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Showing RNF7 — RBX2 is a alias.

RNF7

RING-box protein 2 · UniProt Q9UBF6

Length
113 aa
Mass
12.7 kDa
Annotated
2026-06-10
53 papers in source corpus 33 papers cited in narrative 33 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

RNF7 (SAG/RBX2/ROC2) is the catalytic RING subunit of Cullin-RING E3 ubiquitin ligases, providing the essential ligase activity that drives substrate polyubiquitination and proteasomal turnover across cell-cycle, signaling, and developmental programs (PMID:10851089, PMID:22118770). It partitions cullin specificity by selectively associating with CUL5 (recruited through the Cul5-box of SOCS-box adaptor proteins such as ASB and SOCS2/SOCS7) while RBX1 pairs with CUL2, and it also serves as the RING component of SCF-type CUL1 complexes (e.g., with FBXW7/Fbw7) (PMID:15601820, PMID:16325183, PMID:22118770). Distinct from RBX1, RNF7 selectively engages the K11-linkage E2 enzymes UBCH10 and UBE2S to assemble K11-linked chains (PMID:27910872). Through these complexes RNF7 targets a broad substrate set governing proliferation, survival, and signaling — p27 and IκBα (PMID:12748192), c-Jun via SCF-Fbw7 (PMID:17440073), NF1 (PMID:22118770), NOXA (PMID:20103673), PHLPP1 and DEPTOR to activate the PI3K/AKT/mTOR axis (PMID:27955654), JunB controlling p16-dependent senescence (PMID:25622904), and β-TrCP1 (PMID:27910872) — and it operates within feedback loops in which it is transcriptionally induced by HIF-1, AP-1/c-Jun, and STAT3 while degrading components of those same pathways (PMID:17828303, PMID:17440073, PMID:35562668). Its activity is post-translationally tuned by CKII-mediated phosphorylation at Thr10, required for efficient substrate degradation (PMID:12748192), and by APC/C-CDH1, which both is antagonized by RNF7 in mitosis and degrades RNF7 at G1 (PMID:32905768). Beyond cytoplasmic ligase functions, RNF7 localizes as part of CRL5 to mitochondria to drive Parkin-independent, PINK1-dependent mitophagy essential for cardiac homeostasis (PMID:38873758), and in the developing nervous system its CRL5-SOCS7 activity ubiquitylates Dab1 to terminate Reelin signaling and control neuronal lamination, an activity restrained by let-7 miRNA (PMID:24210661, PMID:29361558, PMID:42012943).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2000 High

    Established that RNF7/SAG is not a passive scaffold but the functional RING ligase subunit of an SCF complex, answering whether it provides catalytic activity essential for viability.

    Evidence Yeast genetics with complementation requiring ligase activity, in vitro ubiquitin ligase assay, and co-IP with Cul1

    PMID:10851089

    Open questions at the time
    • Did not define mammalian substrate range
    • Did not distinguish CUL1 vs other cullin partners
  2. 2001 Medium

    Linked RNF7 to cell-cycle control by showing it promotes S-phase entry through proteasomal degradation of p27, identifying Skp2 as the relevant F-box adaptor.

    Evidence mRNA microinjection, adenoviral overexpression, thymidine incorporation, co-IP, and MG132 treatment

    PMID:11255262

    Open questions at the time
    • Did not reconstitute direct p27 ubiquitination by SAG complex
    • Single-lab cell-based correlation
  3. 2002 Medium

    Connected the RING-H2 motif to CKII regulation, showing the motif mediates CKIIβ binding and is required for proliferation.

    Evidence In vitro binding with purified CKIIβ, co-IP, mutagenesis, and cell-cycle analysis

    PMID:12470599

    Open questions at the time
    • Did not identify the phosphorylated residue
    • Mechanistic link between phosphorylation and ligase output unresolved
  4. 2003 High

    Resolved how CKII modulates RNF7 by mapping phosphorylation to Thr10 and showing it is required for efficient degradation of IκBα and p27.

    Evidence In vitro kinase assay, T10A/T10E mutagenesis, proteasome/CKII inhibition, and cell-cycle readout

    PMID:12748192

    Open questions at the time
    • Did not show how phosphorylation alters complex assembly or E2 engagement
  5. 2005 High

    Defined the structural basis for cullin specificity, demonstrating SAG/RBX2 pairs with CUL5 (not CUL2) and that the SOCS-box Cul5-box determines this partitioning.

    Evidence Reciprocal co-IP, domain-swapping mutagenesis, RNAi functional readout, and analysis of ASB-family adaptors with in vitro ligase reconstitution

    PMID:15601820 PMID:16325183

    Open questions at the time
    • Did not enumerate the full SOCS-box adaptor repertoire
    • Did not address in vivo substrate consequences
  6. 2007 High

    Embedded RNF7 in transcription-coupled feedback loops, showing HIF-1 and AP-1/c-Jun induce RNF7, which in turn degrades HIF-1α and c-Jun.

