{"gene":"MIS18A","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2025,"finding":"Fam72a downregulates MIS18A (Mis18a) expression in a cell cycle-regulated manner upon EGF mitogen stimulation, thereby interfering with the AKT1 signaling pathway and favoring the MAPK1 route to promote cellular proliferation.","method":"Cell-based overexpression/knockdown experiments with EGF stimulation, western blot, signaling pathway analysis","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method set, MIS18A is the downstream target described without direct mechanistic dissection of MIS18A's own function","pmids":["41414706"],"is_preprint":false},{"year":2026,"finding":"ZNF471 physically interacts with MIS18A (co-immunoprecipitation/molecular biology techniques) and suppresses proliferation and metastasis of hepatocellular carcinoma cells through negative regulation of the Wnt/β-catenin signaling pathway and epithelial-mesenchymal transition; this ZNF471-MIS18A axis also increases sensitivity to apatinib and donafenib.","method":"Co-immunoprecipitation / molecular biological interaction assays, transcriptome sequencing, cellular functional assays (proliferation, migration, invasion), pathway reporter assays","journal":"Cellular signalling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, interaction shown but mechanism by which MIS18A itself acts on Wnt/β-catenin not biochemically dissected; abstract does not specify orthogonal validation","pmids":["42155792"],"is_preprint":false},{"year":2024,"finding":"siRNA-mediated knockdown of MIS18A in lung adenocarcinoma cells reduced proliferative and migratory capacities, implicating MIS18A in cell cycle and immune-related pathway regulation.","method":"siRNA knockdown, cell viability/migration assays, RT-qPCR","journal":"Oncology letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach, no pathway reconstitution or mechanistic dissection of MIS18A's molecular function","pmids":["38910901"],"is_preprint":false}],"current_model":"MIS18A is a cell cycle-regulated kinetochore protein whose expression is downregulated by Fam72a and whose protein product physically interacts with ZNF471 to suppress Wnt/β-catenin signaling; loss of MIS18A reduces cancer cell proliferation and migration, but the detailed biochemical mechanism by which MIS18A itself executes these functions remains poorly characterized in the available literature."},"narrative":{"mechanistic_narrative":"MIS18A is a cell cycle-regulated protein implicated in cancer cell proliferation and migration, but its own biochemical mechanism is largely uncharacterized in the available corpus. Its expression is downregulated by Fam72a in a cell cycle-dependent manner following EGF mitogen stimulation, which biases signaling away from the AKT1 route toward MAPK1 to promote proliferation [PMID:41414706]. At the protein level, MIS18A is physically bound by ZNF471, and this interaction is associated with negative regulation of Wnt/β-catenin signaling and epithelial-mesenchymal transition, suppressing proliferation and metastasis in hepatocellular carcinoma cells and increasing sensitivity to apatinib and donafenib [PMID:42155792]. Consistent with a pro-proliferative role, siRNA knockdown of MIS18A in lung adenocarcinoma cells reduces proliferative and migratory capacity [PMID:38910901]. Beyond these expression-level and interaction-level observations, the molecular activity by which MIS18A executes these functions has not been characterized in the available corpus.","teleology":[{"year":2024,"claim":"Established that MIS18A is functionally required for cancer cell proliferation and migration rather than merely correlated with disease, by testing the consequence of its depletion.","evidence":"siRNA knockdown with viability/migration assays and RT-qPCR in lung adenocarcinoma cells","pmids":["38910901"],"confidence":"Low","gaps":["Single knockdown approach without rescue or mechanistic dissection of MIS18A's molecular function","No identification of direct downstream effectors","Pathway involvement inferred rather than reconstituted"]},{"year":2025,"claim":"Addressed how MIS18A levels are controlled during the cell cycle, showing Fam72a downregulates MIS18A upon EGF stimulation to redirect signaling and favor proliferation.","evidence":"Overexpression/knockdown with EGF stimulation, western blot, and signaling pathway analysis","pmids":["41414706"],"confidence":"Low","gaps":["MIS18A treated as a downstream target without dissection of its own function","Mechanism linking MIS18A levels to AKT1 vs MAPK1 balance unresolved","Single lab, single method set"]},{"year":2026,"claim":"Identified a direct physical partner of MIS18A, placing it in a ZNF471-MIS18A axis that negatively regulates Wnt/β-catenin signaling, EMT, and drug sensitivity in hepatocellular carcinoma.","evidence":"Co-immunoprecipitation, transcriptome sequencing, functional assays, and pathway reporter assays in HCC cells","pmids":["42155792"],"confidence":"Low","gaps":["Biochemical mechanism by which MIS18A acts on Wnt/β-catenin not dissected","No orthogonal validation of the interaction specified","Interaction interface and stoichiometry unknown"]},{"year":null,"claim":"The intrinsic molecular activity of MIS18A and how it mechanistically couples its protein interactions to signaling outcomes remain unknown.","evidence":"","pmids":[],"confidence":"Low","gaps":["No defined enzymatic or structural molecular function","No subcellular localization established in the corpus","Direct biochemical link to Wnt/β-catenin or AKT1/MAPK1 not reconstituted"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["ZNF471"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NYP9","full_name":"Protein