FZR1 (Cdh1, fizzy-related protein 1) is one of the two WD40 beta-propeller coactivators of the anaphase-promoting complex/cyclosome (APC/C), the multisubunit RING E3 ubiquitin ligase that drives mitotic exit and G1. FZR1 docks onto the APC/C core through its N-terminal C-box and C-terminal IR tail, which repositions the APC2-APC11 catalytic module and raises the affinity of the APC/C for its E2 enzymes, and it recognises D-box, KEN-box and ABBA degrons on substrates through its propeller, forming a bipartite D-box receptor with APC10. It is not itself catalytic. APC/C-Cdh1 takes over from APC/C-Cdc20 in late anaphase once CDK1 activity falls and remains active through telophase and G1, directing ubiquitination (largely K11-linked chains built by UBE2C/UBE2S) and proteasomal degradation of mitotic cyclins, PLK1, Aurora kinases, CDC20, SKP2, CDC6, geminin, TK1, RRM2, claspin and many other cell-cycle regulators, thereby keeping CDK activity low, completing mitotic exit and restraining S-phase entry. Its activity is switched off at G1/S by cyclin A/CDK2 phosphorylation, which dissociates it from the APC/C, by the pseudosubstrate inhibitor EMI1/FBXO5, and by SCF(cyclin F)-mediated degradation; it is re-engaged by CDC14B dephosphorylation, SIRT2 deacetylation and nuclear PTEN. After DNA damage in G2, Cdc14B-dependent reactivation of APC/C-Cdh1 degrades PLK1 to enforce the G2 checkpoint, and Cdh1-directed turnover of RAD17 and CtIP shapes checkpoint termination and DNA-repair pathway choice. FZR1 is predominantly nuclear with a smaller cytoplasmic pool. Beyond proliferating cells, APC/C-Cdh1 acts in quiescent and post-mitotic cells, including neurons, to clear mitotic and chromatin proteins and support differentiation and neuronal development; heterozygous de novo loss-of-function FZR1 variants cause developmental and epileptic encephalopathy (DEE109).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:10548110 Accumulation of cyclin B1 requires E2F and cyclin-A-dependen... | MODIFY | Summary: IPI with the APC/C core subunit CDC27 (ANAPC3). Lukas et al. showed that non-phosphorylatable Cdh1 assembles with APC even in S phase, defining the CDK-phosphorylation switch that controls Cdh1-APC/C association. The informative molecular function behind this interaction is FZR1's docking onto the APC/C as its coactivator, i.e. anaphase-promoting complex binding. Reason: Generic protein binding carries no functional information. The CDC27 interaction is the coactivator-APC/C association through which FZR1 exerts every one of its functions (C-box/IR-tail docking onto APC3/APC8, structurally resolved in PMID:26083744 and PMID:27120157), so the row is better expressed as GO:0010997 anaphase-promoting complex binding, which the gene already carries by IBA/IEA. Proposed replacements: anaphase-promoting complex binding Supporting Evidence: PMID:10548110 Phosphorylation-deficient mutant Cdh1 or immunodepletion of cyclin A resulted in assembly of active Cdh1-APC even in S-phase cells PMID:27120157 both coactivators associate with the APC/C through their common C-box and Ile-Arg tail motifs |
| GO:0005515 protein binding | IPI PMID:11459826 MAD2B is an inhibitor of the anaphase-promoting complex. | REMOVE | Summary: IPI with MAD2L2 (MAD2B/REV7), an inhibitor that targets CDH1 rather than the APC/C core. MAD2B binds CDH1 and CDC20 and inhibits both CDH1-APC and CDC20-APC. Reason: Generic protein binding (GO:0005515) adds no information about what FZR1 does. Binding by an inhibitor does not correspond to an informative FZR1 molecular function (GO has no 'ubiquitin ligase inhibitor binding' term that would be appropriate here); the relevant activity, APC/C activation, is annotated separately. Removal does not assert that the interaction is false; the biology is captured in the notes and in the specific MF/BP annotations. Supporting Evidence: PMID:11459826 In contrast to MAD2, MAD2B inhibits both CDH1-APC and CDC20-APC. This inhibition is targeted to CDH1 and CDC20, but not directly to APC |