    Evidence siRNA silencing, ubiquitination assays, co-IP, ChIP, EMSA, and luciferase reporters across two studies

    PMID:17440073 PMID:17828303

    Open questions at the time
    • Did not quantify physiological balance of these competing loops
    • Adaptor identity for HIF-1α not fully resolved beyond VHL context
  7. 2008 Medium

    Demonstrated context- and stage-dependent substrate targeting in vivo, with RNF7 degrading c-Jun early and IκBα later during skin carcinogenesis.

    Evidence K14-driven transgenic mouse models, AP-1 reporter mice, UVB exposure, and protein-level readouts

    PMID:17846172 PMID:18258608

    Open questions at the time
    • Mechanism of temporal substrate switching unexplained
    • Single-lab transgenic system
  8. 2010 High

    Established genetic, knockout-level proof that IκBα is a direct SAG-SCF(β-TrCP) substrate and linked RNF7 loss to ROS accumulation and apoptosis, plus identified NOXA as a survival-controlling substrate.

    Evidence Gene-trap Sag elimination in ES cells, in vitro ubiquitination, ROS and NF-κB assays; separate siRNA/half-life study for NOXA

    PMID:20103673 PMID:20638939

    Open questions at the time
    • NOXA finding was Medium-confidence and lacked in vitro ubiquitination
    • Adaptor for NOXA not identified
  9. 2011 High

    Defined an essential developmental role by showing SAG-CUL1-FBXW7 targets NF1, with Sag-null embryonic lethality partially rescued by Nf1 deletion.

    Evidence Conditional knockout mice, ES-cell differentiation, double-knockout epistasis, and biochemical substrate identification

    PMID:22118770

    Open questions at the time
    • Did not separate CUL1- vs CUL5-dependent embryonic functions
  10. 2013 High

    Revealed adaptor-specific neurodevelopmental functions, showing CRL5-SOCS7 ubiquitylates Dab1 to terminate Reelin signaling and control neocortical layering, while parallel work tied SAG/p27 to vasculogenesis.

    Evidence Rbx2 conditional knockouts, Dab1-dependence epistasis, SOCS7 rescue and ubiquitylation assays; endothelial Tie2-Cre knockout with angiogenesis assays

    PMID:24210661 PMID:24213570

    Open questions at the time
    • Did not explain region-specific adaptor selection (neocortex vs cerebellum)
  11. 2014 High

    Expanded the oncogenic substrate network and provided biophysical complex reconstitution, showing RNF7 degrades PHLPP1/DEPTOR to activate AKT/mTOR and degrades p21/p27/NOXA/BIM/DEPTOR in lung tumors; also defined NEDD4-1 as a regulator that degrades RNF7.

    Evidence Conditional knockout tumor models, in vivo/in vitro ubiquitylation, epistasis rescue, full CRL5SOCS2 reconstitution with ITC/native MS, and NEDD4-1 domain-mapping/ubiquitylation

    PMID:24430184 PMID:25216516 PMID:25505247 PMID:27955654

    Open questions at the time
    • NEDD4-1 regulation was Medium-confidence single lab
    • Physiological balance of pro- vs anti-tumor substrates context-dependent
  12. 2015 High

    Linked RNF7 to senescence and identified its physical interaction with PCNA and its E2/cullin partner discrimination from RBX1.

    Evidence Sag/Cdkn2a double-knockout epistasis with JunB substrate identification; BiFC plus co-IP for PCNA; in vitro and cellular APOBEC3G/Vif-Cul5 ubiquitination assays

    PMID:25622904 PMID:25912140 PMID:26030842

    Open questions at the time
    • Functional consequence of PCNA interaction not defined (Medium-confidence)
    • A3G work used a viral hijacked complex
  13. 2016 High

    Defined the biochemical individuality of RNF7 versus RBX1 by showing it selectively binds K11-linkage E2s UBCH10/UBE2S to degrade β-TrCP1, and characterized SAG-dependent neddylation in T-cell function.

    Evidence Co-IP, E2 binding and K11-specific ubiquitylation assays, siRNA; T-cell conditional knockout with GVHD model and MLN4924

    PMID:27543965 PMID:27910872

    Open questions at the time
    • T-cell mechanism (SOCS expression link) was Medium-confidence correlation
    • Did not define which adaptor selects β-TrCP1
  14. 2017 Medium

    Identified a negative-regulatory role of RNF7 in CARMA2/CARD14 NF-κB signaling via MALT1 and NEMO ubiquitination, with psoriasis-associated mutants escaping regulation.

    Evidence Yeast two-hybrid, MALT1/NEMO ubiquitination assays, and NF-κB reporters

    PMID:29194363

    Open questions at the time
    • Direct vs indirect ubiquitination of MALT1/NEMO not fully separated
    • Single-lab system
  15. 2018 High

    Extended adaptor-specific CRL5 function to retinal layering, showing SOCS7-dependent Dab1 control of bipolar/Müller positioning and a SOCS7-independent cone photoreceptor function.

