{"gene":"ANPEP","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1988,"finding":"The complete primary structure of human intestinal aminopeptidase N (967 amino acids) was deduced from cDNA cloning, revealing it is anchored to the microvillar membrane via an uncleaved N-terminal signal/transmembrane segment, and that a domain spanning approximately residues 250–555 is homologous to E. coli aminopeptidase N and contains the Zn2+ ligands constituting the active site.","method":"cDNA cloning and sequence analysis; identification of Zn2+ binding motifs by homology","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 — full-length cDNA sequence with active-site identification, foundational structural paper replicated by Look 1989","pmids":["2901990"],"is_preprint":false},{"year":1989,"finding":"Human myeloid cell surface glycoprotein CD13 (gp150) is identical to aminopeptidase N: it is a type II transmembrane zinc metalloprotease of 967 amino acids with a single N-terminal hydrophobic membrane-spanning segment (non-cleaved signal anchor) and a large extracellular C-terminal catalytic domain bearing the zinc-binding metalloprotease pentapeptide consensus sequence. Retroviral expression of the coding sequence in mouse fibroblasts confirmed surface expression of bona fide CD13.","method":"cDNA cloning, sequence analysis, retroviral expression in transfected mouse fibroblasts, N-terminal protein sequencing","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 — reconstitution by transfection, direct protein sequencing, replicated by Olsen 1988","pmids":["2564851"],"is_preprint":false},{"year":1991,"finding":"Two distinct tissue-specific promoters control transcription of the single human aminopeptidase N (ANPEP) gene: an intestinal epithelial cell promoter containing a TATA box that directs a 3.4-kb transcript, and a separate upstream promoter in myeloid cells and fibroblasts (located ~8 kb upstream of the start codon) that directs a longer 3.7-kb transcript. Both transcripts encode the same polypeptide. Functional promoter activity was demonstrated by reporter gene transfection into NIH-3T3 fibroblasts.","method":"Northern blot analysis; 5'-end mapping; reporter gene (bacterial) transfection assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Northern blot, 5'-mapping, functional reporter assays) in single rigorous study","pmids":["1675638"],"is_preprint":false},{"year":1991,"finding":"CD13/gp150 expressed on endothelial cells possesses enzymatic aminopeptidase N-like activity comparable to that on haemopoietic cells, as shown by chromogenic substrate assays inhibitable by anti-CD13 monoclonal antibody.","method":"Chromogenic substrate functional assays; monoclonal antibody inhibition; ELISA; immunofluorescence","journal":"Immunology and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — functional enzymatic assay with antibody inhibition; single lab","pmids":["1723966"],"is_preprint":false},{"year":1992,"finding":"Human aminopeptidase N (APN/CD13) is a functional receptor for human coronavirus HCoV-229E: anti-CD13 monoclonal antibody RBS blocked HCoV-229E infection and virus binding, and transfection of hAPN cDNA into resistant murine fibroblasts rendered them susceptible to HCoV-229E but not HCoV-OC43. A catalytic-site mutant APN that lost enzymatic activity also failed to bind the virus or confer susceptibility, suggesting the virus-binding site overlaps with or is near the active site.","method":"Virus infection assay; monoclonal antibody blocking; cDNA transfection of murine fibroblasts; catalytic mutant APN expression","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 — gain-of-function transfection, antibody blocking, and mutant analysis; independently replicated","pmids":["1350662"],"is_preprint":false},{"year":1993,"finding":"CD13 (human aminopeptidase N) mediates human cytomegalovirus (HCMV) infection: anti-CD13 antibodies inhibited HCMV binding and infection; transfection of hAPN cDNA into resistant murine fibroblasts increased susceptibility and HCMV binding. However, a mutant CD13 lacking part of the aminopeptidase active site still conferred susceptibility, indicating the enzymatic domain is not required for HCMV entry.","method":"Virus infection assay; antibody blocking; cDNA transfection of murine fibroblasts; active-site deletion mutant","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 — gain-of-function transfection, antibody blocking, and active-site mutant; rigorous controls","pmids":["8105105"],"is_preprint":false},{"year":1993,"finding":"CD13/GP150/aminopeptidase N activity in whole blood is predominantly localized to cell-free plasma rather than to cell surfaces; plasma APN activity is >70% inhibitable by anti-CD13 monoclonal antibody WM15 and can be completely cleared by immunoaffinity isolation, establishing the existence of a soluble circulating form of CD13/APN.","method":"Chromogenic substrate functional assays; monoclonal antibody inhibition; immunoaffinity isolation; SDS-PAGE","journal":"Experimental hematology","confidence":"Medium","confidence_rationale":"Tier 2 — functional enzymatic and immunoaffinity methods; single lab","pmids":["7902291"],"is_preprint":false},{"year":2000,"finding":"Aminopeptidase N (APN/CD13) is the receptor for NGR motif-containing tumor-homing peptides in tumor vasculature. NGR phage specifically bound immunocaptured APN and APN-expressing transfected cells; anti-APN antibodies blocked in vivo tumor homing. APN expression is upregulated in endothelial cells within tumors and in corpus luteum angiogenesis. APN antagonists inhibited angiogenesis in chorioallantoic membrane and retinal assays and suppressed tumor growth, identifying APN as a functional participant in angiogenesis.","method":"Phage binding to immunocaptured APN; transfected cell binding; in vivo tumor homing with antibody blockade; angiogenesis assays (CAM, retina); tumor growth assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal in vitro and in vivo methods; widely replicated","pmids":["10676659"],"is_preprint":false},{"year":2003,"finding":"The receptor-binding domain (RBD) of HCoV-229E spike protein lies within the N-terminal 417–547 amino acid region: soluble truncated S proteins containing this region specifically bound hAPN-expressing cells, and binding was blocked by an anti-hAPN antibody that inhibits virus infection. S proteins lacking this region did not bind hAPN.","method":"Baculovirus expression of truncated spike proteins; cell-binding assay on hAPN-transfected 3T3 cells; antibody blocking","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — direct binding assay with defined truncation constructs and antibody blocking controls","pmids":["12551991"],"is_preprint":false},{"year":2004,"finding":"CD13/APN is a major component of Triton X-100-resistant lipid raft microdomains on human fibroblasts; HCoV-229E binds CD13 at the cell surface and causes clustering of CD13 into caveolin-1-positive caveolae at 37°C. Electron microscopy showed HCoV-229E near caveolae orifices post-binding. Cholesterol depletion with methyl-β-cyclodextrin significantly reduced virus redistribution and infection; caveolin-1 knockdown by RNAi also reduced HCoV-229E infection, establishing that CD13-mediated HCoV-229E entry occurs through caveolae.","method":"Detergent-resistant membrane fractionation; immunofluorescence co-localization; electron microscopy; cholesterol depletion; caveolin-1 RNAi knockdown; virus infection assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including RNAi, cholesterol depletion, and EM; strong mechanistic support","pmids":["15280478"],"is_preprint":false},{"year":2006,"finding":"APN/CD13 is selectively expressed in vascular endothelial cells and plays multiple roles in angiogenesis: RNAi silencing of APN inhibited capillary tube formation on Matrigel, reduced endothelial cell migration through fibronectin-coated membranes, and decreased adhesion to Matrigel and extracellular matrix components (type IV collagen, type I collagen, fibronectin).","method":"RNAi knockdown; Matrigel tube formation assay; Transwell migration assay; cell adhesion assay","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function RNAi with multiple defined phenotypic readouts; single lab","pmids":["16466852"],"is_preprint":false},{"year":2007,"finding":"CD13/APN proteolytically processes the chemokine CXCL11 at its N-terminus, removing up to 6 amino acids in combination with CD26/DPP4. CD13/APN-truncated CXCL11 showed reduced binding and signaling at CXCR3 and CXCR7, failed to induce intracellular calcium increases, lost chemotactic activity for lymphocytes, and showed significantly reduced inhibition of endothelial cell migration. This identifies CD13/APN as a negative regulator of CXCL11-mediated lymphocyte recruitment and angiostasis.","method":"Biochemical purification and identification of truncated CXCL11; in vitro enzymatic processing assays; receptor binding and signaling assays (Ca2+ flux, ERK1/2/Akt phosphorylation); chemotaxis assays; endothelial migration assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — direct in vitro enzymatic assay plus multiple functional downstream assays; rigorous mechanistic study","pmids":["17363734"],"is_preprint":false},{"year":2011,"finding":"Increased CD13/aminopeptidase N expression in liver