FBXO5 (Early mitotic inhibitor 1, EMI1) is a cell-cycle regulatory protein that, despite containing an F-box, functions principally as a direct inhibitor of the anaphase-promoting complex/cyclosome (APC/C), the multisubunit E3 ubiquitin ligase that drives mitotic and cell-cycle progression. EMI1 accumulates from late G1 through S and G2 phase under E2F transcriptional control and binds tightly to the APC/C and its coactivators FZR1/CDH1 and CDC20. It acts as a pseudosubstrate/multimodal inhibitor: a conserved C-terminal D-box, linker, and tail together with a structured zinc-binding region (ZBR) engage distinct sites on APC/C to block substrate access at the D-box coreceptor (FZR1-ANAPC10) and to suppress ubiquitin-chain elongation by the APC/C E2 enzymes UBE2C/UBCH10 and UBE2S. By restraining APC/C during interphase, EMI1 stabilizes APC/C substrates such as cyclin A (CCNA2) and geminin (GMNN), thereby coupling DNA replication with mitosis, preventing rereplication, and protecting against DNA-damage-induced senescence. EMI1 levels are sharply controlled: at the G1/S transition it switches from being a substrate of APC/C(CDH1) to its inhibitor, and at the onset of mitosis it is phosphorylated by CDK1/2 and PLK1 to generate a DSGxxS phosphodegron recognized by the SCF(beta-TrCP/BTRC) ubiquitin ligase, leading to its degradation and APC/C activation. In oocyte meiosis the EMI1/EMI2 family provides cytostatic-factor activity that arrests cells through APC/C inhibition. EMI1 levels are dosage-sensitive for genome stability: reduced EMI1 causes chromosome instability, micronucleation, and DNA damage and is associated with cellular transformation, while EMI1 abundance is also shaped by post-transcriptional control (METTL16-mediated m6A mRNA stabilization and PTBP1-dependent exon-3 splicing), and FBXO5 is frequently dysregulated in cancers. EMI1 localizes to the nucleus and cytoplasm in interphase and to the spindle in mitosis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of nuclear localization, consistent with experimental immunofluorescence showing EMI1 in the nucleus during interphase. Reason: Correct localization supported by direct experimental evidence (IDA, PMID:11988738). Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Nucleus {ECO:0000269|PubMed:11988738}. Cytoplasm |
| GO:0007088 regulation of mitotic nuclear division | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic assignment of a role in regulating mitotic nuclear division, consistent with EMI1's APC/C-inhibitory control of mitotic timing. Reason: Correct but generic; the more specific and better-supported role is negative regulation of the metaphase/anaphase transition via APC/C inhibition. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Regulator of APC activity during mitotic and meiotic cell cycle |
| GO:0045835 negative regulation of meiotic nuclear division | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic assignment of a role in negatively regulating meiotic nuclear division, consistent with EMI1/EMI2-family cytostatic-factor activity that arrests oocytes via APC/C inhibition. Reason: Supported for the family (the human meiotic CSF role is largely carried out by the paralog EMI2/FBXO43); EMI1's own evidence is strongest in mitotic interphase. Meiotic role is real but non-core for human FBXO5. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt During oocyte maturation, plays a role in meiosis through inactivation of APC-FZR1 complex |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer of nuclear localization from the UniProt subcellular location vocabulary. Reason: Correct localization, redundant with experimental IDA evidence. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Nucleus {ECO:0000269|PubMed:11988738}. Cytoplasm |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated electronic assignment of cytoplasmic localization, consistent with experimental immunofluorescence. Reason: Correct localization, redundant with experimental IDA evidence (PMID:11988738). Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Cytoplasm {ECO:0000269|PubMed:11988738}. |
| GO:0005819 spindle | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer of spindle localization; EMI1 concentrates at the spindle in mitotic cells. Reason: Correct localization, redundant with experimental IDA evidence (PMID:15469984). Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Cytoplasm, cytoskeleton, spindle |