    Evidence RBX2 and SOCS7 conditional knockouts, electrophysiology, synaptic marker IHC, and epistasis

    PMID:29361558

    Open questions at the time
    • Adaptor responsible for SOCS7-independent cone function unidentified
  16. 2020 High

    Uncovered reciprocal regulation with APC/C, showing RNF7 competes for UBE2C/UBE2S to inhibit APC/C in mitosis while being degraded by APC/C-CDH1 at G1.

    Evidence Co-IP, competition binding, siRNA, degradation-resistant mutants, and cell-cycle/mitotic assays

    PMID:32905768

    Open questions at the time
    • Did not establish how the E2 competition is balanced under normal cycling
  17. 2024 High

    Established a non-canonical mitochondrial function, showing CRL5/RBX2 localizes to mitochondria and drives Parkin-independent, PINK1-dependent mitophagy essential to prevent dilated cardiomyopathy.

    Evidence Subcellular fractionation, immunogold EM, multiple cardiac conditional/inducible and Parkin double knockouts, proteomics, and mitochondrial function assays

    PMID:38873758

    Open questions at the time
    • Direct demonstration of RBX2-mediated PINK1 ubiquitination chemistry not fully detailed
    • Adaptor recruiting mitochondrial substrates unspecified
  18. 2025 High

    Defined post-transcriptional control of RNF7, showing m6A/YTHDF1 promotes its translation in prostate cancer and let-7 miRNA restrains RBX2 translation to control neocortical migration.

    Evidence YTHDF1 knockdown/overexpression with p27 stability and organoid/xenograft models; let-7 3'UTR reporters, in utero electroporation rescue, and live migration imaging

    PMID:40251202 PMID:42012943

    Open questions at the time
    • YTHDF1 axis was Medium-confidence candidate-screen based
    • Interplay between m6A and let-7 control not jointly examined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How adaptor selection, cullin choice (CUL1 vs CUL5), and E2/linkage usage are dynamically coordinated to specify substrate sets across tissues and subcellular compartments remains unresolved.
  • No unified structural model integrating mitochondrial vs cytoplasmic complexes
  • Rules governing context-dependent substrate prioritization not established
  • Mitochondrial substrate adaptors uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 1
Partners
CUL1CUL5FBXW7NEDD4-1PCNASOCS7UBE2CUBE2S
Complex memberships
CRL5 (CUL5-RBX2)CRL5-SOCS7SCF (CUL1-RBX2)SCF-FBXW7

