{"gene":"NPNT","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2001,"finding":"NPNT (POEM) was identified as a novel extracellular matrix adhesion molecule containing five EGF-like domains, an RGD cell-binding motif, and a MAM domain. Recombinant POEM protein promoted cell adhesion, spreading, and survival. Mutation of the RGD sequence to RGE significantly decreased cell spreading and survival activities, while the MAM domain contributed only to cell adhesion and not spreading/survival. NPNT was identified as a ligand for α8β1 integrin: KA8 cells (K562 stably expressing α8 integrin) showed strong binding and spreading on NPNT, whereas parental K562 cells (expressing α5β1) did not bind NPNT.","method":"Bacterial recombinant protein production, site-directed mutagenesis (RGD→RGE), cell adhesion/spreading assays, stable integrin-expressing cell lines (K562/KA8)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis and defined integrin-expressing cell lines, multiple orthogonal functional assays in a single focused study","pmids":["11546798"],"is_preprint":false},{"year":2007,"finding":"TGF-β strongly inhibited NPNT (POEM) gene expression in mouse osteoblastic MC3T3-E1 cells in a time- and dose-dependent manner. This suppression was mediated through activation of TGF-β receptor I and the ERK1/2 and JNK (c-Jun N-terminal kinase) signaling pathways.","method":"Gene expression analysis in MC3T3-E1 osteoblastic cells with TGF-β treatment, pathway inhibitor experiments targeting TGF-β receptor I, ERK1/2, and JNK","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined pathway (TGF-βRI/ERK/JNK) with pharmacological inhibition and dose-response in a single lab","pmids":["17977532"],"is_preprint":false},{"year":2011,"finding":"TNF-α strongly inhibited NPNT (POEM) expression in MC3T3-E1 osteoblastic cells in a time- and dose-dependent manner through the NF-κB signaling pathway. Over-expression of NPNT rescued TNF-α-induced inhibition of osteoblast differentiation, establishing NPNT as a positive regulator of osteoblast differentiation downstream of TNF-α/NF-κB.","method":"Gene expression analysis in MC3T3-E1 cells with TNF-α treatment, NF-κB pathway inhibition, NPNT overexpression rescue experiment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway placement via inhibition and rescue (overexpression), single lab, two orthogonal approaches","pmids":["21689636"],"is_preprint":false},{"year":2016,"finding":"NPNT is expressed by osteoblasts and functions as a paracrine angiogenic factor. Exogenous recombinant NPNT stimulated endothelial cell migration and tube-like structure formation in vitro, and promoted angiogenesis in an ex vivo fetal mouse metatarsal assay. NPNT activated phosphorylation of ERK1/2 and p38 MAPK in endothelial cells; pharmacological inhibition of ERK1/2 blocked NPNT-induced endothelial migration, tube formation, and angiogenesis, placing ERK1/2 downstream of NPNT in angiogenic signaling.","method":"Recombinant protein treatment of endothelial cells, migration assay, tube formation assay, ex vivo metatarsal angiogenesis assay, kinase phosphorylation assays, ERK1/2 inhibitor rescue experiments","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays (migration, tube formation, ex vivo), pathway inhibition in a single lab","pmids":["27782206"],"is_preprint":false},{"year":2017,"finding":"NPNT is identified as a secreted extracellular matrix protein expressed exclusively around aldosterone-producing glomeruli in normal adrenal zona glomerulosa (ZG) and in ZG-like aldosterone-producing adenomas (APAs). NPNT production is regulated by the canonical Wnt signaling pathway (highest expression in APAs with gain-of-function CTNNB1 mutations). NPNT overexpression increased aldosterone production while NPNT silencing reduced aldosterone, and NPNT exhibited pro-adhesive activity in primary adrenal and APA cells, with binding to cell-surface integrins proposed to stimulate cell-cell contact within glomeruli.","method":"Immunohistochemistry, NPNT overexpression and siRNA silencing in adrenal/APA cells with aldosterone readout, microarray gene expression analysis","journal":"Hypertension (Dallas, Tex. : 1979)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with defined functional output (aldosterone), Wnt pathway linkage, single lab","pmids":["28416583"],"is_preprint":false},{"year":2020,"finding":"A COPD-associated SNP (rs34712979) creates a cryptic splice acceptor site in NPNT, resulting in inclusion of a 3-nucleotide exon extension encoding a serine residue near the N-terminus of the protein. Long-read sequencing identified 13 NPNT isoforms, 6 predicted to be protein coding, with two full-length isoforms differing only in this serine-encoding extension. Colocalisation analysis showed this splicing variant underlies COPD risk, spirometric lung function measures, and NPNT splicing (posterior probability 94%).","method":"Splice quantitative trait locus (sQTL) analysis, short-read RNA sequencing, Oxford Nanopore Technologies long-read sequencing, colocalization analysis with