{"gene":"AGTR1","run_date":"2026-06-09T22:02:42","timeline":{"discoveries":[{"year":2007,"finding":"The AGTR1 3'UTR SNP rs5186 (A1166C) disrupts a binding site for hsa-miR-155; the 1166A allele is downregulated by miR-155 in reporter silencing assays, while the 1166C allele abrogates miR-155-mediated repression, resulting in higher AGTR1 protein levels. Fibroblasts from trisomy 21 individuals (with extra miR-155 gene copies) show lower AGTR1 protein than euploid co-twins.","method":"Luciferase reporter silencing assay; Western blot of AGTR1 protein in matched trisomy 21 vs. euploid fibroblasts","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reporter assay with allele-specific functional readout replicated in endogenous protein measurement; two orthogonal methods in single rigorous study","pmids":["17668390"],"is_preprint":false},{"year":2008,"finding":"CD74 (invariant chain) was identified as an AGTR1-interacting protein via yeast two-hybrid screening of a human kidney cDNA library using the AGTR1 C-terminal tail as bait. The interaction was confirmed by co-immunoprecipitation and co-localization. CD74 binds the membrane-proximal C-terminal tail region previously shown to be required for ER exit, causes retention of AGTR1 in the ER, and promotes its proteasomal degradation, thereby reducing AGTR1 cell-surface density.","method":"Yeast two-hybrid screen; co-immunoprecipitation; co-localization; overexpression in CHO-K1 cells with surface density measurement","journal":"The Journal of endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus co-localization plus functional surface-density readout; single lab but three orthogonal methods","pmids":["18719072"],"is_preprint":false},{"year":2014,"finding":"Tudor-SN (human Tudor staphylococcal nuclease) binds AGTR1 3'UTR RNA and co-localizes with it in stress granules (SGs). Tudor-SN knockdown decreases the recovery kinetics of AGTR1-3'UTR granules, indicating Tudor-SN modulates the dynamics of AGTR1 mRNA-containing SG assembly during stress.","method":"Co-localization imaging; Tudor-SN knockdown with fluorescence recovery assay of AGTR1-3'UTR granule kinetics; co-localization with G3BP-marked SGs","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-localization and KD phenotype, single lab, two methods but no direct binding reconstitution in the abstract","pmids":["24815690"],"is_preprint":false},{"year":2007,"finding":"Allele-specific mRNA quantification of AGTR1 transcripts in placental cDNA showed that haplotypes carrying the 1166C allele (rs5186:A>C) have reduced mRNA abundance compared to 1166A haplotypes, with a greater effect in CC homozygotes than heterozygotes, suggesting feedback-regulated allelic mRNA expression at this locus.","method":"Quantitative transcript haplotype (QTH) analysis; within-individual ratiometric assays of allelic mRNA in placental cDNA; TaqMan assays","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative allele-specific mRNA measurement, single lab, multiple assay approaches converging on same finding","pmids":["17211857"],"is_preprint":false},{"year":2003,"finding":"In mice, Agtr1a promoter polymorphisms between BPL/1 and SPRET strains drive strain-specific differences in Agtr1a mRNA abundance in the adrenal gland in vivo, and drive differential luciferase reporter expression when transfected into PC12 chromaffin cells, demonstrating that natural promoter variation functionally controls Agtr1a expression and thereby influences blood pressure at a chromosome 13 QTL.","method":"Resequencing of Agtr1a locus; in vivo mRNA quantification; luciferase promoter reporter assays in PC12 cells; genome-wide linkage mapping","journal":"Physiological genomics","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vivo mRNA and in vitro reporter assays converge, single lab, mouse ortholog","pmids":["12697907"],"is_preprint":false},{"year":1995,"finding":"Using fluorescence in situ hybridization (FISH), the rat Agtr1a gene was mapped to chromosome 17q12, Agtr1b to 2q24, Agtr2 to Xq34, and human AGTR2 to Xq22, establishing the chromosomal localization of these receptor genes.","method":"Fluorescence in situ hybridization (FISH)","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct FISH mapping, single lab, standard cytogenetics method","pmids":["7606933"],"is_preprint":false},{"year":2019,"finding":"AGTR1 overexpression in breast cancer cells upregulates CXCR4/SDF-1α and activates FAK/RhoA signaling to promote cell migration, invasion, and lymph node metastasis. Knockdown of AGTR1 reduced CXCR4 expression; knockdown of CXCR4 in AGTR1-high cells downregulated FAK/RhoA signaling molecules; losartan (AGTR1 antagonist) decreased CXCR4/SDF-1α levels in vivo and inhibited migration and invasion in vitro.","method":"siRNA knockdown; AGTR1 overexpression; losartan treatment; bioluminescence imaging of orthotopic xenografts; Western blot of FAK/RhoA pathway; Transwell migration/invasion assays","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KD plus pharmacological inhibition plus in vivo imaging, single lab","pmids":["31219799"],"is_preprint":false},{"year":2009,"finding":"Ectopic overexpression of AGTR1 in primary mammary epithelial cells combined with angiotensin II stimulation induces a highly invasive phenotype; this invasion is attenuated by the AGTR1 antagonist losartan. Losartan also reduced tumor growth by 30% in AGTR1-positive breast cancer xenografts.","method":"Ectopic overexpression in primary mammary epithelial cells; angiotensin II stimulation; losartan antagonism; breast cancer xenograft tumor growth assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression plus pharmacological antagonism plus xenograft, single lab, multiple readouts","pmids":["19487683"],"is_preprint":false},{"year":2020,"finding":"miR-155 post-transcriptionally represses AGTR1 via its 3'UTR (confirmed by luciferase reporter assay) in glioblastoma cells. miR-155 overexpression reduces AGTR1 protein, attenuates NF-κB signaling downstream of AGTR1, and decreases CXCR4 and AGTR1 levels, reducing GBM cell proliferation, invasion, foci formation, and anchorage-independent growth; stable miR-155-overexpressing cells form negligible tumors in immunodeficient mice.","method":"Luciferase reporter assay of AGTR1 3'UTR; miR-155 stable overexpression; Western blot; in vitro cell assays; xenograft tumor model","journal":"Neoplasia (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus stable OE with multiple functional readouts plus in vivo model, single