{"gene":"FRMD8","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2018,"finding":"FRMD8 (iTAP) is a component of the iRhom2/ADAM17 sheddase complex, binding directly to the cytoplasmic N-terminus of iRhom proteins; it is necessary to stabilise iRhom2 and ADAM17 at the cell surface, and in its absence iRhom2 and ADAM17 are degraded via the endolysosomal pathway, resulting in reduced ADAM17-mediated shedding of TNFα and EGF receptor ligands.","method":"Co-immunoprecipitation/mass spectrometry screen, reciprocal Co-IP, genetic knockdown/knockout in iPSC-derived human macrophages and mouse tissues, cell-surface stability assays, endolysosomal pathway inhibition experiments","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, MS-based interactome, KO in primary human macrophages and mice, replicated independently in two simultaneous eLife papers (PMIDs 29897336 and 29897333)","pmids":["29897336","29897333"],"is_preprint":false},{"year":2018,"finding":"FRMD8/iTAP binds to iRhom proteins and enhances their cell-surface stability, preventing degradation of iRhom and TACE (ADAM17) in lysosomes; depletion of iTAP in primary human macrophages profoundly impaired TNF production, and tissues from iTAP KO mice show pronounced depletion of active TACE levels.","method":"Immunoprecipitation/mass spectrometry, siRNA knockdown in primary human macrophages, iTAP KO mouse tissue analysis, lysosomal degradation assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-confirmed interaction, KO mouse phenotype, primary human macrophage functional assay, replicated by independent lab (PMID 29897336)","pmids":["29897333"],"is_preprint":false},{"year":2023,"finding":"iTAP/FRMD8 KO mice exhibit defects in inflammatory responses and intestinal epithelial barrier repair; iTAP/FRMD8 also regulates cancer cell growth in a cell-autonomous manner and by modulating the tumor microenvironment, consistent with its role in controlling ADAM17 sheddase complex stability.","method":"iTAP/Frmd8 KO mouse phenotyping, in vivo tumor growth assays, inflammatory challenge experiments","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined phenotypic readouts, single lab, multiple in vivo endpoints","pmids":["36720499"],"is_preprint":false},{"year":2023,"finding":"FRMD8 interacts separately with CDK7 and CDK4, disrupts the CDK7–CDK4 interaction to inhibit CDK4 activation, and competes with MDM2 to bind RB, thereby attenuating MDM2-mediated RB degradation and causing cell-cycle arrest. Frmd8 deficiency in mice accelerates colorectal adenoma formation.","method":"Co-immunoprecipitation, competitive binding assays, CDK4 activation assays, RB stability assays with MDM2, Frmd8 KO mouse AOM/DSS colorectal cancer model, peptide competition experiments","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP for multiple interactions, in vivo KO model, single lab with several orthogonal methods","pmids":["37527040"],"is_preprint":false},{"year":2025,"finding":"FRMD8 interacts with both ERα and UBE3A (an E3 ubiquitin ligase), and disrupts the UBE3A–ERα interaction, thereby blocking UBE3A-mediated ERα degradation; FRMD8 deficiency also suppresses ESR1 transcription via downregulation of FOXO3A, a transcription factor for ESR1.","method":"Co-immunoprecipitation, competitive binding assays, ERα protein stability assays, gene expression analysis, MMTV-Cre; Frmd8; PyMT mouse model, single-cell RNA profiling","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP-based interaction mapping, in vivo KO mouse model, single lab, multiple orthogonal approaches","pmids":["40213945"],"is_preprint":false},{"year":2025,"finding":"In BRCA1-mutant TNBC cells, low FRMD8 expression inhibits cleavage of transmembrane TNF-α (tmTNF-α) and promotes surface tmTNF-α expression by failing to prevent iRhom2 degradation through the endocytic pathway, thereby promoting metastasis.","method":"Library screening, cellular functional assays, in vivo metastasis animal experiments, iRhom2 degradation assays, pharmacological rescue with paclitaxel and etanercept","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo metastasis model, functional rescue experiments, single lab, consistent with established FRMD8/iRhom2/ADAM17 mechanism","pmids":["40619383"],"is_preprint":false},{"year":2026,"finding":"MALAT1 