GWAS, RT-PCR","journal":"medRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — long-read sequencing with functional colocalization and sQTL analysis; preprint, single lab","pmids":["33173926"],"is_preprint":true},{"year":2022,"finding":"Down-regulation of NPNT via siRNA transfection in hepatocellular carcinoma (HCC) cells inhibited cell migration and invasion, and suppressed the FAK/PI3K/AKT signaling pathway, identifying NPNT as a regulator of HCC metastasis acting through this pathway.","method":"siRNA knockdown, wound healing assay, Matrigel Transwell invasion assay, western blot for FAK/PI3K/AKT pathway","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined pathway readout (FAK/PI3K/AKT), multiple functional assays, single lab","pmids":["35304239"],"is_preprint":false},{"year":2022,"finding":"A homozygous null (nonsense) variant in NPNT causes autosomal recessive bilateral renal agenesis in humans, confirmed by detection of complete nonsense-mediated decay of the NPNT transcript, establishing that complete loss of NPNT function can cause failure of kidney development (renal agenesis).","method":"Genome-wide linkage analysis, exome sequencing, RT-PCR demonstrating nonsense-mediated mRNA decay, Sanger sequencing for segregation","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — molecular confirmation of NMD in two families, consistent with known mouse knockout phenotype","pmids":["35246978"],"is_preprint":false},{"year":2025,"finding":"NPNT acts as an antiaging/antifibrotic molecule in the lung via interaction with integrin α3 (ITGA3). NPNT deficiency exacerbates bleomycin-induced senescence in alveolar epithelial cells and worsens fibrosis, while NPNT overexpression in alveolar epithelium improves lung function and resistance to aging and fibrosis. Mechanistically, NPNT inhibits hyperactivation of LATS1 and MOB1, facilitates YAP1 nuclear translocation, and suppresses YAP1 ubiquitination and degradation contingent on NPNT–ITGA3 interaction. Pharmacological elevation of NPNT protein levels with Escin alleviated pulmonary fibrosis in mice.","method":"NPNT knockout and overexpression mouse models, bleomycin-induced fibrosis assay, western blotting for LATS1/MOB1/YAP1 pathway, ubiquitination assay, pharmacological intervention (Escin)","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain- and loss-of-function with pathway mechanistic detail (ITGA3/LATS1/MOB1/YAP1), single lab, multiple orthogonal methods","pmids":["40444575"],"is_preprint":false},{"year":2025,"finding":"The COPD-risk allele rs34712979-A causes a shift in NPNT isoform usage away from the dominant isoform B (excludes exon 3) to isoform A (includes exon 3). AlphaFold protein structural analysis reveals that inclusion of exon 3 disrupts an EGF-like functional domain in NPNT, providing a structural mechanism for how this splicing change impairs NPNT function and increases COPD risk.","method":"Long-read RNA sequencing, sQTL analysis, colocalization with COPD GWAS, AlphaFold in silico protein structural analysis","journal":"The European respiratory journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — sQTL, long-read sequencing, and structural prediction in one study; structural part is in silico only, single lab","pmids":["39978861"],"is_preprint":false},{"year":2017,"finding":"Suppression of nephronectin (NPNT) expression by microRNA-378a-3p in zebrafish and mice significantly induced proteinuria due to loss of integrity of the glomerular filtration barrier, demonstrating that the miR-378a-3p/nephronectin axis regulates podocyte–glomerular basement membrane interaction and glomerular filtration barrier integrity.","method":"microRNA overexpression in zebrafish and mice, proteinuria measurement, glomerular filtration barrier integrity assessment","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function in two model organisms with defined functional readout (proteinuria), single lab/review","pmids":["28938947"],"is_preprint":false},{"year":2022,"finding":"miR-378 directly targets NPNT in A549 human alveolar epithelial cells. miR-378 overexpression increased cell proliferation, migration, and suppressed apoptosis; miR-378 is upregulated while NPNT is downregulated in COPD lung tissues, suggesting a regulatory axis relevant to COPD pathogenesis.","method":"miR-378 overexpression in A549 cells, bioinformatics target prediction confirmed by cell functional assays (CCK-8, colony formation, Transwell, flow cytometry), analysis of public COPD expression data","journal":"PeerJ","confidence":"Low","confidence_rationale":"Tier 3 / Weak — direct miRNA targeting confirmed by functional assays but without luciferase reporter or direct binding validation; single lab","pmids":["36128198"],"is_preprint":false}],"current_model":"NPNT (nephronectin/POEM) is a secreted extracellular matrix protein with EGF-like domains, an RGD motif, and a MAM domain that functions as a ligand for α8β1 integrin (and ITGA3), mediating cell adhesion, spreading, survival, osteoblast differentiation, renal development, angiogenesis, and alveolar epithelial homeostasis; its expression is suppressed by TNF-α via NF-κB and by TGF-β via ERK1/2/JNK, it activates ERK1/2 to drive endothelial angiogenesis, and it interacts with ITGA3 to suppress LATS1/MOB1, promote YAP1 nuclear activity, and prevent cellular senescence and pulmonary fibrosis, with loss-of-function mutations causing renal agenesis in humans."