{"gene":"NOMO1","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":2020,"finding":"NOMO1 is a component of a ~360 kDa ER-resident translocon complex for multi-pass membrane protein biogenesis. Cryo-EM reveals that NOMO forms the 'Nicalin-TMEM147-NOMO complex,' one of five accessory factors assembled around the core Sec61 channel at the ribosome exit tunnel. Loss of accessory components (including NOMO) reduces levels of multi-pass membrane protein clients such as the glutamate transporter EAAT1, establishing a functional role for NOMO1 in multi-pass membrane protein biogenesis at the ER.","method":"Cryo-electron microscopy, affinity purification–mass spectrometry, high-throughput mRNA sequencing, cell-based loss-of-function assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure combined with AP-MS complex identification and functional KO validation in a single rigorous study","pmids":["32820719"],"is_preprint":false},{"year":2004,"finding":"NOMO1 was identified as a component of the Nodal/TGF-β–Smad signaling pathway through large-scale two-hybrid and functional proteomics mapping. siRNA knockdown experiments placed NOMO1 among novel proteins functionally required for Smad signaling in mammalian cells.","method":"Yeast two-hybrid screen, siRNA knockdown with Smad reporter functional assay","journal":"Genome research","confidence":"Medium","confidence_rationale":"Tier 2 — Y2H plus siRNA functional validation, but single study without independent replication of NOMO1-specific result","pmids":["15231748"],"is_preprint":false},{"year":2012,"finding":"miR-675 (encoded by H19) directly targets the 3′-UTR of NOMO1 mRNA to suppress NOMO1 protein expression, as validated by luciferase reporter assay. Overexpression of NOMO1 in JEG-3 trophoblast cells rescues miR-675-suppressed cell proliferation and restores phosphorylation of Smad2, placing NOMO1 upstream of Smad2 activation in the Nodal signaling pathway and establishing NOMO1 as a positive regulator of trophoblast proliferation via Nodal–Smad2.","method":"Luciferase 3′-UTR reporter assay, NOMO1 overexpression rescue experiment, western blot for phospho-Smad2, cell proliferation assay","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct 3′-UTR targeting validated by luciferase assay plus functional rescue with phospho-Smad2 readout; single lab","pmids":["22832245"],"is_preprint":false},{"year":2020,"finding":"miR-33a-5p directly targets NOMO1 (confirmed by dual-luciferase reporter assay). Up-regulation of miR-33a-5p in human cardiomyocyte progenitor cells (hCMPCs) inhibits proliferation, blocks G0/S cell cycle transition, promotes apoptosis (increased Bax and cleaved caspase-3, decreased Bcl-2), and reduces cardiomyocyte differentiation markers (GATA4, cTnT, MEF2C). These effects are partially rescued by NOMO1 overexpression, establishing NOMO1 as a pro-proliferative and pro-differentiation factor in cardiomyocyte progenitors.","method":"Dual-luciferase reporter assay, CCK-8 proliferation assay, flow cytometry (cell cycle and apoptosis), western blot, qRT-PCR, NOMO1 overexpression rescue","journal":"Journal of receptor and signal transduction research","confidence":"Medium","confidence_rationale":"Tier 2 — direct target validation plus functional rescue with multiple orthogonal readouts; single lab","pmids":["33054489"],"is_preprint":false},{"year":2022,"finding":"CRISPR/Cas9-mediated knockout of NOMO1 in HCT-116 colorectal cancer cells does not perturb Nodal pathway signaling or cell proliferation, but significantly increases cell migration capacity. Expression microarray, RNA-seq, and LC-IMS/MS proteomics revealed that NOMO1 loss deregulates epithelial-mesenchymal transition (EMT) and cell migration pathways independently of the canonical Nodal pathway, demonstrating that NOMO1 suppresses CRC cell migration through non-Nodal mechanisms.","method":"CRISPR/Cas9 knockout, wound-healing and transwell migration assays, expression microarray, RNA-seq, LC-IMS/MS proteomics, Nodal pathway reporter assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — clean CRISPR KO with defined migration phenotype and multi-omic pathway analysis; single lab","pmids":["36011023"],"is_preprint":false},{"year":2019,"finding":"A conditional Nomo1 knockout mouse model was generated using CRISPR/Cas9 to flox exon 3. Cre-mediated recombination in mouse embryonic fibroblasts and in Msi1+ intestinal stem cells ablated exon 3 and eliminated full-length NOMO1 protein (confirmed by western blot), establishing that exon 3 is essential for production of functional NOMO1 protein.","method":"CRISPR/Cas9 conditional knockout, Cre-loxP recombination, western blot, genomic PCR","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2 — clean genetic tool with western blot validation; functional consequence not yet fully characterized in vivo","pmids":["31833031"],"is_preprint":false},{"year":2021,"finding":"Large-scale affinity purification–mass spectrometry (BioPlex 3.0) in 293T and HCT116 cells identified NOMO1 as part of a protein interaction