RNF41 (RING finger protein 41; also known as NRDP1, neuregulin receptor degradation protein-1, and FLRF) is a 317-residue RING-type E3 ubiquitin-protein ligase (EC 2.3.2.27). It has an N-terminal RING-type zinc finger (catalytic residues Cys34/His36/Asp56) that recruits a ubiquitin-charged E2 conjugating enzyme, a degenerate SIAH-type zinc finger, and a C-terminal dimerization/substrate-binding domain that engages substrates and the deubiquitinase USP8. RNF41 directs ubiquitination and, for several targets, proteasomal degradation of a defined substrate set. Its best-characterized substrates are the neuregulin receptor tyrosine kinases ErbB3 and ErbB4 (but not EGFR or ErbB2): RNF41 binds the ErbB3 cytoplasmic tail in an activation-independent manner and mediates growth-factor-independent ubiquitination and ER-associated/proteasomal degradation, thereby setting steady-state ErbB3/ErbB4 levels and restraining ErbB2/ErbB3-driven proliferative signaling and tumor growth. RNF41 also ubiquitinates and degrades the giant inhibitor-of-apoptosis protein BIRC6/BRUCE/Apollon, thereby promoting apoptosis, and ubiquitinates the E3 ligase PRKN/Parkin, accelerating its degradation, lowering Parkin activity and increasing reactive oxygen species (linking RNF41 to oxidative stress and Parkinson disease biology and to RNF41-PRKN regulation of late mitophagy). In innate immunity RNF41 polyubiquitinates MYD88 (limiting MyD88-dependent pro-inflammatory cytokines) and promotes TRIF-dependent type I interferon production and TBK1/IRF3 activation, and it ubiquitinates the erythropoietin and interleukin-3 receptors to control hematopoietic progenitor differentiation. RNF41 itself is regulated by autoubiquitination-driven proteasomal turnover that is counteracted by the deubiquitinase USP8 and by sequestration into endoplasmic-reticulum tubules by the reticulon Rtn4A/Nogo-A. It localizes mainly to the cytosol and perinuclear region, with a regulated pool on the ER tubular network.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0071782 endoplasmic reticulum tubular network | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference that RNF41 acts on the ER tubular network. RNF41 ubiquitinates newly synthesized ErbB3 at the ER and can be sequestered into ER tubules by Rtn4A. Reason: Experimentally supported localization (IDA in PMID:27353365) but represents the Rtn4A-sequestered/ER-associated degradation pool; the dominant active compartment is cytosolic/perinuclear. Supporting Evidence: PMID:27353365 Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules |
| GO:0000209 protein polyubiquitination | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA machine-learning assignment of protein polyubiquitination, the core catalytic process of RNF41. Reason: Core biological process directly demonstrated; RNF41 catalyzes polyubiquitin chain assembly on substrates including Parkin and BRUCE. Redundant with the IDA annotations. Supporting Evidence: PMID:18541373 Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells |
| GO:0008270 zinc ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based electronic assignment of zinc ion binding; RNF41 has a RING-type and a SIAH-type zinc finger that coordinate zinc. Reason: Structurally required; the RING and SIAH-type zinc fingers coordinate zinc, essential for the RING fold and catalytic activity. Supporting Evidence: file:human/RNF41/RNF41-uniprot.txt ZN_FING 18..57 |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic assignment of general protein ubiquitination, a parent of the specific polyubiquitination RNF41 catalyzes. Reason: Correct but generic; the specific protein polyubiquitination annotation (GO:0000209) better captures the role. Supporting Evidence: file:human/RNF41/RNF41-uniprot.txt PATHWAY: Protein modification; protein ubiquitination. |
| GO:0019899 enzyme binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning assignment of enzyme binding. RNF41 binds the deubiquitinase USP8 and the E3 ligase Parkin; a generic and uninformative binding term. Reason: Correct but generic - RNF41 does bind enzymes (USP8, Parkin) - but enzyme binding is uninformative; more specific functional terms capture the biology. Supporting Evidence: file:human/RNF41/RNF41-uniprot.txt Interacts with USP8, ERBB3, PRKN and BIRC6 |