},"narrative":{"mechanistic_narrative":"NPNT (nephronectin/POEM) is a secreted extracellular matrix adhesion protein that engages cell-surface integrins to control cell adhesion, survival, and tissue homeostasis across kidney, bone, vasculature, and lung [PMID:11546798]. It contains EGF-like domains, an RGD cell-binding motif, and a MAM domain; the RGD motif drives integrin-dependent cell spreading and survival while the MAM domain contributes to adhesion alone, and NPNT acts as a ligand for α8β1 integrin [PMID:11546798]. NPNT signaling activates ERK1/2 to drive endothelial migration, tube formation, and angiogenesis [PMID:27782206], and in alveolar epithelium it interacts with integrin α3 (ITGA3) to suppress LATS1/MOB1 hyperactivation, promote YAP1 nuclear translocation, and block YAP1 ubiquitination, thereby protecting against cellular senescence and pulmonary fibrosis [PMID:40444575]. Its expression is suppressed by TNF-α through NF-κB and by TGF-β through ERK1/2 and JNK, coupling inflammatory and growth-factor cues to NPNT-dependent osteoblast differentiation [PMID:17977532, PMID:21689636]. NPNT is required for kidney development: a homozygous nonsense variant producing complete nonsense-mediated decay of the transcript causes autosomal recessive bilateral renal agenesis in humans [PMID:35246978], and NPNT supports glomerular filtration barrier integrity [PMID:28938947].","teleology":[{"year":2001,"claim":"Established NPNT's foundational identity as an ECM adhesion molecule and defined which of its domains drive which activities, answering how a secreted protein supports cell adhesion, spreading, and survival.","evidence":"Bacterial recombinant protein, RGD→RGE mutagenesis, and adhesion/spreading assays on α8-integrin-expressing cell lines","pmids":["11546798"],"confidence":"High","gaps":["Downstream intracellular signaling from the integrin not defined","Physiological tissue context not addressed in vitro"]},{"year":2007,"claim":"Placed NPNT under negative growth-factor control by showing TGF-β suppresses its expression, beginning to explain how NPNT levels are tuned in osteoblasts.","evidence":"TGF-β treatment with dose-response and TGF-βRI/ERK/JNK pathway inhibitors in MC3T3-E1 cells","pmids":["17977532"],"confidence":"Medium","gaps":["Functional consequence of suppression not tested here","Single cell line"]},{"year":2011,"claim":"Connected NPNT to inflammatory signaling and bone biology, showing TNF-α/NF-κB suppresses NPNT and that NPNT positively regulates osteoblast differentiation.","evidence":"TNF-α treatment with NF-κB inhibition and NPNT overexpression rescue in MC3T3-E1 cells","pmids":["21689636"],"confidence":"Medium","gaps":["Integrin/receptor mediating osteoblast effect not identified","In vivo bone phenotype not tested"]},{"year":2016,"claim":"Defined NPNT as a paracrine angiogenic factor and identified ERK1/2 as the required downstream signal, extending NPNT function from adhesion to vascular signaling.","evidence":"Recombinant NPNT in endothelial migration/tube-formation assays, ex vivo metatarsal angiogenesis, and ERK1/2 inhibitor rescue","pmids":["27782206"],"confidence":"Medium","gaps":["Integrin receptor on endothelial cells not defined","Direct link to in vivo angiogenesis in disease not shown"]},{"year":2017,"claim":"Demonstrated tissue-specific NPNT roles: Wnt-regulated NPNT promotes aldosterone production in adrenal glomerulosa, and the miR-378a-3p/NPNT axis maintains glomerular filtration barrier integrity.","evidence":"IHC, NPNT overexpression/siRNA with aldosterone readout in adrenal cells; miR-378a-3p overexpression in zebrafish and mice with proteinuria readout","pmids":["28416583","28938947"],"confidence":"Medium","gaps":["Integrin partner in adrenal/podocyte contexts not identified","Mechanism linking adhesion to aldosterone output unresolved"]},{"year":2022,"claim":"Established NPNT as causally required for human kidney development through loss-of-function genetics, and implicated NPNT in cancer metastasis via FAK/PI3K/AKT.","evidence":"Linkage/exome sequencing with NMD confirmation for renal agenesis; siRNA knockdown with FAK/PI3K/AKT readout in HCC cells","pmids":["35246978","35304239"],"confidence":"Medium","gaps":["Cell-autonomous developmental mechanism in kidney not dissected","HCC pathway placement based on knockdown without rescue"]},{"year":2022,"claim":"Proposed a regulatory axis whereby miR-378 targets NPNT in alveolar epithelial cells, linking NPNT downregulation to COPD-relevant phenotypes.","evidence":"miR-378 overexpression in A549 cells with proliferation/migration/apoptosis assays and COPD expression-data analysis","pmids":["36128198"],"confidence":"Low","gaps":["Direct targeting not confirmed by luciferase reporter or binding assay","Single cell line; correlative COPD