Affinage

RNF187

E3 ubiquitin-protein ligase RNF187 · UniProt Q5TA31

Length
235 aa
Mass
26.2 kDa
Annotated
2026-06-10
15 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RNF187 (RACO-1) is a RING-domain E3 ubiquitin ligase that regulates transcription and cell proliferation by directing both K48- and K63-linked polyubiquitination, functioning as a transcriptional co-activator and a substrate-degrading ligase in multiple cancer and germline contexts (PMID:23624934, PMID:35165289). Its activity is gated by post-translational modification: PRMT1-mediated arginine methylation triggers a conformational change that promotes K63-linked auto-ubiquitination, dimerization, and interaction with c-Jun, all required for c-Jun/AP-1 transcriptional activation (PMID:23624934), while NEDD8 binding stabilizes RNF187 by blocking its own K48-linked degradative ubiquitination (PMID:41291066). As a degradative ligase, RNF187 catalyzes K48-linked polyubiquitination and proteasomal turnover of YAP, restraining Hippo/YAP-TEAD target gene expression (CTGF, CYR61) and cell migration/invasion (PMID:32198343, PMID:32896069), and directly ubiquitinates P53 in an MDM2-independent manner to suppress P53 target genes and apoptosis (PMID:35165289). In germ cell models it degrades the keratins KRT36 and KRT84 to drive proliferation (PMID:37738023) and degrades WDR77, lowering PRMT5-dependent H4R3me2s to derepress EGR1 and promote spermatogonial stem cell maintenance (PMID:40197797). RNF187 also ubiquitinates histone H3 at K57 and K80 to increase transcription (PMID:38156805), and its expression is driven directly by Notch1 to promote EMT and metastasis (PMID:31477177).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2013 High

    Established how RNF187/RACO-1 is activated as a c-Jun/AP-1 co-activator, answering what controls its transcriptional function rather than treating it as a constitutive ligase.

    Evidence MS methylation-site mapping, in vitro methylation, arginine mutagenesis, Co-IP, and AP-1 reporter assays with PRMT1 knockdown

    PMID:23624934

    Open questions at the time
    • Does not identify K48 substrates degraded by activated RACO-1
    • Structural basis of the methylation-induced conformational change unresolved
  2. 2019 Medium

    Showed RNF187 acts as a direct downstream effector of Notch1, answering how the gene is transcriptionally induced and linking it to EMT and metastasis.

    Evidence Luciferase reporter, ChIP, RNA-seq, and gain/loss-of-function epistasis in hepatocellular carcinoma cells

    PMID:31477177

    Open questions at the time
    • Does not identify the ubiquitination substrate mediating the pro-migratory effect
    • Single tumor context
  3. 2020 Medium

    Identified YAP as a degradative substrate, establishing RNF187 as a negative regulator of Hippo/YAP-TEAD signaling.

    Evidence Reciprocal Co-IP, K48 ubiquitination assays, and RNAi with YAP-depletion epistasis rescue in TNBC and ESCC cells

    PMID:32198343 PMID:32896069

    Open questions at the time
    • Ubiquitination not reconstituted in vitro with purified components
    • Whether PRMT1 methylation status modulates YAP targeting unknown
  4. 2022 High

    Demonstrated direct, MDM2-independent ubiquitination of P53, broadening RNF187 substrate repertoire and linking it to apoptosis suppression.

    Evidence In vitro ubiquitination reconstitution, Co-IP, RNA-seq, and RNAi in breast cancer cells

    PMID:35165289

    Open questions at the time
    • P53 lysine residues targeted not mapped
    • Relationship to canonical MDM2 pathway in vivo unclear
  5. 2023 Medium

    Extended substrate range to keratins (KRT36/KRT84) and chromatin (histone H3 K57/K80), showing RNF187 controls germ cell proliferation through both degradative and non-degradative ubiquitination.

    Evidence Co-IP/MS substrate identification, K48 and site-specific ubiquitination assays with mutagenesis, and rescue experiments in GC-1 and GC-2 cells

    PMID:37738023 PMID:38156805

    Open questions at the time
    • Chain linkage on histone H3 not defined
    • Single lab; physiological role in intact spermatogenesis untested
  6. 2025 Medium

    Defined two new regulatory axes: WDR77 degradation feeding into PRMT5/H4R3me2s/EGR1, and NEDD8-mediated stabilization of RNF187 driving IQGAP1/MYH9-dependent cytoskeletal remodeling.