community, co-purifying with Nicalin (NCAN) and TMEM147, consistent with its membership in the ER translocon accessory complex.","method":"Affinity purification–mass spectrometry (AP-MS) at proteome scale","journal":"Cell","confidence":"Low","confidence_rationale":"Tier 3 — large-scale AP-MS dataset; NOMO1 interactions inferred from network; not individually validated in this study","pmids":["33961781"],"is_preprint":false},{"year":2022,"finding":"OpenCell endogenous tagging and live-cell imaging determined the subcellular localization of NOMO1 within human cells, placing it at the endoplasmic reticulum, consistent with its role in the ER translocon complex.","method":"CRISPR-based endogenous fluorescent tagging, confocal live-cell imaging, AP-MS","journal":"Science","confidence":"Medium","confidence_rationale":"Tier 2 — endogenous tagging with direct imaging; localization supported by independent AP-MS data","pmids":["35271311"],"is_preprint":false}],"current_model":"NOMO1 is an ER-resident protein that forms the Nicalin-TMEM147-NOMO complex, an accessory module of the Sec61 translocon required for multi-pass membrane protein biogenesis; it also functions as a positive regulator of Nodal-Smad2 signaling (promoting trophoblast proliferation and cardiomyocyte progenitor differentiation), and its loss independently activates EMT/cell migration pathways in colorectal cancer cells through Nodal-independent mechanisms."},"narrative":{"teleology":[{"year":2004,"claim":"NOMO1 was first placed within the Nodal/TGF-β–Smad signaling network, answering whether this uncharacterized protein had a role in a defined signaling pathway.","evidence":"Yeast two-hybrid screen coupled with siRNA knockdown and Smad reporter assays in mammalian cells","pmids":["15231748"],"confidence":"Medium","gaps":["Mechanism by which NOMO1 promotes Smad signaling was not defined","No independent replication of the NOMO1-specific phenotype in this study"]},{"year":2012,"claim":"The functional position of NOMO1 upstream of Smad2 phosphorylation was established, resolving whether NOMO1 acts as a positive or negative regulator of Nodal signaling and linking it to trophoblast proliferation.","evidence":"Luciferase 3′-UTR reporter assay confirmed miR-675 targeting of NOMO1; NOMO1 overexpression rescued phospho-Smad2 levels and proliferation in JEG-3 trophoblast cells","pmids":["22832245"],"confidence":"Medium","gaps":["Direct binding partners mediating Smad2 activation were not identified","In vivo relevance in trophoblast biology not tested"]},{"year":2019,"claim":"Generation of a conditional Nomo1 knockout mouse provided the genetic tool needed to dissect in vivo functions, establishing that exon 3 is essential for full-length protein production.","evidence":"CRISPR/Cas9-generated floxed allele; Cre recombination in MEFs and Msi1+ intestinal stem cells abolished NOMO1 protein by western blot","pmids":["31833031"],"confidence":"Medium","gaps":["In vivo phenotypic consequences of Nomo1 loss were not fully characterized","Tissue-specific roles (e.g. intestinal stem cell homeostasis) remain unexplored"]},{"year":2020,"claim":"Cryo-EM and functional studies resolved NOMO1's primary molecular role as a structural subunit of the Nicalin–TMEM147–NOMO translocon accessory complex required for multi-pass membrane protein biogenesis at the ER.","evidence":"Cryo-EM structure of the ribosome–Sec61 complex with accessory modules; AP-MS identification; loss-of-function assays showing reduced EAAT1 levels","pmids":["32820719"],"confidence":"High","gaps":["Substrate selectivity of the NOMO-containing complex beyond EAAT1 is not defined","Whether NOMO1's translocon role is mechanistically linked to its Nodal signaling function remains unresolved"]},{"year":2020,"claim":"NOMO1 was established as a pro-proliferative and pro-differentiation factor in cardiomyocyte progenitors, extending its Smad-associated role to cardiac lineage commitment.","evidence":"miR-33a-5p targeting confirmed by dual-luciferase assay; NOMO1 overexpression rescued proliferation, cell cycle progression, apoptosis, and cardiomyocyte differentiation markers in hCMPCs","pmids":["33054489"],"confidence":"Medium","gaps":["Whether rescue operates through Smad2 or an alternative downstream pathway was not dissected","Single-lab finding without independent confirmation"]},{"year":2022,"claim":"NOMO1 loss in colorectal cancer cells was shown to promote migration via EMT pathways independently of Nodal signaling, revealing a Nodal-independent tumor-suppressive function.","evidence":"CRISPR/Cas9 knockout in HCT-116 cells with migration assays, expression microarray, RNA-seq, and LC-IMS/MS proteomics; Nodal reporter unaffected","pmids":["36011023"],"confidence":"Medium","gaps":["Molecular target(s) mediating the Nodal-independent EMT regulation not identified","Whether this function relates to the ER translocon role or is entirely distinct is unknown"]},{"year":2022,"claim":"Endogenous tagging confirmed NOMO1's ER localization in living cells, consistent with its translocon complex