{"gene":"ARMC8","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2019,"finding":"ARMC8 interacts specifically with δ-catenins (plakophilins-1, -2, -3 and p0071) as shown by yeast two-hybrid and confirmed by co-immunoprecipitation and co-localization; ARMC8 also interacts specifically with αE-catenin but not with αN-catenin or αT-catenin.","method":"Yeast two-hybrid, co-immunoprecipitation, co-localization","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus yeast two-hybrid and co-localization, single lab, multiple orthogonal methods","pmids":["30482882"],"is_preprint":false},{"year":2019,"finding":"Phylogenetic analysis established that ARMC8 is NOT the human ortholog of yeast Gid5/Vid28; it is a highly ancestral armadillo protein present in metazoans but absent in yeast.","method":"Comparative genome and protein structure analysis across premetazoan and metazoan species","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — comparative genomic and structural analysis, single lab, multiple species examined","pmids":["30482882"],"is_preprint":false},{"year":2016,"finding":"Knockdown of ARMC8 in HepG2 hepatocellular carcinoma cells significantly upregulated α-catenin, β-catenin, and E-cadherin expression and restored E-cadherin to the cell membrane, indicating ARMC8 promotes degradation of α-catenin and disruption of the E-cadherin/catenin complex.","method":"siRNA knockdown, Western blot, immunofluorescence, invasion assay","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with multiple orthogonal readouts (WB, immunofluorescence, functional invasion assay), single lab","pmids":["26944057"],"is_preprint":false},{"year":2015,"finding":"Overexpression of ARMC8 in colon cancer cells upregulated MMP7 and Snail while downregulating p120ctn and α-catenin; siRNA-mediated knockdown had the reverse effect, placing ARMC8 upstream of these invasion-associated factors.","method":"Gene transfection (overexpression), RNAi knockdown, invasion/migration assays, Western blot","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation (OE + KD) with pathway readouts, single lab","pmids":["26081621"],"is_preprint":false},{"year":2015,"finding":"Overexpression of ARMC8 in ovarian cancer cells enhanced invasion/migration and upregulated MMP7 and Snail while downregulating α-catenin, p120ctn, and E-cadherin; siRNA knockdown had the reverse effects.","method":"Gene transfection (overexpression), siRNA knockdown, invasion/migration assays, Western blot","journal":"Human pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation with molecular pathway readouts, single lab","pmids":["26232863"],"is_preprint":false},{"year":2016,"finding":"Knockdown of ARMC8 in osteosarcoma MG-63 cells inhibited proliferation in vitro and xenograft tumor growth in vivo, suppressed EMT, and reduced expression of β-catenin, c-Myc, and cyclin D1, placing ARMC8 upstream of the Wnt/β-catenin pathway.","method":"siRNA knockdown, in vitro proliferation assay, xenograft mouse model, Western blot","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with in vitro and in vivo readouts plus molecular pathway markers, single lab","pmids":["27712595"],"is_preprint":false},{"year":2017,"finding":"Silencing of ARMC8 in bladder carcinoma UMUC3 cells inhibited TGF-β1-induced migration, invasion, and EMT, and suppressed TGF-β1-induced expression of β-catenin, cyclin D1, and c-Myc, establishing ARMC8 as a mediator of TGF-β1-induced EMT through modulation of the Wnt/β-catenin signaling pathway.","method":"siRNA silencing, migration/invasion assays, EMT marker analysis by Western blot, TGF-β1 stimulation","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with functional and molecular readouts under defined stimulation, single lab","pmids":["28081738"],"is_preprint":false},{"year":2021,"finding":"In cutaneous squamous cell carcinoma cells, ARMC8 functions as a tumor suppressor: knockdown promoted proliferation, migration, and invasion via activation of Wnt/β-catenin signaling and EMT, while overexpression inhibited these processes. ARMC8 was identified as a direct downstream target of miR-664.","method":"siRNA knockdown, overexpression, xenograft mouse model, luciferase reporter assay (miR-664 target validation), Western blot","journal":"Journal of dermatological science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation in vitro and in vivo with pathway readouts and miRNA