{"gene":"TMEM92","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2011,"finding":"TMEM92 was classified as a member of the STMC6 protein family (single-transmembrane proteins with conserved 6 cysteines), sharing structural features with Shisa/Shisa-like proteins. The presence of PY motifs in TMEM92 suggests it could interact with WW-domain-containing proteins such as NEDD4 family E3 ubiquitin ligases, implicating it as a transmembrane adaptor; however, this interaction was predicted computationally and not experimentally confirmed in this study.","method":"Sequence similarity searches, pattern-based searches against eukaryotic proteomes, phylogenetic analysis","journal":"Cellular signalling","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only, no experimental validation of interactions or function","pmids":["22120523"],"is_preprint":false},{"year":2020,"finding":"Knockdown of TMEM92 in MDA-MB-231 breast cancer cells inhibited cell viability, invasiveness, and motility, and inactivated EMT (raising E-cadherin, lowering N-cadherin, Vimentin, and Snail protein levels), while overexpression promoted these phenotypes, establishing TMEM92 as a positive regulator of EMT in breast carcinoma cells.","method":"siRNA knockdown and pcDNA3.1-TMEM92 overexpression; CCK-8 assay, clone formation assay, Transwell assay, western blot for EMT markers","journal":"Tissue & cell","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, multiple functional assays (KD + OE with reciprocal phenotypes) but no pathway placement or binding partner identified","pmids":["32835947"],"is_preprint":false},{"year":2026,"finding":"TMEM92 directly associates with the RNA helicase DDX3X and protects it from proteasomal degradation by competitively preventing the E3 ubiquitin ligase TTC3 from binding DDX3X, thereby inhibiting TTC3-mediated K48-linked ubiquitination of DDX3X. Re-expression of DDX3X rescued the anti-tumor effects induced by TMEM92 knockdown, placing TMEM92 upstream of DDX3X in a TMEM92–DDX3X–TTC3 axis that drives TNBC progression and cisplatin resistance.","method":"Protein interaction assays (Co-IP/pulldown), ubiquitination assays, loss-of-function (TMEM92 depletion), rescue experiments (DDX3X re-expression), xenograft tumor models, cisplatin sensitivity assays (IC50 measurement)","journal":"Clinical and translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal binding/interaction assays, ubiquitination mechanistic assay, in vivo rescue and functional rescue, multiple orthogonal methods in a single rigorous study","pmids":["42138474"],"is_preprint":false}],"current_model":"TMEM92 is a single-transmembrane protein that promotes tumor cell proliferation, migration, invasion, and EMT; mechanistically, it directly binds DDX3X and competitively blocks the E3 ubiquitin ligase TTC3 from mediating K48-linked ubiquitination and proteasomal degradation of DDX3X, thereby stabilizing DDX3X to drive breast cancer progression and chemoresistance."},"narrative":{"mechanistic_narrative":"TMEM92 is a single-transmembrane protein that functions as a positive driver of breast cancer cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) [PMID:32835947, PMID:42138474]. Knockdown of TMEM92 in breast carcinoma cells suppresses viability, invasiveness, and motility and reverses EMT (raising E-cadherin while lowering N-cadherin, Vimentin, and Snail), whereas overexpression promotes these phenotypes [PMID:32835947]. Mechanistically, TMEM92 directly associates with the RNA helicase DDX3X and stabilizes it: by competitively blocking the E3 ubiquitin ligase TTC3 from binding DDX3X, TMEM92 inhibits TTC3-mediated K48-linked ubiquitination and proteasomal degradation of DDX3X, and re-expression of DDX3X rescues the anti-tumor effects of TMEM92 depletion, placing TMEM92 upstream of DDX3X in a TMEM92–DDX3X–TTC3 axis that drives triple-negative breast cancer progression and cisplatin resistance [PMID:42138474].","teleology":[{"year":2011,"claim":"Before any functional data existed, the question was what protein class TMEM92 belongs to and what it might do; sequence analysis assigned it to a transmembrane adaptor family, framing it as a candidate signaling/adaptor protein.","evidence":"Sequence similarity, pattern-based searches, and phylogenetic analysis classifying TMEM92 in the STMC6 (Shisa-like) family with PY motifs","pmids":["22120523"],"confidence":"Low","gaps":["Computational prediction only; no experimental validation of any interaction or function","Predicted NEDD4-family/WW-domain interaction