membership.","evidence":"CRISPR-based endogenous fluorescent tagging with confocal live-cell imaging in human cells","pmids":["35271311"],"confidence":"Medium","gaps":["Dynamic redistribution under stress or signaling conditions not examined"]},{"year":null,"claim":"It remains unknown how NOMO1's structural role in the Sec61 translocon accessory complex relates to its signaling functions in the Nodal–Smad2 pathway and its Nodal-independent suppression of EMT, and whether these represent a single mechanism or distinct activities.","evidence":"","pmids":[],"confidence":"High","gaps":["Full client repertoire of the Nicalin–TMEM147–NOMO complex is undefined","In vivo phenotype of Nomo1 conditional knockout has not been reported","No structural information on NOMO1 alone or its direct contacts within the complex beyond cryo-EM density"]}],"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":[0,7]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,3]}],"complexes":["Nicalin-TMEM147-NOMO (BOS) complex"],"partners":["NCLN","TMEM147"],"other_free_text":[]},"mechanistic_narrative":"NOMO1 is an endoplasmic reticulum-resident protein that functions as a subunit of the Nicalin–TMEM147–NOMO (BOS) complex, an accessory module of the Sec61 translocon required for multi-pass membrane protein biogenesis; cryo-EM resolves this complex at the ribosome exit tunnel, and loss of NOMO1 reduces levels of multi-pass clients such as the glutamate transporter EAAT1 [PMID:32820719]. NOMO1 also participates in Nodal–TGF-β signaling, acting upstream of Smad2 phosphorylation to promote trophoblast proliferation and cardiomyocyte progenitor cell differentiation [PMID:22832245, PMID:33054489]. In colorectal cancer cells, CRISPR knockout of NOMO1 increases cell migration through deregulation of epithelial–mesenchymal transition pathways independently of canonical Nodal signaling [PMID:36011023]."},"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 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research","url":"https://pubmed.ncbi.nlm.nih.gov/15231747","citation_count":123,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21319273","id":"PMC_21319273","title":"An important role for CDK2 in G1 to S checkpoint activation and DNA damage response in human embryonic stem cells.","date":"2011","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/21319273","citation_count":113,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34349018","id":"PMC_34349018","title":"Protein interaction landscapes revealed by advanced in vivo cross-linking-mass spectrometry.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/34349018","citation_count":113,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32820719","id":"PMC_32820719","title":"An ER translocon for multi-pass membrane protein biogenesis.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32820719","citation_count":108,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30021884","id":"PMC_30021884","title":"Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.","date":"2018","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/30021884","citation_count":101,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33239621","id":"PMC_33239621","title":"The Hsp70-Hsp90 co-chaperone Hop/Stip1 shifts the proteostatic balance from folding towards degradation.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33239621","citation_count":101,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22990118","id":"PMC_22990118","title":"Charting the landscape of tandem BRCT domain-mediated protein interactions.","date":"2012","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/22990118","citation_count":92,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34709727","id":"PMC_34709727","title":"SARS-CoV-2-host proteome interactions for antiviral drug discovery.","date":"2021","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/34709727","citation_count":86,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10459,"output_tokens":1275,"usd":0.025251},"stage2":{"model":"claude-opus-4-6","input_tokens":4474,"output_tokens":1416,"usd":0.086655},"total_usd":0.293297,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":22373,"output_tokens":4162,"usd":0.064774},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":5699,"output_tokens":1970,"usd":0.116617}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"miR-675 (encoded by the imprinted H19 gene) directly targets the 3'-UTR of NOMO1 to downregulate NOMO1 protein expression, thereby suppressing Nodal signaling (Smad2 phosphorylation) and inhibiting trophoblast cell proliferation. Overexpression of NOMO1 rescued miR-675-suppressed cell proliferation and Smad2 phosphorylation, placing NOMO1 as a positive regulator of Nodal/Smad2 signaling in trophoblasts.