association"]},{"year":2025,"claim":"Resolved a mechanistic pathway for NPNT in lung aging/fibrosis, showing NPNT–ITGA3 interaction restrains LATS1/MOB1 and stabilizes nuclear YAP1 to prevent alveolar epithelial senescence.","evidence":"NPNT knockout/overexpression mouse models with bleomycin fibrosis, LATS1/MOB1/YAP1 western blots, ubiquitination assay, and Escin pharmacological rescue","pmids":["40444575"],"confidence":"Medium","gaps":["Structural basis of NPNT–ITGA3 interaction not defined","How integrin engagement mechanistically suppresses Hippo kinases unresolved"]},{"year":2025,"claim":"Provided a molecular mechanism for the COPD risk allele by showing rs34712979 shifts NPNT splicing to include an exon that disrupts an EGF-like domain.","evidence":"Long-read RNA sequencing, sQTL and GWAS colocalization, and AlphaFold structural prediction","pmids":["39978861"],"confidence":"Medium","gaps":["Domain disruption predicted in silico, not validated functionally","Effect on integrin binding/downstream signaling not measured"]},{"year":null,"claim":"How distinct integrin partners (α8β1, ITGA3) and downstream pathways (ERK1/2, FAK/PI3K/AKT, Hippo/YAP1) are selected in different tissues to produce NPNT's divergent outcomes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of receptor/pathway selection across tissues","No structural model of the NPNT–integrin complex","Roles of individual EGF/MAM domains in signaling beyond adhesion undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,4]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,8]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,10]}],"complexes":[],"partners":["ITGA8","ITGB1","ITGA3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6UXI9","full_name":"Nephronectin","aliases":["Preosteoblast EGF-like repeat protein with MAM domain","Protein EGFL6-like"],"length_aa":565,"mass_kda":61.9,"function":"Functional ligand of integrin alpha-8/beta-1 in kidney development. Regulates the expression of GDNF with integrin alpha-8/beta-1 which is essential for kidney development. May also play a role in the development and function of various tissues, regulating cell adhesion, spreading and survival through the binding of several integrins (By similarity)","subcellular_location":"Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/Q6UXI9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NPNT","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NPNT","total_profiled":1310},"omim":[{"mim_id":"610306","title":"NEPHRONECTIN; NPNT","url":"https://www.omim.org/entry/610306"},{"mim_id":"300239","title":"EPIDERMAL GROWTH FACTOR-LIKE 6; EGFL6","url":"https://www.omim.org/entry/300239"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cell Junctions","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":185.2},{"tissue":"thyroid gland","ntpm":224.8}],"url":"https://www.proteinatlas.org/search/NPNT"},"hgnc":{"alias_symbol":["EGFL6L","POEM"],"prev_symbol":[]},"alphafold":{"accession":"Q6UXI9","domains":[{"cath_id":"2.10.25.10","chopping":"132-170","consensus_level":"medium","plddt":74.1697,"start":132,"end":170},{"cath_id":"2.60.120.200","chopping":"419-559","consensus_level":"high","plddt":80.1863,"start":419,"end":559}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UXI9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UXI9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UXI9-F1-predicted_aligned_error_v6.png","plddt_mean":67.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NPNT","jax_strain_url":"https://www.jax.org/strain/search?query=NPNT"},"sequence":{"accession":"Q6UXI9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6UXI9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6UXI9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UXI9"}},"corpus_meta":[{"pmid":"20354937","id":"PMC_20354937","title":"Peroral endoscopic myotomy (POEM) for esophageal achalasia.","date":"2010","source":"Endoscopy","url":"https://pubmed.ncbi.nlm.nih.gov/20354937","citation_count":1316,"is_preprint":false},{"pmid":"11546798","id":"PMC_11546798","title":"Molecular cloning of POEM: a novel adhesion molecule that interacts with alpha8beta1 integrin.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11546798","citation_count":59,"is_preprint":false},{"pmid":"27782206","id":"PMC_27782206","title":"NPNT is Expressed by Osteoblasts and Mediates Angiogenesis via the Activation of Extracellular Signal-regulated Kinase.