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 SAG/RBX2 binds to Cul1 and the SAG-Cul1 complex has ubiquitin ligase activity promoting poly-ubiquitination of E2/Cdc34 in vitro. This ligase activity is required to rescue lethality caused by ySAG (yeast homolog) deletion, establishing SAG as an essential SCF E3 ubiquitin ligase RING component. Yeast genetics (targeted gene disruption, tetrad analysis, complementation), in vitro ubiquitin ligase assay, co-immunoprecipitation Oncogene High 10851089
2001 SAG/RBX2 overexpression promotes S-phase entry and cell growth under serum starvation by inhibiting p27 accumulation through proteasome-dependent degradation, and SAG binds Skp2 (the F-box protein that promotes p27 ubiquitination) in vivo. Microinjection of SAG mRNA, adenovirus overexpression, DNA transfection, [3H]-thymidine incorporation, co-immunoprecipitation, proteasome inhibitor (MG132) treatment Molecular carcinogenesis Medium 11255262
2002 The Ring-H2 finger motif of SAG/CKBBP1/RBX2 is necessary for direct interaction with the CKIIβ subunit and for efficient phosphorylation by CKII; disruption of the Ring-H2 motif suppresses cell proliferation and causes G1/G0 accumulation. In vitro binding assay with purified CKIIβ, co-immunoprecipitation from cell extracts, cell cycle analysis, stable cell line overexpression Journal of biochemistry and molecular biology Medium 12470599
2003 CKII phosphorylates SAG/CKBBP1/RBX2 at threonine 10; non-phosphorylatable T10A mutant causes accumulation of IκBα and p27Kip1 via reduced proteasomal degradation, demonstrating that CKII-mediated phosphorylation of SAG is required for efficient degradation of these substrates and G1/S transition. In vitro kinase assay, site-directed mutagenesis (T10A and T10E substitutions), proteasome inhibitor and CKII inhibitor treatments, Western blotting, cell cycle analysis The Journal of biological chemistry High 12748192
2004 SAG/RBX2 (Rbx2) specifically associates with Cul5 to form Cul5-Rbx2 modules, while RBX1 associates with Cul2; SOCS-box proteins (BC box + Cul5 box) direct interaction with Cul5-Rbx2, whereas VHL-box proteins (BC box + Cul2 box) interact with Cul2-Rbx1. RNAi knockdown of Cul5-Rbx2 (but not Cul2-Rbx1) did not affect VHL-mediated HIF-2α degradation, demonstrating distinct functional specificity. Co-immunoprecipitation of endogenous complexes, domain-swapping mutagenesis, RNAi knockdown with functional readout (HIF-2α degradation) Genes & development High 15601820
2005 ASB family proteins (containing SOCS-box with BC box and Cul5 box) interact specifically with Cul5-Rbx2 but not Cul2 or Rbx1, and ASB-Cul5-Rbx2 complexes have E3 ubiquitin ligase activity. Co-immunoprecipitation, mutational analysis of BC box and Cul5 box, in vitro ubiquitin ligase assay FEBS letters High 16325183
2007 SAG/RBX2 promotes VHL-mediated HIF-1α ubiquitination and degradation; siRNA silencing of SAG or ROC1 significantly inhibited HIF-1α ubiquitination. SAG forms an in vivo complex with Cul5 and VHL under hypoxia. HIF-1 transcriptionally induces SAG via a consensus HIF-1-binding site in the first intron, establishing an HIF-1–SAG feedback loop. siRNA silencing, ubiquitination assay, co-immunoprecipitation, luciferase reporter assay, ChIP (chromatin immunoprecipitation) Oncogene High 17828303
2007 SAG/RBX2 is a transcriptional target of AP-1 (c-Jun); upon induction by AP-1, SAG promotes c-Jun ubiquitination and degradation via SCF-Fbw7, establishing an AP-1/SAG autofeedback loop. SAG siRNA silencing reduced c-Jun polyubiquitination and blocked Fbw7-induced c-Jun degradation. Luciferase reporter assay, in vitro and in vivo AP-1 binding (EMSA and ChIP), siRNA silencing, polyubiquitination assay, Western blotting Cancer research High 17440073
2007 In transgenic mouse epidermis, SAG/RBX2 targets c-Jun/AP-1 at early stages of skin carcinogenesis (promoting c-Jun degradation and suppressing tumor promotion) and IκBα at later stages (promoting IκBα degradation, activating NF-κB, and reducing apoptosis to enhance tumor growth), demonstrating stage-dependent substrate targeting. K14 promoter-driven transgenic mouse model, in vitro primary culture, in vivo AP-1 luciferase reporter mouse model, Western blotting, AP-1 activity measurement The Journal of cell biology Medium 17846172
2008 SAG/RBX2 promotes degradation of both c-Jun and p27 simultaneously; in a K14-SAG transgenic mouse model, SAG reduced c-Jun and p27 levels and inhibited AP-1 activity after UVB exposure, causing skin hyperplasia without affecting apoptosis or p53/c-Fos/cyclin D1 levels. Transgenic mouse model, Western blotting, AP-1 activity assay, immunohistochemistry, DNA synthesis rate measurement Carcinogenesis Medium 18258608
2008 Cullin-box sequences (Cul2-box and Cul5-box) in BC-box proteins directly determine binding specificity for Cul2-Rbx1 vs. Cul5-Rbx2 modules; spacing between BC- and Cullin-boxes is flexible (3–80 aa), and residues conserved in the Cul2-box are a subset of those in the Cul5-box. Biochemical purification of multisubunit complexes, structure-function mutagenesis, mass spectrometry identification of BC-box proteins The Journal of biological chemistry Medium 18187417
2010 SAG/RBX2 silencing induces apoptosis with accumulation of NOXA, while SAG overexpression reduces NOXA levels and shortens NOXA protein half-life, identifying NOXA as a substrate of SAG E3 ligase. siRNA silencing, Western blotting of apoptosis-associated proteins, protein half-life assay, FACS analysis Clinical cancer research Medium 20103673