lab","pmids":["32896760"],"is_preprint":false},{"year":2014,"finding":"Testosterone reduces AGTR1 mRNA and protein expression in INS-1 pancreatic β-cells cultured in high-glucose medium, decreases p47phox mRNA/protein and superoxide production, and reduces cleaved caspase-3 and apoptosis to levels similar to losartan. AGTR1 siRNA knockdown confirmed that AGTR1 mediates high-glucose-induced β-cell apoptosis; testosterone did not alter AGTR1 expression or apoptosis under basal glucose conditions.","method":"INS-1 cell culture and isolated mouse islets; testosterone and losartan treatment; AGTR1 siRNA knockdown; RT-PCR and Western blot; annexin V/PI apoptosis assay; superoxide/ROS measurement","journal":"The Journal of endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic (siRNA) approaches with multiple molecular and cellular readouts, single lab","pmids":["25512346"],"is_preprint":false},{"year":2023,"finding":"In the central amygdala (CeA) of mice, AT1R (AGTR1)-expressing neurons are localized to GABAergic neurons in the lateral CeA (CeL), the majority co-expressing PKCδ. Conditional CeA-AT1R deletion (via cre-expressing lentiviral delivery in AT1R-Flox mice) enhanced fear extinction acquisition without altering anxiety, locomotion, or fear acquisition. Electrophysiological recordings showed that angiotensin II (1 μM) increased sIPSC amplitude and decreased excitability of CeL-AT1R+ neurons, indicating AGTR1 activation facilitates GABAergic inhibition in the CeL to impede extinction learning.","method":"Transgenic AT1R reporter mice; cre-lentiviral conditional deletion; immunofluorescence co-localization; fear conditioning/extinction behavioral assays; whole-cell electrophysiology of CeL neurons with Ang II application","journal":"Neuropharmacology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic deletion, electrophysiology with ligand application, neuroanatomical localization, and behavioral readout converge in a single rigorous study","pmids":["36801399"],"is_preprint":false},{"year":2023,"finding":"In spontaneously hypertensive rats (SHR), CpG methylation at the Agtr1a promoter in the hypothalamic paraventricular nucleus (PVN) is progressively reduced compared to normotensive WKY rats, correlating with increased Agtr1a mRNA. ChIP-qPCR showed reduced DNMT1/DNMT3A and MBD2 enrichment, and increased TET1-3 enrichment, at the Agtr1a promoter in SHR. Microinjection of DNMT inhibitor RG108 into WKY PVN raised blood pressure and elevated Agtr1a mRNA; microinjection of TET inhibitor C35 into SHR PVN reduced blood pressure and Agtr1a mRNA, establishing a DNMT/TET epigenetic switch as a mechanistic driver of Agtr1a transcription and hypertension.","method":"Methylated DNA immunoprecipitation; bisulfite sequencing-PCR; ChIP-qPCR; stereotaxic microinjection of DNMT/TET inhibitors; arterial blood pressure measurement; RT-qPCR","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal epigenomic methods plus bidirectional pharmacological intervention with causal blood pressure and mRNA readouts in the same study","pmids":["38160798"],"is_preprint":false},{"year":2022,"finding":"Maternal exercise in spontaneously hypertensive rat dams upregulates DNMT1 and DNMT3B expression in mesenteric arteries of offspring, increases CpG methylation at the Agtr1a promoter, reduces AT1R (AGTR1) mRNA and protein expression, decreases Ang II-AT1R-mediated vascular tone, and lowers blood pressure in adult SHR offspring.","method":"Bisulfite sequencing of Agtr1a promoter; Western blot and RT-PCR of AT1R; arterial vascular tone measurements; blood pressure telemetry in offspring","journal":"Hypertension research : official journal of the Japanese Society of Hypertension","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple molecular and physiological readouts, single lab, rat model","pmids":["36539461"],"is_preprint":false},{"year":2023,"finding":"Co-immunoprecipitation in a rat CHF model demonstrated a physical interaction between AGTR1 and aquaporin-1 (AQP1) in the left ventricle. XinLi formula treatment inhibited AGTR1 expression and suppressed the AGTR1–AQP1 interaction, reducing myocardial edema, suggesting the AGTR1–AQP1 complex contributes to cardiac fluid regulation.","method":"Co-immunoprecipitation from left ventricular tissue; Western blot; echocardiography; ELISA; histology","journal":"Phytomedicine : international journal of phytotherapy and phytopharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP from tissue in a pharmacological intervention context, single lab, no reciprocal IP or reconstitution","pmids":["36867964"],"is_preprint":false},{"year":2021,"finding":"In glioblastoma cells (U-87 MG and T98G), Ang II/AGTR1 signaling directly upregulates aromatase gene promoters p I.f and p I.4, increasing local estrogen production, and transactivates estrogen receptor-α in a ligand-independent manner through MAPK activation. Ang II treatment also increases PD-L1 expression, reversible by losartan in vitro and in vivo.","method":"Aromatase promoter reporter assays; RT-PCR; Western blot; losartan pharmacological antagonism; in vivo tumor model","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays plus pharmacological antagonism with in vivo confirmation, single lab, two orthogonal methods","pmids":["34572782"],"is_preprint":false},{"year":2021,"finding":"In vitro enrichment analysis and overexpression experiments in lung adenocarcinoma cell lines indicated that AGTR1 inhibits tumor progression through the PI3K/AKT3 pathway, supported by AGTR1 overexpressing cell construction and tissue sample validation.","method":"AGTR1 overexpression in cell lines; Western blot of PI3K/AKT3 pathway; enrichment analysis; tissue sample protein measurement","journal":"Cancer management and research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single-lab overexpression with pathway Western blot, limited mechanistic depth in abstract","pmids":["34803402"],"is_preprint":false}],"current_model":"AGTR1 (angiotensin II type 1 receptor) is a G protein-coupled receptor whose surface expression is regulated post-translationally by CD74-mediated ER retention and proteasomal degradation, and post-transcriptionally by miR-155 binding to its 3'UTR (disrupted by the rs5186 A1166C SNP), with promoter activity controlled epigenetically via a DNMT/TET methylation switch; upon ligand activation it signals through NF-κB/CXCR4/FAK/RhoA to promote cell migration and invasion, through MAPK to transactivate estrogen receptor-α and upregulate aromatase, and through PI3K/AKT3 in select tissue contexts, while in the central amygdala its activation of GABAergic CeL neurons modulates fear extinction."