{"gene":"MAS1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1988,"finding":"MAS1 (yeast) encodes the smaller 48 kDa subunit of the mitochondrial processing protease (MPP), a metalloprotease localized in the mitochondrial matrix that cleaves amino-terminal targeting sequences from imported mitochondrial precursor proteins. The MAS1 protein participates in its own cleavage during import into mitochondria.","method":"Genetic cloning and sequencing of MAS1, temperature-sensitive mutant analysis, in vitro protease activity assay, mitochondrial fractionation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay, mutagenesis via temperature-sensitive allele, replicated independently across two papers (PMID 3044780 and 2905264) with orthogonal methods","pmids":["3044780","2905264"],"is_preprint":false},{"year":1988,"finding":"The mitochondrial processing protease consists of two non-identical, loosely associated subunits encoded by MAS1 (48 kDa) and MAS2 (51 kDa); attempts to separate the subunits caused loss of enzymatic activity, indicating both subunits are required for catalytic function.","method":"Protein purification of the MPP complex, subunit identification by SDS-PAGE, activity assay after fractionation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — protein purification with reconstitution and activity measurement, confirmed by two independent studies (PMID 2905264 and 3061808)","pmids":["2905264","3061808"],"is_preprint":false},{"year":2017,"finding":"In Candida albicans, Mas1 (ortholog of yeast MAS1) interacts physically with the Hsp40 chaperone Ydj1; loss of MAS1 or YDJ1 perturbs mitochondrial morphology and function, and deletion of YDJ1 impairs import of Su9, a protein cleaved to its mature form by Mas1/Mas2, placing Mas1 downstream of Ydj1 in the mitochondrial protein import pathway.","method":"Co-immunoprecipitation/mass spectrometry protein interaction mapping, deletion mutant analysis, mitochondrial import assay with Su9 substrate, microscopy of mitochondrial morphology","journal":"Microbial cell (Graz, Austria)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction mapping by MS, functional import assay, single lab with multiple orthogonal methods","pmids":["29082232"],"is_preprint":false},{"year":2012,"finding":"Angiotensin-(1-7) acting through the MAS1 receptor (mammalian) attenuates allergic airway inflammation by suppressing phosphorylation of ERK1/2 and IκB-α; these effects were reversed by the selective MAS1 antagonist A779, establishing MAS1 as a required mediator of Ang-(1-7) anti-inflammatory signaling.","method":"Murine ovalbumin asthma model, pharmacological MAS1 antagonism with A779, Western blot for pERK1/2 and pIκB-α, bronchoalveolar lavage cell counts, histology","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological receptor antagonism with defined molecular readouts, single lab, multiple endpoints","pmids":["22339213"],"is_preprint":false},{"year":2017,"finding":"MAS1 receptor (mammalian) internalization after agonist stimulation occurs through both clathrin-coated pits and caveolae in a dynamin-dependent manner; internalized receptor traffics to Rab11-positive slow recycling endosomes rather than lysosomes. ERK1/2 activation by Ang-(1-7) requires β-arrestin2 and proceeds from early endosomes, whereas Akt activation from endosomes is β-arrestin2-independent.","method":"Live-cell imaging of MAS1R-YFP, ligand-binding internalization assay, dominant-negative constructs for Eps15, dynamin, shRNA knockdown of caveolin-1 and β-arrestin2, co-localization with Rab4, Rab11, LysoTracker, Western blot for pERK1/2 and pAkt","journal":"Hypertension","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays (dominant negatives, shRNA, live imaging, co-localization, biochemical), single lab but comprehensive mechanistic dissection","pmids":["28874464"],"is_preprint":false},{"year":2017,"finding":"Low-dose Ang-(1-7) acting through the MAS1 receptor promotes angiogenesis and vasodilation in rat microvascular endothelial cells; downstream signaling components identified include Rho GTPases, PI3K, protein kinase D1, MAPK, and ERK1/2. Pharmacological inhibition of ERK1/2 and p38 MAPK blocked both endothelial tube formation and vasodilation.","method":"In vitro endothelial tube formation assay, pharmacological inhibition of ERK1/2/p38, proteomics and genomics downstream pathway mapping, MAS1 receptor antagonism","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro functional assays with pharmacological inhibitors and multi-omics pathway identification, single lab","pmids":["28082260"],"is_preprint":false},{"year":2018,"finding":"Small molecule MAS1 agonists activate multiple G protein-dependent (Gq, Gi, GTPγS binding) and independent (β-arrestin recruitment, ERK1/2 phosphorylation, Akt phosphorylation, arachidonic acid release, receptor internalization) signaling pathways through recombinant MAS1. In contrast, Ang-(1-7) failed to induce or block signaling in any of these platforms at recombinant MAS1, and radiolabeled Ang-(1-7) showed no specific binding to recombinant MAS1 (negative result). Ang-(1-7) potently inhibited both phases of AT1R-mediated Ang II signaling in rat aortic endothelial cells.","method":"Recombinant MAS1 overexpression in HEK cells, GTPγS binding assay, β-arrestin recruitment assay, Erk1/2 and Akt phosphorylation assay, arachidonic acid release assay, dynamic mass redistribution (DMR) pathway-agnostic assay, radioligand binding assay","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1 / Strong — comprehensive multi-assay characterization with reconstituted recombinant receptor, multiple orthogonal readouts, rigorous negative controls for Ang-(1-7)","pmids":["29928987"],"is_preprint":false},{"year":2019,"finding":"The Ang-(1-7)/MAS1 receptor axis mediates anti-inflammatory effects in allergic asthma at least in part by inhibiting Src kinase-dependent transactivation of EGFR and downstream ERK1/2 phosphorylation; Ang-(1-7) also directly inhibited neutrophil and eosinophil chemotaxis ex vivo, and all effects were reversed by A779 MAS1 antagonism.","method":"Murine OVA asthma model, Western blot for phospho-Src, phospho-EGFR, phospho-ERK1/2, A779 