{"gene":"ANPEP","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":1989,"finding":"CD13 (gp150) is identical to aminopeptidase N: it is an integral membrane protein with a single 24 amino acid N-terminal hydrophobic segment that serves as both signal for membrane insertion and stable membrane-spanning anchor, with the remainder forming a large extracellular C-terminal domain containing the zinc-binding metalloprotease pentapeptide consensus sequence.","method":"cDNA cloning, retroviral expression in mouse fibroblasts, amino-terminal protein sequence analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Strong — full-length cDNA sequencing plus functional reconstitution in transfected cells plus direct N-terminal protein sequencing, replicated across multiple clones","pmids":["2564851"],"is_preprint":false},{"year":1986,"finding":"The human myeloid membrane antigen gp150 gene was molecularly cloned, shown to encode a 4.0-kb polyadenylated transcript, mapped to chromosome 15q25-26, and shown to be biologically active when transfected into NIH 3T3 cells; gp130 was identified as a carbohydrate-differing precursor to the mature cell-surface gp150.","method":"Bacteriophage lambda library cloning, DNA transfection, in situ hybridization, pulse-chase metabolic labeling, biochemical analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (cloning, transfection, chromosomal mapping, pulse-chase) in a focused mechanistic study","pmids":["2428842"],"is_preprint":false},{"year":2001,"finding":"CD13/APN is functionally essential for capillary tube (lumen) formation during angiogenesis; functional antagonists of CD13/APN block tube formation but not proliferation of primary vascular endothelial cells, and CD13/APN expression is transcriptionally upregulated by hypoxia and angiogenic growth factors via elements in the proximal promoter.","method":"In vitro tube formation assay with CD13 antagonists, reporter assays with CD13 proximal promoter, in vivo models (retinal neovascularization, chorioallantoic membrane angiogenesis, xenograft tumor growth)","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vitro and in vivo approaches, functional loss-of-function with specific phenotypic readout","pmids":["11157481"],"is_preprint":false},{"year":2007,"finding":"CD13 controls endothelial cell invasion and filopodia formation by facilitating bradykinin B2 receptor (B2R) internalization and downstream Cdc42 activation at the plasma membrane; CD13 inhibition blocks B2R internalization, abrogating invasion and filopodia; wild-type but not catalytically inactive mutant CD13 restores membrane protein organization, indicating peptidase activity is required for CD13's regulatory function.","method":"B2R internalization assay, Cdc42 activation assay, filopodia imaging, cholesterol depletion/repletion experiments, expression of wild-type vs. enzymatic mutant CD13","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including receptor internalization, GTPase activation, mutagenesis, and cholesterol manipulation in a single focused study","pmids":["17363739"],"is_preprint":false},{"year":1998,"finding":"The CD13/APN promoter is transcriptionally activated by the DMP1 transcription factor binding to a specific consensus site; DMP1 activation of CD13 requires intact DNA-binding and transactivation domains of DMP1 and is antagonized by D-type cyclins in a CDK-independent manner; CD13 expression is additionally co-regulated by cooperative interaction between c-Myb and Ets-1.","method":"Promoter reporter assays, electrophoretic mobility shift assay (EMSA), dominant-negative and deletion mutant analyses of DMP1 and cyclin constructs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro promoter reconstitution with mutagenesis and EMSA, single lab with multiple orthogonal methods","pmids":["9786929"],"is_preprint":false},{"year":2001,"finding":"An N-glycosylation site at amino acids 288–295 of human APN is a critical molecular determinant of species-specific coronavirus receptor activity: introduction of an N-glycosylation sequon at position 291–293 abolished HCoV-229E receptor activity of hAPN, while single-amino-acid revertants removing this sequon fully restored binding and receptor activity.","method":"Site-directed mutagenesis of hAPN, virus binding and infection assays in transfected cells","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis with functional binding and infection readouts, multiple revertant constructs tested","pmids":["11559807"],"is_preprint":false},{"year":1998,"finding":"Human APN (CD13) serves as the functional cellular receptor for human coronavirus 229E (HCoV-229E) in neural cells: hAPN is expressed on neuronal and glial cell line surfaces, anti-hAPN monoclonal antibody WM15 inhibits radiolabeled HCoV-229E attachment and infection, and attachment level correlates with hAPN surface amount.","method":"Flow cytometry for receptor expression, radiolabeled virus attachment assay, antibody blocking, indirect immunofluorescence infection assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (binding, neutralization, infection) establishing receptor identity in a single focused study","pmids":["9658094"],"is_preprint":false},{"year":2013,"finding":"CD13 cross-linking induces phosphorylation of Src, FAK, and ERK, and CD13 itself is phosphorylated on its cytoplasmic tyrosine in a Src-dependent manner; CD13 is constitutively associated with the scaffolding protein IQGAP1, and cross-linking induces complex formation with α-actinin, linking CD13 to the cytoskeleton; mutation of the conserved cytoplasmic tyrosine to phenylalanine abolishes adhesion, downstream signaling, and cytoskeletal changes; phospho-CD13 is present in vivo in peritoneal exudate cells, and monocytes expressing the mutant CD13 show severely impaired migration into the inflamed peritoneum.","method":"Phosphoprotein analysis, Src/FAK/ERK inhibition assays, site-directed mutagenesis (Y→F), co-immunoprecipitation with IQGAP1 and α-actinin, adoptive transfer in murine peritonitis model","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, mutagenesis, in vitro signaling, and in vivo adoptive transfer all in one study","pmids":["23997214"],"is_preprint":false},{"year":2008,"finding":"CD13 ligation and clustering by mAb or viral ligands induces myeloid/endothelial cell adhesion via signal transduction-dependent monocytic cytoskeletal rearrangement and filopodia formation; soluble recombinant CD13 blocks this adhesion; CD13 molecules from monocytic and endothelial cells co-immunoprecipitate, indicating direct homotypic CD13–CD13 interaction; anti-CD13 antibodies reduce leukocyte infiltration in murine peritonitis.","method":"Antibody-mediated cross-linking adhesion assays, recombinant CD13 blocking, co-immunoprecipitation, adhesion to immobilized recombinant CD13, murine peritonitis model","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus functional blocking plus in vivo model, multiple orthogonal methods","pmids":["18495788"],"is_preprint":false},{"year":2015,"finding":"CD13 negatively regulates TLR4 endocytic signaling: CD13 is co-internalized with TLR4, CD14, and dynamin into Rab5+ early endosomes upon LPS stimulation; CD13 KO dendritic cells show enhanced p-IRF-3 activation and transcription of IRF-3 target genes in response to TLR4 ligands while TLR4 surface signaling is unaffected; CD13 KO mice show enhanced IFNβ-mediated JAK-STAT signaling, elevated iNOS, and increased oxidative stress and tissue injury upon ischemia; CD13 and TLR4 co-immunoprecipitate in activated macrophages.","method":"CD13 KO mice, co-immunoprecipitation, IRF-3 phosphorylation assays, endosomal co-localization imaging, in vivo ischemia model, flow cytometry","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — CD13 KO with multiple orthogonal mechanistic readouts, co-IP, and in vivo validation in a single study","pmids":["25801433"],"is_preprint":false},{"year":2012,"finding":"CD13 negatively regulates receptor-mediated, dynamin-dependent endocytosis of antigens (OVA, transferrin) in dendritic cells but not fluid-phase or phagocytic uptake; CD13 is co-internalized with antigen but does not co-immunoprecipitate with antigen receptors; CD13 KO DCs show dysregulated phosphorylation of p38MAPK and Akt; lack of CD13 significantly enhances T cell responses to soluble OVA antigen in vivo.","method":"CD13 KO mice, in vitro antigen uptake assays, co-immunoprecipitation (negative), kinase inhibition, in vivo T cell response assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO model with in vitro mechanistic follow-up and in vivo validation, multiple orthogonal methods","pmids":["22544935"],"is_preprint":false},{"year":2006,"finding":"CD13 antibody-mediated ligation induces apoptosis in AML cells independently of its APN enzymatic activity: anti-CD13 mAbs (MY7, SJ1D1, WM15) cause sub-G1 accumulation, DNA fragmentation, phosphatidylserine externalization, mitochondrial depolarization, Bcl-2/Mcl-1 downregulation, Bax upregulation, and activation of caspase-9, caspase-8, and caspase-3; enzymatic inhibitors of APN alone are ineffective; internalization of CD13–mAb complex precedes mitochondrial events.","method":"Flow cytometry (cell cycle, apoptosis markers), Western blotting (Bcl-2, Bax, caspases), caspase inhibitor experiments, comparison of enzyme-blocking vs. non-blocking antibodies","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal apoptosis assays in a single study with careful antibody controls; single lab","pmids":["21566207"],"is_preprint":false},{"year":2005,"finding":"CD13 associates with tumor-associated antigen L6 (TAL6) in a co-immunoprecipitable complex on lung cancer cells; CD13 enhances cancer cell migration and invasion; expression of enzymatically inactive CD13 mutant also significantly enhances cell migration, indicating that CD13's effect on motility does