},"narrative":{"mechanistic_narrative":"AGTR1 encodes the angiotensin II type 1 receptor, a G protein-coupled receptor whose abundance at the cell surface and within tissues is set by layered post-transcriptional, post-translational, and epigenetic controls, and whose ligand-activated signaling drives both cardiovascular tone and pro-tumorigenic cell behavior [PMID:18719072, PMID:38160798, PMID:31219799]. Surface density is limited post-translationally by CD74, which binds the membrane-proximal AGTR1 C-terminal tail, retains the receptor in the ER, and promotes its proteasomal degradation [PMID:18719072]. Receptor levels are also tuned post-transcriptionally by miR-155, which represses AGTR1 through its 3'UTR; the rs5186 A1166C variant disrupts this miR-155 site, relieving repression and elevating receptor protein [PMID:17668390]. Transcription is governed by a DNMT/TET methylation switch at the Agtr1a promoter, where loss of CpG methylation in the hypothalamic paraventricular nucleus raises receptor expression and blood pressure, and reciprocal DNMT/TET pharmacological manipulation bidirectionally controls expression and hypertension [PMID:38160798, PMID:36539461]. Upon angiotensin II binding, AGTR1 promotes cell migration, invasion, and metastasis via a CXCR4/SDF-1α–FAK/RhoA axis [PMID:31219799, PMID:19487683], transactivates estrogen receptor-α and upregulates aromatase through MAPK signaling [PMID:34572782], and mediates high-glucose-induced β-cell apoptosis through NADPH-oxidase–driven superoxide production [PMID:25512346]. In the central amygdala, AGTR1 marks GABAergic CeL neurons and its activation enhances inhibitory transmission to impede fear extinction [PMID:36801399].","teleology":[{"year":1995,"claim":"Establishing the chromosomal positions of the angiotensin receptor gene family provided the genomic anchor needed to link receptor loci to physiological traits.","evidence":"FISH mapping of rat Agtr1a/Agtr1b/Agtr2 and human AGTR2","pmids":["7606933"],"confidence":"Medium","gaps":["Does not address regulation or function of the human AGTR1 locus","No functional consequence of localization established"]},{"year":2003,"claim":"Whether natural promoter variation could causally control receptor expression and blood pressure was unknown; strain-specific promoter polymorphisms were shown to drive differential Agtr1a mRNA in vivo and reporter expression in vitro.","evidence":"Locus resequencing, in vivo adrenal mRNA quantification, and PC12 luciferase reporters across mouse strains at a chromosome 13 QTL","pmids":["12697907"],"confidence":"Medium","gaps":["Causal transcription factor binding the polymorphic site not identified","Mouse ortholog; human relevance not directly tested"]},{"year":2007,"claim":"The functional consequence of the AGTR1 3'UTR rs5186 variant was unresolved; it was shown to disrupt a miR-155 binding site, with the 1166C allele escaping miR-155 repression and yielding higher receptor protein.","evidence":"Allele-specific luciferase silencing assays and endogenous AGTR1 Western blot in matched trisomy 21 vs euploid fibroblasts; allele-specific mRNA quantification in placental cDNA","pmids":["17668390","17211857"],"confidence":"High","gaps":["In vivo tissue-specific impact of the variant on blood pressure not established","Interplay between miR-155 dosage and other regulatory layers unresolved"]},{"year":2008,"claim":"How AGTR1 cell-surface density is controlled post-translationally was unknown; CD74 was identified as a C-tail-binding partner that retains AGTR1 in the ER and targets it for proteasomal degradation.","evidence":"Yeast two-hybrid screen with AGTR1 C-tail bait, reciprocal co-IP, co-localization, and surface-density measurement in CHO-K1 cells","pmids":["18719072"],"confidence":"High","gaps":["Physiological tissues where CD74 regulates AGTR1 surface density not defined","Whether CD74 retention is signal-regulated unknown"]},{"year":2009,"claim":"Whether AGTR1 signaling could drive an oncogenic phenotype was untested; ectopic AGTR1 plus angiotensin II conferred an invasive phenotype in mammary epithelial cells reversible by losartan.","evidence":"Ectopic overexpression in primary mammary epithelial cells with Ang II stimulation, losartan antagonism, and breast cancer xenograft growth","pmids":["19487683"],"confidence":"Medium","gaps":["Downstream effectors of invasion not defined in this study","Endogenous AGTR1 dependence in patient tumors not addressed"]},{"year":2014,"claim":"Additional RNA-level controls of AGTR1 were probed: Tudor-SN was found to bind the AGTR1 3'UTR and modulate the assembly dynamics of AGTR1 mRNA-containing stress granules.","evidence":"Co-localization imaging, Tudor-SN knockdown with fluorescence-recovery kinetics, and co-localization with G3BP-marked stress granules","pmids":["24815690"],"confidence":"Medium","gaps":["No direct binding reconstitution","Functional consequence for AGTR1 protein output not measured"]},{"year":2014,"claim":"A hormonal link to AGTR1-driven apoptosis was established: testosterone suppresses AGTR1 expression and the resulting NADPH-oxidase superoxide and caspase-3 activation, with siRNA confirming AGTR1 mediates high-glucose β-cell apoptosis.","evidence":"INS-1 cells and mouse islets with testosterone/losartan treatment, AGTR1 siRNA, apoptosis and ROS assays","pmids":["25512346"],"confidence":"Medium","gaps":["Mechanism by which testosterone represses AGTR1 not defined","In vivo relevance to diabetic islet loss not tested"]},{"year":2019,"claim":"The signaling route for AGTR1-driven metastasis was defined: AGTR1 upregulates CXCR4/SDF-1α to activate FAK/RhoA, promoting migration, invasion, and lymph node metastasis.","evidence":"siRNA knockdown, overexpression, losartan treatment, FAK/RhoA Western blots, Transwell assays, and orthotopic xenograft bioluminescence imaging in breast cancer","pmids":["31219799"],"confidence":"Medium","gaps":["G protein and immediate-early effectors upstream of CXCR4 induction not mapped","Single cancer-type focus"]},{"year":2020,"claim":"The miR-155–AGTR1 axis was shown to be functionally tumor-suppressive in another cancer: miR-155 represses AGTR1 via its 3'UTR, attenuating NF-κB and CXCR4 signaling and suppressing glioblastoma growth.","evidence":"Luciferase 3'UTR reporter, stable miR-155 overexpression, Western blot, in vitro transformation assays, and xenograft tumor