intracellular renin is a ligand for tubular (P)RR.\",\n      \"method\": \"Tubular-specific (P)RR transgenic mouse; metabolic cage analysis; ARB, direct renin inhibitor, and bafilomycin pharmacological treatments; urine chemistry; double transgenic cross with alternative renin transgenic mice; histopathology\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model with pharmacological dissection, single lab, multiple physiological readouts\",\n      \"pmids\": [\"35008728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"siRNA knockdown of ATP6AP2/(P)RR in the HTR-8/SVneo first-trimester trophoblast cell line impairs trophoblast proliferation, migration, and invasion in vitro; lentiviral shRNA knockdown of (P)RR in mouse blastocyst trophectoderm reduces placental labyrinth trophoblast number and total surface area, increases maternal blood space, and reduces the fetal-placental weight ratio in vivo, establishing a direct functional requirement for (P)RR in placental development.\",\n      \"method\": \"siRNA knockdown in HTR-8/SVneo cells; xCELLigence real-time cell analysis for proliferation, migration, invasion; lentiviral shRNA knockdown in mouse blastocysts; in vivo embryo transfer; stereological Merz grid analysis of placental compartments\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — both in vitro (multiple functional assays) and in vivo (embryo transfer, placental stereology) with orthogonal methods\",\n      \"pmids\": [\"37588662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Binding of prorenin or renin to (P)RR non-proteolytically activates prorenin and stimulates receptor-mediated intracellular signalling independent of angiotensin II; transgenic rats overexpressing (P)RR develop renal glomerulopathy without elevation of blood glucose or blood pressure, indicating that (P)RR overexpression alone is sufficient for end-organ damage. A peptidic (P)RR blocker (handle-region peptide) prevents diabetic nephropathy and attenuates hypertensive cardiomyopathy/nephropathy.\",\n      \"method\": \"Transgenic rat overexpression; streptozotocin diabetic nephropathy model; chronic infusion of handle-region peptide blocker; renal histopathology; blood pressure and metabolic measurements\",\n      \"journal\": \"Journal of the American Society of Hypertension : JASH\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic and pharmacological interventions, single review/summary paper synthesising multiple experimental studies\",\n      \"pmids\": [\"20409904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"(P)RR acts as an essential accessory protein of vacuolar H+-ATPase (V-ATPase) and also as an adaptor protein of Wnt signalling, in addition to its role as a receptor that non-proteolytically activates prorenin to catalyse angiotensinogen-to-angiotensin I conversion.\",\n      \"method\": \"Review synthesising in vivo and in vitro experimental evidence including receptor binding assays, V-ATPase assembly studies, and Wnt reporter assays from prior experimental work\",\n      \"journal\": \"Current pharmaceutical design\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — narrative review, no new primary experimental data reported in the abstract\",\n      \"pmids\": [\"23844810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"(P)RR overexpression activates the (P)RR/ERK/PPARγ signalling axis and downstream proteins related to fatty acid synthesis and transport in liver, promoting lipid accumulation; the handle-region peptide (HRP) blocker reverses activation of these proteins and reduces intracellular lipid accumulation in renin-stimulated HepG2 cells and in spontaneously hypertensive rats.\",\n      \"method\": \"SHR animal model; HepG2 cell lipid deposition model induced by renin; HRP pharmacological blockade; RNA sequencing; liver H&E and Nile red fluorescence staining; western blot for (P)RR, ERK, PPARγ, and lipid metabolism proteins; immunofluorescence\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — parallel in vitro and in vivo models with multiple molecular readouts, single lab\",\n      \"pmids\": [\"40650317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In vascular plaques, ELABELA-21 treatment reduces PRR (ATP6AP2) protein expression and decreases plasma soluble (P)RR levels, while the APJ inhibitor ML221 further elevates ATP6AP2 mRNA in THP-1 cells, placing (P)RR downstream of APJ-mediated signalling in macrophage inflammation and atherosclerotic plaque biology.\",\n      \"method\": \"ApoE−/− high-fat diet mouse model; ELA-21 administration; immunohistochemistry/protein expression in plaques; plasma sPRR ELISA; in vitro THP-1 foam cell and M1 polarization assays with APJ inhibitor; mRNA quantification\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single preprint lab, indirect evidence placing ATP6AP2 in APJ pathway context without direct mechanistic reconstitution\",\n      \"pmids\": [\"bio_10.1101_2024.11.07.24316940\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Mycolactone-mediated Sec61 inhibition causes loss of ATP6AP1 and ATP6AP2 (both Sec61-dependent co-translational substrates), which are required for Vacuolar-ATPase assembly; loss of these proteins leads to reduced lysosomal biogenesis and acidification, compromising autophagy flux and the ability of phagocytes to combat M. ulcerans infection.