recruits PRC2 (Polycomb Repressive Complex 2) to transcriptionally repress FRMD8; MALAT1 knockdown upregulates FRMD8, which stabilises ADAM17 and enhances its proteolytic activity. RNA pull-down, RIP, and ChIP-PCR assays established the MALAT1–PRC2–FRMD8–ADAM17 regulatory axis in trophoblast cells.","method":"RNA pull-down, RNA immunoprecipitation (RIP), ChIP-PCR, MALAT1 knockdown, pharmacological ADAM17 inhibition, EZH2 inhibition","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal chromatin and RNA-binding assays (RIP, ChIP, pull-down), pharmacological rescue, single lab","pmids":["41985336"],"is_preprint":false}],"current_model":"FRMD8 (iTAP) is a FERM domain-containing adaptor protein that stabilises the iRhom/ADAM17 sheddase complex at the cell surface by binding to the cytoplasmic N-terminus of iRhom proteins and preventing their endolysosomal degradation, thereby promoting ADAM17-mediated shedding of TNFα and EGFR ligands; additionally, FRMD8 independently functions as a cell-cycle regulator by disrupting CDK7–CDK4 and MDM2–RB interactions (stabilising RB and inhibiting CDK4 activation), and protects ERα from UBE3A-mediated degradation while supporting FOXO3A-driven ESR1 transcription, collectively suppressing colorectal and breast cancer cell growth."},"narrative":{"mechanistic_narrative":"FRMD8 (iTAP) is a FERM domain-containing adaptor protein that functions as a stabilising subunit of the iRhom/ADAM17 sheddase complex, governing regulated ectodomain shedding at the cell surface [PMID:29897336, PMID:29897333]. It binds directly to the cytoplasmic N-terminus of iRhom proteins and prevents endolysosomal degradation of iRhom2 and ADAM17 (TACE), thereby maintaining the active sheddase pool; loss of FRMD8 destabilises this complex and impairs ADAM17-mediated shedding of TNFα and EGF receptor ligands [PMID:29897336, PMID:29897333]. Through this activity FRMD8 controls inflammatory responses and intestinal epithelial barrier repair in vivo, and influences cancer cell growth both cell-autonomously and via the tumour microenvironment [PMID:36720499]; in BRCA1-mutant triple-negative breast cancer, low FRMD8 fails to support iRhom2-dependent cleavage of transmembrane TNFα, retaining it at the surface and promoting metastasis [PMID:40619383]. Independently of its sheddase role, FRMD8 acts as a cell-cycle and tumour suppressor: it binds CDK7 and CDK4 to disrupt the CDK7–CDK4 interaction and inhibit CDK4 activation, and competes with MDM2 for RB to attenuate MDM2-mediated RB degradation, with Frmd8 loss accelerating colorectal adenoma formation [PMID:37527040]. FRMD8 also protects estrogen receptor α by disrupting the UBE3A–ERα interaction to block its ubiquitin-mediated degradation, while supporting ESR1 transcription through FOXO3A [PMID:40213945]. FRMD8 expression is itself repressed by MALAT1-directed recruitment of PRC2 to its locus [PMID:41985336].","teleology":[{"year":2018,"claim":"Established FRMD8/iTAP as a previously unrecognised stabilising component of the iRhom2/ADAM17 sheddase complex, answering how the active sheddase machinery is maintained at the cell surface.","evidence":"Co-IP/mass-spectrometry interactome, reciprocal Co-IP, knockdown/knockout in iPSC-derived human macrophages and mouse tissues, cell-surface stability and endolysosomal inhibition assays; replicated in two independent eLife papers","pmids":["29897336","29897333"],"confidence":"High","gaps":["Structural basis of FRMD8 binding to the iRhom N-terminus not resolved","Mechanism by which the complex is diverted from endolysosomal degradation not defined at molecular detail"]},{"year":2018,"claim":"Demonstrated functional consequence of the interaction: FRMD8 depletion impairs TNF production and depletes active TACE, linking the adaptor to inflammatory cytokine output.","evidence":"IP/MS, siRNA knockdown in primary human macrophages, iTAP KO mouse tissue analysis, lysosomal degradation assays","pmids":["29897333"],"confidence":"High","gaps":["Whether FRMD8 selectively affects subsets of ADAM17 substrates not fully delineated"]},{"year":2023,"claim":"Extended the sheddase role to physiology and disease, showing iTAP/FRMD8 controls inflammation, intestinal barrier repair, and cancer growth in vivo.","evidence":"Frmd8 