Mis18-alpha","aliases":["FAPP1-associated protein 1"],"length_aa":233,"mass_kda":25.9,"function":"Required for recruitment of CENPA to centromeres and normal chromosome segregation during mitosis","subcellular_location":"Nucleus; Chromosome; Chromosome, centromere","url":"https://www.uniprot.org/uniprotkb/Q9NYP9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/MIS18A","classification":"Common Essential","n_dependent_lines":1136,"n_total_lines":1208,"dependency_fraction":0.9403973509933775},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HDAC2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MIS18A","total_profiled":1310},"omim":[{"mim_id":"618139","title":"MIS18-BINDING PROTEIN 1; MIS18BP1","url":"https://www.omim.org/entry/618139"},{"mim_id":"618137","title":"MIS18 KINETOCHORE PROTEIN A: MIS18A","url":"https://www.omim.org/entry/618137"},{"mim_id":"612667","title":"HOLLIDAY JUNCTION RECOGNITION PROTEIN; HJURP","url":"https://www.omim.org/entry/612667"},{"mim_id":"606020","title":"OPA-INTERACTING PROTEIN 5; OIP5","url":"https://www.omim.org/entry/606020"},{"mim_id":"604970","title":"AURORA KINASE B; AURKB","url":"https://www.omim.org/entry/604970"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MIS18A"},"hgnc":{"alias_symbol":["B28","FASP1","hMis18alpha"],"prev_symbol":["C21orf46","C21orf45"]},"alphafold":{"accession":"Q9NYP9","domains":[{"cath_id":"-","chopping":"97-172","consensus_level":"high","plddt":94.7524,"start":97,"end":172}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NYP9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NYP9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NYP9-F1-predicted_aligned_error_v6.png","plddt_mean":79.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MIS18A","jax_strain_url":"https://www.jax.org/strain/search?query=MIS18A"},"sequence":{"accession":"Q9NYP9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NYP9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NYP9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NYP9"}},"corpus_meta":[{"pmid":"15897552","id":"PMC_15897552","title":"Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28.","date":"2005","source":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/15897552","citation_count":470,"is_preprint":false},{"pmid":"9708987","id":"PMC_9708987","title":"Interactions of phenol and m-cresol in the insulin hexamer, and their effect on the association properties of B28 pro --> Asp insulin analogues.","date":"1998","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9708987","citation_count":102,"is_preprint":false},{"pmid":"17309503","id":"PMC_17309503","title":"Effectiveness of cell-adsorbed bacteriocin produced by Lactobacillus curvatus CWBI-B28 and selected essential oils to control Listeria monocytogenes in pork meat during cold storage.","date":"2007","source":"Letters in applied microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/17309503","citation_count":18,"is_preprint":false},{"pmid":"16715806","id":"PMC_16715806","title":"Bacteriocin activity by Lactobacillus curvatus CWBI-B28 to inactivate Listeria monocytogenes in cold-smoked salmon during 4 degrees C storage.","date":"2006","source":"Journal of food protection","url":"https://pubmed.ncbi.nlm.nih.gov/16715806","citation_count":18,"is_preprint":false},{"pmid":"34441683","id":"PMC_34441683","title":"Functional Genomic Insights into Probiotic Bacillus siamensis Strain B28 from Traditional Korean Fermented Kimchi.","date":"2021","source":"Foods (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34441683","citation_count":16,"is_preprint":false},{"pmid":"8483809","id":"PMC_8483809","title":"Preparation of N epsilon B28-monoazidobenzoyl insulin-like growth factor I and photoaffinity labeling of insulin-like growth factor I receptor.","date":"1993","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/8483809","citation_count":4,"is_preprint":false},{"pmid":"31576812","id":"PMC_31576812","title":"LncRNAs down-regulate Myh1, Casr, and Mis18a expression in the Substantia Nigra of aged male rats.","date":"2019","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/31576812","citation_count":2,"is_preprint":false},{"pmid":"38910901","id":"PMC_38910901","title":"MIS18A upregulation promotes cell viability, migration and tumor immune evasion in lung adenocarcinoma.","date":"2024","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/38910901","citation_count":1,"is_preprint":false},{"pmid":"41414706","id":"PMC_41414706","title":"Cell cycle-regulated expression of Fam72a from the |Srgap2-Fam72a| master gene leads to Mis18a downregulation.","date":"2025","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/41414706","citation_count":0,"is_preprint":false},{"pmid":"42155792","id":"PMC_42155792","title":"Methylation of zinc-finger protein ZNF471 regulates MIS18A expression and inhibits proliferation and metastasis of hepatocellular carcinoma via negative regulation of the Wnt/β-catenin pathway, as well as enhances sensitivity to apatinib and donafenib.","date":"2026","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/42155792","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7108,"output_tokens":767,"usd":0.016414,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7215,"output_tokens":1381,"usd":0.0353,"stage2_stop_reason":"end_turn"},"total_usd":0.051714,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"Fam72a downregulates MIS18A (Mis18a) expression in a cell cycle-regulated manner upon EGF mitogen stimulation, thereby interfering with the AKT1 signaling pathway and favoring the MAPK1 route to promote cellular proliferation.