cancer stem cells (CSCs) reduces intracellular reactive oxygen species (ROS) levels, promoting CSC survival. TGF-β-induced EMT-like phenotype was associated with increased CD13 expression. Inhibition of CD13 stimulated apoptosis in CD13+ CSCs, establishing CD13 as a scavenger enzyme in the ROS metabolic pathway that protects CSCs from oxidative stress-induced apoptosis.","method":"TGF-β EMT induction; CD13 inhibition (antibody/inhibitor); ROS measurement; apoptosis assay; immunohistochemistry of post-chemotherapy tumor samples","journal":"Annals of surgical oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 — loss-of-function inhibition with ROS and apoptosis readouts; single lab, moderate mechanistic follow-up","pmids":["21879266"],"is_preprint":false},{"year":2012,"finding":"The X-ray crystal structure of the dimeric ectodomain of human aminopeptidase N (hAPN/CD13) was determined at high resolution in complexes with angiotensin IV and the inhibitors amastatin and bestatin. Each monomer adopts the closed form with an internal cavity surrounding the catalytic Zn2+ site. The structure reveals hAPN as the first dimeric M1 family metallopeptidase, with structural features (including substrate-dependent loop ordering and inhibitor-specific cavity access) that provide mechanistic insights into peptide processing, including angiotensin III and IV metabolism.","method":"X-ray crystallography of ectodomain alone and in complex with angiotensin IV, amastatin, bestatin","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structures of native enzyme and multiple inhibitor complexes","pmids":["22932899"],"is_preprint":false},{"year":2017,"finding":"CD13/ANPEP contributes to BRAF-inhibitor resistance in melanoma cells and is upstream of EPHA2 signaling: blocking CD13/ANPEP with a monoclonal antibody induced apoptosis in both BRAFi-sensitive and resistant melanoma cells, and caused dephosphorylation of EPHA2 at S897 (a pro-migratory phosphorylation site). AKT and RSK, which phosphorylate EPHA2-S897, were also dephosphorylated after CD13/ANPEP inhibition, placing CD13/ANPEP upstream of the AKT/RSK→EPHA2 signaling axis.","method":"Antibody-mediated CD13/ANPEP blocking; apoptosis assay; phospho-Western blotting for EPHA2-S897, AKT, RSK; gene expression and proteome profiling","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 — loss-of-function with defined phospho-signaling readouts; single lab","pmids":["29048432"],"is_preprint":false},{"year":2019,"finding":"APN (encoded by ANPEP) serves as a receptor for porcine deltacoronavirus (PDCoV) in porcine alveolar macrophages (PAMs): CRISPR/Cas9 knockout of ANPEP in pigs rendered PAMs resistant to PDCoV infection. However, lung fibroblast-like cells from the same KO pigs remained permissive to PDCoV, demonstrating that APN is cell-type-specific receptor for PDCoV in macrophages but dispensable in fibroblast-like cells.","method":"CRISPR/Cas9 ANPEP knockout in pigs; ex vivo infection of primary PAMs and fibroblast-like cells; in vivo infection of KO pigs","journal":"Virology","confidence":"High","confidence_rationale":"Tier 2 — clean genetic knockout in primary cells and whole animal; rigorous loss-of-function","pmids":["32056711"],"is_preprint":false},{"year":2019,"finding":"X-ray crystal structures of HCoV-229E spike protein receptor-binding domains (RBDs) from multiple viral classes (III–V) in complex with human APN (hAPN) revealed that common core interactions at the hAPN active-site region define specificity for hAPN, while peripheral RBD sequence variation is accommodated by loop plasticity. The cryo-EM structure of the full 229E S-protein shows it can expose portions of its helical core, facilitated by hydrophilic subunit interfaces conserved among coronaviruses.","method":"X-ray crystallography of multiple RBD–hAPN complexes; cryo-EM of full spike protein","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 — multiple crystal structures plus cryo-EM; defines molecular basis of hAPN recognition","pmids":["31650956"],"is_preprint":false}],"current_model":"ANPEP (CD13/aminopeptidase N) is a homodimeric, type II transmembrane zinc metallopeptidase whose large extracellular catalytic domain processes regulatory peptides (including angiotensin III/IV and chemokines such as CXCL11), serves as the entry receptor for human coronavirus HCoV-229E (binding via the viral spike RBD at the enzyme active-site region, with internalization through caveolae) and human cytomegalovirus, participates in angiogenesis and tumor vasculature homing via NGR peptide recognition, reduces ROS in cancer stem cells to promote survival, and functions upstream of AKT/RSK→EPHA2 signaling in BRAF-inhibitor resistance; its expression in myeloid versus intestinal epithelial cells is controlled by two distinct tissue-specific promoters driving the same polypeptide."},"narrative":{"teleology":[{"year":1988,"claim":"Establishing the primary structure and membrane topology of ANPEP resolved how a single-pass type II transmembrane protein anchors its catalytic ectodomain to the brush-border membrane and identified the zinc-binding metalloprotease active site by homology.","evidence":"cDNA cloning and sequence analysis of human intestinal APN","pmids":["2901990"],"confidence":"High","gaps":["No direct demonstration of enzymatic activity from the cloned product","Quaternary structure unknown at this stage"]},{"year":1989,"claim":"Demonstrating that the myeloid surface antigen CD13 is identical to aminopeptidase N unified two fields and showed the enzyme is expressed far beyond the intestinal epithelium.","evidence":"cDNA cloning of CD13, retroviral expression in mouse fibroblasts confirming surface expression, N-terminal protein sequencing","pmids":["2564851"],"confidence":"High","gaps":["Mechanism of enzymatic activity in myeloid context not yet characterized"]},{"year":1991,"claim":"Discovery of two tissue-specific promoters explained how a single ANPEP gene produces the same protein in intestinal epithelium and myeloid/stromal cells through distinct transcriptional programs.","evidence":"Northern blot, 5'-end mapping, and reporter gene assays in fibroblasts","pmids":["1675638"],"confidence":"High","gaps":["Transcription factor identity at each promoter not fully resolved","Chromatin-level regulation not addressed"]},{"year":1992,"claim":"Gain-of-function and antibody-blocking experiments established ANPEP as the functional receptor for HCoV-229E, and a catalytic-site mutant that lost virus binding implied the virus-binding site overlaps with the enzyme active site.","evidence":"Transfection of hAPN into resistant murine fibroblasts; monoclonal antibody blocking; catalytic mutant expression","pmids":["1350662"],"confidence":"High","gaps":["Atomic-resolution binding interface not yet known","Post-entry steps of virus internalization undefined"]},{"year":1993,"claim":"Parallel experiments showed ANPEP also serves as a receptor for HCMV, but unlike HCoV-229E, HCMV entry does not require the enzymatic active site, revealing receptor utilization can be dissociated from catalytic function.","evidence":"Antibody blocking and transfection of hAPN and active-site deletion mutant into murine fibroblasts; HCMV infection assay","pmids":["8105105"],"confidence":"High","gaps":["HCMV-binding epitope on ANPEP not mapped","Whether ANPEP is the sole HCMV receptor unclear"]},{"year":2000,"claim":"Identification of ANPEP as the target of NGR tumor-homing peptides and demonstration that ANPEP antagonism blocks angiogenesis in vivo established a direct functional role for ANPEP in tumor neovascularization.","evidence":"Phage binding, antibody blocking of in vivo tumor homing, CAM and retinal angiogenesis assays, tumor growth inhibition","pmids":["10676659"],"confidence":"High","gaps":["Downstream signaling pathways mediating the pro-angiogenic effect not defined","Whether enzymatic activity is required for angiogenesis not resolved"]},{"year":2004,"claim":"Showing that ANPEP resides in lipid rafts and that HCoV-229E binding triggers ANPEP clustering into caveolin-1-positive caveolae resolved the internalization route, as caveolin-1 knockdown reduced infection.","evidence":"Detergent-resistant membrane fractionation, immunofluorescence, EM, cholesterol depletion, caveolin-1 RNAi in human fibroblasts","pmids":["15280478"],"confidence":"High","gaps":["Whether caveolae-mediated entry applies to all cell types expressing ANPEP not tested"]},{"year":2006,"claim":"RNAi silencing of ANPEP in endothelial cells directly linked its expression to capillary tube formation, migration, and matrix adhesion, moving beyond correlative angiogenesis phenotypes to a cell-autonomous requirement.","evidence":"RNAi knockdown with Matrigel tube formation, Transwell migration, and ECM adhesion assays","pmids":["16466852"],"confidence":"Medium","gaps":["Single-lab study; genetic knockout confirmation lacking","Signaling intermediates downstream of ANPEP in endothelial cells unresolved"]},{"year":2007,"claim":"Demonstrating that ANPEP cleaves the N-terminus of CXCL11 to abolish its chemotactic and angiostatic activities revealed a specific substrate through which ANPEP regulates immunity and vascular biology.","evidence":"In vitro enzymatic processing, receptor binding, Ca²⁺ flux, chemotaxis, and endothelial migration