KO mouse phenotyping, in vivo tumor growth assays, inflammatory challenge experiments","pmids":["36720499"],"confidence":"Medium","gaps":["Cell-autonomous versus microenvironmental contributions not fully separated","Single lab"]},{"year":2023,"claim":"Revealed a sheddase-independent tumour-suppressor function, showing FRMD8 restrains the cell cycle by disrupting CDK7–CDK4 and competing with MDM2 to stabilise RB.","evidence":"Reciprocal Co-IP, competitive and peptide competition binding assays, CDK4 activation and RB stability assays, Frmd8 KO AOM/DSS colorectal model","pmids":["37527040"],"confidence":"Medium","gaps":["Structural detail of the competitive interactions absent","Relationship between this nuclear/cell-cycle role and the membrane sheddase role unclear","Single lab"]},{"year":2025,"claim":"Identified a further regulatory role in hormone receptor stability, with FRMD8 protecting ERα from UBE3A-mediated degradation and supporting ESR1 transcription via FOXO3A.","evidence":"Co-IP, competitive binding and ERα stability assays, gene expression analysis, MMTV-Cre;Frmd8;PyMT mouse model, single-cell RNA profiling","pmids":["40213945"],"confidence":"Medium","gaps":["Subcellular site of the FRMD8–UBE3A–ERα interplay not defined","Mechanism linking FRMD8 to FOXO3A regulation unresolved","Single lab"]},{"year":2025,"claim":"Connected FRMD8 loss to metastasis in BRCA1-mutant TNBC through failure to shed transmembrane TNFα, tying the sheddase mechanism to a clinical cancer phenotype.","evidence":"Library screening, cellular functional assays, in vivo metastasis model, iRhom2 degradation assays, pharmacological rescue with paclitaxel and etanercept","pmids":["40619383"],"confidence":"Medium","gaps":["Generalisability beyond BRCA1-mutant context untested","Single lab"]},{"year":2026,"claim":"Defined upstream transcriptional control of FRMD8, showing MALAT1 recruits PRC2 to repress FRMD8 and thereby tune ADAM17 activity.","evidence":"RNA pull-down, RIP, ChIP-PCR, MALAT1 knockdown, pharmacological ADAM17 and EZH2 inhibition in trophoblast cells","pmids":["41985336"],"confidence":"Medium","gaps":["Direct PRC2 occupancy dynamics at the FRMD8 locus not time-resolved","Relevance of this axis outside trophoblast cells untested","Single lab"]},{"year":null,"claim":"How FRMD8's membrane sheddase-stabilising activity and its distinct nuclear/cell-cycle and receptor-stabilising functions are coordinated within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating the multiple binding partners","Whether subpopulations or post-translational states partition FRMD8 between these roles is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,3,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3]}],"complexes":["iRhom2/ADAM17 sheddase complex"],"partners":["RHBDF2","ADAM17","CDK7","CDK4","RB1","MDM2","ESR1","UBE3A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BZ67","full_name":"FERM domain-containing protein 8","aliases":["Band4.1 inhibitor LRP interactor","Bili","iRhom tail-associated protein","iTAP"],"length_aa":464,"mass_kda":51.2,"function":"Promotes the cell surface stability of iRhom1/RHBDF1 and iRhom2/RHBDF2 and prevents their degradation via the endolysosomal pathway. By acting on iRhoms, involved in ADAM17-mediated shedding of TNF, amphiregulin/AREG, HBEGF and TGFA from the cell surface (PubMed:29897333, PubMed:29897336). Negatively regulates Wnt signaling, possibly by antagonizing the recruitment of AXIN1 to LRP6 (PubMed:19572019)","subcellular_location":"Cytoplasm, cytosol; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9BZ67/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FRMD8","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FRMD8","total_profiled":1310},"omim":[{"mim_id":"618337","title":"FERM DOMAIN-CONTAINING PROTEIN 8; FRMD8","url":"https://www.omim.org/entry/618337"},{"mim_id":"614404","title":"RHOMBOID 5 HOMOLOG 2; RHBDF2","url":"https://www.omim.org/entry/614404"},{"mim_id":"603639","title":"A DISINTEGRIN AND METALLOPROTEINASE DOMAIN 17; ADAM17","url":"https://www.omim.org/entry/603639"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Centriolar satellite","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FRMD8"},"hgnc":{"alias_symbol":["FLJ90369","FKSG44","iTAP"],"prev_symbol":[]},"alphafold":{"accession":"Q9BZ67","domains":[{"cath_id":"3.10.20.90","chopping":"31-129","consensus_level":"medium","plddt":96.2401,"start":31,"end":129},{"cath_id":"1.20.80.10","chopping":"133-208_227-266","consensus_level":"medium","plddt":86.9138,"start":133,"end":266},{"cath_id":"2.30.29.30","chopping":"271-375_411-432","consensus_level":"high","plddt":87.3317,"start":271,"end":432}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BZ67","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BZ67-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BZ67-F1-predicted_aligned_error_v6.png","plddt_mean":79.