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27782206","citation_count":30,"is_preprint":false},{"pmid":"28513838","id":"PMC_28513838","title":"The emerging role of NPNT in tissue injury repair and bone homeostasis.","date":"2017","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28513838","citation_count":26,"is_preprint":false},{"pmid":"23363448","id":"PMC_23363448","title":"Improvement of endocytoscopic findings after per oral endoscopic myotomy (POEM) in esophageal achalasia; does POEM reduce the risk of developing esophageal carcinoma? Per oral endoscopic myotomy, endocytoscopy and carcinogenesis.","date":"2013","source":"BMC gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/23363448","citation_count":25,"is_preprint":false},{"pmid":"21689636","id":"PMC_21689636","title":"Expression of POEM, a positive regulator of osteoblast differentiation, is suppressed by TNF-α.","date":"2011","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/21689636","citation_count":22,"is_preprint":false},{"pmid":"30591862","id":"PMC_30591862","title":"NPNT promotes early-stage bone metastases in breast cancer by regulation of the osteogenic niche.","date":"2018","source":"Journal of bone oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30591862","citation_count":19,"is_preprint":false},{"pmid":"17977532","id":"PMC_17977532","title":"TGF-beta suppresses POEM expression through ERK1/2 and JNK in osteoblasts.","date":"2007","source":"FEBS 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endoscopy","url":"https://pubmed.ncbi.nlm.nih.gov/32780244","citation_count":15,"is_preprint":false},{"pmid":"33471177","id":"PMC_33471177","title":"Long-term (17 years) subjective and objective evaluation of the durability of laparoscopic Heller esophagomyotomy in patients with achalasia of the esophagus (90% of follow-up): a real challenge to POEM.","date":"2021","source":"Surgical endoscopy","url":"https://pubmed.ncbi.nlm.nih.gov/33471177","citation_count":13,"is_preprint":false},{"pmid":"36870548","id":"PMC_36870548","title":"LncRNA ADAMTS9-AS1 inhibits the stemness of lung adenocarcinoma cells by regulating miR-5009-3p/NPNT axis.","date":"2023","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/36870548","citation_count":12,"is_preprint":false},{"pmid":"33173926","id":"PMC_33173926","title":"Characterization of a COPD-Associated NPNT Functional Splicing Genetic Variant in Human Lung Tissue via Long-Read Sequencing.","date":"2020","source":"medRxiv : the preprint server for 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Variants in GFRA1 and NPNT Are Associated with Congenital Anomalies of the Kidney and Urinary Tract.","date":"2022","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/36292572","citation_count":4,"is_preprint":false},{"pmid":"40444575","id":"PMC_40444575","title":"Nephronectin (NPNT) is a Crucial Determinant of Idiopathic Pulmonary Fibrosis: Modulating Cellular Senescence via the ITGA3/YAP1 Signaling Axis.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40444575","citation_count":3,"is_preprint":false},{"pmid":"32762622","id":"PMC_32762622","title":"\"The power of the poem\": using poetic inquiry to explore trans-identities in Namibia.","date":"2020","source":"Arts & health","url":"https://pubmed.ncbi.nlm.nih.gov/32762622","citation_count":2,"is_preprint":false},{"pmid":"27148351","id":"PMC_27148351","title":"POEM: Identifying Joint Additive Effects on Regulatory Circuits.","date":"2016","source":"Frontiers 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Recombinant POEM protein promoted cell adhesion, spreading, and survival. Mutation of the RGD sequence to RGE significantly decreased cell spreading and survival activities, while the MAM domain contributed only to cell adhesion and not spreading/survival. NPNT was identified as a ligand for α8β1 integrin: KA8 cells (K562 stably expressing α8 integrin) showed strong binding and spreading on NPNT, whereas parental K562 cells (expressing α5β1) did not bind NPNT.\",\n      \"method\": \"Bacterial recombinant protein production, site-directed mutagenesis (RGD→RGE), cell adhesion/spreading assays, stable integrin-expressing cell lines (K562/KA8)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis and defined integrin-expressing cell lines, multiple orthogonal functional assays in a single focused study\",\n      \"pmids\": [\"11546798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TGF-β strongly inhibited NPNT (POEM) gene expression in mouse osteoblastic MC3T3-E1 cells in a time- and dose-dependent manner. This suppression was mediated through activation of TGF-β receptor I and the ERK1/2 and JNK (c-Jun N-terminal kinase) signaling pathways.\",\n      \"method\": \"Gene expression analysis in MC3T3-E1 osteoblastic cells with TGF-β treatment, pathway inhibitor experiments targeting TGF-β receptor I, ERK1/2, and JNK\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined pathway (TGF-βRI/ERK/JNK) with pharmacological inhibition and dose-response in a single lab\",\n      \"pmids\": [\"17977532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TNF-α strongly inhibited NPNT (POEM) expression in MC3T3-E1 osteoblastic cells in a time- and dose-dependent manner through the NF-κB signaling pathway. Over-expression of NPNT rescued TNF-α-induced inhibition of osteoblast differentiation, establishing NPNT as a positive regulator of osteoblast differentiation downstream of TNF-α/NF-κB.