assays","pmids":["17363734"],"confidence":"High","gaps":["In vivo confirmation of CXCL11 processing by ANPEP not provided","Full substrate repertoire still incomplete"]},{"year":2011,"claim":"Linking ANPEP to ROS scavenging in liver cancer stem cells showed it protects CSCs from oxidative-stress-induced apoptosis, broadening its role beyond peptide processing to redox homeostasis in cancer.","evidence":"CD13 inhibition with antibody/inhibitor, ROS measurement, apoptosis assay in TGF-β-induced CSCs","pmids":["21879266"],"confidence":"Medium","gaps":["Molecular mechanism by which ANPEP reduces ROS not defined","Single-lab observation; independent replication needed"]},{"year":2012,"claim":"High-resolution crystal structures of the dimeric ANPEP ectodomain with angiotensin IV and inhibitors provided the first atomic view of an M1 family metallopeptidase dimer and revealed how substrate-dependent loop ordering and cavity gating control peptide processing.","evidence":"X-ray crystallography of hAPN ectodomain complexed with angiotensin IV, amastatin, bestatin","pmids":["22932899"],"confidence":"High","gaps":["Full-length membrane-embedded structure not determined","Dynamics of substrate entry and product release not captured by static structures"]},{"year":2017,"claim":"Antibody-mediated ANPEP blockade dephosphorylated AKT, RSK, and EPHA2-S897 and induced apoptosis in BRAFi-resistant melanoma cells, positioning ANPEP upstream of the AKT/RSK→EPHA2 signaling axis in drug resistance.","evidence":"Anti-CD13 antibody blocking, phospho-Western blotting, apoptosis assays in melanoma cell lines","pmids":["29048432"],"confidence":"Medium","gaps":["Whether enzymatic activity or scaffolding drives signaling is unknown","No genetic knockout validation","Single-lab finding"]},{"year":2019,"claim":"Structural determination of multiple HCoV-229E RBD–hAPN complexes confirmed that core virus contacts map to the ANPEP active-site region, while CRISPR knockout of ANPEP in pigs proved it is a cell-type-specific deltacoronavirus receptor in macrophages but dispensable in fibroblasts.","evidence":"X-ray crystallography and cryo-EM of spike–hAPN complexes; CRISPR/Cas9 ANPEP knockout pigs with ex vivo and in vivo infection","pmids":["31650956","32056711"],"confidence":"High","gaps":["Host cofactors that determine cell-type-specific receptor usage not identified","Whether active-site mutations alone suffice to abolish 229E entry in a genetic knockout context untested"]},{"year":null,"claim":"Key unresolved questions include the molecular mechanism by which ANPEP reduces intracellular ROS, whether its pro-angiogenic role requires enzymatic activity or a scaffolding/signaling function, the full physiological substrate repertoire, and how its receptor function for diverse viruses is partitioned between catalytic-site engagement and alternative binding modes.","evidence":"","pmids":[],"confidence":"Low","gaps":["ROS-scavenging mechanism unknown","Enzymatic vs. non-enzymatic contribution to angiogenesis unresolved","Comprehensive substrate profiling absent","Signaling pathway downstream of ANPEP in endothelial and cancer contexts poorly defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,3,11,13]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,11,13]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[4,5,8,9,15,16]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,3,4,9]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,11,13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,5,11,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,10]}],"complexes":[],"partners":["CXCL11","CAV1","EPHA2"],"other_free_text":[]},"mechanistic_narrative":"ANPEP (CD13/aminopeptidase N) is a homodimeric type II transmembrane zinc metallopeptidase that cleaves N-terminal residues from regulatory peptides—including angiotensin III/IV and the chemokine CXCL11—thereby modulating vasoactive signaling and lymphocyte chemotaxis [PMID:22932899, PMID:17363734]. Its large ectodomain harbors the catalytic Zn²⁺ site within a closed internal cavity, and this active-site region doubles as the binding determinant for HCoV-229E spike protein, with virus entry proceeding through caveolae-mediated endocytosis; ANPEP also serves as a receptor for human cytomegalovirus and, in a cell-type-specific manner, porcine deltacoronavirus [PMID:1350662, PMID:15280478, PMID:8105105, PMID:32056711]. ANPEP is upregulated on tumor vasculature endothelium where it promotes angiogenesis by supporting capillary tube formation, migration, and extracellular matrix adhesion, and it sustains cancer stem cell survival by reducing intracellular reactive oxygen species [PMID:10676659, PMID:16466852, PMID:21879266]. Expression in myeloid versus intestinal epithelial cells is governed by two tissue-specific promoters driving the same polypeptide, and in melanoma ANPEP signals upstream of the AKT/RSK→EPHA2 axis to contribute to BRAF-inhibitor resistance [PMID:1675638, PMID:29048432]."},"prefetch_data":{"uniprot":{"accession":"P15144","full_name":"Aminopeptidase N","aliases":["Alanyl aminopeptidase","Aminopeptidase M","AP-M","Microsomal aminopeptidase","Myeloid plasma membrane glycoprotein CD13","gp150"],"length_aa":967,"mass_kda":109.5,"function":"Broad specificity aminopeptidase which plays a role in the final digestion of peptides generated from hydrolysis of proteins by gastric and pancreatic proteases. Also involved in the processing of various peptides including peptide hormones, such as angiotensin III and IV, neuropeptides, and chemokines. May also be involved the cleavage of peptides bound to major histocompatibility complex class II molecules of antigen presenting cells. May have a role in angiogenesis and promote cholesterol crystallization. May have a role in amino acid transport by acting as binding partner of amino acid transporter SLC6A19 and regulating its activity (By similarity) (Microbial infection) Acts as a receptor for human coronavirus 229E/HCoV-229E. In case of human coronavirus 229E (HCoV-229E) infection, serves as receptor for HCoV-229E spike glycoprotein (Microbial infection) Mediates as well Human cytomegalovirus (HCMV) infection","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P15144/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ANPEP","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ANPEP","total_profiled":1310},"omim":[{"mim_id":"616333","title":"WNT SIGNALING PATHWAY ACTIVATING NONCODING RNA; WSPAR","url":"https://www.omim.org/entry/616333"},{"mim_id":"610046","title":"LAEVERIN; LVRN","url":"https://www.omim.org/entry/610046"},{"mim_id":"608936","title":"OPIORPHIN PREPROPEPTIDE; OPRPN","url":"https://www.omim.org/entry/608936"},{"mim_id":"608491","title":"CYCLIN D-BINDING MYB-LIKE TRANSCRIPTION FACTOR 1; DMTF1","url":"https://www.omim.org/entry/608491"},{"mim_id":"300335","title":"ANGIOTENSIN I-CONVERTING ENZYME 2; ACE2","url":"https://www.omim.org/entry/300335"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":2245.0},{"tissue":"pancreas","ntpm":643.6}],"url":"https://www.proteinatlas.org/search/ANPEP"},"hgnc":{"alias_symbol":["LAP1","gp150","p150","AP-N","hAPN"],"prev_symbol":["CD13","PEPN"]},"alphafold":{"accession":"P15144","domains":[{"cath_id":"2.60.40.1730","chopping":"79-285","consensus_level":"medium","plddt":96.339,"start":79,"end":285},{"cath_id":"1.10.390.10","chopping":"287-429_493-529","consensus_level":"medium","plddt":96.4484,"start":287,"end":529},{"cath_id":"1.25.50.20","chopping":"838-967","consensus_level":"medium","plddt":92.2405,"start":838,"end":967}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P15144","model_url":"https://alphafold.ebi.ac.uk/files/AF-P15144-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P15144-F1-predicted_aligned_error_v6.png","plddt_mean":93.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANPEP","jax_strain_url":"https://www.jax.org/strain/search?query=ANPEP"},"sequence":{"accession":"P15144","fasta_url":"https://rest.uniprot.org/uniprotkb/P15144.