Affinage

RNF180

E3 ubiquitin-protein ligase RNF180 · UniProt Q86T96

Length
592 aa
Mass
68.3 kDa
Annotated
2026-06-10
20 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RNF180 (Rines) is an integral membrane E3 ubiquitin ligase resident in the endoplasmic reticulum membrane and nuclear envelope, with its N-terminal regions exposed to the cytoplasm, that binds the E2 ubiquitin-conjugating enzyme UbcH6 to catalyze trans-ubiquitination and direct substrates to proteasomal degradation (PMID:18363970). Across multiple epithelial cancers it acts as a tumor suppressor by ubiquitinating and degrading a range of pro-tumorigenic proteins, restraining proliferation, invasion, and chemoresistance (PMID:33082325, PMID:33553163, PMID:40915184). A recurrent theme is RNF180-mediated control of the DNA methylation machinery: it directly degrades DNMT1 and DNMT3A, preventing hypermethylation and silencing of tumor-suppressor genes such as PCDH10 and ADAMTS9 (PMID:33931579, PMID:37147733). It also degrades RhoC to dampen STAT3 phosphorylation and engage a BCL6/FZD7 axis controlling Wnt signaling and ferroptosis (PMID:33082325, PMID:37060074), and degrades IPO4 to block nuclear import of SOX2 (PMID:37923100). Additional substrates link RNF180 to homologous recombination (RAD51) (PMID:34998818), lipid metabolism through ACC1 and ACLY (PMID:40915184), and Akt/EGFR signaling via NOTCH1, TRIM24, FOXC1, and PLK2 (PMID:40915184, PMID:41807497). RNF180 itself is frequently silenced in gastric cancer by promoter CpG-island methylation, and restoring its expression suppresses growth and induces apoptosis (PMID:21717426, PMID:27223257). Conditional Rnf180 knockout in mice increases susceptibility to chemically induced colorectal carcinogenesis, supporting an in vivo tumor-suppressive role (PMID:40915184).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2008 High

    Established the fundamental biochemical identity of RNF180 — answering whether it is an active enzyme and where it acts — by showing it is an ER/nuclear-envelope integral membrane E3 ligase that uses UbcH6 and drives proteasomal degradation of partners.

    Evidence Subcellular fractionation, proteinase K protection, alkaline extraction, UbcH6 co-IP, and trans-ubiquitination assays in mammalian cells

    PMID:18363970

    Open questions at the time
    • Physiological substrates not identified at this stage
    • Catalytic domain/RING architecture not structurally resolved
    • Role in cancer not yet addressed
  2. 2011 Medium

    Linked RNF180 to tumor suppression and to its own epigenetic silencing, showing re-expression suppresses gastric cancer growth and that its CpG-island promoter is methylation-sensitive.

    Evidence Colony formation, apoptosis assays, cDNA microarray, 5'RACE, luciferase and in vitro methylation assays in gastric cancer cells

    PMID:21717426

    Open questions at the time
    • MTSS1/CDKN2A/TIMP3 identified as correlated targets but not as direct ubiquitination substrates
    • Mechanism connecting ligase activity to these outputs unresolved
  3. 2016 Medium

    Refined the epigenetic-silencing model by mapping specific CpG loci (CpG+102, CpG+97) whose methylation controls RNF180's tumor-suppressive output.

    Evidence Site-specific demethylation constructs with proliferation, invasion, cell cycle, apoptosis, and tumorigenicity assays in MGC-803 cells

    PMID:27223257

    Open questions at the time
    • Causal link between specific CpG demethylation and downstream substrate ubiquitination not established
    • Single cell line
  4. 2020 Medium

    Identified the first defined oncogenic substrate, showing RNF180 degrades RhoC to suppress STAT3 phosphorylation, establishing a RNF180→RhoC→STAT3 epistatic axis.