MAS1 antagonist, ex vivo chemotaxis assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological antagonism of MAS1 with defined phospho-signaling readouts plus ex vivo chemotaxis, single lab, multiple methods","pmids":["31675376"],"is_preprint":false},{"year":2020,"finding":"AT1R (AT1RA) physically interacts with MAS1 receptor and is required for the pro-angiogenic signaling of Ang-(1-7) through MAS1; AT1RA knockout in Dahl salt-sensitive rats impaired Ang-(1-7)-mediated skeletal muscle angiogenesis, endothelial tube formation, and altered the protein complex formed upon Ang-(1-7) binding to Mas1 as shown by tandem mass spectrometry proteomics.","method":"AT1RA knockout rat model, hindlimb angiogenesis assay, in vitro endothelial tube formation, tandem mass spectrometry proteomics of Mas1-associated protein complex","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with functional phenotype plus MS-based protein complex analysis, single lab","pmids":["32324784"],"is_preprint":false},{"year":2022,"finding":"MAS1 overexpression in cardiomyocytes (H9C2 cells and MI rat model) decreased PTEN expression and enhanced phosphorylation of PI3K and AKT; the cardioprotective effect of MAS1 was reversed by PTEN overexpression or PI3K inhibitor LY294002, placing MAS1 upstream of the PTEN/PI3K/AKT pathway in cardiomyocyte survival signaling.","method":"MAS1 overexpression in H9C2 cells and rat MI model, Western blot for PTEN, p-PI3K, p-AKT, pharmacological inhibition with LY294002, PTEN overexpression rescue experiment, cardiomyocyte apoptosis assay","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function overexpression with epistasis rescue by PTEN and pharmacological inhibitor, in vivo and in vitro, single lab","pmids":["35247425"],"is_preprint":false},{"year":2022,"finding":"In pancreatic β-cells (RINm5F), Ang-(1-7) activation of MAS-1 induces intracellular cAMP increase and CREB activation, upregulates CFTR expression, and potentiates glucose-stimulated insulin secretion; MAS-1 inhibition or CFTR RNAi knockdown abolished these effects, placing MAS1 upstream of cAMP/CREB/CFTR in β-cell insulin secretion.","method":"RINm5F cell pharmacology with selective MAS-1 inhibitor, RNAi knockdown of CFTR and MAS-1, cAMP measurement, Western blot for CREB activation, insulin ELISA","journal":"Endocrine connections","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and RNAi-based epistasis with multiple molecular readouts, single lab","pmids":["34825893"],"is_preprint":false},{"year":2025,"finding":"In a pulmonary arterial hypertension (PAH) mouse model, ACE2 therapeutic effect is blocked in Mas1 knockout mice, establishing Mas1 as necessary for ACE2 action. The small-molecule Mas1 agonist AR234960 reproduces the ACE2 effect (sufficient). However, stabilized Ang-(1-7) failed to reproduce ACE2 effectiveness, indicating Ang-(1-7) alone does not activate Mas1 in this context. RNA-seq identified rescue of cytoskeletal and microtubule gene defects as key downstream mechanisms.","method":"Mas1 knockout mouse, PAH animal model, pharmacological Mas1 agonist AR234960, stabilized Ang-(1-7) treatment, RNA-seq downstream pathway analysis","journal":"Pulmonary circulation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout epistasis plus pharmacological rescue, RNA-seq for mechanism, single lab","pmids":["40248213"],"is_preprint":false},{"year":2026,"finding":"Cryo-EM structures of MAS1 (class A GPCR) bound to neuropeptide FF (NPFF) and small-molecule agonist AR234958 in complex with inhibitory G proteins reveal a conserved orthosteric binding pocket. MAS1 uses a non-canonical activation mechanism driven by ligand-induced hydrophobic compression involving residues Y248(6.55), L87(2.60), I84(2.57), and L266(7.39), transmitting mechanical tension to displace TM6 for G protein coupling rather than the canonical W6.48 toggle switch. Functional mutagenesis identified M244(6.51) and F237(6.44) on TM6 as critical molecular switches.","method":"Cryo-EM structure determination, functional mutagenesis of active-site residues, G protein coupling assay, comparative structural analysis with MRGPRX1-X4","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures at multiple states with functional mutagenesis validation, multiple orthogonal methods in single study","pmids":["41912627"],"is_preprint":false},{"year":2025,"finding":"Human CXCL17 activates MAS1 (among 10 human MRGPRs tested) at micromolar concentrations as measured by β-arrestin recruitment and chemotaxis of MAS1-transfected HEK293T cells; removal of the C-terminal fragment of CXCL17 did not affect MAS1 activation, indicating a mechanism distinct from GPR25 activation.","method":"NanoBiT-based β-arrestin recruitment assay in transfected HEK293T cells, chemotaxis assay, C-terminal deletion mutant of CXCL17","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab preprint, β-arrestin recruitment assay only, no validation of endogenous signaling","pmids":[],"is_preprint":true},{"year":2024,"finding":"Overexpression of Mas1 in mammary epithelial cells (EpH4 EV) reversed LPS-induced activation of NF-κB/MAPK signaling pathways and suppressed pro-inflammatory mediators; conversely, siRNA silencing of Mas1 enhanced LPS-induced inflammatory responses. Mas1 overexpression also reversed LPS-induced downregulation of tight junction proteins ZO-1, Occludin, and Claudin-3.","method":"Gene overexpression and siRNA knockdown in EpH4 EV cells, Western blot for NF-κB/MAPK pathway components and tight junction proteins, ELISA for inflammatory mediators","journal":"Frontiers in veterinary science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional genetic manipulation (OE and KD) with pathway-level readouts, single lab","pmids":["39071779"],"is_preprint":false}],"current_model":"Human/mammalian MAS1 is an orphan class A GPCR (structurally resolved by cryo-EM) that couples to inhibitory G proteins via a non-canonical hydrophobic compression mechanism involving TM6 residues M244(6.51) and F237(6.44); it activates Gq, Gi, β-arrestin, ERK1/2, Akt, and PI3K/PTEN downstream pathways depending on cell context, mediates receptor internalization through clathrin/caveolae in a dynamin-dependent manner with slow Rab11 recycling and β-arrestin2-dependent endosomal ERK1/2 signaling, interacts with AT1R to enable pro-angiogenic signaling, and is required for ACE2 therapeutic effects in pulmonary hypertension; in yeast the ortholog encodes the catalytic 48 kDa subunit of the two-subunit (MAS1/MAS2) mitochondrial processing metalloprotease that cleaves presequences from imported mitochondrial precursor proteins."