\",\n      \"method\": \"Gene expression analysis in MC3T3-E1 cells with TNF-α treatment, NF-κB pathway inhibition, NPNT overexpression rescue experiment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway placement via inhibition and rescue (overexpression), single lab, two orthogonal approaches\",\n      \"pmids\": [\"21689636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NPNT is expressed by osteoblasts and functions as a paracrine angiogenic factor. Exogenous recombinant NPNT stimulated endothelial cell migration and tube-like structure formation in vitro, and promoted angiogenesis in an ex vivo fetal mouse metatarsal assay. NPNT activated phosphorylation of ERK1/2 and p38 MAPK in endothelial cells; pharmacological inhibition of ERK1/2 blocked NPNT-induced endothelial migration, tube formation, and angiogenesis, placing ERK1/2 downstream of NPNT in angiogenic signaling.\",\n      \"method\": \"Recombinant protein treatment of endothelial cells, migration assay, tube formation assay, ex vivo metatarsal angiogenesis assay, kinase phosphorylation assays, ERK1/2 inhibitor rescue experiments\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays (migration, tube formation, ex vivo), pathway inhibition in a single lab\",\n      \"pmids\": [\"27782206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NPNT is identified as a secreted extracellular matrix protein expressed exclusively around aldosterone-producing glomeruli in normal adrenal zona glomerulosa (ZG) and in ZG-like aldosterone-producing adenomas (APAs). NPNT production is regulated by the canonical Wnt signaling pathway (highest expression in APAs with gain-of-function CTNNB1 mutations). NPNT overexpression increased aldosterone production while NPNT silencing reduced aldosterone, and NPNT exhibited pro-adhesive activity in primary adrenal and APA cells, with binding to cell-surface integrins proposed to stimulate cell-cell contact within glomeruli.\",\n      \"method\": \"Immunohistochemistry, NPNT overexpression and siRNA silencing in adrenal/APA cells with aldosterone readout, microarray gene expression analysis\",\n      \"journal\": \"Hypertension (Dallas, Tex. : 1979)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with defined functional output (aldosterone), Wnt pathway linkage, single lab\",\n      \"pmids\": [\"28416583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A COPD-associated SNP (rs34712979) creates a cryptic splice acceptor site in NPNT, resulting in inclusion of a 3-nucleotide exon extension encoding a serine residue near the N-terminus of the protein. Long-read sequencing identified 13 NPNT isoforms, 6 predicted to be protein coding, with two full-length isoforms differing only in this serine-encoding extension. Colocalisation analysis showed this splicing variant underlies COPD risk, spirometric lung function measures, and NPNT splicing (posterior probability 94%).\",\n      \"method\": \"Splice quantitative trait locus (sQTL) analysis, short-read RNA sequencing, Oxford Nanopore Technologies long-read sequencing, colocalization analysis with GWAS, RT-PCR\",\n      \"journal\": \"medRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — long-read sequencing with functional colocalization and sQTL analysis; preprint, single lab\",\n      \"pmids\": [\"33173926\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Down-regulation of NPNT via siRNA transfection in hepatocellular carcinoma (HCC) cells inhibited cell migration and invasion, and suppressed the FAK/PI3K/AKT signaling pathway, identifying NPNT as a regulator of HCC metastasis acting through this pathway.\",\n      \"method\": \"siRNA knockdown, wound healing assay, Matrigel Transwell invasion assay, western blot for FAK/PI3K/AKT pathway\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined pathway readout (FAK/PI3K/AKT), multiple functional assays, single lab\",\n      \"pmids\": [\"35304239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A homozygous null (nonsense) variant in NPNT causes autosomal recessive bilateral renal agenesis in humans, confirmed by detection of complete nonsense-mediated decay of the NPNT transcript, establishing that complete loss of NPNT function can cause failure of kidney development (renal agenesis).\",\n      \"method\": \"Genome-wide linkage analysis, exome sequencing, RT-PCR demonstrating nonsense-mediated mRNA decay, Sanger sequencing for segregation\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — molecular confirmation of NMD in two families, consistent with known mouse knockout phenotype\",\n      \"pmids\": [\"35246978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NPNT acts as an antiaging/antifibrotic molecule in the lung via interaction with integrin α3 (ITGA3). NPNT deficiency exacerbates bleomycin-induced senescence in alveolar epithelial cells and worsens fibrosis, while NPNT overexpression in alveolar epithelium improves lung function and resistance to aging and fibrosis. Mechanistically, NPNT inhibits hyperactivation of LATS1 and MOB1, facilitates YAP1 nuclear translocation, and suppresses YAP1 ubiquitination and degradation contingent on NPNT–ITGA3 interaction. Pharmacological elevation of NPNT protein levels with Escin alleviated pulmonary fibrosis in mice.