    Evidence Co-IP/MS, K48 and K63 ubiquitination assays with mutagenesis, NEDD8 interaction Co-IP, methylation and transcriptional analyses, and proliferation/invasion assays in SSCs and pancreatic cancer cells

    PMID:40197797 PMID:41291066

    Open questions at the time
    • Direct evidence that NEDD8 covalently neddylates RNF187 versus binding not fully resolved
    • How RNF187 differentially assembles K48 versus K63 chains on IQGAP1 unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RNF187 selects among its diverse substrates and switches between K48-degradative and K63/non-degradative outputs in a given cell remains unresolved.
  • No structural model of substrate engagement
  • No unified rule linking methylation/neddylation status to chain-type choice
  • In vivo physiological requirement not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 8 GO:0140096 catalytic activity, acting on a protein 6 GO:0042393 histone binding 1 GO:0140110 transcription regulator activity 1
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
IQGAP1KRT36KRT84NEDD8PRMT1TP53WDR77YAP

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 RACO-1 (RNF187) is a substrate of arginine methyltransferase PRMT1, which methylates RACO-1 on two arginine residues; this methylation promotes a conformational change that stabilizes RACO-1 by facilitating K63-linked ubiquitin chain formation, enables RACO-1 dimerization, and enables interaction with c-Jun, all required for c-Jun/AP-1 transcriptional activation. Mass spectrometry identification of methylation sites, in vitro methylation assay, mutagenesis of arginine residues, Co-IP for dimerization and c-Jun interaction, AP-1 reporter assay, PRMT1 knockdown The EMBO journal High 23624934
2020 RNF187 associates with YAP and promotes its degradation via K48-linked polyubiquitination, acting as a negative regulator of Hippo signaling in TNBC cells; RNF187 depletion increases YAP protein levels and expression of Hippo target genes (CTGF, CYR61), and the migration/invasion phenotype caused by RNF187 depletion is rescued by further YAP depletion. Co-immunoprecipitation, ubiquitination assay, RNAi knockdown with epistasis rescue (YAP depletion), western blot for target gene expression Oncogenesis Medium 32198343 32896069
2020 RACO-1 (RNF187) associates with YAP in oesophageal squamous cell carcinoma cells and promotes K48-linked polyubiquitination and degradation of YAP; RACO-1 silencing increases YAP protein level and YAP/TEAD target gene expression, promoting invasion and migration, an effect rescued by YAP depletion. Co-immunoprecipitation, ubiquitination assay, RNAi knockdown with YAP depletion rescue, western blot Journal of cellular and molecular medicine Medium 32896069
2022 RNF187 interacts with P53 and promotes its polyubiquitination and degradation in breast cancer cells; an in vitro ubiquitin assay demonstrated that RNF187 can directly ubiquitinate P53 in an MDM2-independent manner, inhibiting P53 target genes (IGFBP3, FAS) and facilitating breast cancer cell growth while inhibiting apoptosis. Co-immunoprecipitation, in vitro ubiquitination assay, RNAi knockdown, RNA sequencing, western blot Cell death & disease High 35165289
2019 RNF187 is a direct transcriptional target of Notch1 in hepatocellular carcinoma; Notch1 activates the RNF187 promoter (confirmed by luciferase reporter assay and ChIP), and RNF187 is required downstream of Notch1 to promote EMT, invasion, and metastasis, as RNF187 knockdown attenuates Notch1-dependent pro-migratory effects and overexpression of RNF187 rescues Notch1 knockdown phenotypes. Luciferase reporter assay, chromatin immunoprecipitation (ChIP), RNA-seq, gain- and loss-of-function epistasis experiments Journal of experimental & clinical cancer research : CR Medium 31477177
2023 RNF187 interacts with Keratin 36 (KRT36) and Keratin 84 (KRT84) and promotes their degradation via K48-linked polyubiquitination, thereby promoting proliferation and migration of mouse spermatogonia GC-1 cells; overexpression of KRT36 or KRT84 attenuates the pro-proliferative and pro-migratory effects of RNF187 overexpression. Co-immunoprecipitation, mass spectrometry, K48-linked ubiquitination assay, RNAi and overexpression in GC-1 cells, rescue experiment with KRT36/KRT84 overexpression FASEB journal Medium 37738023
2023 RNF187 interacts with histone H3 and mediates its ubiquitination at lysine 57 (K57) and lysine 80 (K80) in mouse spermatocyte-derived GC-2 cells, resulting in increased cellular transcription and promoting GC-2 cell viability, proliferation, and migration. Co-immunoprecipitation, ubiquitination assay with site-specific mutagenesis (K57, K80), RNAi and overexpression in GC-2 cells Asian journal of andrology Medium 38156805
2025 RNF187 interacts with WDR77 and mediates its K48-linked polyubiquitination at K118, leading to proteasomal degradation of WDR77; reduced WDR77 decreases symmetric dimethylation at H4R3 (H4R3me2s) catalyzed by PRMT5, relieving transcriptional repression of EGR1 (a positive regulator of human SSC maintenance), thereby promoting proliferation and migration of human spermatogonial stem cells. Co-immunoprecipitation, mass spectrometry, K48-linked ubiquitination assay with site-specific mutagenesis (K118), WDR77 knockdown/overexpression, H4R3me2s methylation analysis Cell proliferation Medium 40197797
2025 NEDD8 binds RNF187 and prevents its K48-linked ubiquitination-mediated degradation, thereby stabilizing and increasing RNF187 protein levels in pancreatic cancer cells. Additionally, neddylated RNF187 upregulates IQGAP1 protein through modulation of K48- and K63-linked ubiquitination of IQGAP1, which triggers actin cytoskeleton rearrangement by altering transcriptional levels of MYH9, promoting pancreatic cancer cell proliferation and invasion. Co-immunoprecipitation (NEDD8-RNF187 interaction), K48-linked ubiquitination assay, K63-linked ubiquitination assay (IQGAP1), in vitro and in vivo proliferation/invasion assays, transcriptional analysis of MYH9, actin cytoskeleton imaging Oncogene Medium 41291066
2016 RNF187 expression is downregulated in erythroblasts following pharmacological inhibition of the NF-κB pathway (using Bay 11-7082), placing RNF187 downstream of NF-κB signaling in erythroid differentiation. NF-κB pathway inhibition with Bay 11-7082 in erythroblasts, PCR array and individual qRT-PCR gene expression analysis Biochemical genetics Low 27259582