},"narrative":{"mechanistic_narrative":"The MAS1 symbol denotes two mechanistically distinct proteins across the timeline that nonetheless form internally coherent bodies of evidence. In yeast and Candida, MAS1 encodes the smaller 48 kDa subunit of the two-subunit mitochondrial processing protease (MPP), a matrix metalloprotease that cleaves amino-terminal targeting presequences from imported mitochondrial precursor proteins; both the MAS1 and MAS2 (51 kDa) subunits are required for catalytic activity, and MAS1 itself is self-processed during import [PMID:3044780, PMID:2905264, PMID:3061808], with import of MPP substrates such as Su9 placed downstream of the Hsp40 chaperone Ydj1 [PMID:29082232]. In mammals, MAS1 is an orphan class A GPCR whose ligand-induced activation drives both G protein-dependent (Gq, Gi) and G protein-independent (β-arrestin recruitment, ERK1/2, Akt, arachidonic acid release) signaling, characterized comprehensively at recombinant receptor; notably, Ang-(1-7) showed no specific binding or signaling at recombinant MAS1 [PMID:29928987]. Cryo-EM structures of agonist- and Gi-bound MAS1 reveal a non-canonical activation mechanism in which ligand-induced hydrophobic compression transmits tension to displace TM6, with M244(6.51) and F237(6.44) acting as critical molecular switches, in place of the canonical W6.48 toggle [PMID:41912627]. Following agonist stimulation MAS1 internalizes via clathrin- and caveolae-dependent, dynamin-mediated routes into Rab11 slow-recycling endosomes, where β-arrestin2 is required for endosomal ERK1/2 but not Akt activation [PMID:28874464]. Functionally, the receptor mediates anti-inflammatory signaling in allergic airway disease through suppression of ERK1/2, IκB-α, and Src-dependent EGFR transactivation [PMID:22339213, PMID:31675376], pro-angiogenic and vasodilatory signaling in endothelial cells dependent on physical interaction with AT1R [PMID:28082260, PMID:32324784], cardiomyocyte survival via the PTEN/PI3K/AKT pathway [PMID:35247425], and is required for the therapeutic action of ACE2 in pulmonary arterial hypertension [PMID:40248213].","teleology":[{"year":1988,"claim":"Established the identity and catalytic role of MAS1, answering whether the gene product is an enzyme: it is the smaller subunit of the mitochondrial processing protease that removes targeting presequences from imported precursors.","evidence":"Genetic cloning, temperature-sensitive mutant analysis, and in vitro protease assays with mitochondrial fractionation in yeast","pmids":["3044780","2905264"],"confidence":"High","gaps":["Does not resolve which subunit carries the catalytic metal-binding site versus substrate recognition","No structural model of the protease"]},{"year":1988,"claim":"Defined the quaternary requirement for activity, showing MPP is an obligate two-subunit enzyme rather than a single polypeptide.","evidence":"Purification of the MPP complex, subunit resolution by SDS-PAGE, and activity loss upon subunit separation","pmids":["2905264","3061808"],"confidence":"High","gaps":["Stoichiometry and interface of subunit association not defined","Mechanism of activity loss on separation unresolved"]},{"year":2017,"claim":"Placed MAS1/MPP within the import pathway by identifying an upstream chaperone, showing Hsp40 Ydj1 physically and functionally interacts with Mas1 for precursor delivery.","evidence":"Co-IP/MS interaction mapping, deletion mutants, and Su9 mitochondrial import assays in Candida albicans","pmids":["29082232"],"confidence":"Medium","gaps":["Direct versus indirect nature of the Mas1-Ydj1 interaction not fully separated from import defects","Single organism, single lab"]},{"year":2012,"claim":"Identified the mammalian MAS1 receptor as a required mediator of Ang-(1-7) anti-inflammatory signaling, addressing whether the GPCR transduces protective effects in vivo.","evidence":"Murine OVA asthma model with selective antagonist A779 and phospho-ERK1/2 / IκB-α readouts","pmids":["22339213"],"confidence":"Medium","gaps":["Pharmacological antagonism does not prove direct ligand binding to MAS1","Cell-type origin of the signal not localized"]},{"year":2017,"claim":"Dissected MAS1 receptor trafficking and biased signaling, answering how internalized receptor routes and which effectors depend on β-arrestin2.","evidence":"Live-cell imaging, dominant-negative and shRNA perturbation of Eps15/dynamin/caveolin-1/β-arrestin2, and endosomal co-localization","pmids":["28874464"],"confidence":"High","gaps":["Performed with Ang-(1-7) as ligand whose direct binding was later contested","Recycling kinetics not linked to functional outputs"]},{"year":2017,"claim":"Mapped the pro-angiogenic effector cascade downstream of MAS1 in endothelial cells, establishing ERK1/2 and p38 as required for tube formation and vasodilation.","evidence":"In vitro endothelial tube formation, pharmacological ERK1/2/p38 inhibition, and multi-omics pathway mapping","pmids":["28082260"],"confidence":"Medium","gaps":["Pathway members inferred from omics not all functionally validated","Direct receptor-effector coupling not shown"]},{"year":2018,"claim":"Provided the most rigorous test of MAS1 ligand pharmacology, showing small molecules activate Gq/Gi/β-arrestin/ERK/Akt at recombinant MAS1 while Ang-(1-7) neither binds nor signals there.","evidence":"Recombinant MAS1 in HEK cells with GTPγS, β-arrestin recruitment, phospho-ERK/Akt, arachidonic acid release, DMR, and radioligand binding assays","pmids":["29928987"],"confidence":"High","gaps":["Does not explain how Ang-(1-7) effects occur in tissue contexts","Endogenous physiological ligand of MAS1 unresolved"]},{"year":2020,"claim":"Demonstrated that MAS1 pro-angiogenic signaling requires physical partnership with AT1R, addressing a receptor-receptor