2010 Sag gene-trap deletion in mouse embryonic stem cells abrogates IκBα degradation and NF-κB activation; IκBα is identified as a direct substrate of SAG-SCF(β-TrCP) E3 ubiquitin ligase. Sag elimination also increases steady-state ROS levels and enhances radiation-induced apoptosis. Gene-trap strategy (complete Sag elimination), clonogenic survival assay, Western blotting, ROS measurement, NF-κB activation assay, in vitro ubiquitination assay Free radical biology & medicine High 20638939
2011 SAG/RBX2 is an essential RING component of SAG-CUL1-FBXW7 E3 ligase that targets NF1 (neurofibromatosis type 1) for ubiquitin-mediated degradation. Sag knockout mice die at E11.5–12.5 with vascular and neural defects associated with NF1 accumulation and RAS inhibition; simultaneous Nf1 deletion partially rescues these defects, establishing NF1 as a physiological SAG substrate. Conditional knockout mouse, embryonic stem cell differentiation assay, epistasis (double knockout rescue), Western blotting, angiogenesis assays Developmental cell High 22118770
2013 Rbx2 (RNF7), as a core subunit of the Cullin5-RING E3 ubiquitin ligase (CRL5) complex, stops neocortical projection neurons at their target layers by facilitating Dab1 ubiquitylation and turnover through SOCS7-CRL5 complexes. Rbx2 mutation causes neocortical and cerebellar ectopias dependent on Dab1 (Reelin pathway). SOCS7-CRL5 is required for neocortical but not cerebellar layering, revealing adaptor-specific functions. Conditional knockout mouse (Rbx2 mutation), epistasis (Dab1-dependence), ubiquitylation assay (SOCS7-CRL5 stimulates Dab1 ubiquitylation), SOCS7 overexpression rescue experiment Developmental cell High 24210661
2013 Sag endothelial deletion causes embryonic lethality at E15.5 with impaired vasculogenesis; Sag deletion/knockdown in endothelial cells inhibits migration, proliferation, and tube formation, with p27 accumulation responsible for suppression of migration and proliferation. Conditional endothelial-specific knockout mouse (Tie2-Cre), siRNA knockdown in endothelial cells, Matrigel plug angiogenesis assay, in vitro tube formation, Western blotting Oncogene High 24213570
2014 Biophysical reconstitution of the full-size neddylated and unneddylated SOCS2-EloBC-Cul5-Rbx2 (CRL5SOCS2) complex in vitro; the complex exists as a monomer. Affinities of protein-protein interactions within the complex were measured by isothermal titration calorimetry. Recombinant protein expression (E. coli and Sf21 insect cells), pulldown from human cell lysates using phospho-GHR peptides, size exclusion chromatography with multi-angle static light scattering, native MS, traveling wave ion mobility MS, ITC The Journal of biological chemistry High 25505247
2014 SAG/RBX2 promotes ubiquitylation and degradation of PHLPP1 and DEPTOR, leading to activation of the PI3K/AKT/mTOR axis. Simultaneous knockdown of PHLPP1 or DEPTOR partially rescues the growth suppression caused by SAG knockdown. Phlpp1 and Deptor accumulate in Sag-null prostate cancer tissues with corresponding inactivation of Akt/mTOR. Prostate-specific conditional double knockout (Sag/Pten), siRNA knockdown, in vivo and in vitro ubiquitylation assays, Western blotting, epistasis rescue experiment Molecular cancer High 27955654
2014 SAG/RBX2 knockdown suppresses lung tumorigenesis and causes accumulation of tumor suppressor substrates p21, p27, NOXA, and BIM, inactivates NF-κB and mTOR pathways; growth suppression is partially rescued by simultaneous knockdown of p21 or the mTOR inhibitor DEPTOR, establishing these as functional SAG substrates. Conditional knockout mouse (KrasG12D-driven lung tumors), siRNA knockdown, epistasis rescue experiments, Western blotting, cell survival assays The Journal of clinical investigation High 24430184
2014 NEDD4-1 (a HECT-domain E3 ubiquitin ligase) directly binds to the C-terminal RING domain of SAG/RBX2 via its HECT domain and ubiquitylates SAG for proteasome-mediated degradation, thereby identifying SAG as a substrate of NEDD4-1. SAG bridges NEDD4-1 (via its C-terminus) and CUL-5 (via its N-terminus) to form a NEDD4-1/SAG/CUL-5 tri-complex. Co-immunoprecipitation, domain-mapping (HECT vs. RING domain interactions), protein half-life assay (overexpression and silencing), ubiquitylation assay Oncotarget Medium 25216516
2015 Sag deletion induces cellular senescence associated with accumulation of p16 (not p53); mechanistically, Sag deletion causes accumulation of JunB (a SAG-Fbxw7 substrate), a transcription factor that drives p16 transcription. Simultaneous deletion of Cdkn2a (p16 gene) largely rescues senescence, and also rescues Kras(G12D)-induced immortalization abrogated by Sag deletion. Genetic deletion in mouse embryonic fibroblasts, double knockout epistasis (Sag/Cdkn2a), Western blotting, senescence assays Neoplasia High 25622904
2015 RNF7/SAG interacts with PCNA in human cells; this interaction was identified by bimolecular fluorescence complementation screen and validated by co-immunoprecipitation from human cell extracts and by interaction analyses using recombinant proteins. BiFC screen (bimolecular fluorescence complementation), co-immunoprecipitation from human cell extracts, recombinant protein interaction analysis Cell cycle Medium 26030842
2015 Both Rbx1 and Rbx2 can promote ubiquitination of APOBEC3G (A3G) in vitro as part of the HIV-1 Vif-Cul5 E3 ligase complex; however, in cells, only knockdown of endogenous Rbx2 (not Rbx1) impairs Vif-induced A3G degradation. Rbx2 can dose-dependently inhibit Rbx1 interaction with Cul5. In vitro ubiquitination assay, co-immunoprecipitation, siRNA knockdown, Western blotting Biochemical and biophysical research communications Medium 25912140