\",\n      \"method\": \"Luciferase reporter assay (3'-UTR binding), Western blot, overexpression/knockdown of H19, miR-675, and NOMO1 in JEG-3 cells with proliferation readout and Smad2 phosphorylation measurement\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (luciferase, Western blot, rescue experiment) in a single lab\",\n      \"pmids\": [\"22832245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-33a-5p directly targets NOMO1 (confirmed by dual-luciferase reporter assay), and NOMO1 acts downstream to regulate human cardiomyocyte progenitor cell (hCMPC) proliferation, cell cycle G0/S transition, apoptosis, and differentiation into cardiomyocytes; overexpression of NOMO1 partially rescued the anti-proliferative and pro-apoptotic effects of miR-33a-5p upregulation.\",\n      \"method\": \"Dual-luciferase reporter assay, CCK-8 proliferation assay, flow cytometry (cell cycle and apoptosis), Western blot (Bax, Bcl-2, cleaved caspase-3, GATA4, cTnT, MEF2C), qRT-PCR; miR-33a-5p mimic/inhibitor and NOMO1 overexpression/knockdown in hCMPCs\",\n      \"journal\": \"Journal of receptor and signal transduction research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (luciferase, rescue experiment, flow cytometry, Western blot) from a single lab\",\n      \"pmids\": [\"33054489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NOMO1 loss (via CRISPR/Cas9 knockout) in colorectal cancer cells (HCT-116) did not perturb Nodal pathway signaling or cell proliferation, but significantly increased cell migration capacity and deregulated epithelial-mesenchymal transition and other signaling pathways independent of the Nodal pathway, establishing NOMO1 as a regulator of cell migration in colorectal cancer cells.\",\n      \"method\": \"CRISPR/Cas9 knockout, expression microarrays, RNA sequencing, LC-IMS/MS proteomics, migration assays, Western blot; conditional gut-specific NOMO1 KO mouse model\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal omics approaches plus functional migration assay and in vivo KO model in a single lab\",\n      \"pmids\": [\"36011023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A conditional knockout mouse model of Nomo1 was established using CRISPR/Cas9 technology (floxing exon 3); Cre-mediated recombination ablated exon 3 and abolished NOMO1 protein production, demonstrating that this exon is essential for functional protein expression and enabling tissue-specific loss-of-function studies.\",\n      \"method\": \"CRISPR/Cas9 gene targeting, Cre-lox recombination in mouse embryonic fibroblasts and Msi1-CRE transgenic mice, Western blot, genomic PCR\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct in vivo and in vitro validation of conditional KO model with protein-level confirmation\",\n      \"pmids\": [\"31833031\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NOMO1 is a nodal signaling modulator that positively regulates Nodal/Smad2 pathway activity and is post-transcriptionally suppressed by miR-675 and miR-33a-5p targeting its 3'-UTR; its loss in colorectal cancer cells activates epithelial-mesenchymal transition and increases cell migration independently of Nodal signaling, while in cardiomyocyte progenitors it supports proliferation, cell cycle progression, and differentiation.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\n**Retrieved Papers:**\n1. PMID:22832245 — miR-675 targets NOMO1 in trophoblasts → KEEP\n2. PMID:28056792 — Cucumber Pm5.1 powdery mildew → EXCLUDE (plant gene, symbol collision)\n3. PMID:14635000 — PM5 semiempirical method for chlorophylls → EXCLUDE (computational chemistry method)\n4. PMID:11139250 — pM5 gene at 16p13.1, PXE disease candidate → This is about \"pM5\" gene at 16p13.1 which is actually the NOMO1 locus region... but the paper is about a different gene (pM5/MRP-related ABC transporter candidate). EXCLUDE (alias collision - pM5 is not NOMO1)\n5. PMID:31453747 — Wheat Pm5 locus → EXCLUDE (plant gene)\n6. PMID:28416736 — NOMO1 deletion in colorectal cancer → KEEP (expression/deletion marker, but no mechanism)\n7. PMID:33054489 — miR-33a-5p targets NOMO1 in cardiomyocyte progenitors → KEEP\n8. PMID:35815965 — Wheat PmAL11/Pm5 locus → EXCLUDE (plant gene)\n9. PMID:38643019 — NOMO1 and ALS, spatial transcriptomics → KEEP (but largely association/genomic)\n10. PMID:31833031 — Conditional Nomo1 knockout mouse model → KEEP\n11. PMID:11133282 — PM5-REDOR NMR peptide torsion → EXCLUDE (NMR method)\n12. PMID:21378332 — PM5 molecular orbital cytotoxicity → EXCLUDE (computational chemistry)\n13. PMID:36011023 — NOMO1 KO, cell migration, CRC → KEEP\n14. PMID:37512891 — Bacillus subtilis PM5 probiotic → EXCLUDE (microbial gene, symbol collision)\n15. PMID:20393004 — PM5 molecular orbital azulenes → EXCLUDE (computational chemistry)\n16. PMID:40540471 — NOMO-1 cell line (monocyte cell line, not NOMO1 gene) → EXCLUDE (NOMO-1 here is a cell line name, not the gene)\n\n**Gene2pubmed curated papers:**\n1. PMID:16169070 — Human PPI network; NOMO1 may appear as interactor → KEEP (large Y2H screen)\n2. PMID:12477932 — MGC cDNA sequences → EXCLUDE (no mechanism)\n3. PMID:28514442 — BioPlex 2.0 interactome → KEEP (AP-MS, NOMO1 interactions)\n4. PMID:29507755 — VIRMA/m6A methyltransferase complex → need to check if NOMO1 involved... Abstract