formation","pmids":["32896760"],"confidence":"Medium","gaps":["Other miR-155 targets contributing to phenotype not excluded","Endogenous miR-155/AGTR1 ratio in patient tumors not quantified"]},{"year":2021,"claim":"Distinct context-dependent AGTR1 signaling outputs were identified: MAPK-mediated aromatase upregulation and ligand-independent ERα transactivation with PD-L1 induction in glioblastoma, and a reported PI3K/AKT3 tumor-suppressive route in lung adenocarcinoma.","evidence":"Aromatase promoter reporters, RT-PCR, Western blot, and losartan antagonism in glioblastoma; overexpression and pathway Western blot in lung adenocarcinoma lines","pmids":["34572782","34803402"],"confidence":"Medium","gaps":["The lung adenocarcinoma PI3K/AKT3 finding is low-confidence and lacks mechanistic depth","Tissue determinants of pro- vs anti-tumor signaling unresolved"]},{"year":2023,"claim":"A central-nervous-system role for AGTR1 was established: AT1R-expressing GABAergic PKCδ+ neurons in the lateral central amygdala mediate angiotensin II-driven inhibition that impedes fear extinction.","evidence":"AT1R reporter mice, cre-lentiviral conditional deletion, immunofluorescence, fear extinction behavior, and whole-cell electrophysiology with Ang II application","pmids":["36801399"],"confidence":"High","gaps":["Downstream circuit targets of CeL-AT1R inhibition not mapped","Signaling cascade linking receptor to altered excitability undefined"]},{"year":2023,"claim":"The epigenetic transcriptional control of AGTR1 was established as a causal driver of hypertension via a DNMT/TET methylation switch at the promoter.","evidence":"MeDIP, bisulfite-PCR, ChIP-qPCR for DNMT/TET/MBD2, and bidirectional stereotaxic DNMT/TET inhibitor microinjection with blood pressure readouts in SHR vs WKY PVN; maternal-exercise DNMT/methylation modulation in offspring mesenteric arteries","pmids":["38160798","36539461"],"confidence":"High","gaps":["Upstream signals setting DNMT/TET balance at the promoter unknown","Human promoter methylation relevance not directly tested"]},{"year":2023,"claim":"A candidate AGTR1 protein partner in cardiac fluid regulation was reported: AGTR1 physically interacts with aquaporin-1 in failing left ventricle, with the interaction reduced by pharmacological suppression of AGTR1.","evidence":"Co-immunoprecipitation from left ventricular tissue in a rat CHF model with echocardiography and histology","pmids":["36867964"],"confidence":"Low","gaps":["Single co-IP without reciprocal validation or reconstitution","Functional significance of the AGTR1–AQP1 complex not directly demonstrated"]},{"year":null,"claim":"The structural basis by which a single receptor partitions among opposing signaling outputs (pro- vs anti-tumor, GABAergic inhibition, vascular tone) and how its multiple regulatory layers are integrated in vivo remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking CD74 retention, miR-155, and promoter methylation in a single tissue","Determinants of context-dependent effector choice undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[6,7,10,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,10]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,8,11]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[10]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2,8]}],"complexes":[],"partners":["CD74","CXCR4","AQP1","SND1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P30556","full_name":"Type-1 angiotensin II receptor","aliases":["AT1AR","AT1BR","Angiotensin II type-1 receptor","AT1 receptor"],"length_aa":359,"mass_kda":41.1,"function":"Receptor for angiotensin II, a vasoconstricting peptide, which acts as a key regulator of blood pressure and sodium retention by the kidney (PubMed:15611106, PubMed:1567413, PubMed:25913193, PubMed:26420482, PubMed:30639100, PubMed:32079768, PubMed:8987975). The activated receptor in turn couples to G-alpha proteins G(q) (GNAQ, GNA11, GNA14 or GNA15) and thus activates phospholipase C and increases the cytosolic Ca(2+) concentrations, which in turn triggers cellular responses such as stimulation of protein kinase C (PubMed:15611106) (Microbial infection) During SARS coronavirus-2/SARS-CoV-2 infection, it is able to recognize and internalize the complex formed by secreted ACE2 and SARS-CoV-2 spike protein through DNM2/dynamin 2-dependent endocytosis","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P30556/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AGTR1","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/AGTR1","total_profiled":1310},"omim":[{"mim_id":"616797","title":"EFR3 HOMOLOG B; EFR3B","url":"https://www.omim.org/entry/616797"},{"mim_id":"613379","title":"CARBOXYMETHYLENEBUTENOLIDASE-LIKE PROTEIN; CMBL","url":"https://www.omim.org/entry/613379"},{"mim_id":"611798","title":"EFR3 HOMOLOG A; EFR3A","url":"https://www.omim.org/entry/611798"},{"mim_id":"610446","title":"BURULI ULCER, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/610446"},{"mim_id":"609589","title":"MICROTUBULE-ASSOCIATED SCAFFOLD PROTEIN 1; MTUS1","url":"https://www.omim.org/entry/609589"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":90.3},{"tissue":"placenta","ntpm":133.2}],"url":"https://www.proteinatlas.org/search/AGTR1"},"hgnc":{"alias_symbol":["AT1","AT2R1","AGTR1A","AT2R1A","HAT1R","AG2S","AT2R1B","AT1B","ATR1"],"prev_symbol":["AGTR1B"]},"alphafold":{"accession":"P30556","domains":[{"cath_id":"1.20.1070.10","chopping":"21-317","consensus_level":"high","plddt":89.8537,"start":21,"end":317}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P30556","model_url":"https://alphafold.ebi.ac.uk/files/AF-P30556-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P30556-F1-predicted_aligned_error_v6.png","plddt_mean":82.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AGTR1","jax_strain_url":"https://www.jax.org/strain/search?query=AGTR1"},"sequence":{"accession":"P30556","fasta_url":"https://rest.uniprot.org/uniprotkb/P30556.