2016 SAG/RBX2 selectively binds E2s UBCH10 and UBE2S (which mediate K11 ubiquitin linkage), whereas RBX1 exclusively binds CDC34 and UBCH5C (K48 linkage). SAG-CUL5 promotes K11-linked ubiquitylation and degradation of β-TrCP1; silencing UBCH10 or UBE2S (but not UBCH5C) causes β-TrCP1 accumulation. SAG-CUL5-β-TrCP1 forms a complex under physiological conditions. Co-immunoprecipitation, E2 binding assays, ubiquitylation assay (K11 linkage-specific), siRNA silencing, protein half-life assay Scientific reports High 27910872
2016 SAG-dependent neddylation in T cells regulates T cell activation, proliferation, and effector cytokine release. SAG T-cell-specific knockout reduces T cell responses and graft-versus-host disease; mechanistically, SAG-mediated effects in T cells are associated with increased SOCS expression (but not NF-κB translocation). T-cell-specific conditional knockout mouse, in vitro T cell stimulation, in vivo allogeneic bone marrow transplantation model, MLN4924 pharmacological inhibition The American journal of pathology Medium 27543965
2017 RNF7/SAG functions as an E3 ubiquitin ligase that negatively regulates CARMA2sh (CARD14) NF-κB signaling by regulating the ubiquitination state of MALT1 and NEMO. RNF7 interacts with CARMA2 (identified by yeast two-hybrid), and psoriasis-associated CARMA2sh mutants escape this negative regulation by RNF7. Yeast two-hybrid screen (identification of interaction), ubiquitination assays for MALT1 and NEMO, functional NF-κB reporter assays International journal of molecular sciences Medium 29194363
2018 RBX2 is essential for retinal layering and function: depletion of RBX2 mispositions rod bipolar cells, cone photoreceptors, and Müller glia. SOCS7-CRL5 controls rod bipolar cell and Müller glia positioning via sustained DAB1 (Reelin/RELN) signaling, but cone photoreceptor positioning is SOCS7-independent, revealing distinct CRL5 adaptor utilization. RBX2 depletion also reduces ribbon synapses and disrupts cone photoreceptor function. Conditional knockout mouse (RBX2 and SOCS7), electrophysiology, immunohistochemistry for synaptic markers, epistasis analysis Development High 29361558
2018 SAG/RBX2 (Sag) deletion in myeloid cells differentially regulates inflammatory responses: Sag-null macrophages release fewer proinflammatory cytokines, while Sag-null neutrophils release more. SAG depletion alters expression of myeloperoxidase (Mpo) and neutrophil elastase (Elane) in bone marrow cells in response to LPS. LysM-Cre conditional knockout mouse, LPS challenge in vivo, cytokine measurement (ELISA), gene expression analysis Frontiers in immunology Medium 30574150
2020 SAG/RBX2 competes with APC2 for UBE2C/UBE2S binding, acting as a potential endogenous inhibitor of APC/C and regulating G2-to-M progression. SAG knockdown causes premature APC/C activation, mitotic slippage, and resistance to anti-microtubule drugs. Conversely, SAG is itself a substrate of APC/CCDH1 and is degraded at G1 phase; degradation-resistant SAG-R98A/L101A mutant accelerates G1-to-S progression. Co-immunoprecipitation, competition binding assays, siRNA knockdown, degradation-resistant mutant overexpression, cell cycle and mitotic assays Cell reports High 32905768
2022 RNF7/SAG promotes ubiquitination of SOCS1 to activate JAK/STAT3 signaling; STAT3 activation in turn transcriptionally induces RNF7, establishing a STAT3/RNF7 feedback loop. RNF7 overexpression inhibits apoptosis and promotes glycolysis in renal cell carcinoma. Knockdown and overexpression experiments, ubiquitination assay for SOCS1, Western blotting for JAK/STAT3 pathway, luciferase reporter assay, in vivo xenograft Cellular & molecular biology letters Medium 35562668
2024 RBX2/CUL5 (core components of CRL5) localize to mitochondria. RBX2 depletion inhibits mitochondrial ubiquitination and turnover, impairs mitochondrial membrane potential and respiration, and causes cardiomyocyte death. In vivo cardiac-specific Rbx2 deletion suppresses mitophagic activity, causes accumulation of damaged mitochondria, and leads to dilated cardiomyopathy and heart failure. RBX2 controls PINK1 stability in mitochondria. This Parkin-independent mitophagic function does not require Parkin (Parkin deletion has no impact on cardiomyopathy in RBX2-deficient hearts). Subcellular fractionation, immunostaining, immunogold electron microscopy (RBX2/CUL5 mitochondrial localization), cardiomyocyte-specific and adult heart conditional knockout mice, in vitro mitochondrial function assays (membrane potential, respiration), mitophagy assays, proteomics, RNA-sequencing, Western blotting Circulation research High 38873758
2025 YTHDF1 (m6A reader) promotes RNF7 translation in an m6A-dependent manner; elevated RNF7 then promotes degradation of the CDK inhibitor p27, driving prostate cancer cell proliferation. MLN4924 (neddylation inhibitor) inhibits prostate cancer progression in vitro and in vivo through this axis. YTHDF1 knockdown/overexpression, p27 protein stability assay, E3 ligase screening (candidate p27-targeting ligases), xenograft and organoid models, in vitro and in vivo drug treatment Cell death & disease Medium 40251202
2025 Let-7 microRNA directly binds a conserved motif in the 3' UTR of RBX2, reducing its translation and thereby diminishing CRL5 activity. Restoring RBX2 levels rescues pyramidal neuron positioning (without altering let-7-induced fate effects), demonstrating that let-7 regulates RBX2-CRL5 to control neocortical neuron migration independently of fate specification. In utero electroporation, let-7 overexpression and RBX2 rescue experiments in mouse neocortex, 3' UTR reporter assays, live imaging of neuronal migration Proceedings of the National Academy of Sciences High 42012943

