{"gene":"NOMO1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2021,"finding":"NOMO1 is a type I transmembrane protein required to sustain ER morphology: overexpression imposes a sheet morphology on the ER, while depletion of NOMO1 and its orthologs causes collapse of ER morphology with formation of membrane-delineated holes positive for lysosomal marker LAMP1, and increases levels of autophagy markers LC3 and p62/SQSTM1. In vitro reconstitution revealed a 'beads on a string' structure consistent with consecutive immunoglobulin-like domains, and insertion of additional Ig folds correlatively increases the ER intermembrane distance. Genetic epistasis with known ER-shaping proteins Atlastin2 and Climp63 places NOMO1 in the functional network of ER-shaping proteins.","method":"Proteomic screen, overexpression/depletion in cells, in vitro reconstitution, domain insertion mutagenesis, genetic epistasis with Atlastin2 and Climp63","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods in one study: proteomic screen, OE/KD with defined morphological phenotype, in vitro reconstitution with domain mutagenesis, and genetic epistasis analysis","pmids":["34224731"],"is_preprint":false},{"year":2012,"finding":"miR-675 (encoded by H19) directly downregulates NOMO1 protein expression by binding to the 3'-UTR of NOMO1, as validated by luciferase reporter assay. Overexpression of NOMO1 rescues miR-675-suppressed cell proliferation and phosphorylation of Smad2 in JEG-3 trophoblast cells, placing NOMO1 downstream of miR-675 in the Nodal/Smad2 signaling axis controlling trophoblast proliferation.","method":"Luciferase 3'-UTR reporter assay, NOMO1 overexpression rescue experiment, Western blot for Smad2 phosphorylation, H19/miR-675 knockdown","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal functional rescue and reporter assay in single lab with two orthogonal methods","pmids":["22832245"],"is_preprint":false},{"year":2015,"finding":"NOMO1 gene silencing by RNAi in P19 cells inhibits their differentiation into cardiomyocytes, with downregulation of Nodal signaling mediators (Nodal, Cripto, Smad2) and cardiomyocyte-specific markers (cardiac troponin T, Nkx2.5, Gata4, Tbx5), indicating NOMO1 supports Nodal pathway activity required for early cardiogenesis.","method":"RNAi knockdown in P19 cells, Western blot/qPCR for Nodal pathway components and cardiomyocyte differentiation markers","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined cellular phenotype and pathway marker readout, single lab single method set","pmids":["25576386"],"is_preprint":false},{"year":2020,"finding":"miR-33a-5p targets NOMO1 via its 3'-UTR (validated by dual-luciferase reporter assay), and upregulation of miR-33a-5p inhibits human cardiomyocyte progenitor cell (hCMPC) proliferation, G0/S transition, and differentiation into cardiomyocytes while promoting apoptosis; these effects are partially rescued by NOMO1 overexpression, establishing NOMO1 as a functional target of miR-33a-5p in cardiac progenitor biology.","method":"Dual-luciferase reporter assay, miR-33a-5p mimic/inhibitor transfection, NOMO1 overexpression rescue, CCK-8 proliferation assay, flow cytometry (apoptosis/cell cycle), Western blot","journal":"Journal of receptor and signal transduction research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus functional rescue experiment, multiple readouts, single lab","pmids":["33054489"],"is_preprint":false},{"year":2022,"finding":"NOMO1 knockout in HCT-116 colorectal cancer cells (by CRISPR/Cas9) does not perturb Nodal pathway signaling or cell proliferation, but deregulates epithelial-mesenchymal transition and cell migration pathways, significantly increasing migration capacity. Expression microarrays, RNA-seq, and LC-IMS/MS proteomics revealed these Nodal-independent pathway changes.","method":"CRISPR/Cas9 knockout, expression microarrays, RNA-seq, LC-IMS/MS proteomics, cell migration assays, gut-specific conditional KO mouse model","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with multiple orthogonal omics methods and functional migration readout, single lab","pmids":["36011023"],"is_preprint":false},{"year":2025,"finding":"NOMO silencing by siRNA in lung cancer cells counters chemo- and radioresistance through caspase-dependent apoptosis, and antibody array analysis reveals that NOMO inhibition leads to increased phosphorylation of checkpoint kinases Chk1 and