| GO:0005515 protein binding | IPI PMID:11988738 E2F-dependent accumulation of hEmi1 regulates S phase entry ... | REMOVE | Summary: IPI with FBXO5 (Emi1), the G1/S inhibitor of APC/C-Cdh1. Hsu et al. showed that E2F-induced hEmi1 promotes cyclin A accumulation and S-phase entry by inhibiting APC(Cdh1). Reason: Generic protein binding (GO:0005515) adds no information about what FZR1 does. The row records FZR1 as the target of an inhibitor; the functional statement belongs on FBXO5 (ubiquitin ligase inhibitor activity), not on FZR1. Removal does not assert that the interaction is false; the biology is captured in the notes and in the specific MF/BP annotations. Supporting Evidence: PMID:11988738 human Emi1 (hEmi1) functions to promote cyclin A accumulation and S phase entry in somatic cells by inhibiting the APC(Cdh1) complex |
| GO:0005515 protein binding | IPI PMID:16921029 Emi1 stably binds and inhibits the anaphase-promoting comple... | REMOVE | Summary: IPI with FBXO5 (Emi1) acting as a pseudosubstrate inhibitor. Miller et al. showed that Emi1 binds the D-box receptor site on APC/C-Cdh1 and competes with substrates for D-box binding. Reason: Generic protein binding (GO:0005515) adds no information about what FZR1 does. The pseudosubstrate interaction demonstrates that FZR1 possesses a D-box receptor (already captured by GO:1990756), but the row itself only records inhibitor binding. Removal does not assert that the interaction is false; the biology is captured in the notes and in the specific MF/BP annotations. Supporting Evidence: PMID:16921029 the APC/C inhibitor Emi1 tightly binds both the APC/C and its Cdh1 activator, binds to the D-box receptor site on the APC/C Cdh1 , and competes with APC/C substrates for D-box binding |
| GO:0005515 protein binding | IPI PMID:17719540 A bacterial effector targets Mad2L2, an APC inhibitor, to mo... | REMOVE | Summary: IPI with MAD2L2 in the context of the Shigella effector IpaB. The abstract describes IpaB targeting the APC inhibitor Mad2L2 to cause unscheduled APC activation and G2/M arrest; the FZR1-MAD2L2 interaction is a regulatory (inhibitory) contact. Reason: Generic protein binding (GO:0005515) adds no information about what FZR1 does. The full text is not cached, but the abstract makes clear that the paper is about relief of Mad2L2 inhibition by a bacterial effector; no FZR1-specific molecular function follows from the interaction. Removal does not assert that the interaction is false; the biology is captured in the notes and in the specific MF/BP annotations. Supporting Evidence: PMID:17719540 the Shigella effector IpaB, when delivered into epithelial cells, causes cell-cycle arrest by targeting Mad2L2, an anaphase-promoting complex/cyclosome (APC) inhibitor |
| GO:0005515 protein binding | IPI PMID:18662541 The Cdc14B-Cdh1-Plk1 axis controls the G2 DNA-damage-respons... | MODIFY | Summary: IPI with the APC/C core subunit CDC27 (ANAPC3). Bassermann et al. showed that Cdc14B dephosphorylates the four CDK sites of Cdh1 after DNA damage so that Cdh1 can re-associate with the APC/C core (CDC27) in G2. The informative molecular function behind this interaction is FZR1's docking onto the APC/C as its coactivator, i.e. anaphase-promoting complex binding. Reason: Generic protein binding carries no functional information. The CDC27 interaction is the coactivator-APC/C association through which FZR1 exerts every one of its functions (C-box/IR-tail docking onto APC3/APC8, structurally resolved in PMID:26083744 and PMID:27120157), so the row is better expressed as GO:0010997 anaphase-promoting complex binding, which the gene already carries by IBA/IEA. Proposed replacements: anaphase-promoting complex binding Supporting Evidence: PMID:18662541 in response to genotoxic stress, Cdc14B dephosphorylates Cdh1 on the four sites phosphorylated by Cdk2 PMID:27120157 both coactivators associate with the APC/C through their common C-box and Ile-Arg tail motifs |