Source papers

Stage 0 corpus · 53 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1 and Cul5-Rbx2 modules of ubiquitin ligases. Genes & development 411 15601820
2008 Characterization of Cullin-box sequences that direct recruitment of Cul2-Rbx1 and Cul5-Rbx2 modules to Elongin BC-based ubiquitin ligases. The Journal of biological chemistry 168 18187417
2005 ASB proteins interact with Cullin5 and Rbx2 to form E3 ubiquitin ligase complexes. FEBS letters 100 16325183
2011 SAG/RBX2/ROC2 E3 ubiquitin ligase is essential for vascular and neural development by targeting NF1 for degradation. Developmental cell 84 22118770
2010 Validation of SAG/RBX2/ROC2 E3 ubiquitin ligase as an anticancer and radiosensitizing target. Clinical cancer research : an official journal of the American Association for Cancer Research 84 20103673
2010 Small RING Finger Proteins RBX1 and RBX2 of SCF E3 Ubiquitin Ligases: The Role in Cancer and as Cancer Targets. Genes & cancer 83 21103004
2014 Inactivation of SAG/RBX2 E3 ubiquitin ligase suppresses KrasG12D-driven lung tumorigenesis. The Journal of clinical investigation 81 24430184
2012 Functional characterization of SAG/RBX2/ROC2/RNF7, an antioxidant protein and an E3 ubiquitin ligase. Protein & cell 80 23136067
2007 SAG/ROC2/RBX2 is a HIF-1 target gene that promotes HIF-1 alpha ubiquitination and degradation. Oncogene 71 17828303
2000 Yeast homolog of human SAG/ROC2/Rbx2/Hrt2 is essential for cell growth, but not for germination: chip profiling implicates its role in cell cycle regulation. Oncogene 61 10851089
2007 SAG/ROC2/Rbx2 is a novel activator protein-1 target that promotes c-Jun degradation and inhibits 12-O-tetradecanoylphorbol-13-acetate-induced neoplastic transformation. Cancer research 59 17440073
2007 SAG/ROC2 E3 ligase regulates skin carcinogenesis by stage-dependent targeting of c-Jun/AP1 and IkappaB-alpha/NF-kappaB. The Journal of cell biology 51 17846172
2013 Rbx2 regulates neuronal migration through different cullin 5-RING ligase adaptors. Developmental cell 47 24210661
2016 Depletion of SAG/RBX2 E3 ubiquitin ligase suppresses prostate tumorigenesis via inactivation of the PI3K/AKT/mTOR axis. Molecular cancer 45 27955654
2001 Elevated expression of SAG/ROC2/Rbx2/Hrt2 in human colon carcinomas: SAG does not induce neoplastic transformation, but antisense SAG transfection inhibits tumor cell growth. Molecular carcinogenesis 41 11255265
2016 SAG/RBX2 E3 ligase complexes with UBCH10 and UBE2S E2s to ubiquitylate β-TrCP1 via K11-linkage for degradation. Scientific reports 37 27910872
2010 Disruption of Sag/Rbx2/Roc2 induces radiosensitization by increasing ROS levels and blocking NF-kappaB activation in mouse embryonic stem cells. Free radical biology & medicine 34 20638939
2001 Promotion of S-phase entry and cell growth under serum starvation by SAG/ROC2/Rbx2/Hrt2, an E3 ubiquitin ligase component: association with inhibition of p27 accumulation. Molecular carcinogenesis 34 11255262
2008 SAG/ROC2/RBX2 E3 ligase promotes UVB-induced skin hyperplasia, but not skin tumors, by simultaneously targeting c-Jun/AP-1 and p27. Carcinogenesis 33 18258608
2016 SAG/Rbx2-Dependent Neddylation Regulates T-Cell Responses. The American journal of pathology 29 27543965
2014 SAG/RBX2 is a novel substrate of NEDD4-1 E3 ubiquitin ligase and mediates NEDD4-1 induced chemosensitization. Oncotarget 29 25216516
2014 Biophysical studies on interactions and assembly of full-size E3 ubiquitin ligase: suppressor of cytokine signaling 2 (SOCS2)-elongin BC-cullin 5-ring box protein 2 (RBX2). The Journal of biological chemistry 28 25505247
2013 Endothelial deletion of Sag/Rbx2/Roc2 E3 ubiquitin ligase causes embryonic lethality and blocks tumor angiogenesis. Oncogene 28 24213570
2001 SAG/ROC2/Rbx2/Hrt2, a component of SCF E3 ubiquitin ligase: genomic structure, a splicing variant, and two family pseudogenes. DNA and cell biology 25 11506706
2022 RNF7 inhibits apoptosis and sunitinib sensitivity and promotes glycolysis in renal cell carcinoma via the SOCS1/JAK/STAT3 feedback loop. Cellular & molecular biology letters 21 35562668
2015 A fluorescent bimolecular complementation screen reveals MAF1, RNF7 and SETD3 as PCNA-associated proteins in human cells. Cell cycle (Georgetown, Tex.) 21 26030842