| GO:0061630 ubiquitin protein ligase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of ubiquitin protein ligase activity, the core molecular function of RNF41 as a RING-type E3 ligase. Reason: Core molecular function corroborated by direct experimental evidence (IDA); genuine catalytic RING E3 whose RING mutations abolish activity. Supporting Evidence: file:human/RNF41/RNF41-uniprot.txt Full=E3 ubiquitin-protein ligase NRDP1 |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | KEEP AS NON CORE | Summary: High-throughput interactome interaction. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/RNF41/RNF41-uniprot.txt Full=E3 ubiquitin-protein ligase NRDP1 |
| GO:0005515 protein binding | IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc... | KEEP AS NON CORE | Summary: Chaperone interaction-network study interaction. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/RNF41/RNF41-uniprot.txt Full=E3 ubiquitin-protein ligase NRDP1 |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Proteome-scale interactome interaction. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/RNF41/RNF41-uniprot.txt Full=E3 ubiquitin-protein ligase NRDP1 |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | KEEP AS NON CORE | Summary: Interactome perturbation study interaction. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/RNF41/RNF41-uniprot.txt Full=E3 ubiquitin-protein ligase NRDP1 |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | KEEP AS NON CORE | Summary: Quantitative interactome (stoichiometry/abundance) interaction. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/RNF41/RNF41-uniprot.txt Full=E3 ubiquitin-protein ligase NRDP1 |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: Interactome-community study interaction. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/RNF41/RNF41-uniprot.txt Full=E3 ubiquitin-protein ligase NRDP1 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Binary interactome reference-map interaction. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/RNF41/RNF41-uniprot.txt Full=E3 ubiquitin-protein ligase NRDP1 |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Neurodegeneration interactome interaction. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/RNF41/RNF41-uniprot.txt Full=E3 ubiquitin-protein ligase NRDP1 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: Cell-specific interactome interaction. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/RNF41/RNF41-uniprot.txt Full=E3 ubiquitin-protein ligase NRDP1 |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | KEEP AS NON CORE | Summary: Multimodal cell-map interactome interaction. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/RNF41/RNF41-uniprot.txt Full=E3 ubiquitin-protein ligase NRDP1 |
| GO:0042802 identical protein binding | IPI PMID:22493164 Systematic analysis of dimeric E3-RING interactions reveals ... | KEEP AS NON CORE | Summary: Dimeric E3-RING interaction analysis; RNF41 self-associates (its C-terminal domain dimerizes, also forming trimers via the coiled-coil region). A real, informative homotypic interaction. Reason: RNF41 genuinely self-associates (homodimer/oligomer), but this is a structural property supporting rather than defining its core ligase function. Supporting Evidence: file:human/RNF41/RNF41-uniprot.txt Q9H4P4; Q9H4P4: RNF41; NbExp=3; IntAct=EBI-2130266, EBI-2130266 |
| GO:0042802 identical protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Proteome-scale interactome self-interaction (RNF41 homodimerization). A real homotypic interaction. Reason: RNF41 self-associates; supports its function but is not the core catalytic role. Supporting Evidence: file:human/RNF41/RNF41-uniprot.txt Q9H4P4; Q9H4P4: RNF41; NbExp=3; IntAct=EBI-2130266, EBI-2130266 |
| GO:0042802 identical protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | KEEP AS NON CORE | Summary: Interaction-perturbation study self-interaction (RNF41 homodimerization). Reason: RNF41 self-associates; supports its function but is not the core catalytic role. Supporting Evidence: file:human/RNF41/RNF41-uniprot.txt Q9H4P4; Q9H4P4: RNF41; NbExp=3; IntAct=EBI-2130266, EBI-2130266 |
| GO:0005128 erythropoietin receptor binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-transferred (Ensembl Compara) erythropoietin receptor binding; RNF41 ubiquitinates the EPO receptor to control hematopoietic progenitor differentiation (By similarity). Reason: Reflects a real substrate-recognition interaction (EPOR) supporting the hematopoietic role, but is a specific non-core substrate transferred by similarity. Supporting Evidence: file:human/RNF41/RNF41-uniprot.txt Involved in the ubiquitination of erythropoietin (EPO) and interleukin-3 (IL-3) receptors |