dependency.","evidence":"AT1RA knockout rat hindlimb angiogenesis, endothelial tube formation, and tandem MS of the Mas1-associated complex","pmids":["32324784"],"confidence":"Medium","gaps":["Direct heterodimer versus shared-pathway interaction not structurally resolved","Composition of the Mas1 complex only partially defined"]},{"year":2022,"claim":"Connected MAS1 to cardiomyocyte survival by epistasis, placing it upstream of the PTEN/PI3K/AKT axis.","evidence":"MAS1 overexpression in H9C2 cells and rat MI model with PTEN rescue and LY294002 inhibition","pmids":["35247425"],"confidence":"Medium","gaps":["Mechanism of PTEN suppression by MAS1 not defined","Overexpression may not reflect endogenous receptor levels"]},{"year":2022,"claim":"Extended MAS1 signaling to metabolic control, showing it drives cAMP/CREB/CFTR-dependent insulin secretion in β-cells.","evidence":"RINm5F cell pharmacology, CFTR and MAS-1 RNAi, cAMP measurement, CREB Western blot, and insulin ELISA","pmids":["34825893"],"confidence":"Medium","gaps":["G protein coupling underlying cAMP rise not defined","Used Ang-(1-7) as agonist despite contested binding"]},{"year":2024,"claim":"Showed MAS1 restrains epithelial inflammation, with bidirectional genetic manipulation linking it to NF-κB/MAPK suppression and tight-junction preservation.","evidence":"Overexpression and siRNA knockdown in EpH4 EV mammary epithelial cells with pathway and tight-junction protein readouts","pmids":["39071779"],"confidence":"Medium","gaps":["Upstream ligand and receptor coupling not addressed","Single cell line"]},{"year":2025,"claim":"Established MAS1 as necessary and sufficient for ACE2 therapeutic effect in pulmonary hypertension while again decoupling Ang-(1-7) from receptor activation.","evidence":"Mas1 knockout mouse PAH model, small-molecule agonist AR234960 rescue, stabilized Ang-(1-7) failure, and RNA-seq","pmids":["40248213"],"confidence":"Medium","gaps":["Endogenous activating ligand bridging ACE2 to MAS1 unidentified","Cytoskeletal gene rescue is correlative downstream readout"]},{"year":2026,"claim":"Resolved the structural basis of MAS1 activation, defining a non-canonical hydrophobic-compression mechanism and the TM6 switch residues for Gi coupling.","evidence":"Cryo-EM of NPFF- and AR234958-bound MAS1–Gi complexes with functional mutagenesis of M244(6.51) and F237(6.44)","pmids":["41912627"],"confidence":"High","gaps":["Physiological relevance of NPFF as endogenous ligand not established in tissue","Structures do not address β-arrestin-biased conformations"]},{"year":null,"claim":"The endogenous physiological ligand(s) of mammalian MAS1 and the molecular reconciliation between Ang-(1-7)-dependent tissue phenotypes and its lack of direct binding at recombinant MAS1 remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Whether Ang-(1-7) acts via an AT1R/MAS1 complex or an indirect route is undefined","No structure of MAS1 with a confirmed physiological agonist","Relationship between MRGPR/CXCL17/NPFF candidate ligands and native signaling unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[6,12]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,12]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,12]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,2]}],"complexes":["Mitochondrial processing protease (MPP, MAS1/MAS2)"],"partners":["MAS2","YDJ1","AT1R","ARRB2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P04201","full_name":"Proto-oncogene Mas","aliases":[],"length_aa":325,"mass_kda":37.5,"function":"Receptor for angiotensin 1-7 (By similarity). Acts specifically as a functional antagonist of AGTR1 (angiotensin-2 type 1 receptor), although it up-regulates AGTR1 receptor levels (PubMed:15809376, PubMed:16611642). Positive regulation of AGTR1 levels occurs through activation of the G-proteins GNA11 and GNAQ, and stimulation of the protein kinase C signaling cascade (PubMed:15809376, PubMed:16611642). The antagonist effect on AGTR1 function is probably due to AGTR1 being physically altered by MAS1 (PubMed:15809376, PubMed:16611642)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P04201/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAS1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MAS1","total_profiled":1310},"omim":[{"mim_id":"607235","title":"MAS1 ONCOGENE-LIKE; MAS1L","url":"https://www.omim.org/entry/607235"},{"mim_id":"607234","title":"MAS-RELATED G PROTEIN-COUPLED RECEPTOR FAMILY, MEMBER G; MRGPRG","url":"https://www.omim.org/entry/607234"},{"mim_id":"607233","title":"MAS-RELATED G PROTEIN-COUPLED RECEPTOR FAMILY, MEMBER F; MRGPRF","url":"https://www.omim.org/entry/607233"},{"mim_id":"607232","title":"MAS-RELATED G PROTEIN-COUPLED RECEPTOR FAMILY, MEMBER E; MRGPRE","url":"https://www.omim.org/entry/607232"},{"mim_id":"607231","title":"MAS-RELATED G PROTEIN-COUPLED RECEPTOR FAMILY, MEMBER D; MRGPRD","url":"https://www.omim.org/entry/607231"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"brain","ntpm":2.0}],"url":"https://www.proteinatlas.org/search/MAS1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P04201","domains":[{"cath_id":"1.20.1070.10","chopping":"33-301","consensus_level":"high","plddt":90.1049,"start":33,"end":301}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P04201","model_url":"https://alphafold.ebi.ac.uk/files/AF-P04201-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P04201-F1-predicted_aligned_error_v6.png","plddt_mean":83.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAS1","jax_strain_url":"https://www.jax.org/strain/search?query=MAS1"},"sequence":{"accession":"P04201","fasta_url":"https://rest.uniprot.org/uniprotkb/P04201.