{"gene":"TMEM209","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2012,"finding":"TMEM209 is an integral nuclear envelope protein that localizes to the nuclear envelope, Golgi apparatus, and cytoplasm in lung cancer cells. Mass spectrometric analysis identified nucleoporin NUP205 as a TMEM209-interacting protein; TMEM209 stabilizes NUP205 and increases nuclear c-Myc levels. Ectopic overexpression of TMEM209 promoted cell growth, and its attenuation blocked growth.","method":"Mass spectrometry (co-immunoprecipitation/MS), subcellular localization (immunofluorescence), ectopic overexpression and siRNA knockdown with cell growth readouts","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction identified by MS, localization by immunofluorescence, functional rescue by OE/KD; single lab with multiple orthogonal methods","pmids":["22719065"],"is_preprint":false},{"year":2024,"finding":"TMEM209 binds directly to the nuclear import protein KPNB1, competitively blocking the interaction between KPNB1 and the E3 ubiquitin ligase RCHY1, thereby preventing K48-linked ubiquitination and proteasomal degradation of KPNB1. Stabilized KPNB1 activates the Wnt/β-catenin signaling pathway, promoting HCC cell proliferation, migration, invasion, and EMT in vitro and tumor growth and metastasis in vivo.","method":"Co-immunoprecipitation (binding assays), ubiquitination assays, competitive interaction assays, siRNA/shRNA knockdown with in vitro and xenograft in vivo readouts","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for binding, ubiquitination assay, in vitro and in vivo functional validation; single lab with multiple orthogonal methods","pmids":["39414762"],"is_preprint":false},{"year":2026,"finding":"TMEM209 is established as a fourth transmembrane nucleoporin in mammalian cells. Proximity labeling showed TMEM209 is present near inner nuclear membrane proteins and other nucleoporins. TMEM209 localizes to the nuclear pore complex by immunofluorescence microscopy. It biochemically interacts with Nup210 via a region containing its two transmembrane domains. TMEM209 depletion impaired cell growth and delayed entry into S, G2, and M phases of the cell cycle. Conversely, TMEM209 overexpression dissociated Nup210 from the nuclear envelope.","method":"Proximity labeling (BioID), immunofluorescence microscopy, biochemical co-immunoprecipitation/interaction assays with domain mapping, siRNA depletion with cell cycle analysis (flow cytometry), overexpression with nuclear envelope fractionation","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including proximity labeling, co-IP with domain mapping, localization, and functional cell cycle phenotype in a single rigorous study","pmids":["41582553"],"is_preprint":false}],"current_model":"TMEM209 is a transmembrane nucleoporin resident at the nuclear pore complex that physically interacts with Nup210 via its transmembrane domains to support cell cycle progression and proliferation; in cancer contexts it additionally stabilizes NUP205 to elevate nuclear c-Myc, and binds KPNB1 to prevent its RCHY1-mediated ubiquitination and degradation, thereby activating Wnt/β-catenin signaling."},"narrative":{"mechanistic_narrative":"TMEM209 is a transmembrane nucleoporin resident at the nuclear pore complex that supports cell cycle progression and proliferation [PMID:41582553]. It localizes to the nuclear pore complex and is positioned near inner nuclear membrane proteins and other nucleoporins, interacting biochemically with Nup210 through a region containing its two transmembrane domains; its depletion impairs cell growth and delays entry into the S, G2, and M phases, while its overexpression dissociates Nup210 from the nuclear envelope [PMID:41582553]. In cancer contexts, TMEM209 drives growth through additional partners: it stabilizes the nucleoporin NUP205 and elevates nuclear c-Myc to promote lung cancer cell growth [PMID:22719065], and it binds the nuclear import protein KPNB1 to competitively block KPNB1's interaction with the E3 ligase RCHY1, preventing K48-linked ubiquitination and proteasomal degradation of KPNB1 and thereby activating Wnt/β-catenin signaling to promote hepatocellular carcinoma proliferation, migration, invasion, EMT, and metastasis [PMID:39414762]. Beyond these interactions, the structural role of TMEM209 within the pore and the mechanism coupling it to cell cycle timing have not been further characterized in the available corpus.","teleology":[{"year":2012,"claim":"Established TMEM209 as a growth-promoting nuclear envelope protein and identified its first molecular