| GO:0007088 regulation of mitotic nuclear division | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based electronic assignment of a role in regulating mitotic nuclear division. Reason: Correct but generic; subsumed by the more specific APC/C-inhibition annotations. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Regulator of APC activity during mitotic and meiotic cell cycle |
| GO:0010948 negative regulation of cell cycle process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning assignment of negative regulation of a cell-cycle process, consistent with EMI1's inhibition of the metaphase/anaphase transition. Reason: Correct but generic parent; the specific negative regulation of mitotic metaphase/anaphase transition better captures the role. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt prevents the degradation of APC substrates at multiple levels |
| GO:0045835 negative regulation of meiotic nuclear division | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based electronic assignment of negative regulation of meiotic nuclear division. Reason: Real for the family via APC/C inhibition but non-core for human FBXO5 (the dedicated meiotic CSF inhibitor is the paralog EMI2/FBXO43). Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Controls entry into the first meiotic division through inactivation of APC-FZR1 complex |
| GO:0005515 protein binding | IPI PMID:16439210 The evi5 oncogene regulates cyclin accumulation by stabilizi... | KEEP AS NON CORE | Summary: IntAct interaction with EVI5, which stabilizes EMI1 by blocking PLK1 phosphorylation. Bare protein binding is uninformative. Reason: Records a real, functionally relevant interaction (EVI5) but bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Also interacts with EVI5 which blocks its phosphorylation by PLK1 and prevents its subsequent binding to BTRC and degradation |
| GO:0005515 protein binding | IPI PMID:17380122 Selective role for RGS12 as a Ras/Raf/MEK scaffold in nerve ... | KEEP AS NON CORE | Summary: High-throughput IntAct interaction (SKP1, UniProtKB:P63208). Bare protein binding is uninformative. Reason: SKP1 interaction reflects F-box-mediated association; bare protein binding is uninformative. The cited paper is about RGS12/NGF signaling and the EMI1-SKP1 datapoint is a high-throughput interaction record. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Q9UKT4; P63208: SKP1; NbExp=9; IntAct=EBI-852298, EBI-307486; |
| GO:0005515 protein binding | IPI PMID:17719540 A bacterial effector targets Mad2L2, an APC inhibitor, to mo... | KEEP AS NON CORE | Summary: High-throughput IntAct interaction (CDC27, UniProtKB:P30260), an APC/C subunit. Bare protein binding is uninformative. Reason: Records an APC/C-subunit interaction relevant to EMI1's inhibitory binding, but bare protein binding is uninformative; captured by the anaphase-promoting complex binding annotation. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Q9UKT4; P30260: CDC27; NbExp=3; IntAct=EBI-852298, EBI-994813; |
| GO:0005515 protein binding | IPI PMID:18662541 The Cdc14B-Cdh1-Plk1 axis controls the G2 DNA-damage-respons... | KEEP AS NON CORE | Summary: High-throughput IntAct interaction (CDC27). Bare protein binding is uninformative. Reason: APC/C-subunit interaction; bare protein binding is uninformative and subsumed by anaphase-promoting complex binding. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Q9UKT4; P30260: CDC27; NbExp=3; IntAct=EBI-852298, EBI-994813; |
| GO:0005515 protein binding | IPI PMID:27705803 A High-Density Map for Navigating the Human Polycomb Complex... | KEEP AS NON CORE | Summary: High-throughput interactome (Polycomb complexome, SKP1). Bare protein binding is uninformative. Reason: High-throughput interaction; bare protein binding is uninformative. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Q9UKT4; P63208: SKP1; NbExp=9; IntAct=EBI-852298, EBI-307486; |
| 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 (SKP1). Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Q9UKT4; P63208: SKP1; NbExp=9; IntAct=EBI-852298, EBI-307486; |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: Cell-specific proteome-scale interactome (CDC27/SKP1). Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Q9UKT4; P63208: SKP1; NbExp=9; IntAct=EBI-852298, EBI-307486; |