target validation, single lab","pmids":["34016486"],"is_preprint":false},{"year":2023,"finding":"ARMC8 was confirmed as a direct downstream target of miR-455-3p by luciferase reporter assay; miR-455-3p repressed Wnt/β-catenin signaling through binding to ARMC8, and ARMC8 overexpression partially reversed the tumor-suppressive effects of miR-455-3p in gastric cancer cells.","method":"Luciferase reporter assay, miRNA overexpression/inhibition, Western blot, mouse tumor model","journal":"BMC medical genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target validation by luciferase assay plus in vitro and in vivo rescue experiments, single lab","pmids":["37400847"],"is_preprint":false},{"year":2013,"finding":"Yeast Vid28p (proposed ortholog, but phylogenetically refuted as the true ortholog of human ARMC8 by a later study) contains an Armadillo (ARM) domain required for FBPase degradation; deletion of VID28 or mutation of the ARM domain caused Vid vesicles to fail to co-localize with actin patches, and Vid vesicle proteins appeared in the extracellular fraction. Vid28p distributed to Vid vesicles and interacted with other Vid vesicle proteins.","method":"Genetic deletion, ARM domain mutagenesis, fluorescence co-localization, subcellular fractionation","journal":"The Journal of biological chemistry","confidence":"Low","confidence_rationale":"Tier 2 / Weak — rigorous yeast experiments but later phylogenetic analysis (PMID 30482882) established Vid28/Gid5 is NOT the true ortholog of human ARMC8; results may not be directly applicable to ARMC8","pmids":["23393132"],"is_preprint":false}],"current_model":"ARMC8 is an evolutionarily conserved armadillo-repeat protein that directly binds αE-catenin (but not αN- or αT-catenin) and plakophilins-1/2/3/p0071 via its ARM repeats, and promotes α-catenin degradation to disrupt the E-cadherin/catenin adhesion complex; it acts upstream of Wnt/β-catenin signaling and functions as either an oncogene or tumor suppressor depending on cancer context, modulating EMT, invasion, and proliferation through regulation of β-catenin, MMP7, Snail, and E-cadherin levels."},"narrative":{"mechanistic_narrative":"ARMC8 is an evolutionarily ancestral armadillo-repeat protein that regulates the cadherin/catenin cell-adhesion apparatus and Wnt/β-catenin signaling to control epithelial-mesenchymal transition (EMT), invasion, and proliferation in cancer cells [PMID:30482882, PMID:26944057, PMID:27712595]. Through its ARM repeats it binds specifically to αE-catenin (but not αN- or αT-catenin) and to the δ-catenin family plakophilins-1, -2, -3 and p0071 [PMID:30482882]. Functionally, ARMC8 promotes degradation of α-catenin and disruption of the E-cadherin/catenin complex: its depletion in hepatocellular carcinoma cells upregulates α-catenin, β-catenin and E-cadherin and restores E-cadherin to the membrane [PMID:26944057]. ARMC8 acts upstream of Wnt/β-catenin signaling, modulating β-catenin, c-Myc and cyclin D1 levels and the invasion-associated factors MMP7, Snail and p120ctn [PMID:26081621, PMID:27712595], and it mediates TGF-β1-induced EMT through this pathway [PMID:28081738]. Its net effect is context-dependent, behaving as an invasion/proliferation driver in colon, ovarian, osteosarcoma and bladder cells [PMID:26081621, PMID:26232863, PMID:27712595, PMID:28081738] but as a tumor suppressor in cutaneous squamous cell carcinoma [PMID:34016486]; in several contexts ARMC8 is a direct downstream target of repressive microRNAs miR-664 and miR-455-3p [PMID:34016486, PMID:37400847]. Phylogenetic analysis establishes ARMC8 as a highly conserved metazoan armadillo protein that is not the ortholog of yeast Gid5/Vid28 [PMID:30482882].","teleology":[{"year":2015,"claim":"Establishing whether ARMC8 actively drives the invasion machinery, bidirectional manipulation showed it sits upstream of invasion-associated factors and adhesion components.","evidence":"Overexpression and RNAi knockdown in colon and ovarian cancer cells with invasion/migration assays and Western blot of MMP7, Snail, α-catenin, p120ctn, E-cadherin","pmids":["26081621","26232863"],"confidence":"Medium","gaps":["Direct biochemical mechanism linking ARMC8 to MMP7/Snail induction not defined","Whether effects on α-catenin are degradation versus transcription not resolved here"]},{"year":2016,"claim":"Resolving how ARMC8 affects adhesion, knockdown demonstrated it promotes α-catenin