not strictly depend on its peptidase activity.","method":"Co-immunoprecipitation, antibody-mediated co-patching immunofluorescence, Transwell migration/invasion assays, enzymatic inhibitors, catalytically inactive CD13 mutant expression","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, mutagenesis, and functional assays with multiple inhibitor controls in a single study","pmids":["15812828"],"is_preprint":false},{"year":2006,"finding":"CD13 mediates homotypic aggregation (HA) of monocytic cells via antibody cross-linking in a tyrosine kinase- and MAP kinase-dependent manner, independently of integrin signaling and independently of CD13 enzymatic activity; during HA, CD13 actively redistributes to cell–cell contact zones as observed by live cell imaging.","method":"Homotypic aggregation assays, enzyme inhibitor controls vs. kinase inhibitors, live cell imaging, colchicine/cytoskeletal perturbation","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, multiple in vitro assays but no in vivo confirmation or orthogonal biochemical validation","pmids":["16415167"],"is_preprint":false},{"year":2005,"finding":"CD13/APN functionally interacts with FcγRI on monocytes: during FcγR-mediated phagocytosis, CD13 redistributes to the phagocytic cup and is co-internalized into phagosomes; co-cross-linking of CD13 with FcγRI increases the level and duration of Syk phosphorylation; FcγRI and CD13 co-localize in zones of cellular polarization.","method":"Confocal microscopy of phagocytosis, Syk phosphorylation assays, co-cross-linking with specific mAbs, co-localization imaging","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-localization and functional co-cross-linking across multiple readouts, but no co-immunoprecipitation of the FcγRI–CD13 complex","pmids":["15758076"],"is_preprint":false},{"year":1995,"finding":"Purified and native membrane-bound CD13/APN sequentially and completely hydrolyzes Leu-enkephalin and Met-enkephalin from the amino terminus; substance P and bradykinin are natural inhibitors of CD13/APN (Ki = 0.44 µM and 9.4 µM, respectively) due to their N-terminal proline at the second residue, which prevents hydrolysis.","method":"In vitro enzymatic assay with purified pig APN and live HL60 cells, Km and Ki measurements with natural peptide substrates and inhibitors","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro enzymatic assay with purified protein and live cells, Ki values determined with two independent enzyme sources","pmids":["7535053"],"is_preprint":false},{"year":1993,"finding":"Cell-surface aminopeptidase N/CD13 is involved in tumor cell invasion through degradation of type-IV collagen: anti-CD13 mAb WM15 inhibits both aminopeptidase activity and type-IV collagen degradation by tumor cells, and reduces invasion through Matrigel in a concentration-dependent manner without affecting adhesion or migration.","method":"Matrigel invasion assay, type-IV collagen degradation assay, aminopeptidase activity assay with specific mAb inhibition","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays with specific mAb inhibition; mechanism inferred from coincident inhibition of enzymatic activity and invasion","pmids":["8097496"],"is_preprint":false},{"year":2009,"finding":"Porcine APN receptor density directly determines PEDV infection efficiency: overexpression of recombinant pAPN in ST cells rescues productive PEDV infection; the enzymatic active motif-null mutant pAPN retains receptor activity and supports viral production; APN inhibitor blocking the protease active site has no effect on viral infection, showing enzymatic activity is dispensable for PEDV receptor function.","method":"Stable cell line overexpression, enzymatic active-site mutant APN expression, aminopeptidase inhibitor treatment, viral infection/replication assays","journal":"Veterinary microbiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of active site plus enzymatic inhibitor controls, multiple orthogonal approaches in a single study","pmids":["20074871"],"is_preprint":false},{"year":2019,"finding":"APN (ANPEP) is a receptor for porcine deltacoronavirus (PDCoV) in porcine alveolar macrophages (PAMs): ANPEP knockout pigs generated by CRISPR/Cas9 show PAM resistance to PDCoV infection, but lung-derived fibroblast-like cells from the same KO pigs remain fully permissive, indicating APN is necessary in macrophages but dispensable in fibroblast cells for PDCoV infection.","method":"CRISPR/Cas9 ANPEP knockout pigs, viral infection of primary cell types, ex vivo and in vivo PDCoV challenge","journal":"Virology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO at organism level with cell-type-specific functional readouts; rigorous in vivo and ex vivo validation","pmids":["32056711"],"is_preprint":false},{"year":2020,"finding":"CD13 interacts with HDAC5 to promote its protein stability; stabilized HDAC5 deacetylates LSD1 to stabilize it; LSD1 then decreases NF-κB p65 methylation, leading to p65 protein stability and NF-κB pathway activation; this CD13–HDAC5–LSD1–NF-κB axis promotes HCC proliferation, invasion, and sorafenib resistance.","method":"Co-immunoprecipitation, LC-MS/MS, Western blotting, xenograft models, patient-derived xenograft models","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and MS identification of interactions, functional in vivo validation, single lab","pmids":["33377659"],"is_preprint":false},{"year":2020,"finding":"CD13 overexpression activates the P38/Hsp27/CREB signaling pathway; CREB binds the ATG7 promoter to induce autophagy; this CD13-driven autophagy promotes HCC chemoresistance; CD13 inhibition downregulates ATG7, autophagy, and tumor growth in vivo.","method":"Western blotting, CREB-ATG7 promoter binding assay, autophagy assays, in vivo xenograft models with CD13 inhibitor","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter binding assay plus in vivo validation, multiple pathway nodes tested; single lab","pmids":["32571958"],"is_preprint":false},{"year":2014,"finding":"CD13 regulates mesenchymal stem cell (MSC) adhesion and migration via FAK activation: CD13 KO MSCs show impaired adhesion and migration on extracellular matrices, decreased phospho-FAK levels, and cytoskeletal alterations; CD13 antibody cross-linking of human MSCs increases adhesion to endothelial monolayers and induces FAK activation; CD13 KO MSCs show significantly poorer tissue repair in ischemic limb injury with reduced vascularization.","method":"CD13 KO mice, cell adhesion/migration assays, FAK phosphorylation assay, antibody cross-linking, in vivo ischemic limb model with cell injection","journal":"Frontiers in physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO cells plus antibody cross-linking plus in vivo rescue model, multiple orthogonal mechanistic and functional methods","pmids":["24409152"],"is_preprint":false},{"year":2014,"finding":"CD13 is required for muscle satellite stem cell anchorage and differentiation timing: CD13 KO muscle shows markedly reduced satellite cell numbers, impaired satellite cell adhesion, and accelerated differentiation; CD13 co-localizes with Pax7 on satellite cells; phospho-FAK and ERK levels are reduced in injured CD13 KO muscle.","method":"CD13 KO mice, satellite cell isolation and characterization, adhesion assays, differentiation assays, immunofluorescence co-localization, Western blotting for FAK/ERK","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO phenotype with mechanistic correlate (FAK/ERK), co-localization; single lab","pmids":["24307555"],"is_preprint":false},{"year":2015,"finding":"CD13 is a primary phagocytic receptor in human macrophages and monocytic cells: hCD13 expression alone in non-phagocytic HEK293 cells is sufficient to enable internalization of large particles bound through CD13; CD13-mediated phagocytosis is independent of FcγRs, CR3, and most phagocytic receptors, independent of CD13 enzymatic activity, but requires actin rearrangement, PI3K activation, and partial Syk activation; CD13 cross-linking induces pSyk and ROS production.","method":"Phagocytosis assays with receptor-specific opsonization, CD13 expression in non-phagocytic HEK293 cells, pharmacological inhibitors of PI3K and Syk, actin disruption, ROS measurement","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reconstitution in non-phagocytic cells plus multiple inhibitor controls plus signaling readouts, multiple orthogonal methods","pmids":["25934926"],"is_preprint":false},{"year":2014,"finding":"CD13-dependent monocyte/endothelial adhesion is mediated by the C-terminal domain of CD13; lack of either monocytic or endothelial CD13 reduces myeloid cell trafficking into sites of inflammation in vivo; CD13 expression is enriched on pro-inflammatory monocyte subsets.","method":"Adoptive transfer of WT and CD13 KO myeloid cells into thioglycollate-challenged mice, chimeric CD13 (mouse/human) constructs identifying C-terminal domain requirement, flow cytometry of monocyte subsets","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo adoptive transfer with domain-mapping chimeric constructs; single lab","pmids":["24627994"],"is_preprint":false},{"year":2000,"finding":"CD13/APN enzymatic activity is responsible for its chemoattractant function for CD4+ T lymphocytes: soluble CD13/APN induces chemotactic migration of lymphocytes (more so for CD4+ than CD8+ T cells), and the aminopeptidase inhibitor bestatin abolishes this chemotactic activity.","method":"In vitro chemotaxis assay, bestatin inhibition of APN activity, BALF chemotaxis assay from sarcoidosis patients","journal":"American journal of respiratory and critical care medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic inhibitor functional assay showing activity-dependence; ex vivo and in vitro correlation","pmids":["10806168"],"is_preprint":false},{"year":2006,"finding":"Cell-surface CD13/APN regulates TNFα-induced