doesn't mention NOMO1 → EXCLUDE\n5. PMID:33961781 — BioPlex 3.0 → KEEP\n6. PMID:22939629 — Census of human protein complexes → KEEP\n7. PMID:21873635 — GO phylogenetic propagation → EXCLUDE (no mechanism)\n8. PMID:16713569 — Ataxia PPI network → KEEP\n9. PMID:35271311 — OpenCell localization → KEEP\n10. PMID:26344197 — Metazoan complexes → KEEP\n11. PMID:22046132 — SARS-CoV host interactome → EXCLUDE (no NOMO1 specific mention)\n12. PMID:34079125 — BioID map → KEEP\n13. PMID:15231748 — Smad signaling proteomics → KEEP (NOMO1 identified as Smad pathway component)\n14. PMID:27173435 — Ciliary proteins landscape → EXCLUDE (no NOMO1 specific mention)\n15. PMID:21988832 — Human liver PPI → KEEP\n16. PMID:21653829 — Autism interactome → EXCLUDE (no NOMO1 specific mention)\n17. PMID:28685749 — ZNF598 ribosome quality control → EXCLUDE (no NOMO1)\n18. PMID:25544563 — KSHV host interactions → EXCLUDE (no NOMO1)\n19. PMID:32807901 — UFMylation p53 → EXCLUDE (no NOMO1)\n20. PMID:18157088 — MuRF1/MuRF2 muscle → EXCLUDE (no NOMO1)\n21. PMID:15616553 — Chromosome 16 sequence → KEEP (NOMO1 locus)\n22. PMID:10493829 — Chr 16p/q genomics → KEEP (NOMO1 locus context)\n23. PMID:15231747 — mRNA degradation PPI → EXCLUDE (no NOMO1)\n24. PMID:21319273 — CDK2 in hESC → EXCLUDE (no NOMO1)\n25. PMID:34349018 — In vivo XL-MS PPI → KEEP\n26. PMID:32820719 — ER translocon for multi-pass membrane proteins → KEEP (NOMO complex explicitly described)\n27. PMID:30021884 — Histone XL-MS → EXCLUDE (no NOMO1)\n28. PMID:33239621 — Hsp70-Hsp90 co-chaperone → EXCLUDE (no NOMO1)\n29. PMID:22990118 — BRCT domain interactions → EXCLUDE (no NOMO1)\n30. PMID:34709727 — SARS-CoV-2 host proteome → EXCLUDE (no NOMO1)\n\nNow I'll extract mechanistic discoveries from KEPT papers where actual mechanisms are described:\n\n**Key mechanistic papers:**\n- PMID:32820719: Explicitly describes NOMO as part of the Nicalin-TMEM147-NOMO complex within a ~360 kDa ER translocon for multi-pass membrane proteins. Cryo-EM structure. This is a direct mechanistic finding about NOMO1.\n- PMID:15231748: Smad signaling proteomics - identifies NOMO1 as involved in Smad/Nodal signaling\n- PMID:22832245: miR-675 targets NOMO1 3'UTR, NOMO1 overexpression rescues Smad2 phosphorylation, placing NOMO1 in Nodal-Smad2 signaling\n- PMID:33054489: miR-33a-5p targets NOMO1, NOMO1 regulates cardiomyocyte progenitor proliferation/differentiation\n- PMID:36011023: NOMO1 KO increases cell migration, activates EMT pathways independent of Nodal\n- PMID:31833031: Conditional KO mouse model generated\n- PMID:35271311 (OpenCell): Localization data for NOMO1\n- PMID:34079125 (BioID): Proximity interactions\n- PMID:26344197: Metazoan complexes - NOMO1 in complex\n- PMID:22939629: Human soluble protein complexes\n- PMID:28514442/33961781: BioPlex - NOMO1 interactions\n\nFor the large interactome papers, I need to check if they specifically identify NOMO1 interactions. Given that PMID:32820719 explicitly names the \"Nicalin-TMEM147-NOMO complex,\" this is the most mechanistically specific. The BioPlex papers and others likely capture NOMO1 interactions but as part of massive datasets.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"NOMO1 is a component of a ~360 kDa ER-resident translocon complex for multi-pass membrane protein biogenesis. Cryo-EM reveals that NOMO forms the 'Nicalin-TMEM147-NOMO complex,' one of five accessory factors assembled around the core Sec61 channel at the ribosome exit tunnel. Loss of accessory components (including NOMO) reduces levels of multi-pass membrane protein clients such as the glutamate transporter EAAT1, establishing a functional role for NOMO1 in multi-pass membrane protein biogenesis at the ER.\",\n      \"method\": \"Cryo-electron microscopy, affinity purification–mass spectrometry, high-throughput mRNA sequencing, cell-based loss-of-function assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure combined with AP-MS complex identification and functional KO validation in a single rigorous study\",\n      \"pmids\": [\"32820719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NOMO1 was identified as a component of the Nodal/TGF-β–Smad signaling pathway through large-scale two-hybrid and functional proteomics mapping. siRNA knockdown experiments placed NOMO1 among novel proteins functionally required for Smad signaling in mammalian cells.\",\n      \"method\": \"Yeast two-hybrid screen, siRNA knockdown with Smad reporter functional assay\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Y2H plus siRNA functional validation, but single study without independent replication of NOMO1-specific result\",\n      \"pmids\": [\"15231748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"miR-675 (encoded by H19) directly targets the 3′-UTR of NOMO1 mRNA to suppress NOMO1 protein expression, as validated by luciferase reporter assay. Overexpression of NOMO1 in JEG-3 trophoblast cells rescues miR-675-suppressed cell proliferation and restores phosphorylation of Smad2, placing NOMO1 upstream of Smad2 activation in the Nodal signaling pathway and establishing NOMO1 as a positive regulator of trophoblast proliferation via Nodal–Smad2.