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FRMD8","jax_strain_url":"https://www.jax.org/strain/search?query=FRMD8"},"sequence":{"accession":"Q9BZ67","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BZ67.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BZ67/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BZ67"}},"corpus_meta":[{"pmid":"9271576","id":"PMC_9271576","title":"A critical role for tapasin in the assembly and function of multimeric MHC class I-TAP complexes.","date":"1997","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/9271576","citation_count":411,"is_preprint":false},{"pmid":"8943049","id":"PMC_8943049","title":"Deglucosylation of N-linked glycans is an important step in the dissociation of calreticulin-class I-TAP complexes.","date":"1996","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8943049","citation_count":75,"is_preprint":false},{"pmid":"29897336","id":"PMC_29897336","title":"FRMD8 promotes inflammatory and growth factor signalling by stabilising the iRhom/ADAM17 sheddase complex.","date":"2018","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/29897336","citation_count":64,"is_preprint":false},{"pmid":"29897333","id":"PMC_29897333","title":"iTAP, a novel iRhom interactor, controls TNF secretion by policing the stability of iRhom/TACE.","date":"2018","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/29897333","citation_count":56,"is_preprint":false},{"pmid":"37527040","id":"PMC_37527040","title":"FRMD8 targets both CDK4 activation and RB degradation to suppress colon cancer growth.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/37527040","citation_count":11,"is_preprint":false},{"pmid":"36720499","id":"PMC_36720499","title":"The ADAM17 sheddase complex regulator iTAP/Frmd8 modulates inflammation and tumor growth.","date":"2023","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/36720499","citation_count":10,"is_preprint":false},{"pmid":"38734674","id":"PMC_38734674","title":"LINC01002 functions as a ceRNA to regulate FRMD8 by sponging miR-4324 for the development of COVID-19.","date":"2024","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/38734674","citation_count":5,"is_preprint":false},{"pmid":"26653323","id":"PMC_26653323","title":"iTAP: integrated transcriptomics and phenotype database for stress response of Escherichia coli and Saccharomyces cerevisiae.","date":"2015","source":"BMC research notes","url":"https://pubmed.ncbi.nlm.nih.gov/26653323","citation_count":2,"is_preprint":false},{"pmid":"19967742","id":"PMC_19967742","title":"Induced adult stem (iAS) cells and induced transit amplifying progenitor (iTAP) cells-a possible alternative to induced pluripotent stem (iPS) cells?","date":"2010","source":"Journal of tissue engineering and regenerative medicine","url":"https://pubmed.ncbi.nlm.nih.gov/19967742","citation_count":2,"is_preprint":false},{"pmid":"40619383","id":"PMC_40619383","title":"FRMD8 inhibits tumor metastasis in BRCA1-associated TNBC by negatively regulating tmTNF-α.","date":"2025","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/40619383","citation_count":1,"is_preprint":false},{"pmid":"40213945","id":"PMC_40213945","title":"Loss function of tumor suppressor FRMD8 confers resistance to tamoxifen therapy via a dual mechanism.","date":"2025","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/40213945","citation_count":1,"is_preprint":false},{"pmid":"38418026","id":"PMC_38418026","title":"Mechanical load applied by Intraosseous Transcutaneous Amputation Prosthesis (ITAP) during walking on level and sloped treadmill: A case study.","date":"2024","source":"Medical engineering & physics","url":"https://pubmed.ncbi.nlm.nih.gov/38418026","citation_count":1,"is_preprint":false},{"pmid":"41985336","id":"PMC_41985336","title":"Connecting chromatin to cell invasion: MALAT1-PRC2 complex epigenetically controls trophoblast activity via FRMD8-ADAM17-protease inhibitor circuit.","date":"2026","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/41985336","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.09.26.615107","title":"Regulation of tmTNF-α Processing by FRMD8 in Triple-Negative Breast Cancer Metastasis: Insights into Molecular Pathway Dynamics","date":"2024-09-27","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.26.615107","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8981,"output_tokens":2001,"usd":0.028479,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9023,"output_tokens":2912,"usd":0.058958,"stage2_stop_reason":"end_turn"},"total_usd":0.087437,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"FRMD8 (iTAP) is a component of the iRhom2/ADAM17 sheddase complex, binding directly to the cytoplasmic N-terminus of iRhom proteins; it is necessary to stabilise iRhom2 and ADAM17 at the cell surface, and in its absence iRhom2 and ADAM17 are degraded via the endolysosomal pathway, resulting in reduced ADAM17-mediated shedding of TNFα and EGF receptor ligands.\",\n      \"method\": \"Co-immunoprecipitation/mass spectrometry screen, reciprocal Co-IP, genetic knockdown/knockout in iPSC-derived human macrophages and mouse tissues, cell-surface stability assays, endolysosomal pathway inhibition experiments\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, MS-based interactome, KO in primary human macrophages and mice, replicated independently in two simultaneous eLife papers (PMIDs 29897336 and 29897333)\",\n      \"pmids\": [\"29897336\", \"29897333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FRMD8/iTAP binds to iRhom proteins and enhances their cell-surface stability, preventing degradation of iRhom and TACE (ADAM17) in lysosomes; depletion of iTAP in primary human macrophages profoundly impaired TNF production, and tissues from iTAP KO mice show pronounced depletion of active TACE levels.\",\n      \"method\": \"Immunoprecipitation/mass spectrometry, siRNA knockdown in primary human macrophages, iTAP KO mouse tissue analysis, lysosomal degradation assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-confirmed interaction, KO mouse phenotype, primary human macrophage functional assay, replicated by independent lab (PMID 29897336)\",\n      \"pmids\": [\"29897333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"iTAP/FRMD8 KO mice exhibit defects in inflammatory responses and intestinal epithelial barrier repair; iTAP/FRMD8 also regulates cancer cell growth in a cell-autonomous manner and by modulating the tumor microenvironment, consistent with its role in controlling ADAM17 sheddase complex stability.\",\n      \"method\": \"iTAP/Frmd8 KO mouse phenotyping, in vivo tumor growth assays, inflammatory challenge experiments\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined phenotypic readouts, single lab, multiple in vivo endpoints\",\n      \"pmids\": [\"36720499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FRMD8 interacts separately with CDK7 and CDK4, disrupts the CDK7–CDK4 interaction to inhibit CDK4 activation, and competes with MDM2 to bind RB, thereby attenuating MDM2-mediated RB degradation and causing cell-cycle arrest. Frmd8 deficiency in mice accelerates colorectal adenoma formation.\",\n      \"method\": \"Co-immunoprecipitation, competitive binding assays, CDK4 activation assays, RB stability assays with MDM2, Frmd8 KO mouse AOM/DSS colorectal cancer model, peptide competition experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP for multiple interactions, in vivo KO model, single lab with several orthogonal methods\",\n      \"pmids\": [\"37527040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FRMD8 interacts with both ERα and UBE3A (an E3 ubiquitin ligase), and disrupts the UBE3A–ERα interaction, thereby blocking UBE3A-mediated ERα degradation; FRMD8 deficiency also suppresses ESR1 transcription via downregulation of FOXO3A, a transcription factor for ESR1.