partner, linking it to nucleoporin biology and c-Myc.","evidence":"Co-immunoprecipitation/mass spectrometry, immunofluorescence localization, and overexpression/knockdown with growth readouts in lung cancer cells","pmids":["22719065"],"confidence":"Medium","gaps":["Mechanism by which NUP205 stabilization raises nuclear c-Myc not resolved","Whether TMEM209 is a bona fide nucleoporin not yet established at this stage","No structural or domain-level interaction mapping"]},{"year":2024,"claim":"Defined a distinct oncogenic mechanism in which TMEM209 stabilizes a nuclear import factor by shielding it from ubiquitination, connecting it to Wnt/β-catenin signaling.","evidence":"Co-IP, ubiquitination and competitive interaction assays, and knockdown with in vitro and xenograft readouts in HCC","pmids":["39414762"],"confidence":"Medium","gaps":["Structural basis of competitive KPNB1/RCHY1 binding not determined","Single-lab study without reciprocal independent validation","Relationship between this cytoplasmic/import role and the NPC-resident role unclear"]},{"year":2026,"claim":"Resolved TMEM209's core identity as a fourth transmembrane nucleoporin at the nuclear pore complex with a defined Nup210 interaction and a cell cycle progression function.","evidence":"BioID proximity labeling, immunofluorescence, co-IP with transmembrane-domain mapping, and siRNA depletion with flow cytometry cell cycle analysis","pmids":["41582553"],"confidence":"High","gaps":["Functional consequence of TMEM209-driven Nup210 dissociation not defined","Mechanism coupling NPC residence to S/G2/M timing unknown","No structural model of TMEM209 within the pore"]},{"year":null,"claim":"How the NPC-structural role of TMEM209 mechanistically integrates with its cancer-context stabilization of NUP205/c-Myc and KPNB1/Wnt signaling remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model linking pore residence to oncogenic signaling outputs","No structural data on the transmembrane-domain interactions","Tissue/context determinants of which partner program dominates unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1]}],"complexes":["nuclear pore complex"],"partners":["NUP210","NUP205","KPNB1","RCHY1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96SK2","full_name":"Transmembrane protein 209","aliases":[],"length_aa":561,"mass_kda":62.9,"function":"Nuclear envelope protein which in association with NUP205, may be involved in nuclear transport of various nuclear proteins in addition to MYC","subcellular_location":"Membrane; Nucleus envelope; Golgi apparatus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q96SK2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM209","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TMEM209","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear membrane","reliability":"Approved"},{"location":"Nuclear speckles","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMEM209"},"hgnc":{"alias_symbol":["FLJ14803","NET31"],"prev_symbol":[]},"alphafold":{"accession":"Q96SK2","domains":[{"cath_id":"-","chopping":"325-558","consensus_level":"medium","plddt":90.1672,"start":325,"end":558},{"cath_id":"1.10.287","chopping":"24-84","consensus_level":"medium","plddt":83.3867,"start":24,"end":84}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96SK2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96SK2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96SK2-F1-predicted_aligned_error_v6.png","plddt_mean":68.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM209","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM209"},"sequence":{"accession":"Q96SK2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96SK2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96SK2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96SK2"}},"corpus_meta":[{"pmid":"22816737","id":"PMC_22816737","title":"High-throughput sequencing analysis of the chromosome 7q32 deletion reveals IRF5 as a potential tumour suppressor in splenic marginal-zone lymphoma.","date":"2012","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/22816737","citation_count":40,"is_preprint":false},{"pmid":"22719065","id":"PMC_22719065","title":"Critical function for nuclear envelope protein TMEM209 in human pulmonary carcinogenesis.","date":"2012","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/22719065","citation_count":35,"is_preprint":false},{"pmid":"14962666","id":"PMC_14962666","title":"Imprinting analysis of 10 genes and/or transcripts in a 1.5-Mb MEST-flanking region at human chromosome 