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P04201/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P04201"}},"corpus_meta":[{"pmid":"10802648","id":"PMC_10802648","title":"The imprinted antisense RNA at the Igf2r locus overlaps but does not imprint Mas1.","date":"2000","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10802648","citation_count":219,"is_preprint":false},{"pmid":"2905264","id":"PMC_2905264","title":"Import of proteins into yeast mitochondria: the purified matrix processing protease contains two subunits which are encoded by the nuclear MAS1 and MAS2 genes.","date":"1988","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/2905264","citation_count":191,"is_preprint":false},{"pmid":"3044780","id":"PMC_3044780","title":"MAS1, a gene essential for yeast mitochondrial assembly, encodes a subunit of the mitochondrial processing protease.","date":"1988","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/3044780","citation_count":161,"is_preprint":false},{"pmid":"3061808","id":"PMC_3061808","title":"Import of proteins into yeast mitochondria: the nuclear MAS2 gene encodes a component of the processing protease that is homologous to the MAS1-encoded subunit.","date":"1988","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/3061808","citation_count":129,"is_preprint":false},{"pmid":"22339213","id":"PMC_22339213","title":"Angiotensin-(1-7) inhibits allergic inflammation, via the MAS1 receptor, through suppression of ERK1/2- and NF-κB-dependent pathways.","date":"2012","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/22339213","citation_count":127,"is_preprint":false},{"pmid":"28194766","id":"PMC_28194766","title":"Significance of angiotensin 1-7 coupling with MAS1 receptor and other GPCRs to the renin-angiotensin system: IUPHAR Review 22.","date":"2017","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28194766","citation_count":84,"is_preprint":false},{"pmid":"33511992","id":"PMC_33511992","title":"ACE2/Ang-(1-7)/Mas1 axis and the vascular system: vasoprotection to COVID-19-associated vascular 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subunit of the mitochondrial processing protease (MPP), a metalloprotease localized in the mitochondrial matrix that cleaves amino-terminal targeting sequences from imported mitochondrial precursor proteins. The MAS1 protein participates in its own cleavage during import into mitochondria.\",\n      \"method\": \"Genetic cloning and sequencing of MAS1, temperature-sensitive mutant analysis, in vitro protease activity assay, mitochondrial fractionation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay, mutagenesis via temperature-sensitive allele, replicated independently across two papers (PMID 3044780 and 2905264) with orthogonal methods\",\n      \"pmids\": [\"3044780\", \"2905264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"The mitochondrial processing protease consists of two non-identical, loosely associated subunits encoded by MAS1 (48 kDa) and MAS2 (51 kDa); attempts to separate the subunits caused loss of enzymatic activity, indicating both subunits are required for catalytic function.\",\n      \"method\": \"Protein purification of the MPP complex, subunit identification by SDS-PAGE, activity assay after fractionation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — protein purification with reconstitution and activity measurement, confirmed by two independent studies (PMID 2905264 and 3061808)\",\n      \"pmids\": [\"2905264\", \"3061808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In Candida albicans, Mas1 (ortholog of yeast MAS1) interacts physically with the Hsp40 chaperone Ydj1; loss of MAS1 or YDJ1 perturbs mitochondrial morphology and function, and deletion of YDJ1 impairs import of Su9, a protein cleaved to its mature form by Mas1/Mas2, placing Mas1 downstream of Ydj1 in the mitochondrial protein import pathway.\",\n      \"method\": \"Co-immunoprecipitation/mass spectrometry protein interaction mapping, deletion mutant analysis, mitochondrial import assay with Su9 substrate, microscopy of mitochondrial morphology\",\n      \"journal\": \"Microbial cell (Graz, Austria)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction mapping by MS, functional import assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29082232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Angiotensin-(1-7) acting through the MAS1 receptor (mammalian) attenuates allergic airway inflammation by suppressing phosphorylation of ERK1/2 and IκB-α; these effects were reversed by the selective MAS1 antagonist A779, establishing MAS1 as a required mediator of Ang-(1-7) anti-inflammatory signaling.\",\n      \"method\": \"Murine ovalbumin asthma model, pharmacological MAS1 antagonism with A779, Western blot for pERK1/2 and pIκB-α, bronchoalveolar lavage cell counts, histology\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological receptor antagonism with defined molecular readouts, single lab, multiple endpoints\",\n      \"pmids\": [\"22339213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MAS1 receptor (mammalian) internalization after agonist stimulation occurs through both clathrin-coated pits and caveolae in a dynamin-dependent manner; internalized receptor traffics to Rab11-positive slow recycling endosomes rather than lysosomes. ERK1/2 activation by Ang-(1-7) requires β-arrestin2 and proceeds from early endosomes, whereas Akt activation from endosomes is β-arrestin2-independent.\",\n      \"method\": \"Live-cell imaging of MAS1R-YFP, ligand-binding internalization assay, dominant-negative constructs for Eps15, dynamin, shRNA knockdown of caveolin-1 and β-arrestin2, co-localization with Rab4, Rab11, LysoTracker, Western blot for pERK1/2 and pAkt\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays (dominant negatives, shRNA, live imaging, co-localization, biochemical), single lab but comprehensive mechanistic dissection\",\n      \"pmids\": [\"28874464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Low-dose Ang-(1-7) acting through the MAS1 receptor promotes angiogenesis and vasodilation in rat microvascular endothelial cells; downstream signaling components identified include Rho GTPases, PI3K, protein kinase D1, MAPK, and ERK1/2. Pharmacological inhibition of ERK1/2 and p38 MAPK blocked both endothelial tube formation and vasodilation.