neutrophil apoptosis by controlling shedding of TNFRI: APN inhibition (actinonin, bestatin) augments TNFα-induced killing and prevents TNFRI shedding, resulting in enhanced TNFα signaling; an inverse correlation exists between neutrophil APN activity and sensitivity to TNFα-induced apoptosis.","method":"Neutrophil apoptosis assays, TNFRI shedding measurement, APN activity measurement, pharmacological APN inhibitors","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays linking APN activity to TNFRI shedding; single lab","pmids":["16533817"],"is_preprint":false},{"year":2002,"finding":"High cell-surface CD13/aminopeptidase N activity enables leukemic cells to resist endothelial IL-8-induced apoptosis; K562 cells transfected with CD13 acquire resistance to IL-8-induced apoptosis; aminopeptidase inhibitor bestatin restores IL-8-induced apoptosis in CD13-overexpressing cells and increases endothelial IL-8 secretion.","method":"CD13 transfection into K562 cells, apoptosis assays, aminopeptidase inhibitor bestatin treatment, co-culture with endothelial cells, IL-8 ELISA","journal":"Journal of the National Cancer Institute","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function transfection plus pharmacological inhibition with multiple apoptosis readouts; single lab","pmids":["12096087"],"is_preprint":false},{"year":2021,"finding":"CD13 localizes to the apical membrane and associates with Par6 as part of an apical polarity complex; CD13 is required to couple apical protein cargo to Rab11-endosomes and for capture of endosomes at the apical initiation site during epithelial lumen formation; this polarity function utilizes the short intracellular domain of CD13 but is independent of peptidase activity.","method":"CD13 KO cell lines, live imaging, co-immunoprecipitation with Par6, Rab11-endosome colocalization assay, domain deletion/mutation constructs, 3D lumen formation assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO loss-of-function, Co-IP, endosomal tracking, domain mutagenesis, and 3D functional assay all in one study","pmids":["34349123"],"is_preprint":false},{"year":1993,"finding":"CD13/aminopeptidase N activity is present in soluble form in cell-free plasma and represents the predominant quantitative aminopeptidase N activity in flowing blood; immunoaffinity-isolated plasma CD13 has similar electrophoretic characteristics to cell-derived material; lymphocyte-associated aminopeptidase N-like activity is not inhibitable by anti-CD13 antibodies, suggesting a distinct non-CD13 enzyme.","method":"Aminopeptidase N functional assay with chromogenic substrates, anti-CD13 mAb inhibition, immunoaffinity purification from plasma, SDS-PAGE, cell fractionation","journal":"Experimental hematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods establishing plasma form, single lab","pmids":["7902291"],"is_preprint":false},{"year":2010,"finding":"In a CD13 null mouse, lack of CD13 completely ablates anti-CD13-dependent monocyte adhesion to wild-type endothelial cells, but CD13 is dispensable for normal hematopoietic development, proliferation, phagocytosis, and antigen presentation; a slight decrease in actin-independent erythrocyte uptake was observed in CD13 KO cells.","method":"CD13 null mouse generation, hematopoietic profiling, monocyte adhesion assay, in vitro phagocytosis and antigen presentation assays, inflammatory disease models","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with comprehensive phenotypic characterization across multiple cell assays and in vivo models; single lab but thorough","pmids":["20430777"],"is_preprint":false},{"year":2023,"finding":"CD13 facilitates acute post-stroke monocyte and neutrophil transmigration into the brain; CD13 KO mice show reduced acute infarct volume; however, loss of CD13 impairs chronic post-stroke angiogenesis and recovery, associated with reduced CXCL12/CXCR4 signaling and reduced CD13+/lectin+ blood vessels at day 15 post-stroke.","method":"CD13 KO mice, MCAO stroke model, flow cytometry of infiltrating myeloid cells, CXCL12/CXCR4 quantification, angiogenesis assessment, behavioral testing","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple in vivo functional readouts; signaling pathway partially inferred","pmids":["37817190"],"is_preprint":false}],"current_model":"ANPEP/CD13 is a type II transmembrane zinc-dependent metallopeptidase (aminopeptidase N) anchored at the cell surface via an N-terminal signal-anchor helix, with a large extracellular catalytic domain that cleaves neutral amino acids from peptide N-termini; beyond its enzymatic role in degrading regulatory peptides (enkephalins, cytokines) and processing ECM components, CD13 functions as a coronavirus receptor (for HCoV-229E and porcine coronaviruses), an angiogenic regulator essential for endothelial tube formation and B2R-Cdc42-filopodia signaling, an inflammatory adhesion molecule that undergoes Src-dependent cytoplasmic tyrosine phosphorylation to activate FAK/ERK and link to IQGAP1/α-actinin for monocyte trafficking, a negative regulator of TLR4 endocytic signaling and receptor-mediated antigen uptake in dendritic cells, a primary phagocytic receptor, an apical polarity determinant that couples cargo to Rab11-endosomes via its intracellular domain, and a signaling scaffold that engages HDAC5-LSD1-NF-κB and P38/Hsp27/CREB-ATG7 pathways to drive cancer progression and chemoresistance."},"narrative":{"mechanistic_narrative":"ANPEP/CD13 is a cell-surface, zinc-dependent aminopeptidase N that doubles as a multifunctional signaling and adhesion receptor governing vascular morphogenesis, myeloid trafficking, endocytic regulation, and epithelial polarity [PMID:2564851, PMID:11157481, PMID:23997214]. It is a type II integral membrane protein anchored by a single N-terminal hydrophobic signal-anchor segment, with a large extracellular C-terminal domain carrying the zinc-binding metalloprotease consensus that sequentially hydrolyzes neutral N-terminal residues from peptides such as Leu- and Met-enkephalin, while substance P and bradykinin act as natural inhibitors [PMID:2564851, PMID:7535053]. Its enzymatic activity drives a defined subset of functions—chemoattraction of CD4+ T cells, degradation of type-IV collagen to enable tumor invasion, and bradykinin B2 receptor internalization with downstream Cdc42 activation and filopodia formation during endothelial invasion and angiogenic tube formation [PMID:10806168, PMID:8097496, PMID:17363739, PMID:11157481]. Many of its roles, however, are peptidase-independent: a conserved cytoplasmic tyrosine is Src-phosphorylated upon CD13 cross-linking to activate FAK/ERK and recruit IQGAP1 and α-actinin, linking CD13 to the cytoskeleton to drive monocyte adhesion, homotypic aggregation, and inflammatory trafficking through its C-terminal domain, as well as FAK-dependent adhesion of mesenchymal and muscle satellite stem cells [PMID:23997214, PMID:18495788, PMID:16415167, PMID:24627994, PMID:24409152, PMID:24307555]. CD13 also serves as a primary phagocytic receptor sufficient to confer particle uptake on non-phagocytic cells via actin, PI3K, and Syk, and as a negative regulator of TLR4 endocytic (IRF-3) signaling and receptor-mediated antigen uptake in dendritic cells through co-internalization into Rab5 endosomes [PMID:25934926, PMID:25801433, PMID:22544935]. Its short intracellular domain partners with Par6 to couple apical cargo to Rab11-endosomes during epithelial lumen formation [PMID:34349123]. CD13 is the cellular receptor for human coronavirus 229E and porcine coronaviruses (PEDV, PDCoV), with receptor activity governed by an N-glycosylation determinant and largely independent of peptidase activity [PMID:9658094, PMID:11559807, PMID:20074871, PMID:32056711]. In cancer, CD13 stabilizes HDAC5 to drive an LSD1–NF-κB axis and activates P38/Hsp27/CREB–ATG7-dependent autophagy, promoting proliferation, invasion, and chemoresistance [PMID:33377659, PMID:32571958].","teleology":[{"year":1989,"claim":"Establishing that the myeloid antigen CD13/gp150 is identical to aminopeptidase N defined the protein as a single-pass type II membrane metallopeptidase, unifying an immunological marker with an enzymatic activity.","evidence":"cDNA cloning, retroviral expression in fibroblasts, and N-terminal protein sequencing identifying the signal-anchor and zinc-binding consensus","pmids":["2564851","2428842"],"confidence":"High","gaps":["Catalytic mechanism and substrate spectrum not yet defined","Physiological functions beyond peptidase activity unaddressed"]},{"year":1995,"claim":"Defining the natural substrates and inhibitors demonstrated that CD13 sequentially degrades enkephalins and is blocked by proline-bearing peptides, grounding its role in regulatory-peptide turnover.","evidence":"In vitro enzymatic assays with purified pig APN and live HL60 cells, with Km/Ki determination for natural peptides","pmids":["7535053"],"confidence":"High","gaps":["Physiological consequence of enkephalin/peptide cleavage in vivo not established","Full endogenous substrate repertoire incomplete"]},{"year":1998,"claim":"Transcriptional control of CD13 was mapped to DMP1, c-Myb/Ets-1 cooperation and growth/hypoxia signals, explaining its inducible expression in angiogenesis and myeloid contexts.","evidence":"Promoter reporter assays, EMSA, dominant-negative/deletion constructs; hypoxia and growth-factor promoter responsiveness in angiogenesis models","pmids":["9786929","11157481"],"confidence":"High","gaps":["Relative contribution of each transcription factor in vivo unclear","Link between promoter regulation and specific physiological outputs not fully resolved"]},{"year":1998,"claim":"Identification of human APN as the HCoV-229E receptor, refined by an N-glycosylation determinant, revealed a peptidase-independent role of CD13 as a coronavirus entry factor and explained species