\",\n      \"method\": \"NPNT knockout and overexpression mouse models, bleomycin-induced fibrosis assay, western blotting for LATS1/MOB1/YAP1 pathway, ubiquitination assay, pharmacological intervention (Escin)\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain- and loss-of-function with pathway mechanistic detail (ITGA3/LATS1/MOB1/YAP1), single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40444575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The COPD-risk allele rs34712979-A causes a shift in NPNT isoform usage away from the dominant isoform B (excludes exon 3) to isoform A (includes exon 3). AlphaFold protein structural analysis reveals that inclusion of exon 3 disrupts an EGF-like functional domain in NPNT, providing a structural mechanism for how this splicing change impairs NPNT function and increases COPD risk.\",\n      \"method\": \"Long-read RNA sequencing, sQTL analysis, colocalization with COPD GWAS, AlphaFold in silico protein structural analysis\",\n      \"journal\": \"The European respiratory journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — sQTL, long-read sequencing, and structural prediction in one study; structural part is in silico only, single lab\",\n      \"pmids\": [\"39978861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Suppression of nephronectin (NPNT) expression by microRNA-378a-3p in zebrafish and mice significantly induced proteinuria due to loss of integrity of the glomerular filtration barrier, demonstrating that the miR-378a-3p/nephronectin axis regulates podocyte–glomerular basement membrane interaction and glomerular filtration barrier integrity.\",\n      \"method\": \"microRNA overexpression in zebrafish and mice, proteinuria measurement, glomerular filtration barrier integrity assessment\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function in two model organisms with defined functional readout (proteinuria), single lab/review\",\n      \"pmids\": [\"28938947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-378 directly targets NPNT in A549 human alveolar epithelial cells. miR-378 overexpression increased cell proliferation, migration, and suppressed apoptosis; miR-378 is upregulated while NPNT is downregulated in COPD lung tissues, suggesting a regulatory axis relevant to COPD pathogenesis.\",\n      \"method\": \"miR-378 overexpression in A549 cells, bioinformatics target prediction confirmed by cell functional assays (CCK-8, colony formation, Transwell, flow cytometry), analysis of public COPD expression data\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — direct miRNA targeting confirmed by functional assays but without luciferase reporter or direct binding validation; single lab\",\n      \"pmids\": [\"36128198\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NPNT (nephronectin/POEM) is a secreted extracellular matrix protein with EGF-like domains, an RGD motif, and a MAM domain that functions as a ligand for α8β1 integrin (and ITGA3), mediating cell adhesion, spreading, survival, osteoblast differentiation, renal development, angiogenesis, and alveolar epithelial homeostasis; its expression is suppressed by TNF-α via NF-κB and by TGF-β via ERK1/2/JNK, it activates ERK1/2 to drive endothelial angiogenesis, and it interacts with ITGA3 to suppress LATS1/MOB1, promote YAP1 nuclear activity, and prevent cellular senescence and pulmonary fibrosis, with loss-of-function mutations causing renal agenesis in humans.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NPNT (nephronectin/POEM) is a secreted extracellular matrix adhesion protein that engages cell-surface integrins to control cell adhesion, survival, and tissue homeostasis across kidney, bone, vasculature, and lung [#0]. It contains EGF-like domains, an RGD cell-binding motif, and a MAM domain; the RGD motif drives integrin-dependent cell spreading and survival while the MAM domain contributes to adhesion alone, and NPNT acts as a ligand for α8β1 integrin [#0]. NPNT signaling activates ERK1/2 to drive endothelial migration, tube formation, and angiogenesis [#3], and in alveolar epithelium it interacts with integrin α3 (ITGA3) to suppress LATS1/MOB1 hyperactivation, promote YAP1 nuclear translocation, and block YAP1 ubiquitination, thereby protecting against cellular senescence and pulmonary fibrosis [#8]. Its expression is suppressed by TNF-α through NF-κB and by TGF-β through ERK1/2 and JNK, coupling inflammatory and growth-factor cues to NPNT-dependent osteoblast differentiation [#1, #2]. NPNT is required for kidney development: a homozygous nonsense variant producing complete nonsense-mediated decay of the transcript causes autosomal recessive bilateral renal agenesis in humans [#7], and NPNT supports glomerular filtration barrier integrity [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established NPNT's foundational identity as an ECM adhesion molecule and defined which of its domains drive which activities, answering how a secreted protein supports cell adhesion, spreading, and survival.