7q32.","date":"2004","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/14962666","citation_count":16,"is_preprint":false},{"pmid":"39414762","id":"PMC_39414762","title":"TMEM209 promotes hepatocellular carcinoma progression by activating the Wnt/β-catenin signaling pathway through KPNB1 stabilization.","date":"2024","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/39414762","citation_count":7,"is_preprint":false},{"pmid":"34003694","id":"PMC_34003694","title":"Screening of Potential Key Genes Related to Tubal Factor Infertility Based on Competitive Endogenous RNA Network.","date":"2021","source":"Genetic testing and molecular biomarkers","url":"https://pubmed.ncbi.nlm.nih.gov/34003694","citation_count":5,"is_preprint":false},{"pmid":"37226600","id":"PMC_37226600","title":"Quality assessment of traditional Chinese medicine using quality biomarkers: Compound DanShen dripping pills as an example.","date":"2023","source":"Phytochemical analysis : PCA","url":"https://pubmed.ncbi.nlm.nih.gov/37226600","citation_count":3,"is_preprint":false},{"pmid":"41582553","id":"PMC_41582553","title":"The nuclear envelope protein TMEM209 is an integral component of the nuclear pore complex and interacts with Nup210.","date":"2026","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/41582553","citation_count":0,"is_preprint":false},{"pmid":"38305770","id":"PMC_38305770","title":"Risk model based on genes regulating the response of tumor cells to T-cell-mediated killing in esophageal squamous cell carcinoma.","date":"2024","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/38305770","citation_count":0,"is_preprint":false},{"pmid":"41562482","id":"PMC_41562482","title":"Transmembrane Protein GbTMEM209 Inhibits Fibre Elongation via Competitive Interaction With GbHOX3 in Gossypium barbadense.","date":"2026","source":"Plant biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/41562482","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6869,"output_tokens":1016,"usd":0.017923,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7560,"output_tokens":1823,"usd":0.041688,"stage2_stop_reason":"end_turn"},"total_usd":0.059611,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"TMEM209 is an integral nuclear envelope protein that localizes to the nuclear envelope, Golgi apparatus, and cytoplasm in lung cancer cells. Mass spectrometric analysis identified nucleoporin NUP205 as a TMEM209-interacting protein; TMEM209 stabilizes NUP205 and increases nuclear c-Myc levels. Ectopic overexpression of TMEM209 promoted cell growth, and its attenuation blocked growth.\",\n      \"method\": \"Mass spectrometry (co-immunoprecipitation/MS), subcellular localization (immunofluorescence), ectopic overexpression and siRNA knockdown with cell growth readouts\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction identified by MS, localization by immunofluorescence, functional rescue by OE/KD; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22719065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMEM209 binds directly to the nuclear import protein KPNB1, competitively blocking the interaction between KPNB1 and the E3 ubiquitin ligase RCHY1, thereby preventing K48-linked ubiquitination and proteasomal degradation of KPNB1. Stabilized KPNB1 activates the Wnt/β-catenin signaling pathway, promoting HCC cell proliferation, migration, invasion, and EMT in vitro and tumor growth and metastasis in vivo.\",\n      \"method\": \"Co-immunoprecipitation (binding assays), ubiquitination assays, competitive interaction assays, siRNA/shRNA knockdown with in vitro and xenograft in vivo readouts\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for binding, ubiquitination assay, in vitro and in vivo functional validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39414762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TMEM209 is established as a fourth transmembrane nucleoporin in mammalian cells. Proximity labeling showed TMEM209 is present near inner nuclear membrane proteins and other nucleoporins. TMEM209 localizes to the nuclear pore complex by immunofluorescence microscopy. It biochemically interacts with Nup210 via a region containing its two transmembrane domains. TMEM209 depletion impaired cell growth and delayed entry into S, G2, and M phases of the cell cycle. Conversely, TMEM209 overexpression dissociated Nup210 from the nuclear envelope.