\",\n      \"method\": \"Cell-based overexpression/knockdown experiments with EGF stimulation, western blot, signaling pathway analysis\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method set, MIS18A is the downstream target described without direct mechanistic dissection of MIS18A's own function\",\n      \"pmids\": [\"41414706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ZNF471 physically interacts with MIS18A (co-immunoprecipitation/molecular biology techniques) and suppresses proliferation and metastasis of hepatocellular carcinoma cells through negative regulation of the Wnt/β-catenin signaling pathway and epithelial-mesenchymal transition; this ZNF471-MIS18A axis also increases sensitivity to apatinib and donafenib.\",\n      \"method\": \"Co-immunoprecipitation / molecular biological interaction assays, transcriptome sequencing, cellular functional assays (proliferation, migration, invasion), pathway reporter assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, interaction shown but mechanism by which MIS18A itself acts on Wnt/β-catenin not biochemically dissected; abstract does not specify orthogonal validation\",\n      \"pmids\": [\"42155792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"siRNA-mediated knockdown of MIS18A in lung adenocarcinoma cells reduced proliferative and migratory capacities, implicating MIS18A in cell cycle and immune-related pathway regulation.\",\n      \"method\": \"siRNA knockdown, cell viability/migration assays, RT-qPCR\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach, no pathway reconstitution or mechanistic dissection of MIS18A's molecular function\",\n      \"pmids\": [\"38910901\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MIS18A is a cell cycle-regulated kinetochore protein whose expression is downregulated by Fam72a and whose protein product physically interacts with ZNF471 to suppress Wnt/β-catenin signaling; loss of MIS18A reduces cancer cell proliferation and migration, but the detailed biochemical mechanism by which MIS18A itself executes these functions remains poorly characterized in the available literature.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MIS18A is a cell cycle-regulated protein implicated in cancer cell proliferation and migration, but its own biochemical mechanism is largely uncharacterized in the available corpus. Its expression is downregulated by Fam72a in a cell cycle-dependent manner following EGF mitogen stimulation, which biases signaling away from the AKT1 route toward MAPK1 to promote proliferation [#0]. At the protein level, MIS18A is physically bound by ZNF471, and this interaction is associated with negative regulation of Wnt/\\u03b2-catenin signaling and epithelial-mesenchymal transition, suppressing proliferation and metastasis in hepatocellular carcinoma cells and increasing sensitivity to apatinib and donafenib [#1]. Consistent with a pro-proliferative role, siRNA knockdown of MIS18A in lung adenocarcinoma cells reduces proliferative and migratory capacity [#2]. Beyond these expression-level and interaction-level observations, the molecular activity by which MIS18A executes these functions has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2024,\n      \"claim\": \"Established that MIS18A is functionally required for cancer cell proliferation and migration rather than merely correlated with disease, by testing the consequence of its depletion.\",\n      \"evidence\": \"siRNA knockdown with viability/migration assays and RT-qPCR in lung adenocarcinoma cells\",\n      \"pmids\": [\"38910901\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single knockdown approach without rescue or mechanistic dissection of MIS18A's molecular function\", \"No identification of direct downstream effectors\", \"Pathway involvement inferred rather than reconstituted\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Addressed how MIS18A levels are controlled during the cell cycle, showing Fam72a downregulates MIS18A upon EGF stimulation to redirect signaling and favor proliferation.\",\n      \"evidence\": \"Overexpression/knockdown with EGF stimulation, western blot, and signaling pathway analysis\",\n      \"pmids\": [\"41414706\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"MIS18A treated as a downstream target without dissection of its own function\", \"Mechanism linking MIS18A levels to AKT1 vs MAPK1 balance unresolved\", \"Single lab, single method set\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified a direct physical partner of MIS18A, placing it in a ZNF471-MIS18A axis that negatively regulates Wnt/\\u03b2-catenin signaling, EMT, and drug sensitivity in hepatocellular carcinoma.\",\n      \"evidence\": \"Co-immunoprecipitation, transcriptome sequencing, functional assays, and pathway reporter assays in HCC cells\",\n      \"pmids\": [\"42155792\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Biochemical mechanism by which MIS18A acts on Wnt/\\u03b2-catenin not dissected\", \"No orthogonal validation of the interaction specified\", \"Interaction interface and stoichiometry unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intrinsic molecular activity of MIS18A and how it mechanistically couples its protein interactions to signaling outcomes remain unknown.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No defined enzymatic or structural molecular function\", \"No subcellular localization established in the corpus\", \"Direct biochemical link to Wnt/\\u03b2-catenin or AKT1/MAPK1 not reconstituted\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"ZNF471\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"loss","faith_supported":3,"faith_total":3,"faith_pct":100.0}}