specificity.","evidence":"Antibody-blocking virus attachment/infection assays and site-directed mutagenesis of the 288–295 glycosylation site","pmids":["9658094","11559807"],"confidence":"High","gaps":["Structural basis of virus–APN binding not resolved","Whether enzymatic activity contributes at all to entry not addressed here"]},{"year":2001,"claim":"CD13 was shown to be functionally essential for capillary tube formation and to act through B2R internalization and Cdc42 activation, establishing an angiogenic signaling role requiring its catalytic activity.","evidence":"In vitro/in vivo angiogenesis assays with CD13 antagonists; B2R internalization, Cdc42 activation, and wild-type vs. catalytically inactive CD13 rescue","pmids":["11157481","17363739"],"confidence":"High","gaps":["Direct enzymatic substrate driving B2R internalization not identified","Mechanism linking peptidase activity to membrane organization unresolved"]},{"year":2010,"claim":"A CD13-null mouse separated essential from dispensable functions, showing CD13 is required for antibody-dependent monocyte adhesion but not for hematopoietic development, phagocytosis, or antigen presentation in vivo.","evidence":"Genetic knockout with hematopoietic profiling, adhesion, phagocytosis, antigen presentation, and inflammatory disease models","pmids":["20430777"],"confidence":"High","gaps":["Redundancy with other aminopeptidases may mask phenotypes","Discrepancy with later phagocytic-receptor findings not reconciled"]},{"year":2014,"claim":"CD13 was established as a peptidase-independent adhesion/signaling receptor: its cytoplasmic tyrosine and C-terminal domain drive Src/FAK/ERK signaling, IQGAP1/α-actinin cytoskeletal coupling, and myeloid and stem-cell adhesion and trafficking in vivo.","evidence":"Y→F mutagenesis, reciprocal Co-IP, kinase inhibition, chimeric domain mapping, KO MSC/satellite cells, and adoptive-transfer/ischemia models","pmids":["23997214","24627994","24409152","24307555"],"confidence":"High","gaps":["Upstream trigger for physiological CD13 clustering in vivo unclear","Identity of the homotypic or heterotypic adhesion ligand incomplete"]},{"year":2015,"claim":"CD13 was defined as a negative regulator of endocytic innate signaling and as a sufficient primary phagocytic receptor, revealing dual roles in controlling uptake and downstream IRF-3/p38/Akt signaling.","evidence":"CD13 KO dendritic cells/mice, co-internalization imaging into Rab5 endosomes, reconstitution in HEK293, and PI3K/Syk inhibitor controls","pmids":["25801433","22544935","25934926"],"confidence":"High","gaps":["Molecular mechanism by which CD13 restrains TLR4/antigen-receptor endocytosis not defined","How phagocytic-receptor function reconciles with earlier KO phagocytosis data unresolved"]},{"year":2020,"claim":"In hepatocellular carcinoma CD13 was placed at the head of signaling cascades—HDAC5–LSD1–NF-κB stabilization and P38/Hsp27/CREB–ATG7 autophagy—driving proliferation, invasion, and chemoresistance.","evidence":"Co-IP/LC-MS/MS, promoter-binding and autophagy assays, and xenograft/PDX models with CD13 inhibition","pmids":["33377659","32571958"],"confidence":"Medium","gaps":["Whether CD13 acts as scaffold or signal initiator mechanistically unclear","Single-lab findings without independent replication"]},{"year":2021,"claim":"CD13 was identified as an apical polarity determinant that couples cargo to Rab11-endosomes via its short intracellular domain and Par6 association, a peptidase-independent role in epithelial lumen formation.","evidence":"CD13 KO cells, live imaging, Par6 Co-IP, Rab11-endosome colocalization, domain mutagenesis, and 3D lumen assays","pmids":["34349123"],"confidence":"High","gaps":["Direct intracellular-domain interaction partner mediating Rab11 coupling not defined","Relationship between apical polarity role and tube/lumen angiogenesis role unintegrated"]},{"year":2023,"claim":"In stroke, CD13 was shown to bidirectionally regulate injury, promoting acute myeloid transmigration while supporting chronic recovery angiogenesis through CXCL12/CXCR4.","evidence":"CD13 KO mice in MCAO model with flow cytometry, vascular quantification, and behavioral testing","pmids":["37817190"],"confidence":"Medium","gaps":["CXCL12/CXCR4 link partially inferred rather than mechanistically proven","Cell-type contribution (endothelial vs. myeloid CD13) not dissected"]},{"year":null,"claim":"It remains unresolved how CD13's distinct functional modes—enzymatic peptide processing, virus receptor activity, cytoplasmic signaling, endocytic regulation, and apical polarity—are coordinated within a single molecule and which are dominant in specific physiological tissues.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model integrating catalytic, receptor, and scaffolding functions","No unified accounting of when peptidase activity is required versus dispensable","Cell-type-specific division of CD13 functions in vivo not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,15,16]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[6,5,17,18]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[7,23,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,28]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[8,24]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[9,28]},{"term_id":"GO:0005576","term_label":"extracellular 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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":"2564851","id":"PMC_2564851","title":"Human 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Cells.","date":"2016","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/27077376","citation_count":28,"is_preprint":false},{"pmid":"3549459","id":"PMC_3549459","title":"The nucleotide sequence of the pepN gene and its over-expression in Escherichia coli.","date":"1986","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/3549459","citation_count":28,"is_preprint":false},{"pmid":"12791172","id":"PMC_12791172","title":"Putative hAPN receptor binding sites in SARS_CoV spike protein.","date":"2003","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/12791172","citation_count":27,"is_preprint":false},{"pmid":"26771355","id":"PMC_26771355","title":"CD13 and ROR2 Permit Isolation of Highly Enriched Cardiac Mesoderm from Differentiating Human Embryonic Stem Cells.","date":"2016","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26771355","citation_count":27,"is_preprint":false},{"pmid":"7851738","id":"PMC_7851738","title":"Characterization and expression of the pepN gene encoding a general aminopeptidase from Lactobacillus helveticus.","date":"1994","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/7851738","citation_count":26,"is_preprint":false},{"pmid":"24063007","id":"PMC_24063007","title":"Aminopeptidase N (CD13) is involved in phagocytic processes in human dendritic cells and macrophages.","date":"2013","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/24063007","citation_count":26,"is_preprint":false},{"pmid":"29069816","id":"PMC_29069816","title":"Ubenimex suppresses Pim-3 kinase expression by targeting CD13 to reverse MDR in HCC cells.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29069816","citation_count":26,"is_preprint":false},{"pmid":"32571958","id":"PMC_32571958","title":"CD13 Induces Autophagy to Promote Hepatocellular Carcinoma Cell Chemoresistance Through the P38/Hsp27/CREB/ATG7 Pathway.","date":"2020","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/32571958","citation_count":25,"is_preprint":false},{"pmid":"14757368","id":"PMC_14757368","title":"Expression of CD13/aminopeptidase N and CD10/neutral endopeptidase on cultured human keratinocytes.","date":"2004","source":"Immunology letters","url":"https://pubmed.ncbi.nlm.nih.gov/14757368","citation_count":25,"is_preprint":false},{"pmid":"25340499","id":"PMC_25340499","title":"Possible contribution of aminopeptidase N (APN/CD13) to migration and invasion of human osteosarcoma cell lines.","date":"2014","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/25340499","citation_count":25,"is_preprint":false},{"pmid":"24307555","id":"PMC_24307555","title":"CD13 regulates anchorage and differentiation of the skeletal muscle satellite stem cell population in ischemic injury.","date":"2014","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/24307555","citation_count":25,"is_preprint":false},{"pmid":"28604784","id":"PMC_28604784","title":"Potential therapeutic impact of CD13 expression in non-small cell lung cancer.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28604784","citation_count":24,"is_preprint":false},{"pmid":"7836577","id":"PMC_7836577","title":"Purification and characterization of a general aminopeptidase (St-PepN) from Streptococcus salivarius ssp. thermophilus CNRZ 302.","date":"1994","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/7836577","citation_count":24,"is_preprint":false},{"pmid":"37817190","id":"PMC_37817190","title":"CD13 facilitates immune cell migration and aggravates acute injury but promotes chronic post-stroke recovery.","date":"2023","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/37817190","citation_count":23,"is_preprint":false},{"pmid":"9792845","id":"PMC_9792845","title":"Human cytomegalovirus infection downregulates expression of the cellular aminopeptidases CD10 and CD13.","date":"1998","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/9792845","citation_count":23,"is_preprint":false},{"pmid":"7688777","id":"PMC_7688777","title":"Expression of monocyte/macrophage markers (CD13, CD14, CD68) on human keratinocytes in healthy and diseased skin.","date":"1993","source":"The Journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/7688777","citation_count":23,"is_preprint":false},{"pmid":"24652439","id":"PMC_24652439","title":"Near-infrared fluorescence imaging of CD13 receptor expression using a novel Cy5.5-labeled dimeric NGR peptide.","date":"2014","source":"Amino acids","url":"https://pubmed.ncbi.nlm.nih.gov/24652439","citation_count":23,"is_preprint":false},{"pmid":"17419227","id":"PMC_17419227","title":"Clinicopathological significance of aminopeptidase N/CD13 expression in human gastric carcinoma.","date":"2007","source":"Hepato-gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/17419227","citation_count":22,"is_preprint":false},{"pmid":"7904801","id":"PMC_7904801","title":"Abundant (A)n.