\",\n      \"method\": \"In vitro endothelial tube formation assay, pharmacological inhibition of ERK1/2/p38, proteomics and genomics downstream pathway mapping, MAS1 receptor antagonism\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro functional assays with pharmacological inhibitors and multi-omics pathway identification, single lab\",\n      \"pmids\": [\"28082260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Small molecule MAS1 agonists activate multiple G protein-dependent (Gq, Gi, GTPγS binding) and independent (β-arrestin recruitment, ERK1/2 phosphorylation, Akt phosphorylation, arachidonic acid release, receptor internalization) signaling pathways through recombinant MAS1. In contrast, Ang-(1-7) failed to induce or block signaling in any of these platforms at recombinant MAS1, and radiolabeled Ang-(1-7) showed no specific binding to recombinant MAS1 (negative result). Ang-(1-7) potently inhibited both phases of AT1R-mediated Ang II signaling in rat aortic endothelial cells.\",\n      \"method\": \"Recombinant MAS1 overexpression in HEK cells, GTPγS binding assay, β-arrestin recruitment assay, Erk1/2 and Akt phosphorylation assay, arachidonic acid release assay, dynamic mass redistribution (DMR) pathway-agnostic assay, radioligand binding assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — comprehensive multi-assay characterization with reconstituted recombinant receptor, multiple orthogonal readouts, rigorous negative controls for Ang-(1-7)\",\n      \"pmids\": [\"29928987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The Ang-(1-7)/MAS1 receptor axis mediates anti-inflammatory effects in allergic asthma at least in part by inhibiting Src kinase-dependent transactivation of EGFR and downstream ERK1/2 phosphorylation; Ang-(1-7) also directly inhibited neutrophil and eosinophil chemotaxis ex vivo, and all effects were reversed by A779 MAS1 antagonism.\",\n      \"method\": \"Murine OVA asthma model, Western blot for phospho-Src, phospho-EGFR, phospho-ERK1/2, A779 MAS1 antagonist, ex vivo chemotaxis assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological antagonism of MAS1 with defined phospho-signaling readouts plus ex vivo chemotaxis, single lab, multiple methods\",\n      \"pmids\": [\"31675376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AT1R (AT1RA) physically interacts with MAS1 receptor and is required for the pro-angiogenic signaling of Ang-(1-7) through MAS1; AT1RA knockout in Dahl salt-sensitive rats impaired Ang-(1-7)-mediated skeletal muscle angiogenesis, endothelial tube formation, and altered the protein complex formed upon Ang-(1-7) binding to Mas1 as shown by tandem mass spectrometry proteomics.\",\n      \"method\": \"AT1RA knockout rat model, hindlimb angiogenesis assay, in vitro endothelial tube formation, tandem mass spectrometry proteomics of Mas1-associated protein complex\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with functional phenotype plus MS-based protein complex analysis, single lab\",\n      \"pmids\": [\"32324784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MAS1 overexpression in cardiomyocytes (H9C2 cells and MI rat model) decreased PTEN expression and enhanced phosphorylation of PI3K and AKT; the cardioprotective effect of MAS1 was reversed by PTEN overexpression or PI3K inhibitor LY294002, placing MAS1 upstream of the PTEN/PI3K/AKT pathway in cardiomyocyte survival signaling.\",\n      \"method\": \"MAS1 overexpression in H9C2 cells and rat MI model, Western blot for PTEN, p-PI3K, p-AKT, pharmacological inhibition with LY294002, PTEN overexpression rescue experiment, cardiomyocyte apoptosis assay\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function overexpression with epistasis rescue by PTEN and pharmacological inhibitor, in vivo and in vitro, single lab\",\n      \"pmids\": [\"35247425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In pancreatic β-cells (RINm5F), Ang-(1-7) activation of MAS-1 induces intracellular cAMP increase and CREB activation, upregulates CFTR expression, and potentiates glucose-stimulated insulin secretion; MAS-1 inhibition or CFTR RNAi knockdown abolished these effects, placing MAS1 upstream of cAMP/CREB/CFTR in β-cell insulin secretion.\",\n      \"method\": \"RINm5F cell pharmacology with selective MAS-1 inhibitor, RNAi knockdown of CFTR and MAS-1, cAMP measurement, Western blot for CREB activation, insulin ELISA\",\n      \"journal\": \"Endocrine connections\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and RNAi-based epistasis with multiple molecular readouts, single lab\",\n      \"pmids\": [\"34825893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In a pulmonary arterial hypertension (PAH) mouse model, ACE2 therapeutic effect is blocked in Mas1 knockout mice, establishing Mas1 as necessary for ACE2 action. The small-molecule Mas1 agonist AR234960 reproduces the ACE2 effect (sufficient). However, stabilized Ang-(1-7) failed to reproduce ACE2 effectiveness, indicating Ang-(1-7) alone does not activate Mas1 in this context. RNA-seq identified rescue of cytoskeletal and microtubule gene defects as key downstream mechanisms.\",\n      \"method\": \"Mas1 knockout mouse, PAH animal model, pharmacological Mas1 agonist AR234960, stabilized Ang-(1-7) treatment, RNA-seq downstream pathway analysis\",\n      \"journal\": \"Pulmonary circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout epistasis plus pharmacological rescue, RNA-seq for mechanism, single lab\",\n      \"pmids\": [\"40248213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Cryo-EM structures of MAS1 (class A GPCR) bound to neuropeptide FF (NPFF) and small-molecule agonist AR234958 in complex with inhibitory G proteins reveal a conserved orthosteric binding pocket. MAS1 uses a non-canonical activation mechanism driven by ligand-induced hydrophobic compression involving residues Y248(6.55), L87(2.60), I84(2.57), and L266(7.39), transmitting mechanical tension to displace TM6 for G protein coupling rather than the canonical W6.48 toggle switch. Functional mutagenesis identified M244(6.51) and F237(6.44) on TM6 as critical molecular switches.\",\n      \"method\": \"Cryo-EM structure determination, functional mutagenesis of active-site residues, G protein coupling assay, comparative structural analysis with MRGPRX1-X4\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures at multiple states with functional mutagenesis validation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"41912627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Human CXCL17 activates MAS1 (among 10 human MRGPRs tested) at micromolar concentrations as measured by β-arrestin recruitment and chemotaxis of MAS1-transfected HEK293T cells; removal of the C-terminal fragment of CXCL17 did not affect MAS1 activation, indicating a mechanism distinct from GPR25 activation.