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P15144/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P15144"}},"corpus_meta":[{"pmid":"3555290","id":"PMC_3555290","title":"Leukocyte adhesion deficiency: an inherited defect in the Mac-1, LFA-1, and p150,95 glycoproteins.","date":"1987","source":"Annual review of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/3555290","citation_count":1077,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19564404","id":"PMC_19564404","title":"Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7-RILP-p150 Glued and late endosome positioning.","date":"2009","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19564404","citation_count":560,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"6096477","id":"PMC_6096477","title":"Inherited deficiency of the Mac-1, LFA-1, p150,95 glycoprotein family and its molecular basis.","date":"1984","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/6096477","citation_count":475,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2564851","id":"PMC_2564851","title":"Human myeloid plasma membrane glycoprotein CD13 (gp150) is identical to aminopeptidase N.","date":"1989","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/2564851","citation_count":467,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"3038962","id":"PMC_3038962","title":"Stimulated mobilization of monocyte Mac-1 and p150,95 adhesion proteins from an intracellular vesicular compartment to the cell surface.","date":"1987","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/3038962","citation_count":443,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"3594570","id":"PMC_3594570","title":"Heterogeneous mutations in the beta subunit common to the LFA-1, Mac-1, and p150,95 glycoproteins cause leukocyte adhesion deficiency.","date":"1987","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/3594570","citation_count":348,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15326253","id":"PMC_15326253","title":"Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS.","date":"2004","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/15326253","citation_count":348,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2428876","id":"PMC_2428876","title":"Regulated expression of the Mac-1, LFA-1, p150,95 glycoprotein family during leukocyte differentiation.","date":"1986","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/2428876","citation_count":295,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"3327687","id":"PMC_3327687","title":"cDNA cloning and complete primary structure of the alpha subunit of a leukocyte adhesion glycoprotein, p150,95.","date":"1987","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/3327687","citation_count":263,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2521491","id":"PMC_2521491","title":"Adherence of neutrophils to cultured human microvascular endothelial cells. 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functional expression and direct protein sequencing confirming identity\",\n      \"pmids\": [\"2564851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"CD13/GP150/aminopeptidase N enzymatic activity in blood is predominantly localized to cell-free plasma rather than cell surfaces; plasma aminopeptidase N activity is largely inhibitable by anti-CD13 monoclonal antibody WM15 and is dependent on divalent metal ions; immunoaffinity isolation confirmed the plasma form shares electrophoretic characteristics with cell-derived CD13.\",\n      \"method\": \"Functional aminopeptidase activity assay with monoclonal antibody inhibition, immunoaffinity purification, SDS-PAGE, fractionation of blood components\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional assay with antibody blocking and biochemical fractionation in a single study\",\n      \"pmids\": [\"7902291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"CD13/aminopeptidase N (gp150) enzymatic activity is present on endothelial cells and is inhibitable by CD13 monoclonal antibodies, demonstrating functional co-expression with haemopoietic cells.\",\n      \"method\": \"Chromogenic substrate functional assay with monoclonal antibody inhibition on endothelial cells\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional assay with antibody blocking\",\n      \"pmids\": [\"1723966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"The CD11c (p150,95 alpha subunit, ANPEP/CD13 context: note — the p150,95 referenced throughout older papers is CD11c/CD18 integrin, not ANPEP) gene was cloned and localized to human chromosome 15q25-26; the gene is expressed as a 4.0-kb mRNA in myeloid cells and the protein is biologically active when transfected into NIH 3T3 cells.\",\n      \"method\": \"Molecular cloning, transfection, in situ hybridization chromosomal localization\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cloning with functional transfection and chromosomal mapping\",\n      \"pmids\": [\"2428842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ANPEP (aminopeptidase N/CD13) functions as a receptor for porcine deltacoronavirus (PDCoV) in porcine alveolar macrophages: CRISPR/Cas9 knockout of the ANPEP gene in pigs rendered alveolar macrophages resistant to PDCoV infection, although lung fibroblast-like cells remained infectable independently of APN.\",\n      \"method\": \"CRISPR/Cas9 ANPEP knockout pigs, ex vivo infection assay of primary alveolar macrophages and fibroblast-like cells\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean gene knockout in vivo with defined cellular infection phenotype, cell-type-specific receptor function demonstrated\",\n      \"pmids\": [\"32056711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD13/ANPEP targeting by a blocking antibody induces apoptosis in BRAF-inhibitor-sensitive and -resistant melanoma cells and leads to dephosphorylation of EPHA2 on S897, as well as dephosphorylation of AKT and RSK, indicating ANPEP modulates the EPHA2/AKT/RSK signaling axis in melanoma.\",\n      \"method\": \"Anti-CD13 blocking antibody treatment, Western blot for phospho-EPHA2 S897, phospho-AKT, phospho-RSK; apoptosis assays in melanoma cell lines\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — antibody-mediated functional blockade with defined downstream phosphorylation readouts in multiple cell lines\",\n      \"pmids\": [\"29048432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Computational analysis predicted that CD13/ANPEP (hAPN) may serve as a receptor for SARS-CoV S protein, mapping a putative binding site at D757-R761 of the S protein interacting with the P585-A653 domain of CD13, based on molecular modeling and docking simulation.\",\n      \"method\": \"Bioinformatics homology search, phylogenetic analysis, molecular modeling and docking simulation\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational prediction only, no experimental validation\",\n      \"pmids\": [\"12791172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The I-domain of CD11c (alpha subunit of p150,95/CD11c/CD18) binds fibrinogen specifically through its central fragment E domain; binding requires divalent cations (Mg2+, Mn2+) and is abolished by alanine substitutions at putative metal-binding residues Asp242 and Tyr209 in the I-domain.\",\n      \"method\": \"Recombinant I-domain production, direct binding assay, competitive inhibition with fibrinogen fragments, alanine mutagenesis, divalent cation requirement assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — recombinant domain, mutagenesis of active-site residues, and ligand competition assay in a single study\",\n      \"pmids\": [\"10543983\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANPEP encodes aminopeptidase N (CD13/APN), a type II integral membrane zinc metalloprotease with its catalytic domain in the extracellular space; it functions as a cell-surface and soluble plasma peptidase, acts as a receptor for certain coronaviruses (including PDCoV) in macrophages, and modulates downstream signaling (EPHA2/AKT/RSK phosphorylation) in cancer cells, while its I-domain mediates divalent-cation-dependent ligand binding.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\nANPEP = Aminopeptidase N (CD13/APN), a zinc metallopeptidase encoded by the ANPEP gene.\n\nPapers about p150,95 / CD11c / LFA-1 / Mac-1 / leukocyte integrins → EXCLUDE (alias collision: \"p150,95\" is the CD11c integrin, not ANPEP)\nPapers about dynactin p150(Glued) / DCTN1 → EXCLUDE (different gene)\nPapers about CAF-1 p150 / chromatin assembly factor → EXCLUDE (different gene)\nPapers about ADAR1 p150/p110 isoforms → EXCLUDE (different gene)\nPapers about LAP1 (lamina-associated polypeptide 1) → EXCLUDE (different gene)\nPapers about MHV-68 gp150 / EBV gp150 / viral glycoproteins → EXCLUDE (viral proteins)\nPapers about Dictyostelium gp150 → EXCLUDE (symbol collision, non-orthologous organism)\nPapers about PI3K p150/hVps34 → EXCLUDE (different gene)\nPapers about rubella virus P150 → EXCLUDE (viral protein)\nPapers about LAP1 (Medicago MYB) → EXCLUDE (plant gene)\nPapers about LAP-1 beta-lactamase → EXCLUDE (bacterial gene)\nPapers about Lactobacillus LAP1 → EXCLUDE\nPapers about Lentinus edodes LAP1 → EXCLUDE\nPapers about LAP1 (C/EBPβ isoform, sumoylation/COX-2) → EXCLUDE (different gene)\nPapers about p150(sal2) → EXCLUDE (different gene)\nPapers about eIF3 p150 → EXCLUDE (different gene)\nPapers about cervical/gastric carcinoma p150 → EXCLUDE (eIF3 subunit, different gene)\nPapers about Fhit/Ap3A → EXCLUDE (different gene)\nPapers about hVPS34/p150 (PI3K complex) → EXCLUDE\nPapers about EB1/p150(Glued)/microtubule → EXCLUDE (DCTN1)\nPapers about torsinA/LAP1 (nuclear envelope) → EXCLUDE (TOR1AIP1)\nPapers about Huntingtin/REST/p150(Glued) → EXCLUDE (DCTN1)\nPapers about IGF-1R/p150(Glued) nuclear translocation → EXCLUDE (DCTN1)\nPapers about Aurora A/p150(glued) → EXCLUDE (DCTN1)\nPapers about Perry syndrome/p150(Glued) neuron → EXCLUDE (DCTN1)\nPapers about MKK3/6/p150(Glued) → EXCLUDE (DCTN1)\nPapers about HP1/CAF-1 p150 → EXCLUDE\nPapers about MBD1/CAF-1 p150 → EXCLUDE\nPapers about Cdc7-Dbf4/CAF-1 p150 → EXCLUDE\nPapers about CAF-1 p150 gene silencing → EXCLUDE\nPapers about CAF-1 p150 nucleolar → EXCLUDE\nPapers about fission yeast Ssm4p/p150(Glued) → EXCLUDE (DCTN1 ortholog)\nPapers about Aspergillus p150 → EXCLUDE\nPapers about ORP1L/Rab7/p150(Glued) → EXCLUDE (DCTN1)\nPapers about SNX6/p150(Glued) → EXCLUDE (DCTN1)\nPapers about TRAPPC9/p150(Glued)/COPII → EXCLUDE (DCTN1)\nPapers about Par6α/p150(Glued) → EXCLUDE (DCTN1)\nPapers about retrograde signaling/p75NTR/p150Glued → EXCLUDE (DCTN1)\nPapers about dynactin p150 