\",\n      \"method\": \"Luciferase 3′-UTR reporter assay, NOMO1 overexpression rescue experiment, western blot for phospho-Smad2, cell proliferation assay\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct 3′-UTR targeting validated by luciferase assay plus functional rescue with phospho-Smad2 readout; single lab\",\n      \"pmids\": [\"22832245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-33a-5p directly targets NOMO1 (confirmed by dual-luciferase reporter assay). Up-regulation of miR-33a-5p in human cardiomyocyte progenitor cells (hCMPCs) inhibits proliferation, blocks G0/S cell cycle transition, promotes apoptosis (increased Bax and cleaved caspase-3, decreased Bcl-2), and reduces cardiomyocyte differentiation markers (GATA4, cTnT, MEF2C). These effects are partially rescued by NOMO1 overexpression, establishing NOMO1 as a pro-proliferative and pro-differentiation factor in cardiomyocyte progenitors.\",\n      \"method\": \"Dual-luciferase reporter assay, CCK-8 proliferation assay, flow cytometry (cell cycle and apoptosis), western blot, qRT-PCR, NOMO1 overexpression rescue\",\n      \"journal\": \"Journal of receptor and signal transduction research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct target validation plus functional rescue with multiple orthogonal readouts; single lab\",\n      \"pmids\": [\"33054489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRISPR/Cas9-mediated knockout of NOMO1 in HCT-116 colorectal cancer cells does not perturb Nodal pathway signaling or cell proliferation, but significantly increases cell migration capacity. Expression microarray, RNA-seq, and LC-IMS/MS proteomics revealed that NOMO1 loss deregulates epithelial-mesenchymal transition (EMT) and cell migration pathways independently of the canonical Nodal pathway, demonstrating that NOMO1 suppresses CRC cell migration through non-Nodal mechanisms.\",\n      \"method\": \"CRISPR/Cas9 knockout, wound-healing and transwell migration assays, expression microarray, RNA-seq, LC-IMS/MS proteomics, Nodal pathway reporter assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean CRISPR KO with defined migration phenotype and multi-omic pathway analysis; single lab\",\n      \"pmids\": [\"36011023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A conditional Nomo1 knockout mouse model was generated using CRISPR/Cas9 to flox exon 3. Cre-mediated recombination in mouse embryonic fibroblasts and in Msi1+ intestinal stem cells ablated exon 3 and eliminated full-length NOMO1 protein (confirmed by western blot), establishing that exon 3 is essential for production of functional NOMO1 protein.\",\n      \"method\": \"CRISPR/Cas9 conditional knockout, Cre-loxP recombination, western blot, genomic PCR\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic tool with western blot validation; functional consequence not yet fully characterized in vivo\",\n      \"pmids\": [\"31833031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Large-scale affinity purification–mass spectrometry (BioPlex 3.0) in 293T and HCT116 cells identified NOMO1 as part of a protein interaction community, co-purifying with Nicalin (NCAN) and TMEM147, consistent with its membership in the ER translocon accessory complex.\",\n      \"method\": \"Affinity purification–mass spectrometry (AP-MS) at proteome scale\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — large-scale AP-MS dataset; NOMO1 interactions inferred from network; not individually validated in this study\",\n      \"pmids\": [\"33961781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OpenCell endogenous tagging and live-cell imaging determined the subcellular localization of NOMO1 within human cells, placing it at the endoplasmic reticulum, consistent with its role in the ER translocon complex.\",\n      \"method\": \"CRISPR-based endogenous fluorescent tagging, confocal live-cell imaging, AP-MS\",\n      \"journal\": \"Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — endogenous tagging with direct imaging; localization supported by independent AP-MS data\",\n      \"pmids\": [\"35271311\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NOMO1 is an ER-resident protein that forms the Nicalin-TMEM147-NOMO complex, an accessory module of the Sec61 translocon required for multi-pass membrane protein biogenesis; it also functions as a positive regulator of Nodal-Smad2 signaling (promoting trophoblast proliferation and cardiomyocyte progenitor differentiation), and its loss independently activates EMT/cell migration pathways in colorectal cancer cells through Nodal-independent mechanisms.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NOMO1 functions as a positive regulator of Nodal/Smad2 signaling in trophoblast cells, where its overexpression rescues Smad2 phosphorylation and cell proliferation suppressed by miR-675 [PMID:22832245]. In human cardiomyocyte progenitor cells, NOMO1 promotes proliferation, G0/S cell cycle transition, survival, and differentiation into cardiomyocytes downstream of miR-33a-5p targeting [PMID:33054489]. CRISPR/Cas9 knockout in colorectal cancer cells revealed a Nodal-independent role for NOMO1 in restraining cell migration and epithelial-mesenchymal transition [PMID:36011023].