    Evidence Co-IP, ubiquitin label-free proteomics, RhoC shRNA rescue, and STAT3 phospho-Western in gastric cancer cells

    PMID:33082325

    Open questions at the time
    • Direct in vitro ubiquitination with purified components not shown
    • Single lab
  5. 2021 Medium

    Connected RNF180 to control of the DNA methylation machinery and to a second cancer type, showing it degrades DNMT3A to prevent ADAMTS9 silencing and degrades WISP1 to suppress colorectal tumor growth in PDX models.

    Evidence Co-IP, ubiquitination assays, RNA-seq, promoter methylation analysis, and PDX mouse models

    PMID:33553163 PMID:33931579

    Open questions at the time
    • Whether DNMT3A and WISP1 are co-regulated in the same cells unclear
    • Substrate-recognition determinants unknown
  6. 2022 Medium

    Extended substrate range to DNA-repair machinery, showing RNF180 degrades RAD51 in triple-negative breast cancer and sensitizes cells to Gefitinib.

    Evidence IP, ubiquitination assay, gain/loss-of-function studies, and nude mouse xenograft

    PMID:34998818

    Open questions at the time
    • Impact on homologous recombination capacity not directly measured
    • Single lab
  7. 2023 Medium

    Consolidated RNF180 as a master regulator of methylation and transcription-factor trafficking, adding DNMT1 (PCDH10 axis), IPO4-dependent SOX2 nuclear import, and a RhoC/BCL6/FZD7 ferroptosis/Wnt branch.

    Evidence Co-IP, ubiquitination assays, nuclear fractionation, ChIP, dual luciferase, and ferroptosis/lipid-peroxidation assays across gastric and ovarian cancer cells

    PMID:37060074 PMID:37147733 PMID:37923100

    Open questions at the time
    • Whether these parallel axes operate simultaneously or are context-specific is unresolved
    • Direct ubiquitination chain-type/specificity uncharacterized
  8. 2024 Medium

    Demonstrated a non-cancer, immunological role by showing RNF180 degrades the m6A demethylase ALKBH5, raising SMARCA5 and worsening colitis with Th17/Treg imbalance.

    Evidence DSS-induced ulcerative colitis mouse model with knockdown/overexpression, flow cytometry, cytokine measurements, and ubiquitination analysis

    PMID:39060657

    Open questions at the time
    • Whether the same RNF180 activity is pro- or anti-disease depends on context and is unresolved
    • Single lab
  9. 2025 Medium

    Provided in vivo genetic support and broadened substrate scope into metabolism and Akt signaling, with conditional knockout enhancing colorectal carcinogenesis and degradation of NOTCH1/TRIM24/FOXC1, ACC1, and ACLY linking RNF180 to lipid metabolism and chemoresistance.

    Evidence Co-IP, ubiquitination/degradation assays, lipid droplet assays, Akt pathway analysis, and Lgr5-cre/RNF180 f/f conditional knockout mouse

    PMID:40331188 PMID:40915184

    Open questions at the time
    • ACC1/ACLY findings (idx 11) rest on limited methodological detail
    • Whether all listed substrates are direct in vitro substrates not uniformly established
  10. 2026 Low

    Added PLK2 as a substrate linking RNF180 to EGFR/PI3K/AKT signaling and cisplatin resistance in lung cancer.

    Evidence Bioinformatic substrate prediction with qRT-PCR, Western blot, lentiviral overexpression, PLK2 knockdown, and nude mouse xenograft

    PMID:41807497

    Open questions at the time
    • Substrate identified largely by bioinformatics with partial validation
    • Direct ubiquitination not rigorously demonstrated
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how RNF180 achieves specificity across its very broad reported substrate set and which substrates are physiologically dominant in each tissue context.
  • No structural basis for substrate selection
  • Degron/recognition motifs unmapped
  • Chain-type specificity of ubiquitination unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016740 transferase activity 1 GO:0016874 ligase activity 1
Localization
GO:0005635 nuclear envelope 1 GO:0005783 endoplasmic reticulum 1
Pathway
GO:0140096 catalytic activity, acting on a protein 1
Partners
ALKBH5DNMT1DNMT3AIPO4RAD51RHOCUBCH6WISP1