degradation and disassembly of the E-cadherin/catenin complex.","evidence":"siRNA knockdown in HepG2 hepatocellular carcinoma cells with Western blot, immunofluorescence membrane relocalization of E-cadherin, and invasion assay","pmids":["26944057"],"confidence":"Medium","gaps":["Degradation pathway (e.g., ubiquitin-proteasome) and any E3 ligase involvement not identified","Single cell line"]},{"year":2016,"claim":"Connecting ARMC8 to a proliferative signaling axis, knockdown placed it upstream of Wnt/β-catenin in osteosarcoma with both in vitro and in vivo consequences.","evidence":"siRNA knockdown in MG-63 cells with proliferation assays, xenograft tumor model, and Western blot of β-catenin, c-Myc, cyclin D1","pmids":["27712595"],"confidence":"Medium","gaps":["Mechanistic link from ARMC8 to β-catenin stabilization not established","No direct interaction data with Wnt components"]},{"year":2017,"claim":"Defining the upstream stimulus, silencing showed ARMC8 mediates TGF-β1-induced EMT via Wnt/β-catenin.","evidence":"siRNA silencing in bladder UMUC3 cells with TGF-β1 stimulation, migration/invasion assays, and EMT/Wnt marker Western blots","pmids":["28081738"],"confidence":"Medium","gaps":["How TGF-β1 signaling engages ARMC8 not defined","Single cell line"]},{"year":2019,"claim":"Identifying direct binding partners and clarifying evolutionary identity, interaction screening defined ARMC8's catenin-family partners and refuted its assignment as the yeast Gid5/Vid28 ortholog.","evidence":"Yeast two-hybrid, reciprocal co-immunoprecipitation, co-localization, and comparative phylogenetic/structural analysis across species","pmids":["30482882"],"confidence":"Medium","gaps":["Which ARM repeats mediate selective αE-catenin versus αN/αT discrimination not mapped","Whether binding causes catenin degradation directly not tested"]},{"year":2023,"claim":"Establishing context-dependent regulation, miRNA studies showed ARMC8 can act as a tumor suppressor and is a direct target of repressive microRNAs.","evidence":"Luciferase reporter target validation, miRNA over/inhibition, bidirectional ARMC8 manipulation, and xenograft models in cutaneous SCC (miR-664) and gastric cancer (miR-455-3p)","pmids":["34016486","37400847"],"confidence":"Medium","gaps":["Molecular basis for the oncogene-versus-suppressor context switch unexplained","No structural or mechanistic account of how the same protein produces opposite outcomes"]},{"year":null,"claim":"How ARMC8 mechanistically promotes α-catenin degradation and produces opposite effects on Wnt/β-catenin signaling across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No degradation machinery (E3 ligase, proteasome dependence) identified for ARMC8-driven catenin turnover","Structural basis of selective αE-catenin/plakophilin binding unmapped","Determinants of tissue-specific oncogene versus tumor-suppressor behavior unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,5]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,2]}],"complexes":[],"partners":["CTNNA1","PKP1","PKP2","PKP3","PKP4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IUR7","full_name":"Armadillo repeat-containing protein 8","aliases":[],"length_aa":673,"mass_kda":75.5,"function":"Component of the CTLH E3 ubiquitin-protein ligase complex that selectively accepts ubiquitin from UBE2H and mediates ubiquitination and subsequent proteasomal degradation of the transcription factor HBP1","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q8IUR7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ARMC8","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":[{"gene":"RANBP10","stoichiometry":10.0},{"gene":"RANBP9","stoichiometry":10.0},{"gene":"GSPT1","stoichiometry":0.2},{"gene":"HNRNPH1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ARMC8","total_profiled":1310},"omim":[{"mim_id":"618521","title":"ARMADILLO REPEAT-CONTAINING PROTEIN 8; ARMC8","url":"https://www.omim.org/entry/618521"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ARMC8"},"hgnc":{"alias_symbol":["HSPC056","DKFZP434A043","GID5","VID28"],"prev_symbol":[]},"alphafold":{"accession":"Q8IUR7","domains":[{"cath_id":"1.25.10.10","chopping":"562-673","consensus_level":"medium","plddt":95.5765,"start":562,"end":673}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IUR7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IUR7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IUR7-F1-predicted_aligned_error_v6.png","plddt_mean":94.