Chk2, indicating NOMO modulates chemo- and radioresistance via the Chk2 pathway.","method":"siRNA knockdown, cell viability/apoptosis assays, antibody array for phospho-kinase profiling","journal":"Anticancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, antibody array (single method for pathway placement), no mechanistic reconstitution","pmids":["41151896"],"is_preprint":false},{"year":2017,"finding":"NOMO1 protein expression is regulated through the DLX3/H19/miR-675 axis in bone marrow mesenchymal stem cells: DLX3 mutation (Q178R) reduces H19 and miR-675 expression, leading to increased NOMO1 levels and enhanced cell proliferation; restoration of H19 suppresses the elevated NOMO1 expression and proliferation, confirming NOMO1 as a downstream effector of this axis.","method":"Lentiviral overexpression/knockdown, clonogenic and CCK-8 proliferation assays, H19 restoration rescue experiment, Western blot/qPCR for NOMO1","journal":"Clinical science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue experiment with multiple cell-based methods, single lab","pmids":["28963438"],"is_preprint":false}],"current_model":"NOMO1 is a widely conserved type I transmembrane protein with consecutive immunoglobulin-like domains that functions as an ER-shaping protein (maintaining ER sheet morphology and intermembrane distance within a network that includes Atlastin2 and Climp63), supports Nodal/Smad2 signaling required for cardiogenesis and early patterning, is targeted post-transcriptionally by miR-675 and miR-33a-5p at its 3'-UTR, and when lost in colorectal cancer cells promotes cell migration through Nodal-independent EMT pathways; additionally, NOMO modulates chemo- and radioresistance in lung cancer via the Chk2 pathway."},"narrative":{"mechanistic_narrative":"NOMO1 is a type I transmembrane protein that functions as an endoplasmic reticulum-shaping factor, maintaining ER sheet morphology and setting intermembrane distance within a functional network that includes the ER-shaping proteins Atlastin2 and Climp63 [PMID:34224731]. Its extracellular region forms a 'beads on a string' array of consecutive immunoglobulin-like domains, and the number of Ig folds directly scales the ER intermembrane spacing; loss of NOMO1 collapses ER morphology, produces LAMP1-positive membrane holes, and elevates autophagy markers LC3 and p62/SQSTM1 [PMID:34224731]. Beyond ER architecture, NOMO1 supports Nodal/Smad2 signaling: its depletion lowers Smad2 phosphorylation and blocks Nodal-dependent cardiomyocyte differentiation in P19 cells, downregulating Nodal, Cripto, and cardiac markers including Nkx2.5, Gata4, and Tbx5 [PMID:25576386]. NOMO1 protein levels are set post-transcriptionally through direct targeting of its 3'-UTR by miR-675 (within the DLX3/H19/miR-675 axis) and by miR-33a-5p, both of which restrain proliferation and differentiation in trophoblast, mesenchymal stem cell, and cardiac progenitor contexts [PMID:22832245, PMID:33054489, PMID:28963438]. In colorectal cancer cells, NOMO1 loss instead acts independently of Nodal signaling, deregulating epithelial-mesenchymal transition and increasing cell migration [PMID:36011023].","teleology":[{"year":2012,"claim":"Established the first regulatory and functional context for NOMO1, placing it downstream of the H19/miR-675 axis as an effector controlling Smad2-dependent proliferation.","evidence":"Luciferase 3'-UTR reporter, NOMO1 overexpression rescue, and Smad2 phospho-Western in JEG-3 trophoblast cells","pmids":["22832245"],"confidence":"Medium","gaps":["Did not define how NOMO1 mechanistically supports Smad2 phosphorylation","Single cell type; generality of the miR-675–NOMO1 link untested"]},{"year":2015,"claim":"Connected NOMO1 to a developmental program by showing it is required for Nodal-driven cardiomyocyte differentiation.","evidence":"RNAi knockdown in P19 cells with Western/qPCR for Nodal mediators and cardiac differentiation markers","pmids":["25576386"],"confidence":"Medium","gaps":["Mechanism by which NOMO1 sustains Nodal/Cripto/Smad2 signaling unresolved","No in vivo cardiogenesis validation in this study"]},{"year":2017,"claim":"Extended the regulatory logic upstream, showing NOMO1 is the proliferative effector of a DLX3/H19/miR-675 axis where a disease mutation derepresses NOMO1.","evidence":"DLX3 Q178R mutation analysis, H19 restoration rescue, clonogenic/CCK-8 assays in bone marrow mesenchymal stem