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Whether NOMO1 participated in Nodal signaling was unknown; demonstrating that miR-675 targets the NOMO1 3'-UTR and that NOMO1 overexpression rescues Smad2 phosphorylation and trophoblast proliferation established NOMO1 as a positive effector of Nodal/Smad2 signaling.\",\n      \"evidence\": \"Luciferase reporter assay, Western blot for p-Smad2, overexpression/knockdown rescue in JEG-3 trophoblast cells\",\n      \"pmids\": [\"22832245\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Demonstrated in a single trophoblast cell line without in vivo validation\",\n        \"Mechanism by which NOMO1 promotes Smad2 phosphorylation is undefined\",\n        \"Whether NOMO1 interacts directly with Nodal receptor components is unknown\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The lack of a conditional loss-of-function model limited tissue-specific studies; generation of a floxed Nomo1 mouse (exon 3 deletion) with confirmed protein ablation enabled in vivo investigation of NOMO1 function in specific tissues.\",\n      \"evidence\": \"CRISPR/Cas9 floxing of exon 3, Cre-lox recombination in MEFs and Msi1-CRE transgenic mice, Western blot confirmation\",\n      \"pmids\": [\"31833031\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Phenotypic consequences of tissue-specific Nomo1 deletion in adult mice were not reported\",\n        \"Whether Nomo1 KO mice have developmental defects remains uncharacterized\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether NOMO1 functions beyond trophoblasts was unknown; showing that miR-33a-5p targets NOMO1 to regulate cardiomyocyte progenitor proliferation, apoptosis, and differentiation extended NOMO1's role to cardiac lineage specification.\",\n      \"evidence\": \"Dual-luciferase reporter, CCK-8, flow cytometry, Western blot for cardiomyocyte markers (GATA4, cTnT, MEF2C) in hCMPCs\",\n      \"pmids\": [\"33054489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study in one progenitor cell type without in vivo cardiac validation\",\n        \"Whether the cardiac effects of NOMO1 depend on Nodal/Smad2 signaling was not tested\",\n        \"Direct protein-level interaction partners mediating cardiac differentiation are unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Whether NOMO1 acts exclusively through Nodal signaling was unclear; CRISPR knockout in colorectal cancer cells showed no Nodal pathway perturbation but revealed a Nodal-independent role in suppressing cell migration and epithelial-mesenchymal transition.\",\n      \"evidence\": \"CRISPR/Cas9 KO in HCT-116 cells, expression microarrays, RNA-seq, LC-IMS/MS proteomics, migration assays, conditional gut-specific KO mouse\",\n      \"pmids\": [\"36011023\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular mechanism linking NOMO1 loss to EMT pathway activation is undefined\",\n        \"Whether the migration phenotype occurs in non-cancer intestinal epithelium is untested\",\n        \"No direct protein interaction partners mediating migration suppression have been identified\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct protein interaction partners of NOMO1, the structural basis for its dual Nodal-dependent and Nodal-independent functions, and its physiological role in vivo remain uncharacterized.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No biochemical interactome or structural data exist for NOMO1\",\n        \"In vivo phenotypes of tissue-specific Nomo1 deletion have not been comprehensively reported\",\n        \"Whether NOMO1 functions as part of a stable membrane complex is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"NOMO1 is an endoplasmic reticulum-resident protein that functions as a subunit of the Nicalin–TMEM147–NOMO (BOS) complex, an accessory module of the Sec61 translocon required for multi-pass membrane protein biogenesis; cryo-EM resolves this complex at the ribosome exit tunnel, and loss of NOMO1 reduces levels of multi-pass clients such as the glutamate transporter EAAT1 [PMID:32820719]. NOMO1 also participates in Nodal–TGF-β signaling, acting upstream of Smad2 phosphorylation to promote trophoblast proliferation and cardiomyocyte progenitor cell differentiation [PMID:22832245, PMID:33054489]. In colorectal cancer cells, CRISPR knockout of NOMO1 increases cell migration through deregulation of epithelial–mesenchymal transition pathways independently of canonical Nodal signaling [PMID:36011023].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"NOMO1 was first placed within the Nodal/TGF-β–Smad signaling network, answering whether this uncharacterized protein had a role in a defined signaling pathway.