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ARMC8","jax_strain_url":"https://www.jax.org/strain/search?query=ARMC8"},"sequence":{"accession":"Q8IUR7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IUR7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IUR7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IUR7"}},"corpus_meta":[{"pmid":"26232863","id":"PMC_26232863","title":"A novel biomarker ARMc8 promotes the malignant progression of ovarian cancer.","date":"2015","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26232863","citation_count":20,"is_preprint":false},{"pmid":"25119601","id":"PMC_25119601","title":"Armc8 expression was elevated during atypia-to-carcinoma progression and associated with cancer development of breast carcinoma.","date":"2014","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25119601","citation_count":17,"is_preprint":false},{"pmid":"26944057","id":"PMC_26944057","title":"Armc8 regulates the invasive ability of hepatocellular carcinoma through E-cadherin/catenin complex.","date":"2016","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26944057","citation_count":16,"is_preprint":false},{"pmid":"26081621","id":"PMC_26081621","title":"ARMc8 indicates aggressive colon cancers and promotes invasiveness and migration of colon cancer cells.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26081621","citation_count":13,"is_preprint":false},{"pmid":"23393132","id":"PMC_23393132","title":"Vid28 protein is required for the association of vacuole import and degradation (Vid) vesicles with actin patches and the retention of Vid vesicle proteins in the intracellular fraction.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23393132","citation_count":13,"is_preprint":false},{"pmid":"27712595","id":"PMC_27712595","title":"Armadillo Repeat-Containing Protein 8 (ARMC8) Silencing Inhibits Proliferation and Invasion in Osteosarcoma Cells.","date":"2016","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/27712595","citation_count":12,"is_preprint":false},{"pmid":"28081738","id":"PMC_28081738","title":"Silencing of Armadillo Repeat-Containing Protein 8 (ARMc8) Inhibits TGF-β-Induced EMT in Bladder Carcinoma UMUC3 Cells.","date":"2017","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/28081738","citation_count":12,"is_preprint":false},{"pmid":"30482882","id":"PMC_30482882","title":"Armc8 is an evolutionarily conserved armadillo protein involved in cell-cell adhesion complexes through multiple molecular interactions.","date":"2019","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/30482882","citation_count":10,"is_preprint":false},{"pmid":"34016486","id":"PMC_34016486","title":"Downregulation of ARMC8 promotes tumorigenesis through activating Wnt/β-catenin pathway and EMT in cutaneous squamous cell carcinomas.","date":"2021","source":"Journal of dermatological science","url":"https://pubmed.ncbi.nlm.nih.gov/34016486","citation_count":10,"is_preprint":false},{"pmid":"25987023","id":"PMC_25987023","title":"Comparative proteomics and global genome-wide expression data implicate role of ARMC8 in lung cancer.","date":"2015","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/25987023","citation_count":9,"is_preprint":false},{"pmid":"37400847","id":"PMC_37400847","title":"MiR-455-3p inhibits gastric cancer progression by repressing Wnt/β-catenin signaling through binding to ARMC8.","date":"2023","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/37400847","citation_count":7,"is_preprint":false},{"pmid":"32547335","id":"PMC_32547335","title":"MiR-664 Protects Against UVB Radiation-Induced HaCaT Cell Damage via Downregulating ARMC8.","date":"2020","source":"Dose-response : a publication of International Hormesis Society","url":"https://pubmed.ncbi.nlm.nih.gov/32547335","citation_count":4,"is_preprint":false},{"pmid":"30292870","id":"PMC_30292870","title":"Molecular cloning, characterization and expression analysis of ARMC6, ARMC7, ARMC8 from Pacific white shrimp, Litopenaeus vannamei.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/30292870","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9101,"output_tokens":2355,"usd":0.031314,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9486,"output_tokens":2778,"usd":0.05844,"stage2_stop_reason":"end_turn"},"total_usd":0.089754,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"ARMC8 interacts specifically with δ-catenins (plakophilins-1, -2, -3 and p0071) as shown by yeast two-hybrid and confirmed by co-immunoprecipitation and co-localization; ARMC8 also interacts specifically with αE-catenin but not with αN-catenin or αT-catenin.