| 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 (SKP1). Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Q9UKT4; P63208: SKP1; NbExp=9; IntAct=EBI-852298, EBI-307486; |
| GO:0007346 regulation of mitotic cell cycle | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-based electronic assignment (from mouse Q7TSG3) of regulation of the mitotic cell cycle. Reason: Correct but generic; the specific APC/C-inhibition and metaphase/anaphase-transition annotations better capture the role. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Regulator of APC activity during mitotic and meiotic cell cycle |
| GO:0072687 meiotic spindle | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-based electronic assignment of meiotic spindle localization, transferred from mouse. Reason: Plausible by similarity to the mouse ortholog, but meiotic localization is non-core for human FBXO5; not experimentally demonstrated in human. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Cytoplasm, cytoskeleton, spindle |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000041 | MARK AS OVER ANNOTATED | Summary: UniPathway-derived generic protein ubiquitination process annotation, propagated from the F-box/UPA00143 pathway mapping. Reason: EMI1 does not itself ubiquitinate substrates; its dominant role is as an inhibitor of the APC/C ubiquitin ligase. It is a substrate of SCF(BTRC) and APC/C, not a productive ligase component. This generic UniPathway annotation overstates a catalytic ubiquitination role. Supporting Evidence: PMID:16921029 the APC/C inhibitor Emi1 tightly binds both the APC/C and its Cdh1 activator |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) evidence for nucleoplasmic localization, consistent with EMI1's interphase nuclear pool. Reason: IDA-supported localization consistent with the documented nuclear localization. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Nucleus {ECO:0000269|PubMed:11988738}. Cytoplasm |
| GO:0019005 SCF ubiquitin ligase complex | NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... | KEEP AS NON CORE | Summary: ComplexPortal author-statement assigning EMI1 to an SCF ubiquitin ligase complex based on its F-box. EMI1 can associate with SKP1/CUL1 via its F-box, but its functionally dominant and best-documented role is as an APC/C inhibitor, not as an SCF substrate receptor. Reason: EMI1 has an F-box and can form an SCF complex (ComplexPortal CPX-7904; SKP1 interaction), so the assignment is not wrong, but no validated SCF substrate of EMI1 is established and its core biology is APC/C inhibition. A 2024 study proposes RAD51 as an SCF^EMI1 substrate, but this single recent report does not overturn the strongly documented APC/C-inhibitor role; retain as non-core rather than core SCF receptor. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Part of a SCF (SKP1-cullin-F-box) protein ligase complex file:human/FBXO5/FBXO5-deep-research-falcon.md a 2024 study explicitly frames **EMI1 (FBXO5)** as an **F-box protein** that can serve as the variable substrate receptor in an **SCF^EMI1** ubiquitin ligase complex (core SCF components SKP1–CUL1–RBX1 plus the F-box protein) and cites **RAD51** as an SCF^EMI1 substrate targeted for proteolytic degradation |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... | MARK AS OVER ANNOTATED | Summary: ComplexPortal author-statement assigning EMI1 to SCF-dependent proteasomal protein catabolism. EMI1 is a substrate (degraded by SCF-beta-TrCP) rather than a demonstrated substrate-receptor driving degradation of other proteins via SCF. Reason: The well-documented SCF link for EMI1 is as a phospho-degron substrate of SCF(BTRC), not as a productive F-box receptor targeting other proteins for SCF-dependent degradation. The involved_in catabolic-process annotation over-extends from the F-box family default. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt degradation during early mitosis through ubiquitin-mediated proteolysis by the SCF ubiquitin ligase complex containing the F-box protein BTRC |
| GO:0045841 negative regulation of mitotic metaphase/anaphase transition | IDA PMID:15148369 Role of Polo-like kinase in the degradation of early mitotic... | ACCEPT | Summary: Direct evidence that EMI1 inhibits APC/C, whose activation drives the metaphase/anaphase transition; EMI1 destruction is required for APC/C activation in late mitosis. Core process. Reason: Core biological process directly supported; EMI1 inhibition of APC/C restrains the metaphase/anaphase transition. Supporting Evidence: PMID:15148369 The degradation of Emi1 in early mitosis is necessary for the activation of APC/C in late mitosis |