\",\n      \"method\": \"Co-immunoprecipitation, competitive binding assays, ERα protein stability assays, gene expression analysis, MMTV-Cre; Frmd8; PyMT mouse model, single-cell RNA profiling\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP-based interaction mapping, in vivo KO mouse model, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"40213945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In BRCA1-mutant TNBC cells, low FRMD8 expression inhibits cleavage of transmembrane TNF-α (tmTNF-α) and promotes surface tmTNF-α expression by failing to prevent iRhom2 degradation through the endocytic pathway, thereby promoting metastasis.\",\n      \"method\": \"Library screening, cellular functional assays, in vivo metastasis animal experiments, iRhom2 degradation assays, pharmacological rescue with paclitaxel and etanercept\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo metastasis model, functional rescue experiments, single lab, consistent with established FRMD8/iRhom2/ADAM17 mechanism\",\n      \"pmids\": [\"40619383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MALAT1 recruits PRC2 (Polycomb Repressive Complex 2) to transcriptionally repress FRMD8; MALAT1 knockdown upregulates FRMD8, which stabilises ADAM17 and enhances its proteolytic activity. RNA pull-down, RIP, and ChIP-PCR assays established the MALAT1–PRC2–FRMD8–ADAM17 regulatory axis in trophoblast cells.\",\n      \"method\": \"RNA pull-down, RNA immunoprecipitation (RIP), ChIP-PCR, MALAT1 knockdown, pharmacological ADAM17 inhibition, EZH2 inhibition\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal chromatin and RNA-binding assays (RIP, ChIP, pull-down), pharmacological rescue, single lab\",\n      \"pmids\": [\"41985336\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FRMD8 (iTAP) is a FERM domain-containing adaptor protein that stabilises the iRhom/ADAM17 sheddase complex at the cell surface by binding to the cytoplasmic N-terminus of iRhom proteins and preventing their endolysosomal degradation, thereby promoting ADAM17-mediated shedding of TNFα and EGFR ligands; additionally, FRMD8 independently functions as a cell-cycle regulator by disrupting CDK7–CDK4 and MDM2–RB interactions (stabilising RB and inhibiting CDK4 activation), and protects ERα from UBE3A-mediated degradation while supporting FOXO3A-driven ESR1 transcription, collectively suppressing colorectal and breast cancer cell growth.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FRMD8 (iTAP) is a FERM domain-containing adaptor protein that functions as a stabilising subunit of the iRhom/ADAM17 sheddase complex, governing regulated ectodomain shedding at the cell surface [#0]. It binds directly to the cytoplasmic N-terminus of iRhom proteins and prevents endolysosomal degradation of iRhom2 and ADAM17 (TACE), thereby maintaining the active sheddase pool; loss of FRMD8 destabilises this complex and impairs ADAM17-mediated shedding of TNF\\u03b1 and EGF receptor ligands [#0, #1]. Through this activity FRMD8 controls inflammatory responses and intestinal epithelial barrier repair in vivo, and influences cancer cell growth both cell-autonomously and via the tumour microenvironment [#2]; in BRCA1-mutant triple-negative breast cancer, low FRMD8 fails to support iRhom2-dependent cleavage of transmembrane TNF\\u03b1, retaining it at the surface and promoting metastasis [#5]. Independently of its sheddase role, FRMD8 acts as a cell-cycle and tumour suppressor: it binds CDK7 and CDK4 to disrupt the CDK7\\u2013CDK4 interaction and inhibit CDK4 activation, and competes with MDM2 for RB to attenuate MDM2-mediated RB degradation, with Frmd8 loss accelerating colorectal adenoma formation [#3]. FRMD8 also protects estrogen receptor \\u03b1 by disrupting the UBE3A\\u2013ER\\u03b1 interaction to block its ubiquitin-mediated degradation, while supporting ESR1 transcription through FOXO3A [#4]. FRMD8 expression is itself repressed by MALAT1-directed recruitment of PRC2 to its locus [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Established FRMD8/iTAP as a previously unrecognised stabilising component of the iRhom2/ADAM17 sheddase complex, answering how the active sheddase machinery is maintained at the cell surface.