| GO:0005135 interleukin-3 receptor binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-transferred (Ensembl Compara) interleukin-3 receptor binding; RNF41 ubiquitinates the IL-3 receptor to control hematopoietic progenitor differentiation (By similarity). Reason: Reflects a real substrate-recognition interaction (IL3RA/CSF2RB) supporting the hematopoietic role, but is a specific non-core substrate transferred by similarity. Supporting Evidence: file:human/RNF41/RNF41-uniprot.txt Involved in the ubiquitination of erythropoietin (EPO) and interleukin-3 (IL-3) receptors |
| GO:0004842 ubiquitin-protein transferase activity | TAS Reactome:R-HSA-1358789 | ACCEPT | Summary: Reactome curation (self-ubiquitination of RNF41) of ubiquitin-protein transferase activity, the core catalytic molecular function. Reason: Core molecular function; RNF41 is a genuine catalytic RING E3 that transfers ubiquitin from E2 to substrate. Synonymous with ubiquitin protein ligase activity. Supporting Evidence: file:human/RNF41/RNF41-uniprot.txt EC=2.3.2.27 |
| GO:0019904 protein domain specific binding | IPI PMID:27353365 The ER structural protein Rtn4A stabilizes and enhances sign... | KEEP AS NON CORE | Summary: RNF41 binds the core reticulon domain of Rtn4A via its receptor-binding (C-terminal) domain; a specific domain-domain interaction. Reason: Records a real, mechanistically relevant interaction (Rtn4A reticulon domain) that regulates RNF41 localization/activity, but is a binding term rather than RNF41's core function. Supporting Evidence: PMID:27353365 the core reticulon domain is sufficient for mediating interaction with Nrdp1 |
| GO:0030971 receptor tyrosine kinase binding | IPI PMID:27353365 The ER structural protein Rtn4A stabilizes and enhances sign... | KEEP AS NON CORE | Summary: RNF41 binds the receptor tyrosine kinase ErbB3 (and ErbB4) via its C-terminal domain; the substrate-recognition interaction underlying ErbB3/ErbB4 degradation. Reason: Informative substrate-recognition molecular function (ErbB3/ErbB4 binding) supporting the core ErbB3-degradation role; kept as non-core because the catalytic ligase activity is the defining function. Supporting Evidence: PMID:27353365 The C-terminal domain of Nrdp1 is responsible for binding its substrate ErbB3 |
| GO:0045732 positive regulation of protein catabolic process | IMP PMID:27353365 The ER structural protein Rtn4A stabilizes and enhances sign... | KEEP AS NON CORE | Summary: RNF41 promotes proteasomal catabolism of ErbB3 (suppressed by Rtn4A). A regulatory framing of its degradative activity. Reason: Correct but a higher-level regulatory term; the specific proteasomal protein catabolic process annotation better captures the role. Supporting Evidence: PMID:27353365 Rtn4A counteracts the Nrdp1-mediated degradation of ErbB3 |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:27353365 The ER structural protein Rtn4A stabilizes and enhances sign... | ACCEPT | Summary: Direct localization of RNF41 to the cytosolic/perinuclear region (before Rtn4A-induced redistribution to ER tubules). Reason: Experimentally supported core localization; RNF41 is normally cytosolic/perinuclear where it acts on its substrates. Supporting Evidence: PMID:27353365 Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules |
| GO:0071782 endoplasmic reticulum tubular network | IDA PMID:27353365 The ER structural protein Rtn4A stabilizes and enhances sign... | KEEP AS NON CORE | Summary: Direct evidence that RNF41 localizes to ER tubules upon Rtn4A expression; the Rtn4A-sequestered pool where RNF41 is held inactive. Reason: Experimentally supported but represents the Rtn4A-sequestered/ERAD pool rather than the dominant cytosolic/perinuclear active site. Supporting Evidence: PMID:27353365 Rtn4A sequesters Nrdp1 in ER tubules where it cannot act on its substrates |
| GO:0061630 ubiquitin protein ligase activity | IDA PMID:18541373 Parkin is ubiquitinated by Nrdp1 and abrogates Nrdp1-induced... | ACCEPT | Summary: Direct evidence that RNF41 acts as a ubiquitin protein ligase, catalyzing poly-ubiquitin chains on Parkin in vitro and in cells. Core molecular function. Reason: Core molecular function directly demonstrated; RNF41 is a genuine catalytic RING E3 ligase. Supporting Evidence: PMID:18541373 Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells |
| GO:0031267 small GTPase binding | IPI PMID:24056301 The deubiquitylase USP33 discriminates between RALB function... | UNDECIDED | Summary: An interaction recorded in the USP33/RALB study; RNF41 appears as an interactor. The specific RNF41-small GTPase binding cannot be verified from the cached abstract, which concerns USP33 and the RAS-like GTPase RALB. Reason: Cannot verify the RNF41-specific small GTPase binding claim from available text (cached entry is abstract-only and centered on USP33/RALB). Per guidelines, an experimental IPI is not removed on the basis of incomplete cached evidence; defer to the curator. Supporting Evidence: PMID:24056301 The RAS-like GTPase RALB mediates cellular responses to nutrient availability or viral infection |
| GO:0000209 protein polyubiquitination | IDA PMID:18541373 Parkin is ubiquitinated by Nrdp1 and abrogates Nrdp1-induced... | ACCEPT | Summary: Direct evidence that RNF41 catalyzes poly-ubiquitin chains on Parkin. Core biological process. Reason: Core biological process directly demonstrated; RNF41 assembles polyubiquitin chains on its substrate Parkin. Supporting Evidence: PMID:18541373 Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells |
| GO:0010498 proteasomal protein catabolic process | IDA PMID:18541373 Parkin is ubiquitinated by Nrdp1 and abrogates Nrdp1-induced... | ACCEPT | Summary: Direct evidence that RNF41 drives proteasome-dependent degradation of Parkin (and, in other studies, ErbB3 and BRUCE). Core biological process. Reason: Core biological process directly demonstrated; RNF41 targets substrates for proteasomal degradation. Supporting Evidence: PMID:18541373 overexpression of Nrdp1 significantly reduced the endogenous Parkin level in an Nrdp1 dosage-dependent and proteasome-dependent manner |
| GO:2000379 positive regulation of reactive oxygen species metabolic process | IMP PMID:18541373 Parkin is ubiquitinated by Nrdp1 and abrogates Nrdp1-induced... | KEEP AS NON CORE | Summary: Nrdp1 overexpression increases ROS production (abrogated by Parkin co-expression), via the RNF41-Parkin axis. A downstream consequence of degrading Parkin. Reason: Real phenotype but a downstream consequence of RNF41-mediated Parkin degradation, not a core function. Supporting Evidence: PMID:18541373 overexpression of Nrdp1 increased the production of reactive oxygen species (ROS), which was abrogated by co-expression of Parkin |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:24105792 Protein microarray characterization of the S-nitrosoproteome... | ACCEPT | Summary: Protein-microarray (S-nitrosoproteome) detection of RNF41 ubiquitin-protein transferase activity. The catalytic molecular function is correct, though the source is a proteome-scale assay. Reason: Core molecular function; consistent with the well-established catalytic RING E3 activity of RNF41, redundant with the IDA ligase-activity annotation. Supporting Evidence: file:human/RNF41/RNF41-uniprot.txt EC=2.3.2.27 |
| GO:0051865 protein autoubiquitination | IDA PMID:24105792 Protein microarray characterization of the S-nitrosoproteome... | ACCEPT | Summary: RNF41 autoubiquitinates, leading to its own proteasomal degradation (counteracted by USP8). A well-established self-regulatory activity. Reason: Well-supported activity (autoubiquitination regulates RNF41 levels; RING mutations that disrupt ligase activity stabilize RNF41); consistent with a genuine catalytic RING E3. Supporting Evidence: file:human/RNF41/RNF41-uniprot.txt Autoubiquitinated. Autoubiquitination leads to proteasomal degradation. |
| GO:0097191 extrinsic apoptotic signaling pathway | IDA PMID:14765125 Nrdp1-mediated degradation of the gigantic IAP, BRUCE, is a ... | KEEP AS NON CORE | Summary: RNF41 ubiquitinates and degrades the IAP BRUCE/BIRC6, triggering apoptosis. A downstream process of its degradative activity. Reason: Real apoptosis-promoting role via BRUCE degradation, but a downstream biological process rather than the core ligase function. Supporting Evidence: PMID:14765125 Nrdp1 can be important in the initiation of apoptosis by catalyzing ubiquitination and degradation of BRUCE |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1358789 | ACCEPT | Summary: Reactome curation of