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, co-localization\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus yeast two-hybrid and co-localization, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"30482882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Phylogenetic analysis established that ARMC8 is NOT the human ortholog of yeast Gid5/Vid28; it is a highly ancestral armadillo protein present in metazoans but absent in yeast.\",\n      \"method\": \"Comparative genome and protein structure analysis across premetazoan and metazoan species\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — comparative genomic and structural analysis, single lab, multiple species examined\",\n      \"pmids\": [\"30482882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Knockdown of ARMC8 in HepG2 hepatocellular carcinoma cells significantly upregulated α-catenin, β-catenin, and E-cadherin expression and restored E-cadherin to the cell membrane, indicating ARMC8 promotes degradation of α-catenin and disruption of the E-cadherin/catenin complex.\",\n      \"method\": \"siRNA knockdown, Western blot, immunofluorescence, invasion assay\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with multiple orthogonal readouts (WB, immunofluorescence, functional invasion assay), single lab\",\n      \"pmids\": [\"26944057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Overexpression of ARMC8 in colon cancer cells upregulated MMP7 and Snail while downregulating p120ctn and α-catenin; siRNA-mediated knockdown had the reverse effect, placing ARMC8 upstream of these invasion-associated factors.\",\n      \"method\": \"Gene transfection (overexpression), RNAi knockdown, invasion/migration assays, Western blot\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation (OE + KD) with pathway readouts, single lab\",\n      \"pmids\": [\"26081621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Overexpression of ARMC8 in ovarian cancer cells enhanced invasion/migration and upregulated MMP7 and Snail while downregulating α-catenin, p120ctn, and E-cadherin; siRNA knockdown had the reverse effects.\",\n      \"method\": \"Gene transfection (overexpression), siRNA knockdown, invasion/migration assays, Western blot\",\n      \"journal\": \"Human pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation with molecular pathway readouts, single lab\",\n      \"pmids\": [\"26232863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Knockdown of ARMC8 in osteosarcoma MG-63 cells inhibited proliferation in vitro and xenograft tumor growth in vivo, suppressed EMT, and reduced expression of β-catenin, c-Myc, and cyclin D1, placing ARMC8 upstream of the Wnt/β-catenin pathway.\",\n      \"method\": \"siRNA knockdown, in vitro proliferation assay, xenograft mouse model, Western blot\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with in vitro and in vivo readouts plus molecular pathway markers, single lab\",\n      \"pmids\": [\"27712595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Silencing of ARMC8 in bladder carcinoma UMUC3 cells inhibited TGF-β1-induced migration, invasion, and EMT, and suppressed TGF-β1-induced expression of β-catenin, cyclin D1, and c-Myc, establishing ARMC8 as a mediator of TGF-β1-induced EMT through modulation of the Wnt/β-catenin signaling pathway.\",\n      \"method\": \"siRNA silencing, migration/invasion assays, EMT marker analysis by Western blot, TGF-β1 stimulation\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with functional and molecular readouts under defined stimulation, single lab\",\n      \"pmids\": [\"28081738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In cutaneous squamous cell carcinoma cells, ARMC8 functions as a tumor suppressor: knockdown promoted proliferation, migration, and invasion via activation of Wnt/β-catenin signaling and EMT, while overexpression inhibited these processes. ARMC8 was identified as a direct downstream target of miR-664.