Affinage

ARMC8

Armadillo repeat-containing protein 8 · UniProt Q8IUR7

Length
673 aa
Mass
75.5 kDa
Annotated
2026-06-09
13 papers in source corpus 9 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2015 Medium

    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

    PMID:26081621 PMID:26232863

    Open questions at the time
    • Direct biochemical mechanism linking ARMC8 to MMP7/Snail induction not defined
    • Whether effects on α-catenin are degradation versus transcription not resolved here
  2. 2016 Medium

    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

    PMID:26944057

    Open questions at the time
    • Degradation pathway (e.g., ubiquitin-proteasome) and any E3 ligase involvement not identified
    • Single cell line
  3. 2016 Medium

    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

    PMID:27712595

    Open questions at the time
    • Mechanistic link from ARMC8 to β-catenin stabilization not established
    • No direct interaction data with Wnt components
  4. 2017 Medium

    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

    PMID:28081738

    Open questions at the time
    • How TGF-β1 signaling engages ARMC8 not defined
    • Single cell line
  5. 2019 Medium

    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

    PMID:30482882

    Open questions at the time
    • Which ARM repeats mediate selective αE-catenin versus αN/αT discrimination not mapped
    • Whether binding causes catenin degradation directly not tested
  6. 2023 Medium

    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)

    PMID:34016486 PMID:37400847

    Open questions at the time
    • Molecular basis for the oncogene-versus-suppressor context switch unexplained
    • No structural or mechanistic account of how the same protein produces opposite outcomes

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ARMC8 mechanistically promotes α-catenin degradation and produces opposite effects on Wnt/β-catenin signaling across tissues remains unresolved.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2 GO:0008092 cytoskeletal protein binding 1
Pathway
R-HSA-1500931 Cell-Cell communication 2 R-HSA-162582 Signal Transduction 2
Partners
CTNNA1PKP1PKP2PKP3PKP4

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 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. Yeast two-hybrid, co-immunoprecipitation, co-localization Bioscience reports Medium 30482882
2019 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. Comparative genome and protein structure analysis across premetazoan and metazoan species Bioscience reports Medium 30482882
2016 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. siRNA knockdown, Western blot, immunofluorescence, invasion assay Tumour biology Medium 26944057
2015 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. Gene transfection (overexpression), RNAi knockdown, invasion/migration assays, Western blot Tumour biology Medium 26081621
2015 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. Gene transfection (overexpression), siRNA knockdown, invasion/migration assays, Western blot Human pathology Medium 26232863
2016 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. siRNA knockdown, in vitro proliferation assay, xenograft mouse model, Western blot Oncology research Medium 27712595
2017 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. siRNA silencing, migration/invasion assays, EMT marker analysis by Western blot, TGF-β1 stimulation Oncology research Medium 28081738
2021 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. siRNA knockdown, overexpression, xenograft mouse model, luciferase reporter assay (miR-664 target validation), Western blot Journal of dermatological science Medium 34016486
2023 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. Luciferase reporter assay, miRNA overexpression/inhibition, Western blot, mouse tumor model BMC medical genomics Medium 37400847
2013 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. Genetic deletion, ARM domain mutagenesis, fluorescence co-localization, subcellular fractionation The Journal of biological chemistry Low 23393132

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 A novel biomarker ARMc8 promotes the malignant progression of ovarian cancer. Human pathology 20 26232863
2014 Armc8 expression was elevated during atypia-to-carcinoma progression and associated with cancer development of breast carcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 17 25119601
2016 Armc8 regulates the invasive ability of hepatocellular carcinoma through E-cadherin/catenin complex. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 16 26944057
2015 ARMc8 indicates aggressive colon cancers and promotes invasiveness and migration of colon cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 13 26081621
2013 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. The Journal of biological chemistry 13 23393132
2017 Silencing of Armadillo Repeat-Containing Protein 8 (ARMc8) Inhibits TGF-β-Induced EMT in Bladder Carcinoma UMUC3 Cells. Oncology research 12 28081738
2016 Armadillo Repeat-Containing Protein 8 (ARMC8) Silencing Inhibits Proliferation and Invasion in Osteosarcoma Cells. Oncology research 12 27712595
2021 Downregulation of ARMC8 promotes tumorigenesis through activating Wnt/β-catenin pathway and EMT in cutaneous squamous cell carcinomas. Journal of dermatological science 10 34016486
2019 Armc8 is an evolutionarily conserved armadillo protein involved in cell-cell adhesion complexes through multiple molecular interactions. Bioscience reports 10 30482882
2015 Comparative proteomics and global genome-wide expression data implicate role of ARMC8 in lung cancer. Asian Pacific journal of cancer prevention : APJCP 9 25987023
2023 MiR-455-3p inhibits gastric cancer progression by repressing Wnt/β-catenin signaling through binding to ARMC8. BMC medical genomics 7 37400847
2020 MiR-664 Protects Against UVB Radiation-Induced HaCaT Cell Damage via Downregulating ARMC8. Dose-response : a publication of International Hormesis Society 4 32547335
2018 Molecular cloning, characterization and expression analysis of ARMC6, ARMC7, ARMC8 from Pacific white shrimp, Litopenaeus vannamei. Gene 3 30292870

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