cytosolic localization (self-ubiquitination of RNF41). Consistent with the core cytosolic site of action. Reason: Correct core localization; RNF41 is predominantly cytosolic/perinuclear. Supporting Evidence: PMID:27353365 Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1358790 | ACCEPT | Summary: Reactome curation of cytosolic localization (RNF41 ubiquitinates ERBB3). Consistent with the core cytosolic site of action. Reason: Correct core cytosolic localization where RNF41 acts on its substrates. Supporting Evidence: PMID:27353365 Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1358792 | ACCEPT | Summary: Reactome curation of cytosolic localization (RNF41 ubiquitinates activated ERBB3). Consistent with the core cytosolic site of action. Reason: Correct core cytosolic localization where RNF41 acts on its substrates. Supporting Evidence: PMID:27353365 Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1358795 | ACCEPT | Summary: Reactome curation of cytosolic localization (deubiquitination of RNF41 by P-USP8). Consistent with the core cytosolic site of action. Reason: Correct core cytosolic localization where RNF41 acts on its substrates. Supporting Evidence: PMID:27353365 Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1358797 | ACCEPT | Summary: Reactome curation of cytosolic localization (ubiquitinated RNF41 binds P-USP8). Consistent with the core cytosolic site of action. Reason: Correct core cytosolic localization where RNF41 acts on its substrates. Supporting Evidence: PMID:27353365 Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1358798 | ACCEPT | Summary: Reactome curation of cytosolic localization (RNF41 binds neuregulin-activated ERBB3). Consistent with the core cytosolic site of action. Reason: Correct core cytosolic localization where RNF41 acts on its substrates. Supporting Evidence: PMID:27353365 Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1358801 | ACCEPT | Summary: Reactome curation of cytosolic localization (ERBB3 binds RNF41 ubiquitin ligase). Consistent with the core cytosolic site of action. Reason: Correct core cytosolic localization where RNF41 acts on its substrates. Supporting Evidence: PMID:27353365 Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules |
| GO:0005515 protein binding | IPI PMID:11867753 An RBCC protein implicated in maintenance of steady-state ne... | KEEP AS NON CORE | Summary: Interaction with ErbB3 from the original Nrdp1/RBCC identification study. Bare protein binding is uninformative. Reason: Records the foundational substrate interaction (ErbB3) but bare protein binding is uninformative; the receptor tyrosine kinase binding term is more specific. Supporting Evidence: PMID:11867753 Nrdp1 interacts specifically with the neuregulin receptors ErbB3 and ErbB4 |
| GO:0008285 negative regulation of cell population proliferation | IDA PMID:17145873 Loss of Nrdp1 enhances ErbB2/ErbB3-dependent breast tumor ce... | KEEP AS NON CORE | Summary: Nrdp1 suppresses ErbB2/ErbB3-dependent breast tumor cell proliferation; loss of Nrdp1 enhances growth. A downstream consequence of ErbB3 degradation. Reason: Real phenotype (tumor-suppressive) but downstream of RNF41-mediated ErbB3 degradation, not a core molecular function. Supporting Evidence: PMID:17145873 overexpression of Nrdp1 in human breast cancer cells results in the suppression of ErbB3 levels, accompanied by the inhibition of cell growth and motility |
| GO:0030336 negative regulation of cell migration | IMP PMID:17145873 Loss of Nrdp1 enhances ErbB2/ErbB3-dependent breast tumor ce... | KEEP AS NON CORE | Summary: Nrdp1 inhibits breast tumor cell motility/migration via ErbB3 suppression. A downstream consequence of ErbB3 degradation. Reason: Real phenotype but downstream of RNF41-mediated ErbB3 degradation, not a core function. Supporting Evidence: PMID:17145873 the inhibition of cell growth and motility and the attenuation of signal transduction pathways |
| GO:0043408 regulation of MAPK cascade | IDA PMID:17145873 Loss of Nrdp1 enhances ErbB2/ErbB3-dependent breast tumor ce... | KEEP AS NON CORE | Summary: Nrdp1 attenuates ErbB3-driven MAPK signaling. A downstream consequence of ErbB3 degradation. Reason: Real regulatory effect but downstream of RNF41-mediated ErbB3 degradation, not a core function. Supporting Evidence: PMID:17145873 the attenuation of signal transduction pathways |