\",\n      \"evidence\": \"Co-IP/mass-spectrometry interactome, reciprocal Co-IP, knockdown/knockout in iPSC-derived human macrophages and mouse tissues, cell-surface stability and endolysosomal inhibition assays; replicated in two independent eLife papers\",\n      \"pmids\": [\"29897336\", \"29897333\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of FRMD8 binding to the iRhom N-terminus not resolved\", \"Mechanism by which the complex is diverted from endolysosomal degradation not defined at molecular detail\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated functional consequence of the interaction: FRMD8 depletion impairs TNF production and depletes active TACE, linking the adaptor to inflammatory cytokine output.\",\n      \"evidence\": \"IP/MS, siRNA knockdown in primary human macrophages, iTAP KO mouse tissue analysis, lysosomal degradation assays\",\n      \"pmids\": [\"29897333\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FRMD8 selectively affects subsets of ADAM17 substrates not fully delineated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the sheddase role to physiology and disease, showing iTAP/FRMD8 controls inflammation, intestinal barrier repair, and cancer growth in vivo.\",\n      \"evidence\": \"Frmd8 KO mouse phenotyping, in vivo tumor growth assays, inflammatory challenge experiments\",\n      \"pmids\": [\"36720499\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-autonomous versus microenvironmental contributions not fully separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a sheddase-independent tumour-suppressor function, showing FRMD8 restrains the cell cycle by disrupting CDK7\\u2013CDK4 and competing with MDM2 to stabilise RB.\",\n      \"evidence\": \"Reciprocal Co-IP, competitive and peptide competition binding assays, CDK4 activation and RB stability assays, Frmd8 KO AOM/DSS colorectal model\",\n      \"pmids\": [\"37527040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural detail of the competitive interactions absent\", \"Relationship between this nuclear/cell-cycle role and the membrane sheddase role unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a further regulatory role in hormone receptor stability, with FRMD8 protecting ER\\u03b1 from UBE3A-mediated degradation and supporting ESR1 transcription via FOXO3A.\",\n      \"evidence\": \"Co-IP, competitive binding and ER\\u03b1 stability assays, gene expression analysis, MMTV-Cre;Frmd8;PyMT mouse model, single-cell RNA profiling\",\n      \"pmids\": [\"40213945\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Subcellular site of the FRMD8\\u2013UBE3A\\u2013ER\\u03b1 interplay not defined\", \"Mechanism linking FRMD8 to FOXO3A regulation unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected FRMD8 loss to metastasis in BRCA1-mutant TNBC through failure to shed transmembrane TNF\\u03b1, tying the sheddase mechanism to a clinical cancer phenotype.\",\n      \"evidence\": \"Library screening, cellular functional assays, in vivo metastasis model, iRhom2 degradation assays, pharmacological rescue with paclitaxel and etanercept\",\n      \"pmids\": [\"40619383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generalisability beyond BRCA1-mutant context untested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined upstream transcriptional control of FRMD8, showing MALAT1 recruits PRC2 to repress FRMD8 and thereby tune ADAM17 activity.\",\n      \"evidence\": \"RNA pull-down, RIP, ChIP-PCR, MALAT1 knockdown, pharmacological ADAM17 and EZH2 inhibition in trophoblast cells\",\n      \"pmids\": [\"41985336\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PRC2 occupancy dynamics at the FRMD8 locus not time-resolved\", \"Relevance of this axis outside trophoblast cells untested\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FRMD8's membrane sheddase-stabilising activity and its distinct nuclear/cell-cycle and receptor-stabilising functions are coordinated within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating the multiple binding partners\", \"Whether subpopulations or post-translational states partition FRMD8 between these roles is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\"iRhom2/ADAM17 sheddase complex\"],\n    \"partners\": [\"RHBDF2\", \"ADAM17\", \"CDK7\", \"CDK4\", \"RB1\", \"MDM2\", \"ESR1\", \"UBE3A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}