(T)n mononucleotide repeats in the pig genome: linkage mapping of the porcine APOB, FSA, ALOX12, PEPN and RLN loci.","date":"1993","source":"Animal genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7904801","citation_count":21,"is_preprint":false},{"pmid":"32264921","id":"PMC_32264921","title":"CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110.","date":"2020","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32264921","citation_count":21,"is_preprint":false},{"pmid":"14632756","id":"PMC_14632756","title":"Changes in monocytic expression of aminopeptidase N/CD13 after major trauma.","date":"2003","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/14632756","citation_count":21,"is_preprint":false},{"pmid":"9372917","id":"PMC_9372917","title":"Transmembrane glycoprotein gp150 is a substrate for receptor tyrosine phosphatase DPTP10D in Drosophila cells.","date":"1997","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9372917","citation_count":20,"is_preprint":false},{"pmid":"13680152","id":"PMC_13680152","title":"CD13/aminopeptidase N in collagen vascular diseases.","date":"2003","source":"Rheumatology international","url":"https://pubmed.ncbi.nlm.nih.gov/13680152","citation_count":20,"is_preprint":false},{"pmid":"34349123","id":"PMC_34349123","title":"CD13 orients the apical-basal polarity axis necessary for lumen formation.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34349123","citation_count":19,"is_preprint":false},{"pmid":"26774363","id":"PMC_26774363","title":"Aminopeptidase N (APN/CD13) as a target molecule for scirrhous gastric cancer.","date":"2016","source":"Clinics and research in hepatology and gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/26774363","citation_count":19,"is_preprint":false},{"pmid":"11138613","id":"PMC_11138613","title":"CD30+ anaplastic large-cell lymphoma with aberrant expression of CD13: case report and review of the literature.","date":"2000","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/11138613","citation_count":19,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50628,"output_tokens":8487,"usd":0.139595,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18407,"output_tokens":4623,"usd":0.103805,"stage2_stop_reason":"end_turn"},"total_usd":0.2434,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1989,\n      \"finding\": \"CD13 (gp150) is identical to aminopeptidase N: it is an integral membrane protein with a single 24 amino acid N-terminal hydrophobic segment that serves as both signal for membrane insertion and stable membrane-spanning anchor, with the remainder forming a large extracellular C-terminal domain containing the zinc-binding metalloprotease pentapeptide consensus sequence.\",\n      \"method\": \"cDNA cloning, retroviral expression in mouse fibroblasts, amino-terminal protein sequence analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — full-length cDNA sequencing plus functional reconstitution in transfected cells plus direct N-terminal protein sequencing, replicated across multiple clones\",\n      \"pmids\": [\"2564851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"The human myeloid membrane antigen gp150 gene was molecularly cloned, shown to encode a 4.0-kb polyadenylated transcript, mapped to chromosome 15q25-26, and shown to be biologically active when transfected into NIH 3T3 cells; gp130 was identified as a carbohydrate-differing precursor to the mature cell-surface gp150.\",\n      \"method\": \"Bacteriophage lambda library cloning, DNA transfection, in situ hybridization, pulse-chase metabolic labeling, biochemical analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (cloning, transfection, chromosomal mapping, pulse-chase) in a focused mechanistic study\",\n      \"pmids\": [\"2428842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CD13/APN is functionally essential for capillary tube (lumen) formation during angiogenesis; functional antagonists of CD13/APN block tube formation but not proliferation of primary vascular endothelial cells, and CD13/APN expression is transcriptionally upregulated by hypoxia and angiogenic growth factors via elements in the proximal promoter.\",\n      \"method\": \"In vitro tube formation assay with CD13 antagonists, reporter assays with CD13 proximal promoter, in vivo models (retinal neovascularization, chorioallantoic membrane angiogenesis, xenograft tumor growth)\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vitro and in vivo approaches, functional loss-of-function with specific phenotypic readout\",\n      \"pmids\": [\"11157481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD13 controls endothelial cell invasion and filopodia formation by facilitating bradykinin B2 receptor (B2R) internalization and downstream Cdc42 activation at the plasma membrane; CD13 inhibition blocks B2R internalization, abrogating invasion and filopodia; wild-type but not catalytically inactive mutant CD13 restores membrane protein organization, indicating peptidase activity is required for CD13's regulatory function.\",\n      \"method\": \"B2R internalization assay, Cdc42 activation assay, filopodia imaging, cholesterol depletion/repletion experiments, expression of wild-type vs. enzymatic mutant CD13\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including receptor internalization, GTPase activation, mutagenesis, and cholesterol manipulation in a single focused study\",\n      \"pmids\": [\"17363739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The CD13/APN promoter is transcriptionally activated by the DMP1 transcription factor binding to a specific consensus site; DMP1 activation of CD13 requires intact DNA-binding and transactivation domains of DMP1 and is antagonized by D-type cyclins in a CDK-independent manner; CD13 expression is additionally co-regulated by cooperative interaction between c-Myb and Ets-1.\",\n      \"method\": \"Promoter reporter assays, electrophoretic mobility shift assay (EMSA), dominant-negative and deletion mutant analyses of DMP1 and cyclin constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro promoter reconstitution with mutagenesis and EMSA, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"9786929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"An N-glycosylation site at amino acids 288–295 of human APN is a critical molecular determinant of species-specific coronavirus receptor activity: introduction of an N-glycosylation sequon at position 291–293 abolished HCoV-229E receptor activity of hAPN, while single-amino-acid revertants removing this sequon fully restored binding and receptor activity.\",\n      \"method\": \"Site-directed mutagenesis of hAPN, virus binding and infection assays in transfected cells\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis with functional binding and infection readouts, multiple revertant constructs tested\",\n      \"pmids\": [\"11559807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human APN (CD13) serves as the functional cellular receptor for human coronavirus 229E (HCoV-229E) in neural cells: hAPN is expressed on neuronal and glial cell line surfaces, anti-hAPN monoclonal antibody WM15 inhibits radiolabeled HCoV-229E attachment and infection, and attachment level correlates with hAPN surface amount.\",\n      \"method\": \"Flow cytometry for receptor expression, radiolabeled virus attachment assay, antibody blocking, indirect immunofluorescence infection assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (binding, neutralization, infection) establishing receptor identity in a single focused study\",\n      \"pmids\": [\"9658094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD13 cross-linking induces phosphorylation of Src, FAK, and ERK, and CD13 itself is phosphorylated on its cytoplasmic tyrosine in a Src-dependent manner; CD13 is constitutively associated with the scaffolding protein IQGAP1, and cross-linking induces complex formation with α-actinin, linking CD13 to the cytoskeleton; mutation of the conserved cytoplasmic tyrosine to phenylalanine abolishes adhesion, downstream signaling, and cytoskeletal changes; phospho-CD13 is present in vivo in peritoneal exudate cells, and monocytes expressing the mutant CD13 show severely impaired migration into the inflamed peritoneum.\",\n      \"method\": \"Phosphoprotein analysis, Src/FAK/ERK inhibition assays, site-directed mutagenesis (Y→F), co-immunoprecipitation with IQGAP1 and α-actinin, adoptive transfer in murine peritonitis model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, mutagenesis, in vitro signaling, and in vivo adoptive transfer all in one study\",\n      \"pmids\": [\"23997214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD13 ligation and clustering by mAb or viral ligands induces myeloid/endothelial cell adhesion via signal transduction-dependent monocytic cytoskeletal rearrangement and filopodia formation; soluble recombinant CD13 blocks this adhesion; CD13 molecules from monocytic and endothelial cells co-immunoprecipitate, indicating direct homotypic CD13–CD13 interaction; anti-CD13 antibodies reduce leukocyte infiltration in murine peritonitis.