\",\n      \"method\": \"Mycolactone treatment of cells; Sec61 inhibition; TFEB nuclear translocation assay; lysosomal biogenesis and acidification assays; autophagy flux measurements; infection assays with M. ulcerans\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays demonstrating ATP6AP2 requirement for V-ATPase assembly and lysosomal function, single preprint lab\",\n      \"pmids\": [\"bio_10.1101_2025.08.26.671788\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Single-nucleus RNA sequencing of mouse hypothalamic paraventricular nucleus (PVN) shows that Atp6ap2/(P)RR is predominantly expressed in neurons (not astrocytes); DOCA-salt hypertension increases neuronal Atp6ap2 expression, and high-fat diet upregulates Atp6ap2 in vasopressin neurons, indicating cell-type-specific regulation of (P)RR under cardiometabolic stress.\",\n      \"method\": \"Single-nucleus RNA sequencing (snRNA-seq) of PVN from baseline, DOCA-salt hypertension, and high-fat diet mouse models; cell-type-specific gene expression analysis\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — transcriptomic localization only, no functional consequence directly tested for ATP6AP2, single preprint\",\n      \"pmids\": [\"bio_10.1101_2025.08.14.669892\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"(P)RR/(ATP6AP2) is required in cardiovascular tissues for canonical Wnt transduction: offspring of preeclamptic rats show elevated (P)RR expression together with upregulation of PLZF, β-catenin, DVL-1, and PKCα in heart, aorta, and kidney; handle-region peptide treatment abolishes these increases and reverses hypertension, placing (P)RR upstream of canonical Wnt pathway components in cardiovascular regulation.\",\n      \"method\": \"Preeclampsia rat offspring model; HRP pharmacological treatment; immunoblot for (P)RR, PLZF, β-catenin, DVL-1, PKCα; RT-PCR for (P)RR and PLZF; blood pressure measurement; morphological organ assessment\",\n      \"journal\": \"Iranian journal of basic medical sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, indirect pharmacological (HRP) rather than genetic manipulation of (P)RR, correlative protein measurements\",\n      \"pmids\": [\"38629095\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATP6AP2/(P)RR is a multifunctional membrane protein that (i) non-proteolytically activates prorenin/renin to enhance local angiotensin generation, (ii) serves as an essential accessory subunit for vacuolar H⁺-ATPase (V-ATPase) assembly and lysosomal/endosomal acidification, (iii) acts as an adaptor for Wnt co-receptors through Dvl to modulate Wnt/β-catenin signalling (functioning as a repressor when overexpressed), (iv) recruits the transcription factor PLZF to drive a distinct downstream transcriptional programme, and (v) in adipose tissue and placenta controls cell proliferation, migration, energy metabolism, and insulin sensitivity, with its ERK/PPARγ axis additionally implicated in hepatic lipid accumulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATP6AP2, also known as the (pro)renin receptor ((P)RR), is a multifunctional membrane protein that couples local renin-angiotensin signalling to vacuolar H\\u207a-ATPase (V-ATPase) function and developmental/metabolic control [#6, #5]. As an essential V-ATPase accessory protein, it is required for endosomal/lysosomal acidification and lysosomal biogenesis, and its loss compromises autophagy flux [#9]; this V-ATPase function is also necessary for Wnt3a-driven induction of Tcf/Lef-responsive genes, while full-length (P)RR overexpression represses Wnt signalling through Dvl independently of \\u03b2-catenin status [#0]. Distinct from these roles, (P)RR also acts as an adaptor that drives a separate transcriptional programme through the transcription factor PLZF, and knockdown studies resolve the non-overlapping gene sets controlled by its V-ATPase versus PLZF-adaptor functions [#1]. Binding of prorenin or renin non-proteolytically activates prorenin and triggers angiotensin-II-independent intracellular signalling, with receptor overexpression alone sufficient to cause end-organ renal damage [#5]. Tissue-specific genetic studies establish physiological roles in energy homeostasis and development: adipose-specific deletion reduces fat mass and improves insulin sensitivity [#2], (P)RR is required for trophoblast proliferation, migration, invasion and placental labyrinth development [#4], and tubular overexpression produces V-ATPase-dependent hypertension and urinary alkalinization [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that (P)RR is a functional receptor whose ligand binding activates prorenin and drives signalling independent of angiotensin II, and that receptor excess alone causes organ damage \\u2014 defining (P)RR as more than a passive renin-binding protein.