ablation in neurons → EXCLUDE (DCTN1)\nPapers about Xenopus M phase p150(Glued) → EXCLUDE (DCTN1)\nPapers about EB1-p150(Glued) crystal structure → EXCLUDE (DCTN1)\nPapers about CAP-Gly/p150(Glued) cryo-EM → EXCLUDE (DCTN1)\n\n**KEEP papers (ANPEP/CD13/aminopeptidase N):**\n\nFrom retrieved papers:\n- PMID:2564851 (Look 1989) — CD13/gp150 = aminopeptidase N, structure identification ✓\n- PMID:7902291 (Favaloro 1993) — CD13/GP150/aminopeptidase-N activity in plasma ✓\n- PMID:1723966 (Favaloro 1991) — CD13/gp150 on endothelial cells, aminopeptidase activity ✓\n\nFrom gene2pubmed papers:\n- PMID:1350662 (Yeager 1992) — hAPN as receptor for HCoV-229E ✓\n- PMID:10676659 (Pasqualini 2000) — APN as receptor for NGR peptides/angiogenesis ✓\n- PMID:2901990 (Olsen 1988) — complete amino acid sequence of human intestinal aminopeptidase N ✓\n- PMID:12551991 (Bonavia 2003) — HCoV-229E spike RBD binding to hAPN ✓\n- PMID:15280478 (Nomura 2004) — HCoV-229E binds CD13 in rafts, enters via caveolae ✓\n- PMID:8105105 (Söderberg 1993) — CD13 mediates HCMV infection ✓\n- PMID:17363734 (Proost 2007) — CD13/APN processes CXCL11 ✓\n- PMID:1675638 (Shapiro 1991) — separate promoters for APN in myeloid vs. intestinal cells ✓\n- PMID:22932899 (Wong 2012) — X-ray crystal structure of hAPN ✓\n- PMID:31650956 (Li 2019) — HCoV-229E S-protein/hAPN complex structure ✓\n- PMID:21879266 (Kim 2011) — CD13 reduces ROS in liver cancer stem cells ✓\n- PMID:16466852 (Fukasawa 2006) — APN/CD13 in angiogenesis, tube formation, migration ✓\n- PMID:29048432 (Azimi 2017) — CD13/ANPEP, EPHA2 dephosphorylation, apoptosis ✓\n- PMID:32056711 (Stoian 2019) — ANPEP KO pigs, APN as receptor for PDCoV ✓\n- PMID:12791172 (Yu 2003) — putative hAPN/SARS-CoV binding (computational) — mostly computational, LOW value\n- PMID:16818694 (Tokuhara 2006) — APN/CD13 in NSCLC, angiogenesis correlation — expression/prognostic, EXCLUDE from discoveries\n- PMID:15916720 (Hennersdorf 2005) — CD13 upregulation on basophils — expression study, EXCLUDE\n\nAdditional gene2pubmed papers that are proteomics/expression studies without mechanistic findings about ANPEP function → exclude from discoveries (PMIDs: 15326289, 12477932, 24816252, 21873635, 19056867, 15489334, 20360068, 16335952, 19199708, 23533145, 23376485, 15084671, 17192395, 20379614).\n\nNow extracting discoveries from KEPT papers:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1988,\n      \"finding\": \"The complete primary structure of human intestinal aminopeptidase N (967 amino acids) was deduced from cDNA cloning, revealing it is anchored to the microvillar membrane via an uncleaved N-terminal signal/transmembrane segment, and that a domain spanning approximately residues 250–555 is homologous to E. coli aminopeptidase N and contains the Zn2+ ligands constituting the active site.\",\n      \"method\": \"cDNA cloning and sequence analysis; identification of Zn2+ binding motifs by homology\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — full-length cDNA sequence with active-site identification, foundational structural paper replicated by Look 1989\",\n      \"pmids\": [\"2901990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"Human myeloid cell surface glycoprotein CD13 (gp150) is identical to aminopeptidase N: it is a type II transmembrane zinc metalloprotease of 967 amino acids with a single N-terminal hydrophobic membrane-spanning segment (non-cleaved signal anchor) and a large extracellular C-terminal catalytic domain bearing the zinc-binding metalloprotease pentapeptide consensus sequence. Retroviral expression of the coding sequence in mouse fibroblasts confirmed surface expression of bona fide CD13.\",\n      \"method\": \"cDNA cloning, sequence analysis, retroviral expression in transfected mouse fibroblasts, N-terminal protein sequencing\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution by transfection, direct protein sequencing, replicated by Olsen 1988\",\n      \"pmids\": [\"2564851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Two distinct tissue-specific promoters control transcription of the single human aminopeptidase N (ANPEP) gene: an intestinal epithelial cell promoter containing a TATA box that directs a 3.4-kb transcript, and a separate upstream promoter in myeloid cells and fibroblasts (located ~8 kb upstream of the start codon) that directs a longer 3.7-kb transcript. Both transcripts encode the same polypeptide. Functional promoter activity was demonstrated by reporter gene transfection into NIH-3T3 fibroblasts.\",\n      \"method\": \"Northern blot analysis; 5'-end mapping; reporter gene (bacterial) transfection assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Northern blot, 5'-mapping, functional reporter assays) in single rigorous study\",\n      \"pmids\": [\"1675638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"CD13/gp150 expressed on endothelial cells possesses enzymatic aminopeptidase N-like activity comparable to that on haemopoietic cells, as shown by chromogenic substrate assays inhibitable by anti-CD13 monoclonal antibody.\",\n      \"method\": \"Chromogenic substrate functional assays; monoclonal antibody inhibition; ELISA; immunofluorescence\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional enzymatic assay with antibody inhibition; single lab\",\n      \"pmids\": [\"1723966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Human aminopeptidase N (APN/CD13) is a functional receptor for human coronavirus HCoV-229E: anti-CD13 monoclonal antibody RBS blocked HCoV-229E infection and virus binding, and transfection of hAPN cDNA into resistant murine fibroblasts rendered them susceptible to HCoV-229E but not HCoV-OC43. A catalytic-site mutant APN that lost enzymatic activity also failed to bind the virus or confer susceptibility, suggesting the virus-binding site overlaps with or is near the active site.\",\n      \"method\": \"Virus infection assay; monoclonal antibody blocking; cDNA transfection of murine fibroblasts; catalytic mutant APN expression\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — gain-of-function transfection, antibody blocking, and mutant analysis; independently replicated\",\n      \"pmids\": [\"1350662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"CD13 (human aminopeptidase N) mediates human cytomegalovirus (HCMV) infection: anti-CD13 antibodies inhibited HCMV binding and infection; transfection of hAPN cDNA into resistant murine fibroblasts increased susceptibility and HCMV binding. However, a mutant CD13 lacking part of the aminopeptidase active site still conferred susceptibility, indicating the enzymatic domain is not required for HCMV entry.\",\n      \"method\": \"Virus infection assay; antibody blocking; cDNA transfection of murine fibroblasts; active-site deletion mutant\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — gain-of-function transfection, antibody blocking, and active-site mutant; rigorous controls\",\n      \"pmids\": [\"8105105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"CD13/GP150/aminopeptidase N activity in whole blood is predominantly localized to cell-free plasma rather than to cell surfaces; plasma APN activity is >70% inhibitable by anti-CD13 monoclonal antibody WM15 and can be completely cleared by immunoaffinity isolation, establishing the existence of a soluble circulating form of CD13/APN.\",\n      \"method\": \"Chromogenic substrate functional assays; monoclonal antibody inhibition; immunoaffinity isolation; SDS-PAGE\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional enzymatic and immunoaffinity methods; single lab\",\n      \"pmids\": [\"7902291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Aminopeptidase N (APN/CD13) is the receptor for NGR motif-containing tumor-homing peptides in tumor vasculature. NGR phage specifically bound immunocaptured APN and APN-expressing transfected cells; anti-APN antibodies blocked in vivo tumor homing. APN expression is upregulated in endothelial cells within tumors and in corpus luteum angiogenesis. APN antagonists inhibited angiogenesis in chorioallantoic membrane and retinal assays and suppressed tumor growth, identifying APN as a functional participant in angiogenesis.\",\n      \"method\": \"Phage binding to immunocaptured APN; transfected cell binding; in vivo tumor homing with antibody blockade; angiogenesis assays (CAM, retina); tumor growth assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal in vitro and in vivo methods; widely replicated\",\n      \"pmids\": [\"10676659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The receptor-binding domain (RBD) of HCoV-229E spike protein lies within the N-terminal 417–547 amino acid region: soluble truncated S proteins containing this region specifically bound hAPN-expressing cells, and binding was blocked by an anti-hAPN antibody that inhibits virus infection. S proteins lacking this region did not bind hAPN.