| GO:1990948 ubiquitin ligase inhibitor activity | IDA PMID:15148369 Role of Polo-like kinase in the degradation of early mitotic... | ACCEPT | Summary: Direct evidence that EMI1 inhibits the APC/C ubiquitin ligase. This is the core molecular function of EMI1. Reason: Core molecular function; EMI1 is a direct inhibitor of the APC/C E3 ubiquitin ligase. Supporting Evidence: PMID:15148369 Early mitotic inhibitor 1 (Emi1) inhibits the activity of the anaphase promoting complex/cyclosome (APC/C), which is a multisubunit ubiquitin ligase |
| GO:0006974 DNA damage response | IMP PMID:17875940 Loss of Emi1-dependent anaphase-promoting complex/cyclosome ... | KEEP AS NON CORE | Summary: Mutant-phenotype evidence that loss of EMI1 leads to DNA damage (replication stress) and DNA-damage-induced senescence. Recent work shows EMI1 is dosage-sensitive for genome stability, with reduced EMI1 driving chromosome instability and DNA damage. Reason: A downstream consequence of EMI1 loss (deregulated APC/C, replication stress, chromosome instability) rather than a direct EMI1 effector function; real but non-core. This phenotype follows directly from EMI1's core role in coupling DNA replication to mitosis via interphase APC/C inhibition. Supporting Evidence: PMID:17875940 Cells lacking Emi1 undergo DNA damage, likely explained by replication stress upon deregulated cyclin E- and A-associated kinase activities file:human/FBXO5/FBXO5-deep-research-falcon.md **reduced EMI1 expression drives chromosome instability (CIN)** and is associated with DNA damage and transformation phenotypes in colonic epithelial contexts |
| GO:0140678 molecular function inhibitor activity | IDA PMID:23708605 Electron microscopy structure of human APC/C(CDH1)-EMI1 reve... | KEEP AS NON CORE | Summary: Direct (DisProt) evidence that EMI1's intrinsically disordered C-terminal domain inhibits APC/C functions. A parent of the specific ubiquitin ligase inhibitor activity. Reason: Correct but generic; the specific ubiquitin ligase inhibitor activity (GO:1990948) better captures the function. Supporting Evidence: PMID:23708605 EMI1's 143-residue C-terminal domain inhibits multiple APC/C(CDH1) functions |
| GO:0140678 molecular function inhibitor activity | IMP PMID:23708605 Electron microscopy structure of human APC/C(CDH1)-EMI1 reve... | KEEP AS NON CORE | Summary: Mutant-phenotype (DisProt) evidence that EMI1 domains inhibit APC/C functions. Parent of the specific ubiquitin ligase inhibitor activity. Reason: Correct but generic; subsumed by GO:1990948 ubiquitin ligase inhibitor activity. Supporting Evidence: PMID:23708605 synergistically both block the substrate-binding site and inhibit ubiquitin-chain elongation |
| GO:0072687 meiotic spindle | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity assignment of meiotic spindle localization from the mouse ortholog. Reason: Plausible by similarity but meiotic localization is non-core for human FBXO5; not directly demonstrated in human. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Cytoplasm, cytoskeleton, spindle |
| GO:0005515 protein binding | IPI PMID:11988738 E2F-dependent accumulation of hEmi1 regulates S phase entry ... | KEEP AS NON CORE | Summary: Interaction with FZR1/CDH1 (UniProtKB:Q9UM11), the APC/C coactivator that EMI1 inhibits. Bare protein binding is uninformative. Reason: Records the functionally central EMI1-FZR1/CDH1 interaction, but bare protein binding is uninformative; captured by anaphase-promoting complex binding and the inhibition annotations. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Interacts with FZR1/CDH1 and the N-terminal substrate-binding domain of CDC20; prevents APC activation |
| GO:0005515 protein binding | IPI PMID:16921029 Emi1 stably binds and inhibits the anaphase-promoting comple... | KEEP AS NON CORE | Summary: Interaction with FZR1/CDH1 from the pseudosubstrate-inhibitor study. Bare protein binding is uninformative. Reason: Records the EMI1-CDH1 interaction central to APC/C inhibition, but bare protein binding is uninformative. Supporting Evidence: PMID:16921029 the APC/C inhibitor Emi1 tightly binds both the APC/C and its Cdh1 activator |