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P30556/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P30556"}},"corpus_meta":[{"pmid":"22515909","id":"PMC_22515909","title":"Ag2S 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APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/31554351","citation_count":9,"is_preprint":false},{"pmid":"25465759","id":"PMC_25465759","title":"Toxic potential of iron oxide, CdS/Ag₂S composite, CdS and Ag₂S NPs on a fresh water alga Mougeotia sp.","date":"2014","source":"Colloids and surfaces. B, Biointerfaces","url":"https://pubmed.ncbi.nlm.nih.gov/25465759","citation_count":9,"is_preprint":false},{"pmid":"31196347","id":"PMC_31196347","title":"Multifunctional A7R Peptide-Modified Hollow Mesoporous Silica@Ag₂S Nanotheranostics for Photoacoustic/Near-Infrared Fluorescence Imaging-Guided Tumor-Targeted Chemo-Photothermal Therapy.","date":"2019","source":"Journal of biomedical nanotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/31196347","citation_count":9,"is_preprint":false},{"pmid":"36074274","id":"PMC_36074274","title":"Fabrication of a smart drug delivery system based on hollow Ag2S@mSiO2 nanoparticles for fluorescence-guided synergistic photothermal chemotherapy.","date":"2022","source":"Mikrochimica acta","url":"https://pubmed.ncbi.nlm.nih.gov/36074274","citation_count":9,"is_preprint":false},{"pmid":"18646794","id":"PMC_18646794","title":"Observation of rotated-oriented attachment during the growth of Ag2S nanorods under mediation of protein.","date":"2008","source":"The journal of physical chemistry. B","url":"https://pubmed.ncbi.nlm.nih.gov/18646794","citation_count":9,"is_preprint":false},{"pmid":"31858452","id":"PMC_31858452","title":"AGT rs699 and AGTR1 rs5186 gene variants are associated with cardiovascular-related phenotypes in atherosclerotic peripheral arterial obstructive disease.","date":"2019","source":"Irish journal of medical science","url":"https://pubmed.ncbi.nlm.nih.gov/31858452","citation_count":8,"is_preprint":false},{"pmid":"27342049","id":"PMC_27342049","title":"AGTR1 rs3772622 gene polymorphism increase the risk of nonalcoholic fatty liver disease patients suffer coronary artery disease in Northern Chinese Han population.","date":"2016","source":"Lipids in health and disease","url":"https://pubmed.ncbi.nlm.nih.gov/27342049","citation_count":8,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55051,"output_tokens":4527,"usd":0.116529,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12565,"output_tokens":4558,"usd":0.088387,"stage2_stop_reason":"end_turn"},"total_usd":0.204916,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"The AGTR1 3'UTR SNP rs5186 (A1166C) disrupts a binding site for hsa-miR-155; the 1166A allele is downregulated by miR-155 in reporter silencing assays, while the 1166C allele abrogates miR-155-mediated repression, resulting in higher AGTR1 protein levels. Fibroblasts from trisomy 21 individuals (with extra miR-155 gene copies) show lower AGTR1 protein than euploid co-twins.\",\n      \"method\": \"Luciferase reporter silencing assay; Western blot of AGTR1 protein in matched trisomy 21 vs. euploid fibroblasts\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reporter assay with allele-specific functional readout replicated in endogenous protein measurement; two orthogonal methods in single rigorous study\",\n      \"pmids\": [\"17668390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD74 (invariant chain) was identified as an AGTR1-interacting protein via yeast two-hybrid screening of a human kidney cDNA library using the AGTR1 C-terminal tail as bait. The interaction was confirmed by co-immunoprecipitation and co-localization. CD74 binds the membrane-proximal C-terminal tail region previously shown to be required for ER exit, causes retention of AGTR1 in the ER, and promotes its proteasomal degradation, thereby reducing AGTR1 cell-surface density.\",\n      \"method\": \"Yeast two-hybrid screen; co-immunoprecipitation; co-localization; overexpression in CHO-K1 cells with surface density measurement\",\n      \"journal\": \"The Journal of endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus co-localization plus functional surface-density readout; single lab but three orthogonal methods\",\n      \"pmids\": [\"18719072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Tudor-SN (human Tudor staphylococcal nuclease) binds AGTR1 3'UTR RNA and co-localizes with it in stress granules (SGs). Tudor-SN knockdown decreases the recovery kinetics of AGTR1-3'UTR granules, indicating Tudor-SN modulates the dynamics of AGTR1 mRNA-containing SG assembly during stress.\",\n      \"method\": \"Co-localization imaging; Tudor-SN knockdown with fluorescence recovery assay of AGTR1-3'UTR granule kinetics; co-localization with G3BP-marked SGs\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-localization and KD phenotype, single lab, two methods but no direct binding reconstitution in the abstract\",\n      \"pmids\": [\"24815690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Allele-specific mRNA quantification of AGTR1 transcripts in placental cDNA showed that haplotypes carrying the 1166C allele (rs5186:A>C) have reduced mRNA abundance compared to 1166A haplotypes, with a greater effect in CC homozygotes than heterozygotes, suggesting feedback-regulated allelic mRNA expression at this locus.\",\n      \"method\": \"Quantitative transcript haplotype (QTH) analysis; within-individual ratiometric assays of allelic mRNA in placental cDNA; TaqMan assays\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative allele-specific mRNA measurement, single lab, multiple assay approaches converging on same finding\",\n      \"pmids\": [\"17211857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In mice, Agtr1a promoter polymorphisms between BPL/1 and SPRET strains drive strain-specific differences in Agtr1a mRNA abundance in the adrenal gland in vivo, and drive differential luciferase reporter expression when transfected into PC12 chromaffin cells, demonstrating that natural promoter variation functionally controls Agtr1a expression and thereby influences blood pressure at a chromosome 13 QTL.\",\n      \"method\": \"Resequencing of Agtr1a locus; in vivo mRNA quantification; luciferase promoter reporter assays in PC12 cells; genome-wide linkage mapping\",\n      \"journal\": \"Physiological genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vivo mRNA and in vitro reporter assays converge, single lab, mouse ortholog\",\n      \"pmids\": [\"12697907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Using fluorescence in situ hybridization (FISH), the rat Agtr1a gene was mapped to chromosome 17q12, Agtr1b to 2q24, Agtr2 to Xq34, and human AGTR2 to Xq22, establishing the chromosomal localization of these receptor genes.