cells","pmids":["28963438"],"confidence":"Medium","gaps":["Direct molecular consequence of elevated NOMO1 on proliferation machinery not defined","Does not address whether ER-shaping function underlies the proliferative effect"]},{"year":2020,"claim":"Demonstrated a second microRNA controls NOMO1, broadening its post-transcriptional regulation in cardiac progenitor biology.","evidence":"Dual-luciferase 3'-UTR reporter, miR-33a-5p mimic/inhibitor, NOMO1 overexpression rescue, proliferation/cell-cycle/apoptosis assays in hCMPCs","pmids":["33054489"],"confidence":"Medium","gaps":["Whether miR-33a-5p and miR-675 co-regulate NOMO1 in the same cells unknown","Downstream effectors of NOMO1 in progenitor proliferation not mapped"]},{"year":2021,"claim":"Defined the core molecular function of NOMO1 as an ER-shaping protein whose Ig-domain array sets ER intermembrane distance, the first structural-mechanistic account.","evidence":"Proteomic screen, overexpression/depletion morphology phenotypes, in vitro reconstitution, Ig-fold insertion mutagenesis, genetic epistasis with Atlastin2 and Climp63","pmids":["34224731"],"confidence":"High","gaps":["How ER-shaping activity relates to its Nodal/Smad2 signaling roles is unintegrated","Direct binding partners within the ER-shaping network not biochemically resolved"]},{"year":2022,"claim":"Revealed context-dependent NOMO1 function: in colorectal cancer its loss acts independently of Nodal signaling to deregulate EMT and enhance migration.","evidence":"CRISPR/Cas9 knockout in HCT-116, expression microarrays, RNA-seq, LC-IMS/MS proteomics, migration assays, gut-specific conditional KO mouse","pmids":["36011023"],"confidence":"Medium","gaps":["Molecular link between NOMO1 loss and EMT pathway activation not identified","Reconciliation with Nodal-dependence seen in developmental contexts unexplained"]},{"year":2025,"claim":"Implicated NOMO in cancer treatment resistance via checkpoint kinase signaling.","evidence":"siRNA knockdown in lung cancer cells, viability/apoptosis assays, antibody array showing increased Chk1/Chk2 phosphorylation","pmids":["41151896"],"confidence":"Low","gaps":["Pathway placement rests on a single antibody array without mechanistic reconstitution","Whether NOMO acts directly on Chk2 or via ER stress/apoptosis is undefined"]},{"year":null,"claim":"How NOMO1's ER-shaping activity mechanistically connects to its roles in Nodal/Smad2 signaling, EMT/migration, and checkpoint-kinase-dependent treatment resistance remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying mechanism linking ER architecture to signaling phenotypes","Direct molecular partners of NOMO1 beyond epistatic network not biochemically established","Tissue-specific determinants of Nodal-dependent versus Nodal-independent behavior unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0]}],"pathway":[],"complexes":[],"partners":["ATL2","CKAP4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15155","full_name":"BOS complex subunit NOMO1","aliases":["Nodal modulator 1","pM5 protein"],"length_aa":1222,"mass_kda":134.3,"function":"Component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes (PubMed:32820719, PubMed:36261522). The MPT complex takes over after the SEC61 complex: following membrane insertion of the first few transmembrane segments of proteins by the SEC61 complex, the MPT complex occludes the lateral gate of the SEC61 complex to promote insertion of subsequent transmembrane regions (PubMed:36261522)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q15155/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NOMO1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1047,"dependency_fraction":0.0009551098376313276},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NCLN","stoichiometry":10.0},{"gene":"RNF40","stoichiometry":0.2},{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NOMO1","total_profiled":1310},"omim":[{"mim_id":"615509","title":"MICRO RNA 675; MIR675","url":"https://www.omim.org/entry/615509"},{"mim_id":"609159","title":"NODAL MODULATOR 3; NOMO3","url":"https://www.omim.org/entry/609159"},{"mim_id":"609158","title":"NODAL MODULATOR 2; NOMO2","url":"https://www.omim.org/entry/609158"},{"mim_id":"609157","title":"NODAL MODULATOR 1; NOMO1","url":"https://www.omim.org/entry/609157"},{"mim_id":"103280","title":"H19, IMPRINTED MATERNALLY EXPRESSED NONCODING