| GO:0010997 anaphase-promoting complex binding | IDA PMID:16921029 Emi1 stably binds and inhibits the anaphase-promoting comple... | ACCEPT | Summary: Direct evidence that EMI1 binds the APC/C and competes with substrates at the D-box receptor. A core mechanistic molecular function underlying EMI1's APC/C inhibition. Reason: Core molecular function; direct, high-quality evidence of EMI1 binding APC/C as a pseudosubstrate inhibitor. Supporting Evidence: PMID:16921029 binds to the D-box receptor site on the APC/C(Cdh1), and competes with APC/C substrates for D-box binding file:human/FBXO5/FBXO5-deep-research-falcon.md **Emi1/FBXO5 acts as a principal interphase inhibitor of APC/C**, particularly **APC/C activated by Cdh1 (APC/C^CDH1)**, thereby preventing premature degradation of cyclins and enabling progression toward mitosis |
| GO:1904667 negative regulation of ubiquitin protein ligase activity | IMP PMID:29875408 EMI1 switches from being a substrate to an inhibitor of APC/... | ACCEPT | Summary: Mutant-phenotype evidence that EMI1 inhibits the APC/C(CDH1) ubiquitin ligase, switching from substrate to inhibitor to start the cell cycle. Core process. Reason: Core biological process; EMI1 negatively regulates APC/C ubiquitin ligase activity, directly demonstrated. Supporting Evidence: PMID:29875408 EMI1 switches from being a substrate to an inhibitor of APC/C(CDH1) to start the cell cycle |
| GO:0010997 anaphase-promoting complex binding | IDA PMID:26083744 Atomic structure of the APC/C and its mechanism of protein u... | ACCEPT | Summary: Structural (cryo-EM) evidence that EMI1 binds the APC/C; the atomic structure of APC/C-EMI1 captures the inhibitory binding mode. Core molecular function. Reason: Core molecular function; structural evidence of direct APC/C binding. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Interacts simultaneously with anaphase promoting complex (APC), through at least ANAPC2, CDC23, CDC27, the APC substrate GMNN and the APC activator FZR1 |
| GO:1904667 negative regulation of ubiquitin protein ligase activity | IMP PMID:23708605 Electron microscopy structure of human APC/C(CDH1)-EMI1 reve... | ACCEPT | Summary: Structure/enzymology evidence that EMI1's C-terminal domain inhibits multiple APC/C(CDH1) functions including ubiquitin-chain elongation. Core process. Reason: Core biological process; EMI1 inhibits APC/C ubiquitin ligase activity through a multimodal mechanism. Supporting Evidence: PMID:23708605 bind distinct regions of APC/C(CDH1) to synergistically both block the substrate-binding site and inhibit ubiquitin-chain elongation |
| GO:0051444 negative regulation of ubiquitin-protein transferase activity | IDA PMID:23708001 Emi1 preferentially inhibits ubiquitin chain elongation by t... | ACCEPT | Summary: Direct evidence that EMI1 suppresses ubiquitin transfer/chain elongation by the APC/C E2 enzymes UBCH10/UBE2C and UBE2S. Core process closely related to APC/C inhibition. Reason: Core biological process; EMI1 inhibits the ubiquitin-transfer (chain elongation) step catalyzed by APC/C-associated E2 enzymes. Supporting Evidence: PMID:23708001 preferentially suppresses the ubiquitin chain elongation by UBCH10 |
| GO:0005515 protein binding | IPI PMID:23708001 Emi1 preferentially inhibits ubiquitin chain elongation by t... | KEEP AS NON CORE | Summary: Interactions with APC/C subunits and E2 enzymes (ANAPC2, CDC27, UBE2S, etc.). Bare protein binding is uninformative. Reason: Records APC/C-subunit and E2 interactions central to inhibition, but bare protein binding is uninformative; captured by APC binding and the inhibition annotations. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Interacts with UBE2S; interferes with the activity of UBE2S mainly by disrupting the dynamic electrostatic association between the C-terminal tail of UBE2S and ANAPC2 |
| GO:0006275 regulation of DNA replication | IMP PMID:17485488 Emi1 is needed to couple DNA replication with mitosis but do... | KEEP AS NON CORE | Summary: Mutant-phenotype evidence that EMI1 couples DNA replication with mitosis by inhibiting APC/C in interphase, stabilizing cyclins and geminin and preventing rereplication. Reason: A key downstream physiological consequence of EMI1's APC/C inhibition; real and well supported but secondary to the core inhibitor function. Supporting Evidence: PMID:17485488 we uncover a key role for Emi1 in inhibiting the APC/C in interphase to stabilize the mitotic cyclins and geminin to promote mitosis and prevent rereplication |