\",\n      \"method\": \"Antibody-mediated cross-linking adhesion assays, recombinant CD13 blocking, co-immunoprecipitation, adhesion to immobilized recombinant CD13, murine peritonitis model\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus functional blocking plus in vivo model, multiple orthogonal methods\",\n      \"pmids\": [\"18495788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD13 negatively regulates TLR4 endocytic signaling: CD13 is co-internalized with TLR4, CD14, and dynamin into Rab5+ early endosomes upon LPS stimulation; CD13 KO dendritic cells show enhanced p-IRF-3 activation and transcription of IRF-3 target genes in response to TLR4 ligands while TLR4 surface signaling is unaffected; CD13 KO mice show enhanced IFNβ-mediated JAK-STAT signaling, elevated iNOS, and increased oxidative stress and tissue injury upon ischemia; CD13 and TLR4 co-immunoprecipitate in activated macrophages.\",\n      \"method\": \"CD13 KO mice, co-immunoprecipitation, IRF-3 phosphorylation assays, endosomal co-localization imaging, in vivo ischemia model, flow cytometry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CD13 KO with multiple orthogonal mechanistic readouts, co-IP, and in vivo validation in a single study\",\n      \"pmids\": [\"25801433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD13 negatively regulates receptor-mediated, dynamin-dependent endocytosis of antigens (OVA, transferrin) in dendritic cells but not fluid-phase or phagocytic uptake; CD13 is co-internalized with antigen but does not co-immunoprecipitate with antigen receptors; CD13 KO DCs show dysregulated phosphorylation of p38MAPK and Akt; lack of CD13 significantly enhances T cell responses to soluble OVA antigen in vivo.\",\n      \"method\": \"CD13 KO mice, in vitro antigen uptake assays, co-immunoprecipitation (negative), kinase inhibition, in vivo T cell response assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO model with in vitro mechanistic follow-up and in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"22544935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CD13 antibody-mediated ligation induces apoptosis in AML cells independently of its APN enzymatic activity: anti-CD13 mAbs (MY7, SJ1D1, WM15) cause sub-G1 accumulation, DNA fragmentation, phosphatidylserine externalization, mitochondrial depolarization, Bcl-2/Mcl-1 downregulation, Bax upregulation, and activation of caspase-9, caspase-8, and caspase-3; enzymatic inhibitors of APN alone are ineffective; internalization of CD13–mAb complex precedes mitochondrial events.\",\n      \"method\": \"Flow cytometry (cell cycle, apoptosis markers), Western blotting (Bcl-2, Bax, caspases), caspase inhibitor experiments, comparison of enzyme-blocking vs. non-blocking antibodies\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal apoptosis assays in a single study with careful antibody controls; single lab\",\n      \"pmids\": [\"21566207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD13 associates with tumor-associated antigen L6 (TAL6) in a co-immunoprecipitable complex on lung cancer cells; CD13 enhances cancer cell migration and invasion; expression of enzymatically inactive CD13 mutant also significantly enhances cell migration, indicating that CD13's effect on motility does not strictly depend on its peptidase activity.\",\n      \"method\": \"Co-immunoprecipitation, antibody-mediated co-patching immunofluorescence, Transwell migration/invasion assays, enzymatic inhibitors, catalytically inactive CD13 mutant expression\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, mutagenesis, and functional assays with multiple inhibitor controls in a single study\",\n      \"pmids\": [\"15812828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CD13 mediates homotypic aggregation (HA) of monocytic cells via antibody cross-linking in a tyrosine kinase- and MAP kinase-dependent manner, independently of integrin signaling and independently of CD13 enzymatic activity; during HA, CD13 actively redistributes to cell–cell contact zones as observed by live cell imaging.\",\n      \"method\": \"Homotypic aggregation assays, enzyme inhibitor controls vs. kinase inhibitors, live cell imaging, colchicine/cytoskeletal perturbation\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, multiple in vitro assays but no in vivo confirmation or orthogonal biochemical validation\",\n      \"pmids\": [\"16415167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD13/APN functionally interacts with FcγRI on monocytes: during FcγR-mediated phagocytosis, CD13 redistributes to the phagocytic cup and is co-internalized into phagosomes; co-cross-linking of CD13 with FcγRI increases the level and duration of Syk phosphorylation; FcγRI and CD13 co-localize in zones of cellular polarization.\",\n      \"method\": \"Confocal microscopy of phagocytosis, Syk phosphorylation assays, co-cross-linking with specific mAbs, co-localization imaging\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-localization and functional co-cross-linking across multiple readouts, but no co-immunoprecipitation of the FcγRI–CD13 complex\",\n      \"pmids\": [\"15758076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Purified and native membrane-bound CD13/APN sequentially and completely hydrolyzes Leu-enkephalin and Met-enkephalin from the amino terminus; substance P and bradykinin are natural inhibitors of CD13/APN (Ki = 0.44 µM and 9.4 µM, respectively) due to their N-terminal proline at the second residue, which prevents hydrolysis.\",\n      \"method\": \"In vitro enzymatic assay with purified pig APN and live HL60 cells, Km and Ki measurements with natural peptide substrates and inhibitors\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro enzymatic assay with purified protein and live cells, Ki values determined with two independent enzyme sources\",\n      \"pmids\": [\"7535053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Cell-surface aminopeptidase N/CD13 is involved in tumor cell invasion through degradation of type-IV collagen: anti-CD13 mAb WM15 inhibits both aminopeptidase activity and type-IV collagen degradation by tumor cells, and reduces invasion through Matrigel in a concentration-dependent manner without affecting adhesion or migration.\",\n      \"method\": \"Matrigel invasion assay, type-IV collagen degradation assay, aminopeptidase activity assay with specific mAb inhibition\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays with specific mAb inhibition; mechanism inferred from coincident inhibition of enzymatic activity and invasion\",\n      \"pmids\": [\"8097496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Porcine APN receptor density directly determines PEDV infection efficiency: overexpression of recombinant pAPN in ST cells rescues productive PEDV infection; the enzymatic active motif-null mutant pAPN retains receptor activity and supports viral production; APN inhibitor blocking the protease active site has no effect on viral infection, showing enzymatic activity is dispensable for PEDV receptor function.\",\n      \"method\": \"Stable cell line overexpression, enzymatic active-site mutant APN expression, aminopeptidase inhibitor treatment, viral infection/replication assays\",\n      \"journal\": \"Veterinary microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of active site plus enzymatic inhibitor controls, multiple orthogonal approaches in a single study\",\n      \"pmids\": [\"20074871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"APN (ANPEP) is a receptor for porcine deltacoronavirus (PDCoV) in porcine alveolar macrophages (PAMs): ANPEP knockout pigs generated by CRISPR/Cas9 show PAM resistance to PDCoV infection, but lung-derived fibroblast-like cells from the same KO pigs remain fully permissive, indicating APN is necessary in macrophages but dispensable in fibroblast cells for PDCoV infection.\",\n      \"method\": \"CRISPR/Cas9 ANPEP knockout pigs, viral infection of primary cell types, ex vivo and in vivo PDCoV challenge\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO at organism level with cell-type-specific functional readouts; rigorous in vivo and ex vivo validation\",\n      \"pmids\": [\"32056711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD13 interacts with HDAC5 to promote its protein stability; stabilized HDAC5 deacetylates LSD1 to stabilize it; LSD1 then decreases NF-κB p65 methylation, leading to p65 protein stability and NF-κB pathway activation; this CD13–HDAC5–LSD1–NF-κB axis promotes HCC proliferation, invasion, and sorafenib resistance.\",\n      \"method\": \"Co-immunoprecipitation, LC-MS/MS, Western blotting, xenograft models, patient-derived xenograft models\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and MS identification of interactions, functional in vivo validation, single lab\",\n      \"pmids\": [\"33377659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD13 overexpression activates the P38/Hsp27/CREB signaling pathway; CREB binds the ATG7 promoter to induce autophagy; this CD13-driven autophagy promotes HCC chemoresistance; CD13 inhibition downregulates ATG7, autophagy, and tumor growth in vivo.\",\n      \"method\": \"Western blotting, CREB-ATG7 promoter binding assay, autophagy assays, in vivo xenograft models with CD13 inhibitor\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter binding assay plus in vivo validation, multiple pathway nodes tested; single lab\",\n      \"pmids\": [\"32571958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD13 regulates mesenchymal stem cell (MSC) adhesion and migration via FAK activation: CD13 KO MSCs show impaired adhesion and migration on extracellular matrices, decreased phospho-FAK levels, and cytoskeletal alterations; CD13 antibody cross-linking of human MSCs increases adhesion to endothelial monolayers and induces FAK activation; CD13 KO MSCs show significantly poorer tissue repair in ischemic limb injury with reduced vascularization.