\",\n      \"evidence\": \"Bacterial recombinant protein, RGD→RGE mutagenesis, and adhesion/spreading assays on α8-integrin-expressing cell lines\",\n      \"pmids\": [\"11546798\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream intracellular signaling from the integrin not defined\", \"Physiological tissue context not addressed in vitro\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Placed NPNT under negative growth-factor control by showing TGF-β suppresses its expression, beginning to explain how NPNT levels are tuned in osteoblasts.\",\n      \"evidence\": \"TGF-β treatment with dose-response and TGF-βRI/ERK/JNK pathway inhibitors in MC3T3-E1 cells\",\n      \"pmids\": [\"17977532\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of suppression not tested here\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected NPNT to inflammatory signaling and bone biology, showing TNF-α/NF-κB suppresses NPNT and that NPNT positively regulates osteoblast differentiation.\",\n      \"evidence\": \"TNF-α treatment with NF-κB inhibition and NPNT overexpression rescue in MC3T3-E1 cells\",\n      \"pmids\": [\"21689636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Integrin/receptor mediating osteoblast effect not identified\", \"In vivo bone phenotype not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined NPNT as a paracrine angiogenic factor and identified ERK1/2 as the required downstream signal, extending NPNT function from adhesion to vascular signaling.\",\n      \"evidence\": \"Recombinant NPNT in endothelial migration/tube-formation assays, ex vivo metatarsal angiogenesis, and ERK1/2 inhibitor rescue\",\n      \"pmids\": [\"27782206\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Integrin receptor on endothelial cells not defined\", \"Direct link to in vivo angiogenesis in disease not shown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated tissue-specific NPNT roles: Wnt-regulated NPNT promotes aldosterone production in adrenal glomerulosa, and the miR-378a-3p/NPNT axis maintains glomerular filtration barrier integrity.\",\n      \"evidence\": \"IHC, NPNT overexpression/siRNA with aldosterone readout in adrenal cells; miR-378a-3p overexpression in zebrafish and mice with proteinuria readout\",\n      \"pmids\": [\"28416583\", \"28938947\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Integrin partner in adrenal/podocyte contexts not identified\", \"Mechanism linking adhesion to aldosterone output unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established NPNT as causally required for human kidney development through loss-of-function genetics, and implicated NPNT in cancer metastasis via FAK/PI3K/AKT.\",\n      \"evidence\": \"Linkage/exome sequencing with NMD confirmation for renal agenesis; siRNA knockdown with FAK/PI3K/AKT readout in HCC cells\",\n      \"pmids\": [\"35246978\", \"35304239\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-autonomous developmental mechanism in kidney not dissected\", \"HCC pathway placement based on knockdown without rescue\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Proposed a regulatory axis whereby miR-378 targets NPNT in alveolar epithelial cells, linking NPNT downregulation to COPD-relevant phenotypes.\",\n      \"evidence\": \"miR-378 overexpression in A549 cells with proliferation/migration/apoptosis assays and COPD expression-data analysis\",\n      \"pmids\": [\"36128198\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct targeting not confirmed by luciferase reporter or binding assay\", \"Single cell line; correlative COPD association\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved a mechanistic pathway for NPNT in lung aging/fibrosis, showing NPNT–ITGA3 interaction restrains LATS1/MOB1 and stabilizes nuclear YAP1 to prevent alveolar epithelial senescence.\",\n      \"evidence\": \"NPNT knockout/overexpression mouse models with bleomycin fibrosis, LATS1/MOB1/YAP1 western blots, ubiquitination assay, and Escin pharmacological rescue\",\n      \"pmids\": [\"40444575\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of NPNT–ITGA3 interaction not defined\", \"How integrin engagement mechanistically suppresses Hippo kinases unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided a molecular mechanism for the COPD risk allele by showing rs34712979 shifts NPNT splicing to include an exon that disrupts an EGF-like domain.\",\n      \"evidence\": \"Long-read RNA sequencing, sQTL and GWAS colocalization, and AlphaFold structural prediction\",\n      \"pmids\": [\"39978861\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Domain disruption predicted in silico, not validated functionally\", \"Effect on integrin binding/downstream signaling not measured\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How distinct integrin partners (α8β1, ITGA3) and downstream pathways (ERK1/2, FAK/PI3K/AKT, Hippo/YAP1) are selected in different tissues to produce NPNT's divergent outcomes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of receptor/pathway selection across tissues\", \"No structural model of the NPNT–integrin complex\", \"Roles of individual EGF/MAM domains in signaling beyond adhesion undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ITGA8\", \"ITGB1\", \"ITGA3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}