\",\n      \"method\": \"Baculovirus expression of truncated spike proteins; cell-binding assay on hAPN-transfected 3T3 cells; antibody blocking\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding assay with defined truncation constructs and antibody blocking controls\",\n      \"pmids\": [\"12551991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD13/APN is a major component of Triton X-100-resistant lipid raft microdomains on human fibroblasts; HCoV-229E binds CD13 at the cell surface and causes clustering of CD13 into caveolin-1-positive caveolae at 37°C. Electron microscopy showed HCoV-229E near caveolae orifices post-binding. Cholesterol depletion with methyl-β-cyclodextrin significantly reduced virus redistribution and infection; caveolin-1 knockdown by RNAi also reduced HCoV-229E infection, establishing that CD13-mediated HCoV-229E entry occurs through caveolae.\",\n      \"method\": \"Detergent-resistant membrane fractionation; immunofluorescence co-localization; electron microscopy; cholesterol depletion; caveolin-1 RNAi knockdown; virus infection assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including RNAi, cholesterol depletion, and EM; strong mechanistic support\",\n      \"pmids\": [\"15280478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"APN/CD13 is selectively expressed in vascular endothelial cells and plays multiple roles in angiogenesis: RNAi silencing of APN inhibited capillary tube formation on Matrigel, reduced endothelial cell migration through fibronectin-coated membranes, and decreased adhesion to Matrigel and extracellular matrix components (type IV collagen, type I collagen, fibronectin).\",\n      \"method\": \"RNAi knockdown; Matrigel tube formation assay; Transwell migration assay; cell adhesion assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function RNAi with multiple defined phenotypic readouts; single lab\",\n      \"pmids\": [\"16466852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD13/APN proteolytically processes the chemokine CXCL11 at its N-terminus, removing up to 6 amino acids in combination with CD26/DPP4. CD13/APN-truncated CXCL11 showed reduced binding and signaling at CXCR3 and CXCR7, failed to induce intracellular calcium increases, lost chemotactic activity for lymphocytes, and showed significantly reduced inhibition of endothelial cell migration. This identifies CD13/APN as a negative regulator of CXCL11-mediated lymphocyte recruitment and angiostasis.\",\n      \"method\": \"Biochemical purification and identification of truncated CXCL11; in vitro enzymatic processing assays; receptor binding and signaling assays (Ca2+ flux, ERK1/2/Akt phosphorylation); chemotaxis assays; endothelial migration assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct in vitro enzymatic assay plus multiple functional downstream assays; rigorous mechanistic study\",\n      \"pmids\": [\"17363734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Increased CD13/aminopeptidase N expression in liver cancer stem cells (CSCs) reduces intracellular reactive oxygen species (ROS) levels, promoting CSC survival. TGF-β-induced EMT-like phenotype was associated with increased CD13 expression. Inhibition of CD13 stimulated apoptosis in CD13+ CSCs, establishing CD13 as a scavenger enzyme in the ROS metabolic pathway that protects CSCs from oxidative stress-induced apoptosis.\",\n      \"method\": \"TGF-β EMT induction; CD13 inhibition (antibody/inhibitor); ROS measurement; apoptosis assay; immunohistochemistry of post-chemotherapy tumor samples\",\n      \"journal\": \"Annals of surgical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — loss-of-function inhibition with ROS and apoptosis readouts; single lab, moderate mechanistic follow-up\",\n      \"pmids\": [\"21879266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The X-ray crystal structure of the dimeric ectodomain of human aminopeptidase N (hAPN/CD13) was determined at high resolution in complexes with angiotensin IV and the inhibitors amastatin and bestatin. Each monomer adopts the closed form with an internal cavity surrounding the catalytic Zn2+ site. The structure reveals hAPN as the first dimeric M1 family metallopeptidase, with structural features (including substrate-dependent loop ordering and inhibitor-specific cavity access) that provide mechanistic insights into peptide processing, including angiotensin III and IV metabolism.\",\n      \"method\": \"X-ray crystallography of ectodomain alone and in complex with angiotensin IV, amastatin, bestatin\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structures of native enzyme and multiple inhibitor complexes\",\n      \"pmids\": [\"22932899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD13/ANPEP contributes to BRAF-inhibitor resistance in melanoma cells and is upstream of EPHA2 signaling: blocking CD13/ANPEP with a monoclonal antibody induced apoptosis in both BRAFi-sensitive and resistant melanoma cells, and caused dephosphorylation of EPHA2 at S897 (a pro-migratory phosphorylation site). AKT and RSK, which phosphorylate EPHA2-S897, were also dephosphorylated after CD13/ANPEP inhibition, placing CD13/ANPEP upstream of the AKT/RSK→EPHA2 signaling axis.\",\n      \"method\": \"Antibody-mediated CD13/ANPEP blocking; apoptosis assay; phospho-Western blotting for EPHA2-S897, AKT, RSK; gene expression and proteome profiling\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — loss-of-function with defined phospho-signaling readouts; single lab\",\n      \"pmids\": [\"29048432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"APN (encoded by ANPEP) serves as a receptor for porcine deltacoronavirus (PDCoV) in porcine alveolar macrophages (PAMs): CRISPR/Cas9 knockout of ANPEP in pigs rendered PAMs resistant to PDCoV infection. However, lung fibroblast-like cells from the same KO pigs remained permissive to PDCoV, demonstrating that APN is cell-type-specific receptor for PDCoV in macrophages but dispensable in fibroblast-like cells.\",\n      \"method\": \"CRISPR/Cas9 ANPEP knockout in pigs; ex vivo infection of primary PAMs and fibroblast-like cells; in vivo infection of KO pigs\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic knockout in primary cells and whole animal; rigorous loss-of-function\",\n      \"pmids\": [\"32056711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"X-ray crystal structures of HCoV-229E spike protein receptor-binding domains (RBDs) from multiple viral classes (III–V) in complex with human APN (hAPN) revealed that common core interactions at the hAPN active-site region define specificity for hAPN, while peripheral RBD sequence variation is accommodated by loop plasticity. The cryo-EM structure of the full 229E S-protein shows it can expose portions of its helical core, facilitated by hydrophilic subunit interfaces conserved among coronaviruses.\",\n      \"method\": \"X-ray crystallography of multiple RBD–hAPN complexes; cryo-EM of full spike protein\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple crystal structures plus cryo-EM; defines molecular basis of hAPN recognition\",\n      \"pmids\": [\"31650956\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANPEP (CD13/aminopeptidase N) is a homodimeric, type II transmembrane zinc metallopeptidase whose large extracellular catalytic domain processes regulatory peptides (including angiotensin III/IV and chemokines such as CXCL11), serves as the entry receptor for human coronavirus HCoV-229E (binding via the viral spike RBD at the enzyme active-site region, with internalization through caveolae) and human cytomegalovirus, participates in angiogenesis and tumor vasculature homing via NGR peptide recognition, reduces ROS in cancer stem cells to promote survival, and functions upstream of AKT/RSK→EPHA2 signaling in BRAF-inhibitor resistance; its expression in myeloid versus intestinal epithelial cells is controlled by two distinct tissue-specific promoters driving the same polypeptide.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ANPEP (CD13/aminopeptidase N) is a type II integral membrane zinc metallopeptidase with a large extracellular catalytic domain, identified by cDNA cloning and protein sequencing as identical to the myeloid antigen gp150 [PMID:2564851]. Its aminopeptidase activity is present on endothelial cells, hematopoietic cells, and as a soluble divalent-cation-dependent form in plasma [PMID:1723966, PMID:7902291]. ANPEP serves as a cell-type-specific receptor for porcine deltacoronavirus in alveolar macrophages, as demonstrated by CRISPR/Cas9 knockout in pigs [PMID:32056711], and antibody-mediated blockade of CD13 in melanoma cells induces apoptosis through dephosphorylation of the EPHA2/AKT/RSK signaling axis [PMID:29048432].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Establishing the molecular identity of CD13: cDNA cloning revealed that the myeloid surface antigen gp150/CD13 is aminopeptidase N, a type II membrane zinc metalloprotease, unifying an immunological marker with a known enzymatic activity.\",\n      \"evidence\": \"cDNA cloning, retroviral expression in mouse fibroblasts, and N-terminal protein sequencing\",\n      \"pmids\": [\"2564851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Physiological substrates in vivo not identified\",\n        \"Tissue distribution beyond myeloid cells not systematically characterized\",\n        \"No structural model of the full-length protein\"\n      ]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Extending ANPEP function beyond hematopoietic lineages: demonstration of enzymatic aminopeptidase activity on endothelial cells showed the enzyme is not myeloid-restricted and may function in vascular biology.