via PY motifs never tested","No cellular role established"]},{"year":2020,"claim":"The first functional question — whether TMEM92 has a role in cancer cell behavior — was answered by showing it is a positive regulator of EMT and malignant phenotypes in breast carcinoma cells.","evidence":"siRNA knockdown and overexpression in MDA-MB-231 cells with CCK-8, clone formation, Transwell, and western blot for EMT markers","pmids":["32835947"],"confidence":"Medium","gaps":["No binding partner or molecular mechanism identified","Single cell line, single lab","No in vivo validation"]},{"year":2026,"claim":"The mechanistic question of how TMEM92 drives tumor phenotypes was answered by identifying a direct partner, DDX3X, and a degradation-control mechanism: TMEM92 stabilizes DDX3X by competing with the E3 ligase TTC3.","evidence":"Co-IP/pulldown, ubiquitination assays, TMEM92 depletion with DDX3X rescue, xenograft models, and cisplatin IC50 measurement in TNBC","pmids":["42138474"],"confidence":"High","gaps":["Structural basis of TMEM92–DDX3X and TMEM92/TTC3 competition not defined","How a transmembrane protein engages the helicase and ligase spatially is unresolved","Downstream effectors linking stabilized DDX3X to EMT not mapped"]},{"year":null,"claim":"It remains unknown whether the TMEM92–DDX3X–TTC3 axis operates beyond breast cancer and whether the originally predicted PY-motif/NEDD4-family interactions contribute to TMEM92 function.","evidence":"","pmids":[],"confidence":"Low","gaps":["No data on TMEM92 function in normal tissues or other tumor types","Predicted WW-domain/E3 ligase interactions remain untested","Membrane topology and trafficking of TMEM92 not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[2]}],"localization":[],"pathway":[{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2]}],"complexes":[],"partners":["DDX3X","TTC3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6UXU6","full_name":"Transmembrane protein 92","aliases":[],"length_aa":159,"mass_kda":17.2,"function":"","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q6UXU6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM92","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TMEM92","total_profiled":1310},"omim":[{"mim_id":"619604","title":"TRANSMEMBRANE PROTEIN 92; TMEM92","url":"https://www.omim.org/entry/619604"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Nucleoplasm","reliability":"Uncertain"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"intestine","ntpm":17.9},{"tissue":"stomach 1","ntpm":10.4}],"url":"https://www.proteinatlas.org/search/TMEM92"},"hgnc":{"alias_symbol":["FLJ33318"],"prev_symbol":[]},"alphafold":{"accession":"Q6UXU6","domains":[{"cath_id":"-","chopping":"24-50","consensus_level":"medium","plddt":69.2767,"start":24,"end":50},{"cath_id":"1.20.5","chopping":"54-86","consensus_level":"medium","plddt":83.2276,"start":54,"end":86}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UXU6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UXU6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UXU6-F1-predicted_aligned_error_v6.png","plddt_mean":67.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM92","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM92"},"sequence":{"accession":"Q6UXU6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6UXU6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6UXU6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UXU6"}},"corpus_meta":[{"pmid":"25558065","id":"PMC_25558065","title":"Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.","date":"2014","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/25558065","citation_count":381,"is_preprint":false},{"pmid":"22120523","id":"PMC_22120523","title":"Unexpected diversity in Shisa-like proteins suggests the importance of their roles as transmembrane adaptors.","date":"2011","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/22120523","citation_count":55,"is_preprint":false},{"pmid":"25422915","id":"PMC_25422915","title":"MiR-23a/-24-induced gene silencing results in mesothelial cell integration of pancreatic cancer.","date":"2014","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25422915","citation_count":41,"is_preprint":false},{"pmid":"34809653","id":"PMC_34809653","title":"A network pharmacology approach to reveal the pharmacological targets and biological mechanism of compound kushen injection for treating pancreatic cancer based on WGCNA and in vitro experiment validation.","date":"2021","source":"Chinese medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34809653","citation_count":33,"is_preprint":false},{"pmid":"33247987","id":"PMC_33247987","title":"A novel long noncoding RNA, TMEM92-AS1, promotes gastric cancer progression by binding to YBX1 to mediate CCL5.","date":"2021","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33247987","citation_count":21,"is_preprint":false},{"pmid":"36185246","id":"PMC_36185246","title":"A stratification system of ferroptosis and iron-metabolism related LncRNAs guides the prediction of the survival of patients with esophageal squamous cell carcinoma.