2020 Long non-coding RNA RNF7 promotes the cardiac fibrosis in rat model via miR-543/THBS1 axis and TGFβ1 activation. Aging 18 31913855
2018 RBX2 maintains final retinal cell position in a DAB1-dependent and -independent fashion. Development (Cambridge, England) 17 29361558
2018 SAG/RBX2 E3 Ubiquitin Ligase Differentially Regulates Inflammatory Responses of Myeloid Cell Subsets. Frontiers in immunology 17 30574150
2017 PNPLA3 and RNF7 Gene Variants are Associated with the Risk of Developing Liver Fibrosis and Cirrhosis in an Eastern European Population. Journal of gastrointestinal and liver diseases : JGLD 17 28338112
2017 RNF7 knockdown inhibits prostate cancer tumorigenesis by inactivation of ERK1/2 pathway. Scientific reports 15 28252001
2024 Ubiquitin Ligase RBX2/SAG Regulates Mitochondrial Ubiquitination and Mitophagy. Circulation research 14 38873758
2020 The Negative Cross-Talk between SAG/RBX2/ROC2 and APC/C E3 Ligases in Regulation of Cell Cycle Progression and Drug Resistance. Cell reports 14 32905768
2017 The E3 Ubiquitin Ligase RNF7 Negatively Regulates CARD14/CARMA2sh Signaling. International journal of molecular sciences 14 29194363
2003 Phosphorylation of threonine 10 on CKBBP1/SAG/ROC2/Rbx2 by protein kinase CKII promotes the degradation of IkappaBalpha and p27Kip1. The Journal of biological chemistry 14 12748192
2015 Both Rbx1 and Rbx2 exhibit a functional role in the HIV-1 Vif-Cullin5 E3 ligase complex in vitro. Biochemical and biophysical research communications 13 25912140
2020 Transgenic expression of Sag/Rbx2 E3 causes early stage tumor promotion, late stage cytogenesis and acinar loss in the Kras-PDAC model. Neoplasia (New York, N.Y.) 10 32339950
2022 RNF7 promotes glioma growth via the PI3K/AKT signalling axis. Journal of cellular and molecular medicine 9 36578229
2015 Inactivation of Sag/Rbx2/Roc2 e3 ubiquitin ligase triggers senescence and inhibits kras-induced immortalization. Neoplasia (New York, N.Y.) 9 25622904
2025 YTHDF1/RNF7/p27 axis promotes prostate cancer progression. Cell death & disease 7 40251202
2023 RNF7 Induces Skeletal Muscle Cell Apoptosis and Arrests Cell Autophagy via Upregulation of THBS1 and Inactivation of the PI3K/Akt Signaling Pathway in a Rat Sepsis Model. Infection and immunity 6 36920202
2023 Advancements and perspectives of RBX2 as a molecular hallmark in cancer. Gene 6 37820940
2018 Comparative Analysis of cul5 and rbx2 Expression in the Developing and Adult Murine Brain and Their Essentiality During Mouse Embryogenesis. Developmental dynamics : an official publication of the American Association of Anatomists 5 30269386
2002 The Ring-H2 finger motif of CKBBP1/SAG is necessary for interaction with protein kinase CKII and optimal cell proliferation. Journal of biochemistry and molecular biology 4 12470599
2023 RNF7 Facilitated the Tumorigenesis of Pancreatic Cancer by Activating PI3K/Akt Signaling Pathway. Oxidative medicine and cellular longevity 3 36644576
2025 The ubiquitin conjugating enzyme E2 F (UBE2F)-RING-box protein 2 (RBX2)-mediated neddylation of Cullin5 facilitates pseudorabies virus replication. International journal of biological macromolecules 2 41478481
2024 The Ubiquitin Ligase RBX2/SAG Regulates Mitochondrial Ubiquitination and Mitophagy. bioRxiv : the preprint server for biology 2 38464205
2026 Uncoupling neocortical neuron fate and migration via a Let-7-RBX2 axis. Proceedings of the National Academy of Sciences of the United States of America 1 42012943
2025 RNF7-Mediated ROS Targets Malignant Phenotype and Radiotherapy Sensitivity in Glioma With Different IDH1 Genotypes. Molecular carcinogenesis 1 39783768
2025 Uncoupling Neocortical Neuron Fate and Migration via a Let-7-RBX2 Axis. bioRxiv : the preprint server for biology 1 41000670
2023 Sag/Rbx2 Partial Inactivation Sensitizes Mice to Radiation and Radiation-Induced Tumorigenesis1. Radiation research 1 36745565
2026 SAG/RBX2/ROC2/RNF7 dual E3 ligase: From target identification, validation to drug discovery. Biochimica et biophysica acta. Reviews on cancer 0 41610919
2024 [High RNF7 expression enhances PD-1 resistance of non-small cell lung cancer cells by promoting CXCL1 expression and myeloid-derived suppressor cell recruitment via activating NF-κB signaling]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 0 39505338

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