TRANSCRIPT; H19","url":"https://www.omim.org/entry/103280"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"pancreas","ntpm":132.5}],"url":"https://www.proteinatlas.org/search/NOMO1"},"hgnc":{"alias_symbol":["PM5"],"prev_symbol":[]},"alphafold":{"accession":"Q15155","domains":[{"cath_id":"2.60.40.10","chopping":"35-121","consensus_level":"medium","plddt":87.7599,"start":35,"end":121},{"cath_id":"2.60.40.10","chopping":"132-215","consensus_level":"high","plddt":90.8789,"start":132,"end":215},{"cath_id":"2.60.40.10","chopping":"218-323","consensus_level":"high","plddt":85.6223,"start":218,"end":323},{"cath_id":"2.60.40.1120","chopping":"333-402","consensus_level":"high","plddt":79.4793,"start":333,"end":402},{"cath_id":"2.60.40,2.60.40","chopping":"409-501","consensus_level":"high","plddt":76.5476,"start":409,"end":501},{"cath_id":"2.60.40,2.60.40","chopping":"505-589","consensus_level":"medium","plddt":82.5286,"start":505,"end":589},{"cath_id":"2.60.40.1140","chopping":"801-875","consensus_level":"medium","plddt":81.3444,"start":801,"end":875},{"cath_id":"2.60.40.1120","chopping":"1057-1150","consensus_level":"high","plddt":89.854,"start":1057,"end":1150}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15155","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15155-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15155-F1-predicted_aligned_error_v6.png","plddt_mean":81.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NOMO1","jax_strain_url":"https://www.jax.org/strain/search?query=NOMO1"},"sequence":{"accession":"Q15155","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15155.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15155/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15155"}},"corpus_meta":[{"pmid":"22832245","id":"PMC_22832245","title":"The imprinted H19 gene regulates human placental trophoblast cell proliferation via encoding miR-675 that targets Nodal Modulator 1 (NOMO1).","date":"2012","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/22832245","citation_count":134,"is_preprint":false},{"pmid":"10942240","id":"PMC_10942240","title":"Calicheamicin-conjugated humanized anti-CD33 monoclonal antibody (gemtuzumab zogamicin, CMA-676) shows cytocidal effect on CD33-positive leukemia cell lines, but is inactive on P-glycoprotein-expressing sublines.","date":"2000","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/10942240","citation_count":117,"is_preprint":false},{"pmid":"23474756","id":"PMC_23474756","title":"Aberrant Mer receptor tyrosine kinase expression contributes to leukemogenesis in acute myeloid leukemia.","date":"2013","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23474756","citation_count":90,"is_preprint":false},{"pmid":"17244794","id":"PMC_17244794","title":"Helicobacter pylori heat-shock protein 60 induces interleukin-8 via a Toll-like receptor (TLR)2 and mitogen-activated protein (MAP) kinase pathway in human monocytes.","date":"2007","source":"Journal of medical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/17244794","citation_count":79,"is_preprint":false},{"pmid":"15160920","id":"PMC_15160920","title":"Expression of HOX genes in acute leukemia cell lines with and without MLL translocations.","date":"2004","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/15160920","citation_count":52,"is_preprint":false},{"pmid":"28428443","id":"PMC_28428443","title":"Mechanisms of Pinometostat (EPZ-5676) Treatment-Emergent Resistance in MLL-Rearranged Leukemia.","date":"2017","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/28428443","citation_count":51,"is_preprint":false},{"pmid":"1845845","id":"PMC_1845845","title":"FDP D-dimer induces the secretion of interleukin-1, urokinase-type plasminogen activator, and plasminogen activator inhibitor-2 in a human promonocytic leukemia cell line.","date":"1991","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/1845845","citation_count":51,"is_preprint":false},{"pmid":"11470562","id":"PMC_11470562","title":"5-Aminolaevulinic acid-mediated photodynamic therapy in multidrug resistant leukemia cells.","date":"2001","source":"Journal of photochemistry and photobiology. 