\",\n      \"method\": \"siRNA knockdown, overexpression, xenograft mouse model, luciferase reporter assay (miR-664 target validation), Western blot\",\n      \"journal\": \"Journal of dermatological science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation in vitro and in vivo with pathway readouts and miRNA target validation, single lab\",\n      \"pmids\": [\"34016486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ARMC8 was confirmed as a direct downstream target of miR-455-3p by luciferase reporter assay; miR-455-3p repressed Wnt/β-catenin signaling through binding to ARMC8, and ARMC8 overexpression partially reversed the tumor-suppressive effects of miR-455-3p in gastric cancer cells.\",\n      \"method\": \"Luciferase reporter assay, miRNA overexpression/inhibition, Western blot, mouse tumor model\",\n      \"journal\": \"BMC medical genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target validation by luciferase assay plus in vitro and in vivo rescue experiments, single lab\",\n      \"pmids\": [\"37400847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Yeast Vid28p (proposed ortholog, but phylogenetically refuted as the true ortholog of human ARMC8 by a later study) contains an Armadillo (ARM) domain required for FBPase degradation; deletion of VID28 or mutation of the ARM domain caused Vid vesicles to fail to co-localize with actin patches, and Vid vesicle proteins appeared in the extracellular fraction. Vid28p distributed to Vid vesicles and interacted with other Vid vesicle proteins.\",\n      \"method\": \"Genetic deletion, ARM domain mutagenesis, fluorescence co-localization, subcellular fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — rigorous yeast experiments but later phylogenetic analysis (PMID 30482882) established Vid28/Gid5 is NOT the true ortholog of human ARMC8; results may not be directly applicable to ARMC8\",\n      \"pmids\": [\"23393132\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ARMC8 is an evolutionarily conserved armadillo-repeat protein that directly binds αE-catenin (but not αN- or αT-catenin) and plakophilins-1/2/3/p0071 via its ARM repeats, and promotes α-catenin degradation to disrupt the E-cadherin/catenin adhesion complex; it acts upstream of Wnt/β-catenin signaling and functions as either an oncogene or tumor suppressor depending on cancer context, modulating EMT, invasion, and proliferation through regulation of β-catenin, MMP7, Snail, and E-cadherin levels.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ARMC8 is an evolutionarily ancestral armadillo-repeat protein that regulates the cadherin/catenin cell-adhesion apparatus and Wnt/\\u03b2-catenin signaling to control epithelial-mesenchymal transition (EMT), invasion, and proliferation in cancer cells [#0, #2, #5]. Through its ARM repeats it binds specifically to \\u03b1E-catenin (but not \\u03b1N- or \\u03b1T-catenin) and to the \\u03b4-catenin family plakophilins-1, -2, -3 and p0071 [#0]. Functionally, ARMC8 promotes degradation of \\u03b1-catenin and disruption of the E-cadherin/catenin complex: its depletion in hepatocellular carcinoma cells upregulates \\u03b1-catenin, \\u03b2-catenin and E-cadherin and restores E-cadherin to the membrane [#2]. ARMC8 acts upstream of Wnt/\\u03b2-catenin signaling, modulating \\u03b2-catenin, c-Myc and cyclin D1 levels and the invasion-associated factors MMP7, Snail and p120ctn [#3, #5], and it mediates TGF-\\u03b21-induced EMT through this pathway [#6]. Its net effect is context-dependent, behaving as an invasion/proliferation driver in colon, ovarian, osteosarcoma and bladder cells [#3, #4, #5, #6] but as a tumor suppressor in cutaneous squamous cell carcinoma [#7]; in several contexts ARMC8 is a direct downstream target of repressive microRNAs miR-664 and miR-455-3p [#7, #8]. Phylogenetic analysis establishes ARMC8 as a highly conserved metazoan armadillo protein that is not the ortholog of yeast Gid5/Vid28 [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Establishing whether ARMC8 actively drives the invasion machinery, bidirectional manipulation showed it sits upstream of invasion-associated factors and adhesion components.\",\n      \"evidence\": \"Overexpression and RNAi knockdown in colon and ovarian cancer cells with invasion/migration assays and Western blot of MMP7, Snail, \\u03b1-catenin, p120ctn, E-cadherin\",\n      \"pmids\": [\n        \"26081621\",\n        \"26232863\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct biochemical mechanism linking ARMC8 to MMP7/Snail induction not defined\",\n        \"Whether effects on \\u03b1-catenin are degradation versus transcription not resolved here\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolving how ARMC8 affects adhesion, knockdown demonstrated it promotes \\u03b1-catenin degradation and disassembly of the E-cadherin/catenin complex.