\",\n      \"evidence\": \"Transgenic rat overexpression, streptozotocin diabetic nephropathy model, and handle-region peptide blockade with renal histopathology\",\n      \"pmids\": [\"20409904\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular signalling cascade downstream of prorenin binding not resolved\", \"Mechanism by which receptor overexpression causes glomerulopathy unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Dissected the Wnt-related role, showing (P)RR represses Wnt signalling via Dvl when overexpressed, while its V-ATPase activity (not PLZF or renin activity) is required for Wnt3a-induced Tcf/Lef gene expression \\u2014 separating its molecular functions in one pathway.\",\n      \"evidence\": \"Tcf/Lef reporter assays, endogenous axin2 quantification, siRNA knockdown and overexpression in HEK293T and HepG2 cells\",\n      \"pmids\": [\"23022225\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of Dvl interaction not defined\", \"Reconciliation of repressor versus required-for-induction roles incomplete\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved that the V-ATPase and PLZF-adaptor functions of (P)RR drive distinct, partly overlapping transcriptional programmes, establishing that its molecular roles map onto separable downstream gene networks.\",\n      \"evidence\": \"siRNA knockdown, PLZF overexpression, microarray and ChIP-chip with pharmacological inhibitors (genistein, bafilomycin) and qPCR validation\",\n      \"pmids\": [\"23469216\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PLZF target genes not fully validated\", \"Cell-type generality of the programmes untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated a genetic, tissue-autonomous role for (P)RR in energy homeostasis, where adipose deletion reduces adiposity and improves insulin sensitivity \\u2014 placing (P)RR in metabolic control beyond the cardiovascular system.\",\n      \"evidence\": \"AP2-Cre conditional knockout mice with metabolic cage, glucose tolerance, plasma insulin/C-peptide, adipocyte histomorphometry and adiponectin assays\",\n      \"pmids\": [\"27689008\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which molecular function (V-ATPase vs renin vs Wnt) drives the metabolic phenotype unknown\", \"Mechanism linking (P)RR loss to elevated adiponectin not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed that tubular (P)RR overexpression produces V-ATPase-dependent hypertension and urine alkalinization reversed by bafilomycin, anchoring (P)RR's blood-pressure role to its V-ATPase function in the kidney.\",\n      \"evidence\": \"Tubular-specific transgenic mice with pharmacological dissection (ARB, renin inhibitor, bafilomycin), urine chemistry and double-transgenic renin crosses\",\n      \"pmids\": [\"35008728\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of physiological tubular ligand not proven\", \"Single-lab transgenic model\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established a developmental requirement for (P)RR in placentation, where knockdown impairs trophoblast function and disrupts placental labyrinth architecture in vivo.\",\n      \"evidence\": \"siRNA in HTR-8/SVneo cells with xCELLigence assays plus lentiviral shRNA in mouse blastocysts, embryo transfer and placental stereology\",\n      \"pmids\": [\"37588662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular pathway mediating trophoblast effects not identified\", \"Relationship to renin/V-ATPase/Wnt functions untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked (P)RR to hepatic lipid metabolism via an ERK/PPAR\\u03b3 axis, with the handle-region peptide reversing lipid accumulation \\u2014 extending the receptor's signalling output to fatty acid synthesis/transport.\",\n      \"evidence\": \"SHR model and renin-stimulated HepG2 lipid deposition with HRP blockade, RNA-seq, Nile red staining and western blot for ERK/PPAR\\u03b3\",\n      \"pmids\": [\"40650317\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct receptor-to-ERK coupling not reconstituted\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mechanistically confirmed (P)RR as a Sec61-dependent co-translational substrate required for V-ATPase assembly, lysosomal acidification and autophagy, connecting it to phagocyte antimicrobial function.\",\n      \"evidence\": \"Mycolactone/Sec61 inhibition with TFEB translocation, lysosomal acidification, autophagy flux and M. ulcerans infection assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.08.26.671788\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Direct structural role within assembled V-ATPase not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the distinct molecular functions of (P)RR \\u2014 prorenin activation, V-ATPase accessory role, Wnt/Dvl adaptor, and PLZF recruitment \\u2014 are selected and balanced within a given cell type, and which one drives each tissue phenotype, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking molecular functions to specific physiological outputs\", \"Ligand selectivity and context-dependent function not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 0]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [\"V-ATPase\"],\n    \"partners\": [\"renin\", \"DVL\", \"PLZF\", \"ATP6AP1\", \"SEC61\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}