\",\n      \"method\": \"NanoBiT-based β-arrestin recruitment assay in transfected HEK293T cells, chemotaxis assay, C-terminal deletion mutant of CXCL17\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab preprint, β-arrestin recruitment assay only, no validation of endogenous signaling\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Overexpression of Mas1 in mammary epithelial cells (EpH4 EV) reversed LPS-induced activation of NF-κB/MAPK signaling pathways and suppressed pro-inflammatory mediators; conversely, siRNA silencing of Mas1 enhanced LPS-induced inflammatory responses. Mas1 overexpression also reversed LPS-induced downregulation of tight junction proteins ZO-1, Occludin, and Claudin-3.\",\n      \"method\": \"Gene overexpression and siRNA knockdown in EpH4 EV cells, Western blot for NF-κB/MAPK pathway components and tight junction proteins, ELISA for inflammatory mediators\",\n      \"journal\": \"Frontiers in veterinary science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional genetic manipulation (OE and KD) with pathway-level readouts, single lab\",\n      \"pmids\": [\"39071779\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human/mammalian MAS1 is an orphan class A GPCR (structurally resolved by cryo-EM) that couples to inhibitory G proteins via a non-canonical hydrophobic compression mechanism involving TM6 residues M244(6.51) and F237(6.44); it activates Gq, Gi, β-arrestin, ERK1/2, Akt, and PI3K/PTEN downstream pathways depending on cell context, mediates receptor internalization through clathrin/caveolae in a dynamin-dependent manner with slow Rab11 recycling and β-arrestin2-dependent endosomal ERK1/2 signaling, interacts with AT1R to enable pro-angiogenic signaling, and is required for ACE2 therapeutic effects in pulmonary hypertension; in yeast the ortholog encodes the catalytic 48 kDa subunit of the two-subunit (MAS1/MAS2) mitochondrial processing metalloprotease that cleaves presequences from imported mitochondrial precursor proteins.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"The MAS1 symbol denotes two mechanistically distinct proteins across the timeline that nonetheless form internally coherent bodies of evidence. In yeast and Candida, MAS1 encodes the smaller 48 kDa subunit of the two-subunit mitochondrial processing protease (MPP), a matrix metalloprotease that cleaves amino-terminal targeting presequences from imported mitochondrial precursor proteins; both the MAS1 and MAS2 (51 kDa) subunits are required for catalytic activity, and MAS1 itself is self-processed during import [#0, #1], with import of MPP substrates such as Su9 placed downstream of the Hsp40 chaperone Ydj1 [#2]. In mammals, MAS1 is an orphan class A GPCR whose ligand-induced activation drives both G protein-dependent (Gq, Gi) and G protein-independent (\\u03b2-arrestin recruitment, ERK1/2, Akt, arachidonic acid release) signaling, characterized comprehensively at recombinant receptor; notably, Ang-(1-7) showed no specific binding or signaling at recombinant MAS1 [#6]. Cryo-EM structures of agonist- and Gi-bound MAS1 reveal a non-canonical activation mechanism in which ligand-induced hydrophobic compression transmits tension to displace TM6, with M244(6.51) and F237(6.44) acting as critical molecular switches, in place of the canonical W6.48 toggle [#12]. Following agonist stimulation MAS1 internalizes via clathrin- and caveolae-dependent, dynamin-mediated routes into Rab11 slow-recycling endosomes, where \\u03b2-arrestin2 is required for endosomal ERK1/2 but not Akt activation [#4]. Functionally, the receptor mediates anti-inflammatory signaling in allergic airway disease through suppression of ERK1/2, I\\u03baB-\\u03b1, and Src-dependent EGFR transactivation [#3, #7], pro-angiogenic and vasodilatory signaling in endothelial cells dependent on physical interaction with AT1R [#5, #8], cardiomyocyte survival via the PTEN/PI3K/AKT pathway [#9], and is required for the therapeutic action of ACE2 in pulmonary arterial hypertension [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Established the identity and catalytic role of MAS1, answering whether the gene product is an enzyme: it is the smaller subunit of the mitochondrial processing protease that removes targeting presequences from imported precursors.\",\n      \"evidence\": \"Genetic cloning, temperature-sensitive mutant analysis, and in vitro protease assays with mitochondrial fractionation in yeast\",\n      \"pmids\": [\"3044780\", \"2905264\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve which subunit carries the catalytic metal-binding site versus substrate recognition\", \"No structural model of the protease\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Defined the quaternary requirement for activity, showing MPP is an obligate two-subunit enzyme rather than a single polypeptide.\",\n      \"evidence\": \"Purification of the MPP complex, subunit resolution by SDS-PAGE, and activity loss upon subunit separation\",\n      \"pmids\": [\"2905264\", \"3061808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and interface of subunit association not defined\", \"Mechanism of activity loss on separation unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed MAS1/MPP within the import pathway by identifying an upstream chaperone, showing Hsp40 Ydj1 physically and functionally interacts with Mas1 for precursor delivery.\",\n      \"evidence\": \"Co-IP/MS interaction mapping, deletion mutants, and Su9 mitochondrial import assays in Candida albicans\",\n      \"pmids\": [\"29082232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect nature of the Mas1-Ydj1 interaction not fully separated from import defects\", \"Single organism, single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified the mammalian MAS1 receptor as a required mediator of Ang-(1-7) anti-inflammatory signaling, addressing whether the GPCR transduces protective effects in vivo.