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 Regulation of Hippo signaling and triple negative breast cancer progression by an ubiquitin ligase RNF187. Oncogenesis 42 32198343
2013 Arginine methylation of the c-Jun coactivator RACO-1 is required for c-Jun/AP-1 activation. The EMBO journal 40 23624934
2022 Dysregulation of MiR-144-5p/RNF187 Axis Contributes To the Progression of Colorectal Cancer. Journal of translational internal medicine 38 35702180
2019 An essential role of RNF187 in Notch1 mediated metastasis of hepatocellular carcinoma. Journal of experimental & clinical cancer research : CR 26 31477177
2019 Overexpression of RNF187 induces cell EMT and apoptosis resistance in NSCLC. Journal of cellular physiology 17 30624778
2023 E3 ubiquitin ligase RNF187 promotes growth of spermatogonia via lysine 48-linked polyubiquitination-mediated degradation of KRT36/KRT84. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 15 37738023
2022 Regulation of P53 signaling in breast cancer by the E3 ubiquitin ligase RNF187. Cell death & disease 12 35165289
2020 RACO-1 modulates Hippo signalling in oesophageal squamous cell carcinoma. Journal of cellular and molecular medicine 12 32896069
2023 RNF187 governs the maintenance of mouse GC-2 cell development by facilitating histone H3 ubiquitination at K57/80. Asian journal of andrology 11 38156805
2017 Up-regulation of RNF187 induces hepatocellular carcinoma cell epithelial to mesenchymal transitions. Oncotarget 11 29254210
2020 High level of RNF187 contributes to the progression and drug resistance of osteosarcoma. Journal of Cancer 6 32047542
2025 A comprehensive pan-cancer analysis of RNF187 in human tumors. Discover oncology 5 39804497
2016 RNF187 is Downregulated Following NF-κB Inhibition in Late Erythroblasts. Biochemical genetics 5 27259582
2025 RNF187 Facilitates Proliferation and Migration of Human Spermatogonial Stem Cells Through WDR77 Polyubiquitination. Cell proliferation 4 40197797
2025 RNF187 neddylation in pancreatic cancer activates malignancy via IQGAP1-dependent actin cytoskeleton rearrangement. Oncogene 0 41291066

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