\",\n      \"evidence\": \"siRNA knockdown in HepG2 hepatocellular carcinoma cells with Western blot, immunofluorescence membrane relocalization of E-cadherin, and invasion assay\",\n      \"pmids\": [\n        \"26944057\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Degradation pathway (e.g., ubiquitin-proteasome) and any E3 ligase involvement not identified\",\n        \"Single cell line\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connecting ARMC8 to a proliferative signaling axis, knockdown placed it upstream of Wnt/\\u03b2-catenin in osteosarcoma with both in vitro and in vivo consequences.\",\n      \"evidence\": \"siRNA knockdown in MG-63 cells with proliferation assays, xenograft tumor model, and Western blot of \\u03b2-catenin, c-Myc, cyclin D1\",\n      \"pmids\": [\n        \"27712595\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanistic link from ARMC8 to \\u03b2-catenin stabilization not established\",\n        \"No direct interaction data with Wnt components\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defining the upstream stimulus, silencing showed ARMC8 mediates TGF-\\u03b21-induced EMT via Wnt/\\u03b2-catenin.\",\n      \"evidence\": \"siRNA silencing in bladder UMUC3 cells with TGF-\\u03b21 stimulation, migration/invasion assays, and EMT/Wnt marker Western blots\",\n      \"pmids\": [\n        \"28081738\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How TGF-\\u03b21 signaling engages ARMC8 not defined\",\n        \"Single cell line\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying direct binding partners and clarifying evolutionary identity, interaction screening defined ARMC8's catenin-family partners and refuted its assignment as the yeast Gid5/Vid28 ortholog.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-immunoprecipitation, co-localization, and comparative phylogenetic/structural analysis across species\",\n      \"pmids\": [\n        \"30482882\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Which ARM repeats mediate selective \\u03b1E-catenin versus \\u03b1N/\\u03b1T discrimination not mapped\",\n        \"Whether binding causes catenin degradation directly not tested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Establishing context-dependent regulation, miRNA studies showed ARMC8 can act as a tumor suppressor and is a direct target of repressive microRNAs.\",\n      \"evidence\": \"Luciferase reporter target validation, miRNA over/inhibition, bidirectional ARMC8 manipulation, and xenograft models in cutaneous SCC (miR-664) and gastric cancer (miR-455-3p)\",\n      \"pmids\": [\n        \"34016486\",\n        \"37400847\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular basis for the oncogene-versus-suppressor context switch unexplained\",\n        \"No structural or mechanistic account of how the same protein produces opposite outcomes\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ARMC8 mechanistically promotes \\u03b1-catenin degradation and produces opposite effects on Wnt/\\u03b2-catenin signaling across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No degradation machinery (E3 ligase, proteasome dependence) identified for ARMC8-driven catenin turnover\",\n        \"Structural basis of selective \\u03b1E-catenin/plakophilin binding unmapped\",\n        \"Determinants of tissue-specific oncogene versus tumor-suppressor behavior unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0008092\",\n        \"supporting_discovery_ids\": [\n          0\n        ]\n      },\n      {\n        \"term_id\": \"GO:0098772\",\n        \"supporting_discovery_ids\": [\n          2,\n          5\n        ]\n      }\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-162582\",\n        \"supporting_discovery_ids\": [\n          5,\n          6\n        ]\n      },\n      {\n        \"term_id\": \"R-HSA-1500931\",\n        \"supporting_discovery_ids\": [\n          0,\n          2\n        ]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CTNNA1\",\n      \"PKP1\",\n      \"PKP2\",\n      \"PKP3\",\n      \"PKP4\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}