\",\n      \"method\": \"Fluorescence in situ hybridization (FISH)\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct FISH mapping, single lab, standard cytogenetics method\",\n      \"pmids\": [\"7606933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AGTR1 overexpression in breast cancer cells upregulates CXCR4/SDF-1α and activates FAK/RhoA signaling to promote cell migration, invasion, and lymph node metastasis. Knockdown of AGTR1 reduced CXCR4 expression; knockdown of CXCR4 in AGTR1-high cells downregulated FAK/RhoA signaling molecules; losartan (AGTR1 antagonist) decreased CXCR4/SDF-1α levels in vivo and inhibited migration and invasion in vitro.\",\n      \"method\": \"siRNA knockdown; AGTR1 overexpression; losartan treatment; bioluminescence imaging of orthotopic xenografts; Western blot of FAK/RhoA pathway; Transwell migration/invasion assays\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KD plus pharmacological inhibition plus in vivo imaging, single lab\",\n      \"pmids\": [\"31219799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Ectopic overexpression of AGTR1 in primary mammary epithelial cells combined with angiotensin II stimulation induces a highly invasive phenotype; this invasion is attenuated by the AGTR1 antagonist losartan. Losartan also reduced tumor growth by 30% in AGTR1-positive breast cancer xenografts.\",\n      \"method\": \"Ectopic overexpression in primary mammary epithelial cells; angiotensin II stimulation; losartan antagonism; breast cancer xenograft tumor growth assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression plus pharmacological antagonism plus xenograft, single lab, multiple readouts\",\n      \"pmids\": [\"19487683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-155 post-transcriptionally represses AGTR1 via its 3'UTR (confirmed by luciferase reporter assay) in glioblastoma cells. miR-155 overexpression reduces AGTR1 protein, attenuates NF-κB signaling downstream of AGTR1, and decreases CXCR4 and AGTR1 levels, reducing GBM cell proliferation, invasion, foci formation, and anchorage-independent growth; stable miR-155-overexpressing cells form negligible tumors in immunodeficient mice.\",\n      \"method\": \"Luciferase reporter assay of AGTR1 3'UTR; miR-155 stable overexpression; Western blot; in vitro cell assays; xenograft tumor model\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus stable OE with multiple functional readouts plus in vivo model, single lab\",\n      \"pmids\": [\"32896760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Testosterone reduces AGTR1 mRNA and protein expression in INS-1 pancreatic β-cells cultured in high-glucose medium, decreases p47phox mRNA/protein and superoxide production, and reduces cleaved caspase-3 and apoptosis to levels similar to losartan. AGTR1 siRNA knockdown confirmed that AGTR1 mediates high-glucose-induced β-cell apoptosis; testosterone did not alter AGTR1 expression or apoptosis under basal glucose conditions.\",\n      \"method\": \"INS-1 cell culture and isolated mouse islets; testosterone and losartan treatment; AGTR1 siRNA knockdown; RT-PCR and Western blot; annexin V/PI apoptosis assay; superoxide/ROS measurement\",\n      \"journal\": \"The Journal of endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic (siRNA) approaches with multiple molecular and cellular readouts, single lab\",\n      \"pmids\": [\"25512346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In the central amygdala (CeA) of mice, AT1R (AGTR1)-expressing neurons are localized to GABAergic neurons in the lateral CeA (CeL), the majority co-expressing PKCδ. Conditional CeA-AT1R deletion (via cre-expressing lentiviral delivery in AT1R-Flox mice) enhanced fear extinction acquisition without altering anxiety, locomotion, or fear acquisition. Electrophysiological recordings showed that angiotensin II (1 μM) increased sIPSC amplitude and decreased excitability of CeL-AT1R+ neurons, indicating AGTR1 activation facilitates GABAergic inhibition in the CeL to impede extinction learning.\",\n      \"method\": \"Transgenic AT1R reporter mice; cre-lentiviral conditional deletion; immunofluorescence co-localization; fear conditioning/extinction behavioral assays; whole-cell electrophysiology of CeL neurons with Ang II application\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic deletion, electrophysiology with ligand application, neuroanatomical localization, and behavioral readout converge in a single rigorous study\",\n      \"pmids\": [\"36801399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In spontaneously hypertensive rats (SHR), CpG methylation at the Agtr1a promoter in the hypothalamic paraventricular nucleus (PVN) is progressively reduced compared to normotensive WKY rats, correlating with increased Agtr1a mRNA. ChIP-qPCR showed reduced DNMT1/DNMT3A and MBD2 enrichment, and increased TET1-3 enrichment, at the Agtr1a promoter in SHR. Microinjection of DNMT inhibitor RG108 into WKY PVN raised blood pressure and elevated Agtr1a mRNA; microinjection of TET inhibitor C35 into SHR PVN reduced blood pressure and Agtr1a mRNA, establishing a DNMT/TET epigenetic switch as a mechanistic driver of Agtr1a transcription and hypertension.\",\n      \"method\": \"Methylated DNA immunoprecipitation; bisulfite sequencing-PCR; ChIP-qPCR; stereotaxic microinjection of DNMT/TET inhibitors; arterial blood pressure measurement; RT-qPCR\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal epigenomic methods plus bidirectional pharmacological intervention with causal blood pressure and mRNA readouts in the same study\",\n      \"pmids\": [\"38160798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Maternal exercise in spontaneously hypertensive rat dams upregulates DNMT1 and DNMT3B expression in mesenteric arteries of offspring, increases CpG methylation at the Agtr1a promoter, reduces AT1R (AGTR1) mRNA and protein expression, decreases Ang II-AT1R-mediated vascular tone, and lowers blood pressure in adult SHR offspring.\",\n      \"method\": \"Bisulfite sequencing of Agtr1a promoter; Western blot and RT-PCR of AT1R; arterial vascular tone measurements; blood pressure telemetry in offspring\",\n      \"journal\": \"Hypertension research : official journal of the Japanese Society of Hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple molecular and physiological readouts, single lab, rat model\",\n      \"pmids\": [\"36539461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Co-immunoprecipitation in a rat CHF model demonstrated a physical interaction between AGTR1 and aquaporin-1 (AQP1) in the left ventricle. XinLi formula treatment inhibited AGTR1 expression and suppressed the AGTR1–AQP1 interaction, reducing myocardial edema, suggesting the AGTR1–AQP1 complex contributes to cardiac fluid regulation.