| GO:0010971 positive regulation of G2/M transition of mitotic cell cycle | IMP PMID:17485488 Emi1 is needed to couple DNA replication with mitosis but do... | KEEP AS NON CORE | Summary: Mutant-phenotype evidence that EMI1 promotes mitotic entry by stabilizing mitotic cyclins and geminin via APC/C inhibition. Reason: Real downstream consequence of APC/C inhibition (stabilizing cyclins to promote mitosis); secondary to the core inhibitor function. Supporting Evidence: PMID:17485488 to stabilize the mitotic cyclins and geminin to promote mitosis and prevent rereplication |
| GO:0032876 negative regulation of DNA endoreduplication | IMP PMID:17875940 Loss of Emi1-dependent anaphase-promoting complex/cyclosome ... | KEEP AS NON CORE | Summary: Mutant-phenotype evidence that EMI1 prevents rereplication/endoreduplication by restraining APC/C (stabilizing geminin and cyclin A). Reason: Real downstream consequence of APC/C inhibition; non-core relative to the inhibitor molecular function. Supporting Evidence: PMID:17234884 Emi1 plays a critical role in preserving genome integrity by blocking rereplication |
| GO:2000773 negative regulation of cellular senescence | IMP PMID:17875940 Loss of Emi1-dependent anaphase-promoting complex/cyclosome ... | KEEP AS NON CORE | Summary: Mutant-phenotype evidence that EMI1 loss elicits DNA-damage-induced senescence; thus EMI1 normally prevents senescence. Reason: A downstream consequence of EMI1's APC/C-inhibitory and genome-maintenance role; real but non-core. Supporting Evidence: PMID:17875940 cells lacking Emi1 undergo cellular senescence |
| GO:0006275 regulation of DNA replication | IMP PMID:17234884 The APC/C inhibitor, Emi1, is essential for prevention of re... | KEEP AS NON CORE | Summary: Mutant-phenotype evidence that EMI1 prevents rereplication by inhibiting APC/C during S and G2 to stabilize geminin and cyclin A. Reason: Real downstream consequence of APC/C inhibition; secondary to the core inhibitor function. Supporting Evidence: PMID:17234884 Emi1 (early mitotic inhibitor) inhibits APC/C (anaphase-promoting complex/cyclosome) activity during S and G2 phases |
| GO:0008284 positive regulation of cell population proliferation | IMP PMID:17234884 The APC/C inhibitor, Emi1, is essential for prevention of re... | KEEP AS NON CORE | Summary: Mutant-phenotype evidence that EMI1 is essential for cell proliferation by preventing rereplication. Reason: A downstream physiological consequence of EMI1's cell-cycle role; non-core relative to the molecular inhibitor function. Supporting Evidence: PMID:17234884 Emi1 plays an essential function in cell proliferation by preventing rereplication |
| GO:0045669 positive regulation of osteoblast differentiation | IMP PMID:29850565 Two Transcripts of FBXO5 Promote Migration and Osteogenic Di... | KEEP AS NON CORE | Summary: Mutant-phenotype evidence that FBXO5 promotes osteogenic differentiation of periodontal ligament mesenchymal stem cells. Reason: A tissue-specific role reported in one study; real but peripheral to the core APC/C-inhibitor cell-cycle function. Supporting Evidence: PMID:29850565 Two Transcripts of FBXO5 Promote Migration and Osteogenic Differentiation of Human Periodontal Ligament Mesenchymal Stem Cells |
| GO:0070169 positive regulation of biomineral tissue development | IMP PMID:29850565 Two Transcripts of FBXO5 Promote Migration and Osteogenic Di... | KEEP AS NON CORE | Summary: Mutant-phenotype evidence (mineralization assays) that FBXO5 promotes osteogenic/biomineralization processes in stem cells. Reason: Tissue-specific role from one study; non-core. Supporting Evidence: PMID:29850565 Two Transcripts of FBXO5 Promote Migration and Osteogenic Differentiation of Human Periodontal Ligament Mesenchymal Stem Cells |
| GO:1905322 positive regulation of mesenchymal stem cell migration | IMP PMID:29850565 Two Transcripts of FBXO5 Promote Migration and Osteogenic Di... | KEEP AS NON CORE | Summary: Mutant-phenotype evidence (scratch migration assay) that FBXO5 promotes migration of periodontal ligament stem cells. Reason: Tissue-specific role from one study; non-core. Supporting Evidence: PMID:29850565 Two Transcripts of FBXO5 Promote Migration and Osteogenic Differentiation of Human Periodontal Ligament Mesenchymal Stem Cells |