\",\n      \"evidence\": \"Chromogenic substrate assay with monoclonal antibody inhibition on cultured endothelial cells\",\n      \"pmids\": [\"1723966\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional significance of endothelial ANPEP activity not determined\",\n        \"No in vivo loss-of-function data in endothelium\"\n      ]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Identifying a soluble circulating form: most blood aminopeptidase N activity resides in cell-free plasma rather than on cell surfaces, establishing ANPEP as both a membrane-bound and a soluble peptidase.\",\n      \"evidence\": \"Fractionation of blood, functional assay with anti-CD13 antibody inhibition and immunoaffinity purification\",\n      \"pmids\": [\"7902291\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of shedding or release of soluble form not established\",\n        \"Physiological role of circulating ANPEP activity unknown\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linking ANPEP to pro-survival signaling in cancer: antibody blockade of CD13 in melanoma cells caused apoptosis and reduced phosphorylation of EPHA2 (S897), AKT, and RSK, revealing a role for ANPEP in maintaining the EPHA2/AKT/RSK signaling axis.\",\n      \"evidence\": \"Anti-CD13 blocking antibody treatment with Western blot phospho-protein readouts and apoptosis assays in BRAF-inhibitor-sensitive and -resistant melanoma lines\",\n      \"pmids\": [\"29048432\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether ANPEP enzymatic activity or its non-catalytic surface interactions mediate the signaling effect is unknown\",\n        \"Direct physical interaction between ANPEP and EPHA2 not demonstrated\",\n        \"No genetic loss-of-function confirmation in cancer models\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing ANPEP as a cell-type-specific coronavirus receptor: CRISPR/Cas9 ANPEP-knockout pigs showed that alveolar macrophages require ANPEP for porcine deltacoronavirus entry, while lung fibroblast-like cells do not, demonstrating receptor function is cell-type-dependent.\",\n      \"evidence\": \"CRISPR/Cas9 ANPEP knockout pigs with ex vivo PDCoV infection of primary alveolar macrophages and fibroblasts\",\n      \"pmids\": [\"32056711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of PDCoV spike–ANPEP interaction not resolved\",\n        \"Alternative receptor(s) used by PDCoV in fibroblast-like cells not identified\",\n        \"Whether human ANPEP functions analogously for human coronaviruses not experimentally confirmed in this study\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the physiological peptide substrates that drive ANPEP's in vivo functions, the mechanism by which ANPEP couples to intracellular signaling (enzymatic vs. scaffolding), and the structural basis for its dual role as peptidase and viral receptor.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of full-length human ANPEP in complex with substrates or viral ligands\",\n        \"In vivo loss-of-function phenotype in mammals beyond viral susceptibility not characterized\",\n        \"Mechanism linking ANPEP surface expression to EPHA2/AKT signaling not determined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"EPHA2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I need to fix the pathway entries - they should use Reactome IDs, not GO IDs. Let me reconsider.\n\n```json\n{\n  \"mechanistic_narrative\": \"ANPEP (CD13/aminopeptidase N) is a type II integral membrane zinc metallopeptidase with a large extracellular catalytic domain, identified by cDNA cloning and protein sequencing as identical to the myeloid antigen gp150 [PMID:2564851]. Its aminopeptidase activity is present on endothelial cells, hematopoietic cells, and as a soluble divalent-cation-dependent form in plasma [PMID:1723966, PMID:7902291]. ANPEP serves as a cell-type-specific receptor for porcine deltacoronavirus in alveolar macrophages, as demonstrated by CRISPR/Cas9 knockout in pigs [PMID:32056711], and antibody-mediated blockade of CD13 in melanoma cells induces apoptosis through dephosphorylation of the EPHA2/AKT/RSK signaling axis [PMID:29048432].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Establishing the molecular identity of CD13: cDNA cloning revealed that the myeloid surface antigen gp150/CD13 is aminopeptidase N, a type II membrane zinc metalloprotease, unifying an immunological marker with a known enzymatic activity.\",\n      \"evidence\": \"cDNA cloning, retroviral expression in mouse fibroblasts, and N-terminal protein sequencing\",\n      \"pmids\": [\"2564851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Physiological substrates in vivo not identified\",\n        \"Tissue distribution beyond myeloid cells not systematically characterized\",\n        \"No structural model of the full-length protein\"\n      ]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Extending ANPEP function beyond hematopoietic lineages: demonstration of enzymatic aminopeptidase activity on endothelial cells showed the enzyme is not myeloid-restricted and may function in vascular biology.\",\n      \"evidence\": \"Chromogenic substrate assay with monoclonal antibody inhibition on cultured endothelial cells\",\n      \"pmids\": [\"1723966\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional significance of endothelial ANPEP activity not determined\",\n        \"No in vivo loss-of-function data in endothelium\"\n      ]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Identifying a soluble circulating form: most blood aminopeptidase N activity resides in cell-free plasma rather than on cell surfaces, establishing ANPEP as both a membrane-bound and a soluble peptidase.\",\n      \"evidence\": \"Fractionation of blood, functional assay with anti-CD13 antibody inhibition and immunoaffinity purification\",\n      \"pmids\": [\"7902291\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of shedding or release of soluble form not established\",\n        \"Physiological role of circulating ANPEP activity unknown\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linking ANPEP to pro-survival signaling in cancer: antibody blockade of CD13 in melanoma cells caused apoptosis and reduced phosphorylation of EPHA2 (S897), AKT, and RSK, revealing a role for ANPEP in maintaining the EPHA2/AKT/RSK signaling axis.\",\n      \"evidence\": \"Anti-CD13 blocking antibody treatment with Western blot phospho-protein readouts and apoptosis assays in BRAF-inhibitor-sensitive and -resistant melanoma lines\",\n      \"pmids\": [\"29048432\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether ANPEP enzymatic activity or its non-catalytic surface interactions mediate the signaling effect is unknown\",\n        \"Direct physical interaction between ANPEP and EPHA2 not demonstrated\",\n        \"No genetic loss-of-function confirmation in cancer models\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing ANPEP as a cell-type-specific coronavirus receptor: CRISPR/Cas9 ANPEP-knockout pigs showed that alveolar macrophages require ANPEP for porcine deltacoronavirus entry, while lung fibroblast-like cells do not, demonstrating receptor function is cell-type-dependent.\",\n      \"evidence\": \"CRISPR/Cas9 ANPEP knockout pigs with ex vivo PDCoV infection of primary alveolar macrophages and fibroblasts\",\n      \"pmids\": [\"32056711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of PDCoV spike-ANPEP interaction not resolved\",\n        \"Alternative receptor(s) used by PDCoV in fibroblast-like cells not identified\",\n        \"Whether human ANPEP functions analogously for human coronaviruses not experimentally confirmed in this study\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the physiological peptide substrates that drive ANPEP's in vivo functions, the mechanism by which ANPEP couples to intracellular signaling (enzymatic vs. scaffolding), and the structural basis for its dual role as peptidase and viral receptor.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of full-length human ANPEP in complex with substrates or viral ligands\",\n        \"In vivo loss-of-function phenotype in mammals beyond viral susceptibility not characterized\",\n        \"Mechanism linking ANPEP surface expression to EPHA2/AKT signaling not determined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"EPHA2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"ANPEP (CD13/aminopeptidase N) is a homodimeric type II transmembrane zinc metallopeptidase that cleaves N-terminal residues from regulatory peptides—including angiotensin III/IV and the chemokine CXCL11—thereby modulating vasoactive signaling and lymphocyte chemotaxis [PMID:22932899, PMID:17363734]. Its large ectodomain harbors the catalytic Zn²⁺ site within a closed internal cavity, and this active-site region doubles as the binding determinant for HCoV-229E spike protein, with virus entry proceeding through caveolae-mediated endocytosis; ANPEP also serves as a receptor for human cytomegalovirus and, in a cell-type-specific manner, porcine deltacoronavirus [PMID:1350662, PMID:15280478, PMID:8105105, PMID:32056711]. ANPEP is upregulated on tumor vasculature endothelium where it promotes angiogenesis by supporting capillary tube formation, migration, and extracellular matrix adhesion, and it sustains cancer stem cell survival by reducing intracellular reactive oxygen species [PMID:10676659, PMID:16466852, PMID:21879266]. Expression in myeloid versus intestinal epithelial cells is governed by two tissue-specific promoters driving the same polypeptide, and in melanoma ANPEP signals upstream of the AKT/RSK→EPHA2 axis to contribute to BRAF-inhibitor resistance [PMID:1675638, PMID:29048432].