\",\n      \"method\": \"Co-immunoprecipitation from left ventricular tissue; Western blot; echocardiography; ELISA; histology\",\n      \"journal\": \"Phytomedicine : international journal of phytotherapy and phytopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP from tissue in a pharmacological intervention context, single lab, no reciprocal IP or reconstitution\",\n      \"pmids\": [\"36867964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In glioblastoma cells (U-87 MG and T98G), Ang II/AGTR1 signaling directly upregulates aromatase gene promoters p I.f and p I.4, increasing local estrogen production, and transactivates estrogen receptor-α in a ligand-independent manner through MAPK activation. Ang II treatment also increases PD-L1 expression, reversible by losartan in vitro and in vivo.\",\n      \"method\": \"Aromatase promoter reporter assays; RT-PCR; Western blot; losartan pharmacological antagonism; in vivo tumor model\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays plus pharmacological antagonism with in vivo confirmation, single lab, two orthogonal methods\",\n      \"pmids\": [\"34572782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In vitro enrichment analysis and overexpression experiments in lung adenocarcinoma cell lines indicated that AGTR1 inhibits tumor progression through the PI3K/AKT3 pathway, supported by AGTR1 overexpressing cell construction and tissue sample validation.\",\n      \"method\": \"AGTR1 overexpression in cell lines; Western blot of PI3K/AKT3 pathway; enrichment analysis; tissue sample protein measurement\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single-lab overexpression with pathway Western blot, limited mechanistic depth in abstract\",\n      \"pmids\": [\"34803402\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AGTR1 (angiotensin II type 1 receptor) is a G protein-coupled receptor whose surface expression is regulated post-translationally by CD74-mediated ER retention and proteasomal degradation, and post-transcriptionally by miR-155 binding to its 3'UTR (disrupted by the rs5186 A1166C SNP), with promoter activity controlled epigenetically via a DNMT/TET methylation switch; upon ligand activation it signals through NF-κB/CXCR4/FAK/RhoA to promote cell migration and invasion, through MAPK to transactivate estrogen receptor-α and upregulate aromatase, and through PI3K/AKT3 in select tissue contexts, while in the central amygdala its activation of GABAergic CeL neurons modulates fear extinction.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AGTR1 encodes the angiotensin II type 1 receptor, a G protein-coupled receptor whose abundance at the cell surface and within tissues is set by layered post-transcriptional, post-translational, and epigenetic controls, and whose ligand-activated signaling drives both cardiovascular tone and pro-tumorigenic cell behavior [#1, #11, #6]. Surface density is limited post-translationally by CD74, which binds the membrane-proximal AGTR1 C-terminal tail, retains the receptor in the ER, and promotes its proteasomal degradation [#1]. Receptor levels are also tuned post-transcriptionally by miR-155, which represses AGTR1 through its 3'UTR; the rs5186 A1166C variant disrupts this miR-155 site, relieving repression and elevating receptor protein [#0]. Transcription is governed by a DNMT/TET methylation switch at the Agtr1a promoter, where loss of CpG methylation in the hypothalamic paraventricular nucleus raises receptor expression and blood pressure, and reciprocal DNMT/TET pharmacological manipulation bidirectionally controls expression and hypertension [#11, #12]. Upon angiotensin II binding, AGTR1 promotes cell migration, invasion, and metastasis via a CXCR4/SDF-1\\u03b1\\u2013FAK/RhoA axis [#6, #7], transactivates estrogen receptor-\\u03b1 and upregulates aromatase through MAPK signaling [#14], and mediates high-glucose-induced \\u03b2-cell apoptosis through NADPH-oxidase\\u2013driven superoxide production [#9]. In the central amygdala, AGTR1 marks GABAergic CeL neurons and its activation enhances inhibitory transmission to impede fear extinction [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing the chromosomal positions of the angiotensin receptor gene family provided the genomic anchor needed to link receptor loci to physiological traits.\",\n      \"evidence\": \"FISH mapping of rat Agtr1a/Agtr1b/Agtr2 and human AGTR2\",\n      \"pmids\": [\"7606933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address regulation or function of the human AGTR1 locus\", \"No functional consequence of localization established\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Whether natural promoter variation could causally control receptor expression and blood pressure was unknown; strain-specific promoter polymorphisms were shown to drive differential Agtr1a mRNA in vivo and reporter expression in vitro.\",\n      \"evidence\": \"Locus resequencing, in vivo adrenal mRNA quantification, and PC12 luciferase reporters across mouse strains at a chromosome 13 QTL\",\n      \"pmids\": [\"12697907\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal transcription factor binding the polymorphic site not identified\", \"Mouse ortholog; human relevance not directly tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"The functional consequence of the AGTR1 3'UTR rs5186 variant was unresolved; it was shown to disrupt a miR-155 binding site, with the 1166C allele escaping miR-155 repression and yielding higher receptor protein.\",\n      \"evidence\": \"Allele-specific luciferase silencing assays and endogenous AGTR1 Western blot in matched trisomy 21 vs euploid fibroblasts; allele-specific mRNA quantification in placental cDNA\",\n      \"pmids\": [\"17668390\", \"17211857\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo tissue-specific impact of the variant on blood pressure not established\", \"Interplay between miR-155 dosage and other regulatory layers unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"How AGTR1 cell-surface density is controlled post-translationally was unknown; CD74 was identified as a C-tail-binding partner that retains AGTR1 in the ER and targets it for proteasomal degradation.\",\n      \"evidence\": \"Yeast two-hybrid screen with AGTR1 C-tail bait, reciprocal co-IP, co-localization, and surface-density measurement in CHO-K1 cells\",\n      \"pmids\": [\"18719072\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological tissues where CD74 regulates AGTR1 surface density not defined\", \"Whether CD74 retention is signal-regulated unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Whether AGTR1 signaling could drive an oncogenic phenotype was untested; ectopic AGTR1 plus angiotensin II conferred an invasive phenotype in mammary epithelial cells reversible by losartan.