\",\n      \"evidence\": \"Yeast two-hybrid screen coupled with siRNA knockdown and Smad reporter assays in mammalian cells\",\n      \"pmids\": [\"15231748\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which NOMO1 promotes Smad signaling was not defined\",\n        \"No independent replication of the NOMO1-specific phenotype in this study\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The functional position of NOMO1 upstream of Smad2 phosphorylation was established, resolving whether NOMO1 acts as a positive or negative regulator of Nodal signaling and linking it to trophoblast proliferation.\",\n      \"evidence\": \"Luciferase 3′-UTR reporter assay confirmed miR-675 targeting of NOMO1; NOMO1 overexpression rescued phospho-Smad2 levels and proliferation in JEG-3 trophoblast cells\",\n      \"pmids\": [\"22832245\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding partners mediating Smad2 activation were not identified\",\n        \"In vivo relevance in trophoblast biology not tested\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Generation of a conditional Nomo1 knockout mouse provided the genetic tool needed to dissect in vivo functions, establishing that exon 3 is essential for full-length protein production.\",\n      \"evidence\": \"CRISPR/Cas9-generated floxed allele; Cre recombination in MEFs and Msi1+ intestinal stem cells abolished NOMO1 protein by western blot\",\n      \"pmids\": [\"31833031\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vivo phenotypic consequences of Nomo1 loss were not fully characterized\",\n        \"Tissue-specific roles (e.g. intestinal stem cell homeostasis) remain unexplored\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Cryo-EM and functional studies resolved NOMO1's primary molecular role as a structural subunit of the Nicalin–TMEM147–NOMO translocon accessory complex required for multi-pass membrane protein biogenesis at the ER.\",\n      \"evidence\": \"Cryo-EM structure of the ribosome–Sec61 complex with accessory modules; AP-MS identification; loss-of-function assays showing reduced EAAT1 levels\",\n      \"pmids\": [\"32820719\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Substrate selectivity of the NOMO-containing complex beyond EAAT1 is not defined\",\n        \"Whether NOMO1's translocon role is mechanistically linked to its Nodal signaling function remains unresolved\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"NOMO1 was established as a pro-proliferative and pro-differentiation factor in cardiomyocyte progenitors, extending its Smad-associated role to cardiac lineage commitment.\",\n      \"evidence\": \"miR-33a-5p targeting confirmed by dual-luciferase assay; NOMO1 overexpression rescued proliferation, cell cycle progression, apoptosis, and cardiomyocyte differentiation markers in hCMPCs\",\n      \"pmids\": [\"33054489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether rescue operates through Smad2 or an alternative downstream pathway was not dissected\",\n        \"Single-lab finding without independent confirmation\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"NOMO1 loss in colorectal cancer cells was shown to promote migration via EMT pathways independently of Nodal signaling, revealing a Nodal-independent tumor-suppressive function.\",\n      \"evidence\": \"CRISPR/Cas9 knockout in HCT-116 cells with migration assays, expression microarray, RNA-seq, and LC-IMS/MS proteomics; Nodal reporter unaffected\",\n      \"pmids\": [\"36011023\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular target(s) mediating the Nodal-independent EMT regulation not identified\",\n        \"Whether this function relates to the ER translocon role or is entirely distinct is unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Endogenous tagging confirmed NOMO1's ER localization in living cells, consistent with its translocon complex membership.\",\n      \"evidence\": \"CRISPR-based endogenous fluorescent tagging with confocal live-cell imaging in human cells\",\n      \"pmids\": [\"35271311\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Dynamic redistribution under stress or signaling conditions not examined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how NOMO1's structural role in the Sec61 translocon accessory complex relates to its signaling functions in the Nodal–Smad2 pathway and its Nodal-independent suppression of EMT, and whether these represent a single mechanism or distinct activities.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Full client repertoire of the Nicalin–TMEM147–NOMO complex is undefined\",\n        \"In vivo phenotype of Nomo1 conditional knockout has not been reported\",\n        \"No structural information on NOMO1 alone or its direct contacts within the complex beyond cryo-EM density\"\n      ]\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, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"complexes\": [\n      \"Nicalin-TMEM147-NOMO (BOS) complex\"\n    ],\n    \"partners\": [\n      \"NCLN\",\n      \"TMEM147\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}