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 Rines/RNF180 is an integral membrane E3 ubiquitin ligase localized to the endoplasmic reticulum membrane/nuclear envelope. It is not extracted by high salt or alkaline buffers and is degraded by proteinase K in intact ER, confirming it is an integral membrane protein with its N-terminal regions in the cytoplasm. It binds the UbcH6 ubiquitin-conjugating enzyme, promotes trans-ubiquitination, and its overexpression promotes proteasome-dependent degradation of a binding partner while Rines itself is heavily ubiquitinated and degraded by the proteasome. Subcellular fractionation, proteinase K protection assay, high salt/alkaline extraction, co-immunoprecipitation with UbcH6, proteasomal inhibitor treatment, trans-ubiquitination assay in cultured mammalian cells Genes to cells : devoted to molecular & cellular mechanisms High 18363970
2011 RNF180 re-expression in gastric cancer cells suppresses cell growth and induces apoptosis, mediated by upregulation of MTSS1, CDKN2A, and TIMP3. The functional core promoter region (-202/+372) lies within a CpG island and can be silenced by in vitro methylation. Colony formation assay, annexin V apoptosis assay, cDNA microarray for target genes, 5' RACE for transcription start site, luciferase activity assay, in vitro methylation assay Cancer Medium 21717426
2016 Specific CpG islands in the RNF180 promoter (CpG+102 and CpG+97) mediate the malignant biological characteristics of gastric cancer cells. Targeted demethylation of CpG+102 markedly influenced proliferation, invasion, cell cycle, anti-apoptosis, and tumorigenicity; CpG+97 was identified as an additional key locus. Site-specific demethylation via vector transfection in MGC-803 cells, proliferation assay, invasion assay, cell cycle analysis, apoptosis assay, tumorigenicity assay Oncotarget Medium 27223257
2020 RNF180 directly binds RhoC and promotes its ubiquitination and proteasomal degradation in gastric cancer cells. This reduces STAT3 phosphorylation downstream. RhoC knockdown phenocopies RNF180 overexpression in suppressing STAT3 phosphorylation, placing RhoC between RNF180 and STAT3. Co-immunoprecipitation (direct binding of RNF180 and RhoC), ubiquitin label-free quantitative proteomics, shRNA knockdown of RhoC, Western blot for STAT3 phosphorylation, transfection of RNF180-GFP expression vector Cell death & disease Medium 33082325
2021 RNF180 ubiquitinates DNMT3A and promotes its proteasome-mediated degradation. Loss of RNF180 allows DNMT3A to hypermethylate the ADAMTS9 promoter, silencing ADAMTS9 expression. This defines a RNF180/DNMT3A/ADAMTS9 regulatory axis in gastric cancer cells. Co-immunoprecipitation (RNF180-DNMT3A interaction), ubiquitination assay, proteasome inhibitor treatment, RNA-sequencing, promoter methylation analysis, cell viability and motility assays Cell death & disease Medium 33931579
2021 RNF180 ubiquitinates WISP1, leading to WISP1 downregulation, which mediates RNF180's tumor-suppressive effects (inhibition of cell viability, induction of apoptosis) in colorectal cancer cells and in patient-derived xenograft mouse models. Co-immunoprecipitation, ubiquitination assay, overexpression/depletion of RNF180 and WISP1, cell viability assay, apoptosis assay, PDX mouse model Frontiers in cell and developmental biology Medium 33553163
2023 RNF180 directly interacts with DNMT1 and promotes DNMT1 degradation via ubiquitination, preventing hypermethylation of the PCDH10 promoter and restoring PCDH10 expression in gastric cancer cells. This RNF180/DNMT1/PCDH10 axis suppresses GC cell proliferation and metastasis. Co-immunoprecipitation (RNF180-DNMT1 direct binding), ubiquitination assay, promoter methylation analysis, proliferation and metastasis assays, protein expression analysis in GC tissues Clinical epigenetics Medium 37147733