| GO:0051896 regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IDA PMID:17145873 Loss of Nrdp1 enhances ErbB2/ErbB3-dependent breast tumor ce... | KEEP AS NON CORE | Summary: Nrdp1 attenuates ErbB3-driven PI3K/AKT signaling. A downstream consequence of ErbB3 degradation. Reason: Real regulatory effect but downstream of RNF41-mediated ErbB3 degradation, not a core function. Supporting Evidence: PMID:17145873 the attenuation of signal transduction pathways |
| GO:2000377 regulation of reactive oxygen species metabolic process | IMP PMID:18541373 Parkin is ubiquitinated by Nrdp1 and abrogates Nrdp1-induced... | KEEP AS NON CORE | Summary: RNF41 regulates ROS levels via the Parkin axis (knockdown lowers ROS). A downstream consequence of degrading Parkin. Reason: Real phenotype but downstream of RNF41-mediated Parkin degradation; the more specific positive-regulation term also captures this. Supporting Evidence: PMID:18541373 suppression of Nrdp1 by shRNA conferred SH-SY5Y cells a lower ROS level |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:18541373 Parkin is ubiquitinated by Nrdp1 and abrogates Nrdp1-induced... | ACCEPT | Summary: Direct evidence of RNF41 ubiquitin-protein transferase activity (catalyzing poly-Ub chains on Parkin). Core molecular function. Reason: Core molecular function directly demonstrated; genuine catalytic RING E3. Supporting Evidence: PMID:18541373 Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells |
| GO:0000209 protein polyubiquitination | IDA PMID:14765125 Nrdp1-mediated degradation of the gigantic IAP, BRUCE, is a ... | ACCEPT | Summary: Direct evidence that RNF41 catalyzes ubiquitination of BRUCE/BIRC6. Core biological process. Reason: Core biological process directly demonstrated; RNF41 ubiquitinates the giant IAP BRUCE. Supporting Evidence: PMID:14765125 purified Nrdp1 catalyzes BRUCE ubiquitination |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:14765125 Nrdp1-mediated degradation of the gigantic IAP, BRUCE, is a ... | ACCEPT | Summary: Direct evidence that purified RNF41 catalyzes BRUCE ubiquitination with an E2 (UbcH5c). Core molecular function. Reason: Core molecular function directly demonstrated in a reconstituted assay; genuine catalytic RING E3. Supporting Evidence: PMID:14765125 In the presence of an exogenous E2, UbcH5c, purified Nrdp1 catalyzes BRUCE ubiquitination |
| GO:0005515 protein binding | IPI PMID:14765125 Nrdp1-mediated degradation of the gigantic IAP, BRUCE, is a ... | KEEP AS NON CORE | Summary: Interaction with BRUCE/BIRC6 (a substrate). Bare protein binding is uninformative. Reason: Records a real substrate interaction (BRUCE) but bare protein binding is uninformative per curation guidelines. Supporting Evidence: PMID:14765125 Nrdp1 associates with BRUCE/apollon, a 530 kDa membrane-associated IAP |
| GO:0005515 protein binding | IPI PMID:15314180 Stabilization of the E3 ubiquitin ligase Nrdp1 by the deubiq... | KEEP AS NON CORE | Summary: Interaction with the deubiquitinase USP8 (which stabilizes RNF41). Bare protein binding is uninformative. Reason: Records a real, functionally important interaction (USP8) but bare protein binding is uninformative per curation guidelines. Supporting Evidence: PMID:15314180 we identified the deubiquitinating enzyme USP8 (also called Ubpy) as a protein that physically interacts with Nrdp1 |
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Download this section (compressed HTML)Q: How is RNF41 substrate choice (ErbB3/ErbB4 vs BRUCE vs Parkin vs MYD88/cytokine receptors) coordinated, and is it governed by localization (cytosol/perinuclear vs ER tubules), USP8 status, or stimulus?
Q: To what extent does the RNF41-PRKN pathway controlling autophagosome-lysosome fusion in late mitophagy depend on RNF41 catalytic activity versus scaffolding, and how does it relate to RNF41's pro-oxidant effect via Parkin degradation?
Experiment: Perform quantitative ubiquitinome/proteome profiling in RNF41-knockout versus wild-type cells, with and without USP8 and Rtn4A perturbation, to define the endogenous RNF41 substrate repertoire and how localization controls substrate selection.
Experiment: Reconstitute RNF41-mediated ubiquitination in vitro with wild-type and RING-mutant (C34S/H36Q, D56V) RNF41 against ErbB3, BRUCE and Parkin with defined E2 panels to compare catalytic efficiency and chain types across substrates.
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