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36185246","citation_count":9,"is_preprint":false},{"pmid":"36324509","id":"PMC_36324509","title":"Construction and analysis of a lncRNA-miRNA-mRNA competing endogenous RNA network from inflamed and normal synovial tissues after anterior cruciate ligament and/or meniscus injuries.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36324509","citation_count":8,"is_preprint":false},{"pmid":"32835947","id":"PMC_32835947","title":"Transmembrane protein 92 performs a tumor-promoting function in breast carcinoma by contributing to the cell growth, invasion, migration and epithelial-mesenchymal transition.","date":"2020","source":"Tissue & cell","url":"https://pubmed.ncbi.nlm.nih.gov/32835947","citation_count":5,"is_preprint":false},{"pmid":"37265785","id":"PMC_37265785","title":"The expression characteristics of transmembrane protein genes in pancreatic ductal adenocarcinoma through comprehensive analysis of bulk and single-cell RNA sequence.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37265785","citation_count":5,"is_preprint":false},{"pmid":"34432777","id":"PMC_34432777","title":"[Identification of Novel Differentially Expressing Long Non- Coding RNAs with Oncogenic Potential].","date":"2021","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/34432777","citation_count":5,"is_preprint":false},{"pmid":"42138474","id":"PMC_42138474","title":"TMEM92 shields DDX3X from TTC3-mediated degradation to confer chemoresistance in triple-negative breast cancer.","date":"2026","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/42138474","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8540,"output_tokens":958,"usd":0.019995,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7459,"output_tokens":1608,"usd":0.038747,"stage2_stop_reason":"end_turn"},"total_usd":0.058742,"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\": 2011,\n      \"finding\": \"TMEM92 was classified as a member of the STMC6 protein family (single-transmembrane proteins with conserved 6 cysteines), sharing structural features with Shisa/Shisa-like proteins. The presence of PY motifs in TMEM92 suggests it could interact with WW-domain-containing proteins such as NEDD4 family E3 ubiquitin ligases, implicating it as a transmembrane adaptor; however, this interaction was predicted computationally and not experimentally confirmed in this study.\",\n      \"method\": \"Sequence similarity searches, pattern-based searches against eukaryotic proteomes, phylogenetic analysis\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only, no experimental validation of interactions or function\",\n      \"pmids\": [\"22120523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Knockdown of TMEM92 in MDA-MB-231 breast cancer cells inhibited cell viability, invasiveness, and motility, and inactivated EMT (raising E-cadherin, lowering N-cadherin, Vimentin, and Snail protein levels), while overexpression promoted these phenotypes, establishing TMEM92 as a positive regulator of EMT in breast carcinoma cells.\",\n      \"method\": \"siRNA knockdown and pcDNA3.1-TMEM92 overexpression; CCK-8 assay, clone formation assay, Transwell assay, western blot for EMT markers\",\n      \"journal\": \"Tissue & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, multiple functional assays (KD + OE with reciprocal phenotypes) but no pathway placement or binding partner identified\",\n      \"pmids\": [\"32835947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TMEM92 directly associates with the RNA helicase DDX3X and protects it from proteasomal degradation by competitively preventing the E3 ubiquitin ligase TTC3 from binding DDX3X, thereby inhibiting TTC3-mediated K48-linked ubiquitination of DDX3X. Re-expression of DDX3X rescued the anti-tumor effects induced by TMEM92 knockdown, placing TMEM92 upstream of DDX3X in a TMEM92–DDX3X–TTC3 axis that drives TNBC progression and cisplatin resistance.