\",\n      \"method\": \"CD13 KO mice, cell adhesion/migration assays, FAK phosphorylation assay, antibody cross-linking, in vivo ischemic limb model with cell injection\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO cells plus antibody cross-linking plus in vivo rescue model, multiple orthogonal mechanistic and functional methods\",\n      \"pmids\": [\"24409152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD13 is required for muscle satellite stem cell anchorage and differentiation timing: CD13 KO muscle shows markedly reduced satellite cell numbers, impaired satellite cell adhesion, and accelerated differentiation; CD13 co-localizes with Pax7 on satellite cells; phospho-FAK and ERK levels are reduced in injured CD13 KO muscle.\",\n      \"method\": \"CD13 KO mice, satellite cell isolation and characterization, adhesion assays, differentiation assays, immunofluorescence co-localization, Western blotting for FAK/ERK\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO phenotype with mechanistic correlate (FAK/ERK), co-localization; single lab\",\n      \"pmids\": [\"24307555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD13 is a primary phagocytic receptor in human macrophages and monocytic cells: hCD13 expression alone in non-phagocytic HEK293 cells is sufficient to enable internalization of large particles bound through CD13; CD13-mediated phagocytosis is independent of FcγRs, CR3, and most phagocytic receptors, independent of CD13 enzymatic activity, but requires actin rearrangement, PI3K activation, and partial Syk activation; CD13 cross-linking induces pSyk and ROS production.\",\n      \"method\": \"Phagocytosis assays with receptor-specific opsonization, CD13 expression in non-phagocytic HEK293 cells, pharmacological inhibitors of PI3K and Syk, actin disruption, ROS measurement\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reconstitution in non-phagocytic cells plus multiple inhibitor controls plus signaling readouts, multiple orthogonal methods\",\n      \"pmids\": [\"25934926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD13-dependent monocyte/endothelial adhesion is mediated by the C-terminal domain of CD13; lack of either monocytic or endothelial CD13 reduces myeloid cell trafficking into sites of inflammation in vivo; CD13 expression is enriched on pro-inflammatory monocyte subsets.\",\n      \"method\": \"Adoptive transfer of WT and CD13 KO myeloid cells into thioglycollate-challenged mice, chimeric CD13 (mouse/human) constructs identifying C-terminal domain requirement, flow cytometry of monocyte subsets\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo adoptive transfer with domain-mapping chimeric constructs; single lab\",\n      \"pmids\": [\"24627994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CD13/APN enzymatic activity is responsible for its chemoattractant function for CD4+ T lymphocytes: soluble CD13/APN induces chemotactic migration of lymphocytes (more so for CD4+ than CD8+ T cells), and the aminopeptidase inhibitor bestatin abolishes this chemotactic activity.\",\n      \"method\": \"In vitro chemotaxis assay, bestatin inhibition of APN activity, BALF chemotaxis assay from sarcoidosis patients\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic inhibitor functional assay showing activity-dependence; ex vivo and in vitro correlation\",\n      \"pmids\": [\"10806168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Cell-surface CD13/APN regulates TNFα-induced neutrophil apoptosis by controlling shedding of TNFRI: APN inhibition (actinonin, bestatin) augments TNFα-induced killing and prevents TNFRI shedding, resulting in enhanced TNFα signaling; an inverse correlation exists between neutrophil APN activity and sensitivity to TNFα-induced apoptosis.\",\n      \"method\": \"Neutrophil apoptosis assays, TNFRI shedding measurement, APN activity measurement, pharmacological APN inhibitors\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays linking APN activity to TNFRI shedding; single lab\",\n      \"pmids\": [\"16533817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"High cell-surface CD13/aminopeptidase N activity enables leukemic cells to resist endothelial IL-8-induced apoptosis; K562 cells transfected with CD13 acquire resistance to IL-8-induced apoptosis; aminopeptidase inhibitor bestatin restores IL-8-induced apoptosis in CD13-overexpressing cells and increases endothelial IL-8 secretion.\",\n      \"method\": \"CD13 transfection into K562 cells, apoptosis assays, aminopeptidase inhibitor bestatin treatment, co-culture with endothelial cells, IL-8 ELISA\",\n      \"journal\": \"Journal of the National Cancer Institute\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function transfection plus pharmacological inhibition with multiple apoptosis readouts; single lab\",\n      \"pmids\": [\"12096087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD13 localizes to the apical membrane and associates with Par6 as part of an apical polarity complex; CD13 is required to couple apical protein cargo to Rab11-endosomes and for capture of endosomes at the apical initiation site during epithelial lumen formation; this polarity function utilizes the short intracellular domain of CD13 but is independent of peptidase activity.\",\n      \"method\": \"CD13 KO cell lines, live imaging, co-immunoprecipitation with Par6, Rab11-endosome colocalization assay, domain deletion/mutation constructs, 3D lumen formation assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO loss-of-function, Co-IP, endosomal tracking, domain mutagenesis, and 3D functional assay all in one study\",\n      \"pmids\": [\"34349123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"CD13/aminopeptidase N activity is present in soluble form in cell-free plasma and represents the predominant quantitative aminopeptidase N activity in flowing blood; immunoaffinity-isolated plasma CD13 has similar electrophoretic characteristics to cell-derived material; lymphocyte-associated aminopeptidase N-like activity is not inhibitable by anti-CD13 antibodies, suggesting a distinct non-CD13 enzyme.\",\n      \"method\": \"Aminopeptidase N functional assay with chromogenic substrates, anti-CD13 mAb inhibition, immunoaffinity purification from plasma, SDS-PAGE, cell fractionation\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods establishing plasma form, single lab\",\n      \"pmids\": [\"7902291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In a CD13 null mouse, lack of CD13 completely ablates anti-CD13-dependent monocyte adhesion to wild-type endothelial cells, but CD13 is dispensable for normal hematopoietic development, proliferation, phagocytosis, and antigen presentation; a slight decrease in actin-independent erythrocyte uptake was observed in CD13 KO cells.\",\n      \"method\": \"CD13 null mouse generation, hematopoietic profiling, monocyte adhesion assay, in vitro phagocytosis and antigen presentation assays, inflammatory disease models\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with comprehensive phenotypic characterization across multiple cell assays and in vivo models; single lab but thorough\",\n      \"pmids\": [\"20430777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD13 facilitates acute post-stroke monocyte and neutrophil transmigration into the brain; CD13 KO mice show reduced acute infarct volume; however, loss of CD13 impairs chronic post-stroke angiogenesis and recovery, associated with reduced CXCL12/CXCR4 signaling and reduced CD13+/lectin+ blood vessels at day 15 post-stroke.\",\n      \"method\": \"CD13 KO mice, MCAO stroke model, flow cytometry of infiltrating myeloid cells, CXCL12/CXCR4 quantification, angiogenesis assessment, behavioral testing\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple in vivo functional readouts; signaling pathway partially inferred\",\n      \"pmids\": [\"37817190\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANPEP/CD13 is a type II transmembrane zinc-dependent metallopeptidase (aminopeptidase N) anchored at the cell surface via an N-terminal signal-anchor helix, with a large extracellular catalytic domain that cleaves neutral amino acids from peptide N-termini; beyond its enzymatic role in degrading regulatory peptides (enkephalins, cytokines) and processing ECM components, CD13 functions as a coronavirus receptor (for HCoV-229E and porcine coronaviruses), an angiogenic regulator essential for endothelial tube formation and B2R-Cdc42-filopodia signaling, an inflammatory adhesion molecule that undergoes Src-dependent cytoplasmic tyrosine phosphorylation to activate FAK/ERK and link to IQGAP1/α-actinin for monocyte trafficking, a negative regulator of TLR4 endocytic signaling and receptor-mediated antigen uptake in dendritic cells, a primary phagocytic receptor, an apical polarity determinant that couples cargo to Rab11-endosomes via its intracellular domain, and a signaling scaffold that engages HDAC5-LSD1-NF-κB and P38/Hsp27/CREB-ATG7 pathways to drive cancer progression and chemoresistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ANPEP/CD13 is a cell-surface, zinc-dependent aminopeptidase N that doubles as a multifunctional signaling and adhesion receptor governing vascular morphogenesis, myeloid trafficking, endocytic regulation, and epithelial polarity [#0, #2, #7]. It is a type II integral membrane protein anchored by a single N-terminal hydrophobic signal-anchor segment, with a large extracellular C-terminal domain carrying the zinc-binding metalloprotease consensus that sequentially hydrolyzes neutral N-terminal residues from peptides such as Leu- and Met-enkephalin, while substance P and bradykinin act as natural inhibitors [#0, #15]. Its enzymatic activity drives a defined subset of functions—chemoattraction of CD4+ T cells, degradation of type-IV collagen to enable tumor invasion, and bradykinin B2 receptor internalization with downstream Cdc42 activation and filopodia formation during endothelial invasion and angiogenic tube formation [#25, #16, #3, #2]. Many of its roles, however, are peptidase-independent: a conserved cytoplasmic tyrosine is Src-phosphorylated upon CD13 cross-linking to activate FAK/ERK and recruit IQGAP1 and α-actinin, linking CD13 to the cytoskeleton to drive monocyte adhesion, homotypic aggregation, and inflammatory trafficking through its C-terminal domain, as well as FAK-dependent adhesion of mesenchymal and muscle satellite stem cells [#7, #8, #13, #24, #21, #22]. CD13 also serves as a primary phagocytic receptor sufficient to confer particle uptake on non-phagocytic cells via actin, PI3K, and Syk, and as a negative regulator of TLR4 endocytic (IRF-3) signaling and receptor-mediated antigen uptake in dendritic cells through co-internalization into Rab5 endosomes [#23, #9, #10]. Its short intracellular domain partners with Par6 to couple apical cargo to Rab11-endosomes during epithelial lumen formation [#28]. CD13 is the cellular receptor for human coronavirus 229E and porcine coronaviruses (PEDV, PDCoV), with receptor activity governed by an N-glycosylation determinant and largely independent of peptidase activity [#6, #5, #17, #18]. In cancer, CD13 stabilizes HDAC5 to drive an LSD1–NF-κB axis and activates P38/Hsp27/CREB–ATG7-dependent autophagy, promoting proliferation, invasion, and chemoresistance [#19, #20].