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genomics","url":"https://pubmed.ncbi.nlm.nih.gov/40133836","citation_count":2,"is_preprint":false},{"pmid":"40540471","id":"PMC_40540471","title":"NOMO-1 cells expressing an NF-κB luciferase reporter gene facilitate a simple, rapid monocyte activation test that can detect a wide range of pyrogens.","date":"2025","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/40540471","citation_count":0,"is_preprint":false},{"pmid":"41151896","id":"PMC_41151896","title":"Nodal Modulator Regulates Chemo- and Radioresistance in Lung Cancer via the Chk2 Pathway.","date":"2025","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/41151896","citation_count":0,"is_preprint":false},{"pmid":"40909732","id":"PMC_40909732","title":"Effective imaging and treatment of Acute Myeloid Leukemia with radiotheranostics targeting the activated conformation of integrin-βeta2.","date":"2025","source":"bioRxiv : the preprint server for 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laboratory","url":"https://pubmed.ncbi.nlm.nih.gov/40923732","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":30348,"output_tokens":2115,"usd":0.061385,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9049,"output_tokens":2650,"usd":0.055747,"stage2_stop_reason":"end_turn"},"total_usd":0.117132,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"NOMO1 is a type I transmembrane protein required to sustain ER morphology: overexpression imposes a sheet morphology on the ER, while depletion of NOMO1 and its orthologs causes collapse of ER morphology with formation of membrane-delineated holes positive for lysosomal marker LAMP1, and increases levels of autophagy markers LC3 and p62/SQSTM1. In vitro reconstitution revealed a 'beads on a string' structure consistent with consecutive immunoglobulin-like domains, and insertion of additional Ig folds correlatively increases the ER intermembrane distance. Genetic epistasis with known ER-shaping proteins Atlastin2 and Climp63 places NOMO1 in the functional network of ER-shaping proteins.\",\n      \"method\": \"Proteomic screen, overexpression/depletion in cells, in vitro reconstitution, domain insertion mutagenesis, genetic epistasis with Atlastin2 and Climp63\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods in one study: proteomic screen, OE/KD with defined morphological phenotype, in vitro reconstitution with domain mutagenesis, and genetic epistasis analysis\",\n      \"pmids\": [\"34224731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"miR-675 (encoded by H19) directly downregulates NOMO1 protein expression by binding to the 3'-UTR of NOMO1, as validated by luciferase reporter assay. Overexpression of NOMO1 rescues miR-675-suppressed cell proliferation and phosphorylation of Smad2 in JEG-3 trophoblast cells, placing NOMO1 downstream of miR-675 in the Nodal/Smad2 signaling axis controlling trophoblast proliferation.\",\n      \"method\": \"Luciferase 3'-UTR reporter assay, NOMO1 overexpression rescue experiment, Western blot for Smad2 phosphorylation, H19/miR-675 knockdown\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional rescue and reporter assay in single lab with two orthogonal methods\",\n      \"pmids\": [\"22832245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NOMO1 gene silencing by RNAi in P19 cells inhibits their differentiation into cardiomyocytes, with downregulation of Nodal signaling mediators (Nodal, Cripto, Smad2) and cardiomyocyte-specific markers (cardiac troponin T, Nkx2.5, Gata4, Tbx5), indicating NOMO1 supports Nodal pathway activity required for early cardiogenesis.\",\n      \"method\": \"RNAi knockdown in P19 cells, Western blot/qPCR for Nodal pathway components and cardiomyocyte differentiation markers\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined cellular phenotype and pathway marker readout, single lab single method set\",\n      \"pmids\": [\"25576386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-33a-5p targets NOMO1 via its 3'-UTR (validated by dual-luciferase reporter assay), and upregulation of miR-33a-5p inhibits human cardiomyocyte progenitor cell (hCMPC) proliferation, G0/S transition, and differentiation into cardiomyocytes while promoting apoptosis; these effects are partially rescued by NOMO1 overexpression, establishing NOMO1 as a functional target of miR-33a-5p in cardiac progenitor biology.