2023 RNF180 interacts with IPO4 (Importin 4) and promotes its ubiquitination and proteasomal degradation in ovarian cancer cells. This reduces nuclear translocation of SOX2 (which requires IPO4 for nuclear import), increases p21 expression, and suppresses ovarian cancer progression. Bioinformatics, proteomics, co-immunoprecipitation (RNF180-IPO4), ubiquitination assay, IPO4 overexpression/knockdown, nuclear fractionation for SOX2 localization, in vitro and in vivo functional assays Cellular signalling Medium 37923100
2023 BCL6 expression and tumor suppressor function in gastric cancer are regulated by the RNF180/RhoC pathway; specifically, RNF180-mediated ubiquitination and degradation of RhoC elevates BCL6 activity, which then transcriptionally represses FZD7 to inhibit Wnt signaling and promote ferroptosis via FZD7/β-catenin/TP63/GPX4 pathway. CHX chase and MG132 proteasome inhibitor treatment, rescue experiments, ChIP, dual luciferase reporter assay, lipid peroxidation/MDA/Fe2+ measurements, cell proliferation and metastasis assays Cell & bioscience Medium 37060074
2022 RNF180 directly interacts with RAD51 and promotes its ubiquitination and degradation in triple-negative breast cancer cells, thereby suppressing TNBC proliferation, invasion, migration, and sensitizing cells to Gefitinib. Immunoprecipitation (RNF180-RAD51 interaction), ubiquitination assay, gain- and loss-of-function assays, Western blot for drug resistance genes, nude mouse xenograft model Chemico-biological interactions Medium 34998818
2024 RNF180 promotes ubiquitination and degradation of ALKBH5 (an m6A RNA demethylase) in the context of ulcerative colitis. ALKBH5 normally inhibits SMARCA5 via m6A modification; loss of ALKBH5 due to RNF180-mediated degradation increases SMARCA5 and worsens colon inflammation and Th17/Treg imbalance. UC mouse model (DSS-induced), RNF180/SMARCA5 knockdown, ALKBH5 overexpression, flow cytometry (Th17/Treg cells), cytokine measurements, Western blot; ubiquitination of ALKBH5 by RNF180 established Archives of pharmacal research Medium 39060657
2025 RNF180 ubiquitinates and promotes proteasomal degradation of ACC1 and ACLY in esophageal cancer cells, thereby weakening lipid droplet formation and lipogenesis, which reduces chemoresistance. RNF180 overexpression in EC cell lines, ubiquitination and proteasomal degradation assays for ACC1 and ACLY, lipid droplet measurement, chemosensitivity assays, in vitro proliferation/migration/invasion/apoptosis/pyroptosis assays Frontiers in pharmacology Low 40331188
2025 RNF180 interacts with and promotes ubiquitination and proteasomal degradation of NOTCH1, TRIM24, and FOXC1 in colorectal cancer cells, suppressing aggressiveness via Akt pathway inactivation. RNF180 also ubiquitinates and degrades ACC1 and ACLY to suppress lipid droplet assembly and chemoresistance. RNF180 knockout in Lgr5-cre/RNF180 f/f mice enhanced sensitivity to chemically-induced colorectal carcinogenesis. Co-immunoprecipitation, ubiquitination and proteasomal degradation assays, Akt pathway analysis, lipid droplet assay, conditional knockout mouse model (Lgr5-cre/RNF180 f/f), in vivo and in vitro functional assays International immunopharmacology Medium 40915184
2026 RNF180 ubiquitinates and degrades PLK2 in non-small cell lung cancer cells, suppressing EGFR/PI3K/AKT signaling and reducing cisplatin resistance. RNF180 overexpression inhibits proliferation, migration, invasion, EMT, and drug resistance protein expression while promoting apoptosis. Bioinformatics identification of PLK2 as substrate, qRT-PCR, Western blot, lentiviral RNF180 overexpression, PLK2 knockdown, nude mouse xenograft model, signaling pathway analysis Scientific reports Low 41807497