\",\n      \"evidence\": \"Murine OVA asthma model with selective antagonist A779 and phospho-ERK1/2 / I\\u03baB-\\u03b1 readouts\",\n      \"pmids\": [\"22339213\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pharmacological antagonism does not prove direct ligand binding to MAS1\", \"Cell-type origin of the signal not localized\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Dissected MAS1 receptor trafficking and biased signaling, answering how internalized receptor routes and which effectors depend on \\u03b2-arrestin2.\",\n      \"evidence\": \"Live-cell imaging, dominant-negative and shRNA perturbation of Eps15/dynamin/caveolin-1/\\u03b2-arrestin2, and endosomal co-localization\",\n      \"pmids\": [\"28874464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Performed with Ang-(1-7) as ligand whose direct binding was later contested\", \"Recycling kinetics not linked to functional outputs\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapped the pro-angiogenic effector cascade downstream of MAS1 in endothelial cells, establishing ERK1/2 and p38 as required for tube formation and vasodilation.\",\n      \"evidence\": \"In vitro endothelial tube formation, pharmacological ERK1/2/p38 inhibition, and multi-omics pathway mapping\",\n      \"pmids\": [\"28082260\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathway members inferred from omics not all functionally validated\", \"Direct receptor-effector coupling not shown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided the most rigorous test of MAS1 ligand pharmacology, showing small molecules activate Gq/Gi/\\u03b2-arrestin/ERK/Akt at recombinant MAS1 while Ang-(1-7) neither binds nor signals there.\",\n      \"evidence\": \"Recombinant MAS1 in HEK cells with GTP\\u03b3S, \\u03b2-arrestin recruitment, phospho-ERK/Akt, arachidonic acid release, DMR, and radioligand binding assays\",\n      \"pmids\": [\"29928987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not explain how Ang-(1-7) effects occur in tissue contexts\", \"Endogenous physiological ligand of MAS1 unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated that MAS1 pro-angiogenic signaling requires physical partnership with AT1R, addressing a receptor-receptor dependency.\",\n      \"evidence\": \"AT1RA knockout rat hindlimb angiogenesis, endothelial tube formation, and tandem MS of the Mas1-associated complex\",\n      \"pmids\": [\"32324784\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct heterodimer versus shared-pathway interaction not structurally resolved\", \"Composition of the Mas1 complex only partially defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected MAS1 to cardiomyocyte survival by epistasis, placing it upstream of the PTEN/PI3K/AKT axis.\",\n      \"evidence\": \"MAS1 overexpression in H9C2 cells and rat MI model with PTEN rescue and LY294002 inhibition\",\n      \"pmids\": [\"35247425\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of PTEN suppression by MAS1 not defined\", \"Overexpression may not reflect endogenous receptor levels\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended MAS1 signaling to metabolic control, showing it drives cAMP/CREB/CFTR-dependent insulin secretion in \\u03b2-cells.\",\n      \"evidence\": \"RINm5F cell pharmacology, CFTR and MAS-1 RNAi, cAMP measurement, CREB Western blot, and insulin ELISA\",\n      \"pmids\": [\"34825893\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"G protein coupling underlying cAMP rise not defined\", \"Used Ang-(1-7) as agonist despite contested binding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed MAS1 restrains epithelial inflammation, with bidirectional genetic manipulation linking it to NF-\\u03baB/MAPK suppression and tight-junction preservation.\",\n      \"evidence\": \"Overexpression and siRNA knockdown in EpH4 EV mammary epithelial cells with pathway and tight-junction protein readouts\",\n      \"pmids\": [\"39071779\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream ligand and receptor coupling not addressed\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established MAS1 as necessary and sufficient for ACE2 therapeutic effect in pulmonary hypertension while again decoupling Ang-(1-7) from receptor activation.\",\n      \"evidence\": \"Mas1 knockout mouse PAH model, small-molecule agonist AR234960 rescue, stabilized Ang-(1-7) failure, and RNA-seq\",\n      \"pmids\": [\"40248213\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous activating ligand bridging ACE2 to MAS1 unidentified\", \"Cytoskeletal gene rescue is correlative downstream readout\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved the structural basis of MAS1 activation, defining a non-canonical hydrophobic-compression mechanism and the TM6 switch residues for Gi coupling.\",\n      \"evidence\": \"Cryo-EM of NPFF- and AR234958-bound MAS1\\u2013Gi complexes with functional mutagenesis of M244(6.51) and F237(6.44)\",\n      \"pmids\": [\"41912627\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of NPFF as endogenous ligand not established in tissue\", \"Structures do not address \\u03b2-arrestin-biased conformations\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The endogenous physiological ligand(s) of mammalian MAS1 and the molecular reconciliation between Ang-(1-7)-dependent tissue phenotypes and its lack of direct binding at recombinant MAS1 remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Ang-(1-7) acts via an AT1R/MAS1 complex or an indirect route is undefined\", \"No structure of MAS1 with a confirmed physiological agonist\", \"Relationship between MRGPR/CXCL17/NPFF candidate ligands and native signaling unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6, 12]},\n      {\"term_id\": \"GO:0004930\", \"supporting_discovery_ids\": [6, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 12]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0009536\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 12]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [\"Mitochondrial processing protease (MPP, MAS1/MAS2)\"],\n    \"partners\": [\"MAS2\", \"YDJ1\", \"AT1R\", \"ARRB2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}