\",\n      \"method\": \"Dual-luciferase reporter assay, miR-33a-5p mimic/inhibitor transfection, NOMO1 overexpression rescue, CCK-8 proliferation assay, flow cytometry (apoptosis/cell cycle), Western blot\",\n      \"journal\": \"Journal of receptor and signal transduction research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus functional rescue experiment, multiple readouts, single lab\",\n      \"pmids\": [\"33054489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NOMO1 knockout in HCT-116 colorectal cancer cells (by CRISPR/Cas9) does not perturb Nodal pathway signaling or cell proliferation, but deregulates epithelial-mesenchymal transition and cell migration pathways, significantly increasing migration capacity. Expression microarrays, RNA-seq, and LC-IMS/MS proteomics revealed these Nodal-independent pathway changes.\",\n      \"method\": \"CRISPR/Cas9 knockout, expression microarrays, RNA-seq, LC-IMS/MS proteomics, cell migration assays, gut-specific conditional KO mouse model\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with multiple orthogonal omics methods and functional migration readout, single lab\",\n      \"pmids\": [\"36011023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NOMO silencing by siRNA in lung cancer cells counters chemo- and radioresistance through caspase-dependent apoptosis, and antibody array analysis reveals that NOMO inhibition leads to increased phosphorylation of checkpoint kinases Chk1 and Chk2, indicating NOMO modulates chemo- and radioresistance via the Chk2 pathway.\",\n      \"method\": \"siRNA knockdown, cell viability/apoptosis assays, antibody array for phospho-kinase profiling\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, antibody array (single method for pathway placement), no mechanistic reconstitution\",\n      \"pmids\": [\"41151896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NOMO1 protein expression is regulated through the DLX3/H19/miR-675 axis in bone marrow mesenchymal stem cells: DLX3 mutation (Q178R) reduces H19 and miR-675 expression, leading to increased NOMO1 levels and enhanced cell proliferation; restoration of H19 suppresses the elevated NOMO1 expression and proliferation, confirming NOMO1 as a downstream effector of this axis.\",\n      \"method\": \"Lentiviral overexpression/knockdown, clonogenic and CCK-8 proliferation assays, H19 restoration rescue experiment, Western blot/qPCR for NOMO1\",\n      \"journal\": \"Clinical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue experiment with multiple cell-based methods, single lab\",\n      \"pmids\": [\"28963438\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NOMO1 is a widely conserved type I transmembrane protein with consecutive immunoglobulin-like domains that functions as an ER-shaping protein (maintaining ER sheet morphology and intermembrane distance within a network that includes Atlastin2 and Climp63), supports Nodal/Smad2 signaling required for cardiogenesis and early patterning, is targeted post-transcriptionally by miR-675 and miR-33a-5p at its 3'-UTR, and when lost in colorectal cancer cells promotes cell migration through Nodal-independent EMT pathways; additionally, NOMO modulates chemo- and radioresistance in lung cancer via the Chk2 pathway.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NOMO1 is a type I transmembrane protein that functions as an endoplasmic reticulum-shaping factor, maintaining ER sheet morphology and setting intermembrane distance within a functional network that includes the ER-shaping proteins Atlastin2 and Climp63 [#0]. Its extracellular region forms a 'beads on a string' array of consecutive immunoglobulin-like domains, and the number of Ig folds directly scales the ER intermembrane spacing; loss of NOMO1 collapses ER morphology, produces LAMP1-positive membrane holes, and elevates autophagy markers LC3 and p62/SQSTM1 [#0]. Beyond ER architecture, NOMO1 supports Nodal/Smad2 signaling: its depletion lowers Smad2 phosphorylation and blocks Nodal-dependent cardiomyocyte differentiation in P19 cells, downregulating Nodal, Cripto, and cardiac markers including Nkx2.5, Gata4, and Tbx5 [#2]. NOMO1 protein levels are set post-transcriptionally through direct targeting of its 3'-UTR by miR-675 (within the DLX3/H19/miR-675 axis) and by miR-33a-5p, both of which restrain proliferation and differentiation in trophoblast, mesenchymal stem cell, and cardiac progenitor contexts [#1, #3, #6]. In colorectal cancer cells, NOMO1 loss instead acts independently of Nodal signaling, deregulating epithelial-mesenchymal transition and increasing cell migration [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established the first regulatory and functional context for NOMO1, placing it downstream of the H19/miR-675 axis as an effector controlling Smad2-dependent proliferation.