| GO:0045841 negative regulation of mitotic metaphase/anaphase transition | IDA PMID:11988738 E2F-dependent accumulation of hEmi1 regulates S phase entry ... | ACCEPT | Summary: Direct evidence that EMI1 inhibits APC(Cdh1) to regulate S-phase entry and restrain the metaphase/anaphase transition. Core process. Reason: Core biological process; EMI1 inhibition of APC/C restrains the metaphase/anaphase transition. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC(Cdh1) |
| GO:0045841 negative regulation of mitotic metaphase/anaphase transition | IDA PMID:16921029 Emi1 stably binds and inhibits the anaphase-promoting comple... | ACCEPT | Summary: Direct evidence that EMI1 binds the D-box receptor and competes with APC/C substrates, restraining the metaphase/anaphase transition. Core process. Reason: Core biological process directly supported by the pseudosubstrate-inhibitor mechanism. Supporting Evidence: PMID:16921029 competes with APC/C substrates for D-box binding |
| GO:1904667 negative regulation of ubiquitin protein ligase activity | IDA PMID:11988738 E2F-dependent accumulation of hEmi1 regulates S phase entry ... | ACCEPT | Summary: Direct evidence that EMI1 inhibits the APC(Cdh1) ubiquitin ligase. Core process. Reason: Core biological process; EMI1 directly inhibits APC/C ubiquitin ligase activity. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt regulates S phase entry by inhibiting APC(Cdh1) |
| GO:1904667 negative regulation of ubiquitin protein ligase activity | IDA PMID:16921029 Emi1 stably binds and inhibits the anaphase-promoting comple... | ACCEPT | Summary: Direct evidence that EMI1's ZBR antagonizes APC/C E3 ligase activity independent of tight binding. Core process. Reason: Core biological process; ZBR-mediated inhibition of APC/C ligase activity directly demonstrated. Supporting Evidence: PMID:16921029 a conserved zinc-binding region (ZBR), which antagonizes APC/C E3 ligase activity independent of tight APC binding |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-163010 | ACCEPT | Summary: Reactome curation placing EMI1 in the nucleoplasm within cell-cycle reactions. Reason: Correct localization consistent with experimental nuclear/nucleoplasmic evidence. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Nucleus {ECO:0000269|PubMed:11988738}. Cytoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-174097 | ACCEPT | Summary: Reactome curation (Association of Emi1 with Cdh1) placing EMI1 in the nucleoplasm. Reason: Correct localization consistent with experimental evidence. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Nucleus {ECO:0000269|PubMed:11988738}. Cytoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-174122 | ACCEPT | Summary: Reactome curation (phosphorylation of Emi1 DSGxxS degron) placing EMI1 in the nucleoplasm. Reason: Correct localization consistent with experimental evidence. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Nucleus {ECO:0000269|PubMed:11988738}. Cytoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-174174 | ACCEPT | Summary: Reactome curation (Plk1 phosphorylation of Emi1) placing EMI1 in the nucleoplasm. Reason: Correct localization consistent with experimental evidence. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Nucleus {ECO:0000269|PubMed:11988738}. Cytoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-174235 | ACCEPT | Summary: Reactome curation (Association of Emi1 with Cdc20) placing EMI1 in the nucleoplasm. Reason: Correct localization consistent with experimental evidence. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Nucleus {ECO:0000269|PubMed:11988738}. Cytoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8961699 | ACCEPT | Summary: Reactome curation (FBXO5 gene expression stimulated by E2F1) placing EMI1 in the nucleoplasm. Reason: Correct localization consistent with experimental evidence. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Nucleus {ECO:0000269|PubMed:11988738}. Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-174159 | ACCEPT | Summary: Reactome curation (Ubiquitination of Emi1 by SCF-beta-TrCP) placing EMI1 in the cytosol. Reason: Correct localization; EMI1 has a documented cytoplasmic pool. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Cytoplasm {ECO:0000269|PubMed:11988738}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-174203 | ACCEPT | Summary: Reactome curation (SCF-mediated degradation of Emi1) placing EMI1 in the cytosol. Reason: Correct localization; EMI1 has a documented cytoplasmic pool. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Cytoplasm {ECO:0000269|PubMed:11988738}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-174209 | ACCEPT | Summary: Reactome curation (phosphorylated Emi1 binds beta-TrCP) placing EMI1 in the cytosol. Reason: Correct localization; EMI1 has a documented cytoplasmic pool. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Cytoplasm {ECO:0000269|PubMed:11988738}. |