\",\n      \"method\": \"Protein interaction assays (Co-IP/pulldown), ubiquitination assays, loss-of-function (TMEM92 depletion), rescue experiments (DDX3X re-expression), xenograft tumor models, cisplatin sensitivity assays (IC50 measurement)\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding/interaction assays, ubiquitination mechanistic assay, in vivo rescue and functional rescue, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"42138474\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM92 is a single-transmembrane protein that promotes tumor cell proliferation, migration, invasion, and EMT; mechanistically, it directly binds DDX3X and competitively blocks the E3 ubiquitin ligase TTC3 from mediating K48-linked ubiquitination and proteasomal degradation of DDX3X, thereby stabilizing DDX3X to drive breast cancer progression and chemoresistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMEM92 is a single-transmembrane protein that functions as a positive driver of breast cancer cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) [#1, #2]. Knockdown of TMEM92 in breast carcinoma cells suppresses viability, invasiveness, and motility and reverses EMT (raising E-cadherin while lowering N-cadherin, Vimentin, and Snail), whereas overexpression promotes these phenotypes [#1]. Mechanistically, TMEM92 directly associates with the RNA helicase DDX3X and stabilizes it: by competitively blocking the E3 ubiquitin ligase TTC3 from binding DDX3X, TMEM92 inhibits TTC3-mediated K48-linked ubiquitination and proteasomal degradation of DDX3X, and re-expression of DDX3X rescues the anti-tumor effects of TMEM92 depletion, placing TMEM92 upstream of DDX3X in a TMEM92–DDX3X–TTC3 axis that drives triple-negative breast cancer progression and cisplatin resistance [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Before any functional data existed, the question was what protein class TMEM92 belongs to and what it might do; sequence analysis assigned it to a transmembrane adaptor family, framing it as a candidate signaling/adaptor protein.\",\n      \"evidence\": \"Sequence similarity, pattern-based searches, and phylogenetic analysis classifying TMEM92 in the STMC6 (Shisa-like) family with PY motifs\",\n      \"pmids\": [\"22120523\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Computational prediction only; no experimental validation of any interaction or function\",\n        \"Predicted NEDD4-family/WW-domain interaction via PY motifs never tested\",\n        \"No cellular role established\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The first functional question — whether TMEM92 has a role in cancer cell behavior — was answered by showing it is a positive regulator of EMT and malignant phenotypes in breast carcinoma cells.\",\n      \"evidence\": \"siRNA knockdown and overexpression in MDA-MB-231 cells with CCK-8, clone formation, Transwell, and western blot for EMT markers\",\n      \"pmids\": [\"32835947\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No binding partner or molecular mechanism identified\",\n        \"Single cell line, single lab\",\n        \"No in vivo validation\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"The mechanistic question of how TMEM92 drives tumor phenotypes was answered by identifying a direct partner, DDX3X, and a degradation-control mechanism: TMEM92 stabilizes DDX3X by competing with the E3 ligase TTC3.\",\n      \"evidence\": \"Co-IP/pulldown, ubiquitination assays, TMEM92 depletion with DDX3X rescue, xenograft models, and cisplatin IC50 measurement in TNBC\",\n      \"pmids\": [\"42138474\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of TMEM92–DDX3X and TMEM92/TTC3 competition not defined\",\n        \"How a transmembrane protein engages the helicase and ligase spatially is unresolved\",\n        \"Downstream effectors linking stabilized DDX3X to EMT not mapped\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether the TMEM92–DDX3X–TTC3 axis operates beyond breast cancer and whether the originally predicted PY-motif/NEDD4-family interactions contribute to TMEM92 function.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No data on TMEM92 function in normal tissues or other tumor types\",\n        \"Predicted WW-domain/E3 ligase interactions remain untested\",\n        \"Membrane topology and trafficking of TMEM92 not characterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DDX3X\", \"TTC3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":3,"faith_total":3,"faith_pct":100.0}}