\",\n      \"evidence\": \"Luciferase 3'-UTR reporter, NOMO1 overexpression rescue, and Smad2 phospho-Western in JEG-3 trophoblast cells\",\n      \"pmids\": [\"22832245\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define how NOMO1 mechanistically supports Smad2 phosphorylation\", \"Single cell type; generality of the miR-675–NOMO1 link untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected NOMO1 to a developmental program by showing it is required for Nodal-driven cardiomyocyte differentiation.\",\n      \"evidence\": \"RNAi knockdown in P19 cells with Western/qPCR for Nodal mediators and cardiac differentiation markers\",\n      \"pmids\": [\"25576386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which NOMO1 sustains Nodal/Cripto/Smad2 signaling unresolved\", \"No in vivo cardiogenesis validation in this study\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended the regulatory logic upstream, showing NOMO1 is the proliferative effector of a DLX3/H19/miR-675 axis where a disease mutation derepresses NOMO1.\",\n      \"evidence\": \"DLX3 Q178R mutation analysis, H19 restoration rescue, clonogenic/CCK-8 assays in bone marrow mesenchymal stem cells\",\n      \"pmids\": [\"28963438\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular consequence of elevated NOMO1 on proliferation machinery not defined\", \"Does not address whether ER-shaping function underlies the proliferative effect\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated a second microRNA controls NOMO1, broadening its post-transcriptional regulation in cardiac progenitor biology.\",\n      \"evidence\": \"Dual-luciferase 3'-UTR reporter, miR-33a-5p mimic/inhibitor, NOMO1 overexpression rescue, proliferation/cell-cycle/apoptosis assays in hCMPCs\",\n      \"pmids\": [\"33054489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether miR-33a-5p and miR-675 co-regulate NOMO1 in the same cells unknown\", \"Downstream effectors of NOMO1 in progenitor proliferation not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the core molecular function of NOMO1 as an ER-shaping protein whose Ig-domain array sets ER intermembrane distance, the first structural-mechanistic account.\",\n      \"evidence\": \"Proteomic screen, overexpression/depletion morphology phenotypes, in vitro reconstitution, Ig-fold insertion mutagenesis, genetic epistasis with Atlastin2 and Climp63\",\n      \"pmids\": [\"34224731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ER-shaping activity relates to its Nodal/Smad2 signaling roles is unintegrated\", \"Direct binding partners within the ER-shaping network not biochemically resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed context-dependent NOMO1 function: in colorectal cancer its loss acts independently of Nodal signaling to deregulate EMT and enhance migration.\",\n      \"evidence\": \"CRISPR/Cas9 knockout in HCT-116, expression microarrays, RNA-seq, LC-IMS/MS proteomics, migration assays, gut-specific conditional KO mouse\",\n      \"pmids\": [\"36011023\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between NOMO1 loss and EMT pathway activation not identified\", \"Reconciliation with Nodal-dependence seen in developmental contexts unexplained\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated NOMO in cancer treatment resistance via checkpoint kinase signaling.\",\n      \"evidence\": \"siRNA knockdown in lung cancer cells, viability/apoptosis assays, antibody array showing increased Chk1/Chk2 phosphorylation\",\n      \"pmids\": [\"41151896\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway placement rests on a single antibody array without mechanistic reconstitution\", \"Whether NOMO acts directly on Chk2 or via ER stress/apoptosis is undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NOMO1's ER-shaping activity mechanistically connects to its roles in Nodal/Smad2 signaling, EMT/migration, and checkpoint-kinase-dependent treatment resistance remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying mechanism linking ER architecture to signaling phenotypes\", \"Direct molecular partners of NOMO1 beyond epistatic network not biochemically established\", \"Tissue-specific determinants of Nodal-dependent versus Nodal-independent behavior unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ATL2\", \"CKAP4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}