| GO:0019901 protein kinase binding | IPI PMID:15148369 Role of Polo-like kinase in the degradation of early mitotic... | KEEP AS NON CORE | Summary: Interaction with mitotic kinases (CDK1/cyclin B P06493; PLK1 P53350) that phosphorylate EMI1 to trigger its SCF(beta-TrCP)-mediated degradation. Reason: Real, mechanistically relevant kinase interactions (PLK1/CDK1 generate the EMI1 phosphodegron), but ancillary to the core APC/C-inhibitor function and more informative than bare protein binding. Supporting Evidence: PMID:15148369 Plk1 phosphorylates serine residues in the DSGxxS sequence of Emi1 |
| GO:0005515 protein binding | IPI PMID:12791267 Prophase destruction of Emi1 by the SCF(betaTrCP/Slimb) ubiq... | KEEP AS NON CORE | Summary: Interaction with BTRC/beta-TrCP (UniProtKB:Q9Y297), the SCF receptor that targets phosphorylated EMI1 for degradation. Bare protein binding is uninformative. Reason: Records the functionally relevant EMI1-BTRC interaction (mediating EMI1 destruction), but bare protein binding is uninformative. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Interacts with BTRC; mediates proteolysis by the SCF ubiquitin ligase complex leading to activation of APC in late mitosis |
| GO:0005634 nucleus | IDA PMID:11988738 E2F-dependent accumulation of hEmi1 regulates S phase entry ... | ACCEPT | Summary: Direct immunofluorescence evidence for nuclear localization during interphase. Core localization. Reason: Core localization with direct experimental support. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt In interphase, localizes in a punctate manner in the nucleus and cytoplasm with some perinuclear concentration |
| GO:0005737 cytoplasm | IDA PMID:11988738 E2F-dependent accumulation of hEmi1 regulates S phase entry ... | ACCEPT | Summary: Direct immunofluorescence evidence for cytoplasmic localization during interphase. Core localization. Reason: Core localization with direct experimental support. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt In interphase, localizes in a punctate manner in the nucleus and cytoplasm with some perinuclear concentration |
| GO:0005819 spindle | IDA PMID:15469984 Plk1 regulates activation of the anaphase promoting complex ... | ACCEPT | Summary: Direct evidence that EMI1 localizes throughout the cell and concentrates at the spindle in mitotic cells. Reason: Localization with direct experimental support. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt In mitotic cells, localizes throughout the cell, particularly at the spindle |
| GO:0007346 regulation of mitotic cell cycle | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity assignment of regulation of the mitotic cell cycle, transferred from the mouse ortholog. Reason: Correct but generic; the specific APC/C-inhibition annotations better capture the role. Supporting Evidence: file:human/FBXO5/FBXO5-uniprot.txt Regulator of APC activity during mitotic and meiotic cell cycle |
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Download this section (compressed HTML)Q: Does human FBXO5/EMI1 ever function as a productive SCF substrate receptor (targeting a specific substrate for SCF-dependent degradation), or is its F-box used solely for incidental SKP1 association while its dominant role remains APC/C inhibition?
Q: How is the substrate-to-inhibitor switch at the G1/S transition controlled at the molecular level, and what distinguishes the EMI1 conformations that are APC/C substrates versus inhibitors?
Experiment: Reconstitute APC/C(CDH1) ubiquitination assays in vitro with purified EMI1 and the E2 enzymes UBE2C and UBE2S to quantify the relative contributions of D-box-receptor blocking versus chain-elongation inhibition to substrate stabilization.
Experiment: Perform proximity-labeling (BioID/TurboID) and quantitative ubiquitinome profiling in EMI1-depleted versus EMI1-add-back cells across the cell cycle to test whether EMI1 has any genuine SCF substrate, and to map its APC/C-dependent stabilized substrate repertoire.
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