\",\n      \"method\": \"Proximity labeling (BioID), immunofluorescence microscopy, biochemical co-immunoprecipitation/interaction assays with domain mapping, siRNA depletion with cell cycle analysis (flow cytometry), overexpression with nuclear envelope fractionation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including proximity labeling, co-IP with domain mapping, localization, and functional cell cycle phenotype in a single rigorous study\",\n      \"pmids\": [\"41582553\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM209 is a transmembrane nucleoporin resident at the nuclear pore complex that physically interacts with Nup210 via its transmembrane domains to support cell cycle progression and proliferation; in cancer contexts it additionally stabilizes NUP205 to elevate nuclear c-Myc, and binds KPNB1 to prevent its RCHY1-mediated ubiquitination and degradation, thereby activating Wnt/β-catenin signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMEM209 is a transmembrane nucleoporin resident at the nuclear pore complex that supports cell cycle progression and proliferation [#2]. It localizes to the nuclear pore complex and is positioned near inner nuclear membrane proteins and other nucleoporins, interacting biochemically with Nup210 through a region containing its two transmembrane domains; its depletion impairs cell growth and delays entry into the S, G2, and M phases, while its overexpression dissociates Nup210 from the nuclear envelope [#2]. In cancer contexts, TMEM209 drives growth through additional partners: it stabilizes the nucleoporin NUP205 and elevates nuclear c-Myc to promote lung cancer cell growth [#0], and it binds the nuclear import protein KPNB1 to competitively block KPNB1's interaction with the E3 ligase RCHY1, preventing K48-linked ubiquitination and proteasomal degradation of KPNB1 and thereby activating Wnt/\\u03b2-catenin signaling to promote hepatocellular carcinoma proliferation, migration, invasion, EMT, and metastasis [#1]. Beyond these interactions, the structural role of TMEM209 within the pore and the mechanism coupling it to cell cycle timing have not been further characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established TMEM209 as a growth-promoting nuclear envelope protein and identified its first molecular partner, linking it to nucleoporin biology and c-Myc.\",\n      \"evidence\": \"Co-immunoprecipitation/mass spectrometry, immunofluorescence localization, and overexpression/knockdown with growth readouts in lung cancer cells\",\n      \"pmids\": [\"22719065\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which NUP205 stabilization raises nuclear c-Myc not resolved\",\n        \"Whether TMEM209 is a bona fide nucleoporin not yet established at this stage\",\n        \"No structural or domain-level interaction mapping\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a distinct oncogenic mechanism in which TMEM209 stabilizes a nuclear import factor by shielding it from ubiquitination, connecting it to Wnt/\\u03b2-catenin signaling.\",\n      \"evidence\": \"Co-IP, ubiquitination and competitive interaction assays, and knockdown with in vitro and xenograft readouts in HCC\",\n      \"pmids\": [\"39414762\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis of competitive KPNB1/RCHY1 binding not determined\",\n        \"Single-lab study without reciprocal independent validation\",\n        \"Relationship between this cytoplasmic/import role and the NPC-resident role unclear\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved TMEM209's core identity as a fourth transmembrane nucleoporin at the nuclear pore complex with a defined Nup210 interaction and a cell cycle progression function.\",\n      \"evidence\": \"BioID proximity labeling, immunofluorescence, co-IP with transmembrane-domain mapping, and siRNA depletion with flow cytometry cell cycle analysis\",\n      \"pmids\": [\"41582553\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of TMEM209-driven Nup210 dissociation not defined\",\n        \"Mechanism coupling NPC residence to S/G2/M timing unknown\",\n        \"No structural model of TMEM209 within the pore\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the NPC-structural role of TMEM209 mechanistically integrates with its cancer-context stabilization of NUP205/c-Myc and KPNB1/Wnt signaling remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No unified model linking pore residence to oncogenic signaling outputs\",\n        \"No structural data on the transmembrane-domain interactions\",\n        \"Tissue/context determinants of which partner program dominates unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\"nuclear pore complex\"],\n    \"partners\": [\"NUP210\", \"NUP205\", \"KPNB1\", \"RCHY1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}