\",\n      \"evidence\": \"Ectopic overexpression in primary mammary epithelial cells with Ang II stimulation, losartan antagonism, and breast cancer xenograft growth\",\n      \"pmids\": [\"19487683\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors of invasion not defined in this study\", \"Endogenous AGTR1 dependence in patient tumors not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Additional RNA-level controls of AGTR1 were probed: Tudor-SN was found to bind the AGTR1 3'UTR and modulate the assembly dynamics of AGTR1 mRNA-containing stress granules.\",\n      \"evidence\": \"Co-localization imaging, Tudor-SN knockdown with fluorescence-recovery kinetics, and co-localization with G3BP-marked stress granules\",\n      \"pmids\": [\"24815690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct binding reconstitution\", \"Functional consequence for AGTR1 protein output not measured\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"A hormonal link to AGTR1-driven apoptosis was established: testosterone suppresses AGTR1 expression and the resulting NADPH-oxidase superoxide and caspase-3 activation, with siRNA confirming AGTR1 mediates high-glucose \\u03b2-cell apoptosis.\",\n      \"evidence\": \"INS-1 cells and mouse islets with testosterone/losartan treatment, AGTR1 siRNA, apoptosis and ROS assays\",\n      \"pmids\": [\"25512346\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which testosterone represses AGTR1 not defined\", \"In vivo relevance to diabetic islet loss not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The signaling route for AGTR1-driven metastasis was defined: AGTR1 upregulates CXCR4/SDF-1\\u03b1 to activate FAK/RhoA, promoting migration, invasion, and lymph node metastasis.\",\n      \"evidence\": \"siRNA knockdown, overexpression, losartan treatment, FAK/RhoA Western blots, Transwell assays, and orthotopic xenograft bioluminescence imaging in breast cancer\",\n      \"pmids\": [\"31219799\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"G protein and immediate-early effectors upstream of CXCR4 induction not mapped\", \"Single cancer-type focus\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The miR-155\\u2013AGTR1 axis was shown to be functionally tumor-suppressive in another cancer: miR-155 represses AGTR1 via its 3'UTR, attenuating NF-\\u03baB and CXCR4 signaling and suppressing glioblastoma growth.\",\n      \"evidence\": \"Luciferase 3'UTR reporter, stable miR-155 overexpression, Western blot, in vitro transformation assays, and xenograft tumor formation\",\n      \"pmids\": [\"32896760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Other miR-155 targets contributing to phenotype not excluded\", \"Endogenous miR-155/AGTR1 ratio in patient tumors not quantified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Distinct context-dependent AGTR1 signaling outputs were identified: MAPK-mediated aromatase upregulation and ligand-independent ER\\u03b1 transactivation with PD-L1 induction in glioblastoma, and a reported PI3K/AKT3 tumor-suppressive route in lung adenocarcinoma.\",\n      \"evidence\": \"Aromatase promoter reporters, RT-PCR, Western blot, and losartan antagonism in glioblastoma; overexpression and pathway Western blot in lung adenocarcinoma lines\",\n      \"pmids\": [\"34572782\", \"34803402\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The lung adenocarcinoma PI3K/AKT3 finding is low-confidence and lacks mechanistic depth\", \"Tissue determinants of pro- vs anti-tumor signaling unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A central-nervous-system role for AGTR1 was established: AT1R-expressing GABAergic PKC\\u03b4+ neurons in the lateral central amygdala mediate angiotensin II-driven inhibition that impedes fear extinction.\",\n      \"evidence\": \"AT1R reporter mice, cre-lentiviral conditional deletion, immunofluorescence, fear extinction behavior, and whole-cell electrophysiology with Ang II application\",\n      \"pmids\": [\"36801399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream circuit targets of CeL-AT1R inhibition not mapped\", \"Signaling cascade linking receptor to altered excitability undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The epigenetic transcriptional control of AGTR1 was established as a causal driver of hypertension via a DNMT/TET methylation switch at the promoter.\",\n      \"evidence\": \"MeDIP, bisulfite-PCR, ChIP-qPCR for DNMT/TET/MBD2, and bidirectional stereotaxic DNMT/TET inhibitor microinjection with blood pressure readouts in SHR vs WKY PVN; maternal-exercise DNMT/methylation modulation in offspring mesenteric arteries\",\n      \"pmids\": [\"38160798\", \"36539461\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals setting DNMT/TET balance at the promoter unknown\", \"Human promoter methylation relevance not directly tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A candidate AGTR1 protein partner in cardiac fluid regulation was reported: AGTR1 physically interacts with aquaporin-1 in failing left ventricle, with the interaction reduced by pharmacological suppression of AGTR1.\",\n      \"evidence\": \"Co-immunoprecipitation from left ventricular tissue in a rat CHF model with echocardiography and histology\",\n      \"pmids\": [\"36867964\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single co-IP without reciprocal validation or reconstitution\", \"Functional significance of the AGTR1\\u2013AQP1 complex not directly demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis by which a single receptor partitions among opposing signaling outputs (pro- vs anti-tumor, GABAergic inhibition, vascular tone) and how its multiple regulatory layers are integrated in vivo remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking CD74 retention, miR-155, and promoter methylation in a single tissue\", \"Determinants of context-dependent effector choice undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6, 7, 10, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 10]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 8, 11]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CD74\",\n      \"CXCR4\",\n      \"AQP1\",\n      \"SND1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}