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Establishing the primary structure and membrane topology of ANPEP resolved how a single-pass type II transmembrane protein anchors its catalytic ectodomain to the brush-border membrane and identified the zinc-binding metalloprotease active site by homology.\",\n      \"evidence\": \"cDNA cloning and sequence analysis of human intestinal APN\",\n      \"pmids\": [\"2901990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No direct demonstration of enzymatic activity from the cloned product\", \"Quaternary structure unknown at this stage\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Demonstrating that the myeloid surface antigen CD13 is identical to aminopeptidase N unified two fields and showed the enzyme is expressed far beyond the intestinal epithelium.\",\n      \"evidence\": \"cDNA cloning of CD13, retroviral expression in mouse fibroblasts confirming surface expression, N-terminal protein sequencing\",\n      \"pmids\": [\"2564851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of enzymatic activity in myeloid context not yet characterized\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Discovery of two tissue-specific promoters explained how a single ANPEP gene produces the same protein in intestinal epithelium and myeloid/stromal cells through distinct transcriptional programs.\",\n      \"evidence\": \"Northern blot, 5'-end mapping, and reporter gene assays in fibroblasts\",\n      \"pmids\": [\"1675638\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcription factor identity at each promoter not fully resolved\", \"Chromatin-level regulation not addressed\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Gain-of-function and antibody-blocking experiments established ANPEP as the functional receptor for HCoV-229E, and a catalytic-site mutant that lost virus binding implied the virus-binding site overlaps with the enzyme active site.\",\n      \"evidence\": \"Transfection of hAPN into resistant murine fibroblasts; monoclonal antibody blocking; catalytic mutant expression\",\n      \"pmids\": [\"1350662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution binding interface not yet known\", \"Post-entry steps of virus internalization undefined\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Parallel experiments showed ANPEP also serves as a receptor for HCMV, but unlike HCoV-229E, HCMV entry does not require the enzymatic active site, revealing receptor utilization can be dissociated from catalytic function.\",\n      \"evidence\": \"Antibody blocking and transfection of hAPN and active-site deletion mutant into murine fibroblasts; HCMV infection assay\",\n      \"pmids\": [\"8105105\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"HCMV-binding epitope on ANPEP not mapped\", \"Whether ANPEP is the sole HCMV receptor unclear\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of ANPEP as the target of NGR tumor-homing peptides and demonstration that ANPEP antagonism blocks angiogenesis in vivo established a direct functional role for ANPEP in tumor neovascularization.\",\n      \"evidence\": \"Phage binding, antibody blocking of in vivo tumor homing, CAM and retinal angiogenesis assays, tumor growth inhibition\",\n      \"pmids\": [\"10676659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling pathways mediating the pro-angiogenic effect not defined\", \"Whether enzymatic activity is required for angiogenesis not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showing that ANPEP resides in lipid rafts and that HCoV-229E binding triggers ANPEP clustering into caveolin-1-positive caveolae resolved the internalization route, as caveolin-1 knockdown reduced infection.\",\n      \"evidence\": \"Detergent-resistant membrane fractionation, immunofluorescence, EM, cholesterol depletion, caveolin-1 RNAi in human fibroblasts\",\n      \"pmids\": [\"15280478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether caveolae-mediated entry applies to all cell types expressing ANPEP not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"RNAi silencing of ANPEP in endothelial cells directly linked its expression to capillary tube formation, migration, and matrix adhesion, moving beyond correlative angiogenesis phenotypes to a cell-autonomous requirement.\",\n      \"evidence\": \"RNAi knockdown with Matrigel tube formation, Transwell migration, and ECM adhesion assays\",\n      \"pmids\": [\"16466852\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study; genetic knockout confirmation lacking\", \"Signaling intermediates downstream of ANPEP in endothelial cells unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that ANPEP cleaves the N-terminus of CXCL11 to abolish its chemotactic and angiostatic activities revealed a specific substrate through which ANPEP regulates immunity and vascular biology.\",\n      \"evidence\": \"In vitro enzymatic processing, receptor binding, Ca²⁺ flux, chemotaxis, and endothelial migration assays\",\n      \"pmids\": [\"17363734\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo confirmation of CXCL11 processing by ANPEP not provided\", \"Full substrate repertoire still incomplete\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linking ANPEP to ROS scavenging in liver cancer stem cells showed it protects CSCs from oxidative-stress-induced apoptosis, broadening its role beyond peptide processing to redox homeostasis in cancer.\",\n      \"evidence\": \"CD13 inhibition with antibody/inhibitor, ROS measurement, apoptosis assay in TGF-β-induced CSCs\",\n      \"pmids\": [\"21879266\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which ANPEP reduces ROS not defined\", \"Single-lab observation; independent replication needed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"High-resolution crystal structures of the dimeric ANPEP ectodomain with angiotensin IV and inhibitors provided the first atomic view of an M1 family metallopeptidase dimer and revealed how substrate-dependent loop ordering and cavity gating control peptide processing.\",\n      \"evidence\": \"X-ray crystallography of hAPN ectodomain complexed with angiotensin IV, amastatin, bestatin\",\n      \"pmids\": [\"22932899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length membrane-embedded structure not determined\", \"Dynamics of substrate entry and product release not captured by static structures\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Antibody-mediated ANPEP blockade dephosphorylated AKT, RSK, and EPHA2-S897 and induced apoptosis in BRAFi-resistant melanoma cells, positioning ANPEP upstream of the AKT/RSK→EPHA2 signaling axis in drug resistance.\",\n      \"evidence\": \"Anti-CD13 antibody blocking, phospho-Western blotting, apoptosis assays in melanoma cell lines\",\n      \"pmids\": [\"29048432\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether enzymatic activity or scaffolding drives signaling is unknown\", \"No genetic knockout validation\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Structural determination of multiple HCoV-229E RBD–hAPN complexes confirmed that core virus contacts map to the ANPEP active-site region, while CRISPR knockout of ANPEP in pigs proved it is a cell-type-specific deltacoronavirus receptor in macrophages but dispensable in fibroblasts.\",\n      \"evidence\": \"X-ray crystallography and cryo-EM of spike–hAPN complexes; CRISPR/Cas9 ANPEP knockout pigs with ex vivo and in vivo infection\",\n      \"pmids\": [\"31650956\", \"32056711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Host cofactors that determine cell-type-specific receptor usage not identified\", \"Whether active-site mutations alone suffice to abolish 229E entry in a genetic knockout context untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the molecular mechanism by which ANPEP reduces intracellular ROS, whether its pro-angiogenic role requires enzymatic activity or a scaffolding/signaling function, the full physiological substrate repertoire, and how its receptor function for diverse viruses is partitioned between catalytic-site engagement and alternative binding modes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"ROS-scavenging mechanism unknown\", \"Enzymatic vs. non-enzymatic contribution to angiogenesis unresolved\", \"Comprehensive substrate profiling absent\", \"Signaling pathway downstream of ANPEP in endothelial and cancer contexts poorly defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 3, 11, 13]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 11, 13]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [4, 5, 8, 9, 15, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 3, 4, 9]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 11, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 5, 11, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CXCL11\",\n      \"CAV1\",\n      \"EPHA2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}