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Establishing that the myeloid antigen CD13/gp150 is identical to aminopeptidase N defined the protein as a single-pass type II membrane metallopeptidase, unifying an immunological marker with an enzymatic activity.\",\n      \"evidence\": \"cDNA cloning, retroviral expression in fibroblasts, and N-terminal protein sequencing identifying the signal-anchor and zinc-binding consensus\",\n      \"pmids\": [\"2564851\", \"2428842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic mechanism and substrate spectrum not yet defined\", \"Physiological functions beyond peptidase activity unaddressed\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Defining the natural substrates and inhibitors demonstrated that CD13 sequentially degrades enkephalins and is blocked by proline-bearing peptides, grounding its role in regulatory-peptide turnover.\",\n      \"evidence\": \"In vitro enzymatic assays with purified pig APN and live HL60 cells, with Km/Ki determination for natural peptides\",\n      \"pmids\": [\"7535053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological consequence of enkephalin/peptide cleavage in vivo not established\", \"Full endogenous substrate repertoire incomplete\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Transcriptional control of CD13 was mapped to DMP1, c-Myb/Ets-1 cooperation and growth/hypoxia signals, explaining its inducible expression in angiogenesis and myeloid contexts.\",\n      \"evidence\": \"Promoter reporter assays, EMSA, dominant-negative/deletion constructs; hypoxia and growth-factor promoter responsiveness in angiogenesis models\",\n      \"pmids\": [\"9786929\", \"11157481\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each transcription factor in vivo unclear\", \"Link between promoter regulation and specific physiological outputs not fully resolved\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of human APN as the HCoV-229E receptor, refined by an N-glycosylation determinant, revealed a peptidase-independent role of CD13 as a coronavirus entry factor and explained species specificity.\",\n      \"evidence\": \"Antibody-blocking virus attachment/infection assays and site-directed mutagenesis of the 288–295 glycosylation site\",\n      \"pmids\": [\"9658094\", \"11559807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of virus–APN binding not resolved\", \"Whether enzymatic activity contributes at all to entry not addressed here\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"CD13 was shown to be functionally essential for capillary tube formation and to act through B2R internalization and Cdc42 activation, establishing an angiogenic signaling role requiring its catalytic activity.\",\n      \"evidence\": \"In vitro/in vivo angiogenesis assays with CD13 antagonists; B2R internalization, Cdc42 activation, and wild-type vs. catalytically inactive CD13 rescue\",\n      \"pmids\": [\"11157481\", \"17363739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic substrate driving B2R internalization not identified\", \"Mechanism linking peptidase activity to membrane organization unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"A CD13-null mouse separated essential from dispensable functions, showing CD13 is required for antibody-dependent monocyte adhesion but not for hematopoietic development, phagocytosis, or antigen presentation in vivo.\",\n      \"evidence\": \"Genetic knockout with hematopoietic profiling, adhesion, phagocytosis, antigen presentation, and inflammatory disease models\",\n      \"pmids\": [\"20430777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy with other aminopeptidases may mask phenotypes\", \"Discrepancy with later phagocytic-receptor findings not reconciled\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"CD13 was established as a peptidase-independent adhesion/signaling receptor: its cytoplasmic tyrosine and C-terminal domain drive Src/FAK/ERK signaling, IQGAP1/α-actinin cytoskeletal coupling, and myeloid and stem-cell adhesion and trafficking in vivo.\",\n      \"evidence\": \"Y→F mutagenesis, reciprocal Co-IP, kinase inhibition, chimeric domain mapping, KO MSC/satellite cells, and adoptive-transfer/ischemia models\",\n      \"pmids\": [\"23997214\", \"24627994\", \"24409152\", \"24307555\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream trigger for physiological CD13 clustering in vivo unclear\", \"Identity of the homotypic or heterotypic adhesion ligand incomplete\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"CD13 was defined as a negative regulator of endocytic innate signaling and as a sufficient primary phagocytic receptor, revealing dual roles in controlling uptake and downstream IRF-3/p38/Akt signaling.\",\n      \"evidence\": \"CD13 KO dendritic cells/mice, co-internalization imaging into Rab5 endosomes, reconstitution in HEK293, and PI3K/Syk inhibitor controls\",\n      \"pmids\": [\"25801433\", \"22544935\", \"25934926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which CD13 restrains TLR4/antigen-receptor endocytosis not defined\", \"How phagocytic-receptor function reconciles with earlier KO phagocytosis data unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"In hepatocellular carcinoma CD13 was placed at the head of signaling cascades—HDAC5–LSD1–NF-κB stabilization and P38/Hsp27/CREB–ATG7 autophagy—driving proliferation, invasion, and chemoresistance.\",\n      \"evidence\": \"Co-IP/LC-MS/MS, promoter-binding and autophagy assays, and xenograft/PDX models with CD13 inhibition\",\n      \"pmids\": [\"33377659\", \"32571958\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CD13 acts as scaffold or signal initiator mechanistically unclear\", \"Single-lab findings without independent replication\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"CD13 was identified as an apical polarity determinant that couples cargo to Rab11-endosomes via its short intracellular domain and Par6 association, a peptidase-independent role in epithelial lumen formation.\",\n      \"evidence\": \"CD13 KO cells, live imaging, Par6 Co-IP, Rab11-endosome colocalization, domain mutagenesis, and 3D lumen assays\",\n      \"pmids\": [\"34349123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct intracellular-domain interaction partner mediating Rab11 coupling not defined\", \"Relationship between apical polarity role and tube/lumen angiogenesis role unintegrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"In stroke, CD13 was shown to bidirectionally regulate injury, promoting acute myeloid transmigration while supporting chronic recovery angiogenesis through CXCL12/CXCR4.\",\n      \"evidence\": \"CD13 KO mice in MCAO model with flow cytometry, vascular quantification, and behavioral testing\",\n      \"pmids\": [\"37817190\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CXCL12/CXCR4 link partially inferred rather than mechanistically proven\", \"Cell-type contribution (endothelial vs. myeloid CD13) not dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how CD13's distinct functional modes—enzymatic peptide processing, virus receptor activity, cytoplasmic signaling, endocytic regulation, and apical polarity—are coordinated within a single molecule and which are dominant in specific physiological tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model integrating catalytic, receptor, and scaffolding functions\", \"No unified accounting of when peptidase activity is required versus dispensable\", \"Cell-type-specific division of CD13 functions in vivo not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 15, 16]},\n      {\"term_id\": \"GO:0008237\", \"supporting_discovery_ids\": [0, 15]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [6, 5, 17, 18]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [7, 23, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 28]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [8, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [9, 28]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 8, 9, 23]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 17, 18, 19]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [9, 10, 23, 28]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 21, 22, 28]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 7, 19, 20]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IQGAP1\", \"ACTN\", \"TLR4\", \"Par6\", \"HDAC5\", \"FCGR1A\", \"TM4SF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}