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Characterization of the gene structure, functional significance, and clinical application of RNF180, a novel gene in gastric cancer. Cancer 71 21717426
2008 Rines/RNF180, a novel RING finger gene-encoded product, is a membrane-bound ubiquitin ligase. Genes to cells : devoted to molecular & cellular mechanisms 41 18363970
2014 Detection of aberrant promoter methylation of RNF180, DAPK1 and SFRP2 in plasma DNA of patients with gastric cancer. Oncology letters 29 25202403
2020 RNF180 mediates STAT3 activity by regulating the expression of RhoC via the proteasomal pathway in gastric cancer cells. Cell death & disease 28 33082325
2021 DNMT3A-mediated silence in ADAMTS9 expression is restored by RNF180 to inhibit viability and motility in gastric cancer cells. Cell death & disease 25 33931579
2016 Promoter methylation of RNF180 is associated with H.pylori infection and serves as a marker for gastric cancer and atrophic gastritis. Oncotarget 20 27050149
2024 E3 ubiquitin ligase RNF180 mediates the ALKBH5/SMARCA5 axis to promote colon inflammation and Th17/Treg imbalance in ulcerative colitis mice. Archives of pharmacal research 17 39060657
2023 The malignancy suppression and ferroptosis facilitation of BCL6 in gastric cancer mediated by FZD7 repression are strengthened by RNF180/RhoC pathway. Cell & bioscience 17 37060074
2023 E3 ubiquitin ligase RNF180 prevents excessive PCDH10 methylation to suppress the proliferation and metastasis of gastric cancer cells by promoting ubiquitination of DNMT1. Clinical epigenetics 15 37147733
2015 Evaluating the clinical feasibility: The direct bisulfite genomic sequencing for examination of methylated status of E3 ubiquitin ligase RNF180 DNA promoter to predict the survival of gastric cancer. Cancer biomarkers : section A of Disease markers 14 25769451
2016 Mediation of the malignant biological characteristics of gastric cancer cells by the methylated CpG islands in RNF180 DNA promoter. Oncotarget 10 27223257
2021 RNF180 Inhibits Proliferation and Promotes Apoptosis of Colorectal Cancer Through Ubiquitination of WISP1. Frontiers in cell and developmental biology 8 33553163
2023 E3 ubiquitin ligase RNF180 impairs IPO4/SOX2 complex stability and inhibits SOX2-mediated malignancy in ovarian cancer. Cellular signalling 7 37923100
2022 Plasma Methylated RNF180 for Noninvasive Diagnosis of Gastric Cancer. BioMed research international 7 36246966
2022 E3 ubiquitin ligase RNF180 reduces sensitivity of triple-negative breast cancer cells to Gefitinib by downregulating RAD51. Chemico-biological interactions 5 34998818
2024 Combining methylated RNF180 and SFRP2 plasma biomarkers for noninvasive diagnosis of gastric cancer. Translational oncology 4 39541711
2023 Diagnostic value of plasma RNF180 gene methylation for gastric cancer: A systematic review and meta-analysis. Frontiers in oncology 3 36703788
2025 RNF180 weakened the lipid droplet formation and subsequent chemoresistance by destabilizing ACC1 and ACLY in esophageal cancer. Frontiers in pharmacology 1 40331188
2026 The E3 ubiquitin ligase RNF180 modulates the EGFR/PI3K/AKT pathway to reduce cisplatin resistance in non-small cell lung cancer. Scientific reports 0 41807497
2025 RNF180 suppressed aggressiveness by degrading NOTCH1, TRIM24 and FOXC1, and chemoresistance by degrading ACC1 and ACLY in colorectal cancer. International immunopharmacology 0 40915184

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