| GO:0005515 protein binding | IPI PMID:18662541 The Cdc14B-Cdh1-Plk1 axis controls the G2 DNA-damage-respons... | MODIFY | Summary: IPI with PLK1. PLK1 carries a D-box and is degraded by APC/C-Cdh1 in late M/G1 and, after DNA damage, in G2. The functional content of this interaction is degron-dependent substrate recruitment by the FZR1 WD40 propeller for APC/C-mediated ubiquitination. Reason: Generic protein binding is uninformative. The cited work documents PLK1 as an APC/C-Cdh1 substrate whose recognition by FZR1 leads to ubiquitination and proteasomal degradation, which is exactly the ubiquitin-like ligase-substrate adaptor activity (GO:1990756) that FZR1 already carries by IDA (PMID:14701726). Removing the generic term does not dispute the interaction. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:18662541 in response to genotoxic stress in G2, the phosphatase Cdc14B translocates from the nucleolus to the nucleoplasm and induces the activation of the ubiquitin ligase APC/C(Cdh1), with the consequent degradation of Plk1, a prominent mitotic kinase PMID:18662541 Cdh1-dependent degradation of Plk1 is required for an efficient DNA damage-induced G2 checkpoint |
| GO:0005515 protein binding | IPI PMID:18662541 The Cdc14B-Cdh1-Plk1 axis controls the G2 DNA-damage-respons... | MODIFY | Summary: IPI with CLSPN (Claspin). Bassermann et al. identified Claspin as an APC/C-Cdh1 substrate in G1 and reconstituted its ubiquitination in vitro. The functional content of this interaction is degron-dependent substrate recruitment by the FZR1 WD40 propeller for APC/C-mediated ubiquitination. Reason: Generic protein binding is uninformative. The cited work documents CLSPN (Claspin) as an APC/C-Cdh1 substrate whose recognition by FZR1 leads to ubiquitination and proteasomal degradation, which is exactly the ubiquitin-like ligase-substrate adaptor activity (GO:1990756) that FZR1 already carries by IDA (PMID:14701726). Removing the generic term does not dispute the interaction. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:18662541 Claspin, which we show to be an APC/C(Cdh1) substrate in G1, is targeted for degradation |
| GO:0005515 protein binding | IPI PMID:20424596 Proteolysis of Rad17 by Cdh1/APC regulates checkpoint termin... | MODIFY | Summary: IPI with RAD17. Zhang et al. showed that UV-induced Rad17 turnover is mediated by Cdh1/APC and that a degradation-resistant Rad17 prevents checkpoint termination (abstract only cached; the curator read the full text). The functional content of this interaction is degron-dependent substrate recruitment by the FZR1 WD40 propeller for APC/C-mediated ubiquitination. Reason: Generic protein binding is uninformative. The cited work documents RAD17 as an APC/C-Cdh1 substrate whose recognition by FZR1 leads to ubiquitination and proteasomal degradation, which is exactly the ubiquitin-like ligase-substrate adaptor activity (GO:1990756) that FZR1 already carries by IDA (PMID:14701726). Removing the generic term does not dispute the interaction. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:20424596 UV-induced Rad17 oscillation is mediated by Cdh1/APC, a ubiquitin-protein ligase |
| GO:0005515 protein binding | IPI PMID:20802534 Hypoxia and cell cycle regulation of the von Hippel-Lindau t... | REMOVE | Summary: IPI with VHL (UniProtKB:P40337). Liu et al. found that pVHL stably associates with Cdh1 and 'appeared to be' an APC/C-Cdh1 ubiquitylation substrate during the cell cycle. Reason: Generic protein binding (GO:0005515) adds no information about what FZR1 does. The paper itself hedges on whether pVHL is a physiological APC/C-Cdh1 substrate and notes other ligases also target pVHL, so the interaction cannot confidently be promoted to substrate-adaptor activity; as a bare binding statement it is uninformative. Removal does not assert that the interaction is false; the biology is captured in the notes and in the specific MF/BP annotations. Supporting Evidence: PMID:20802534 pVHL stably associated with Cdh1 and appeared to be a ubiquitylation substrate for APC/CCdh1 |
| GO:0005515 protein binding | IPI PMID:20802534 Hypoxia and cell cycle regulation of the von Hippel-Lindau t... | REMOVE | Summary: IPI with VHL (UniProtKB:P40337-1). Liu et al. found that pVHL stably associates with Cdh1 and 'appeared to be' an APC/C-Cdh1 ubiquitylation substrate during the cell cycle. Reason: Generic protein binding (GO:0005515) adds no information about what FZR1 does. The paper itself hedges on whether pVHL is a physiological APC/C-Cdh1 substrate and notes other ligases also target pVHL, so the interaction cannot confidently be promoted to substrate-adaptor activity; as a bare binding statement it is uninformative. Removal does not assert that the interaction is false; the biology is captured in the notes and in the specific MF/BP annotations. Supporting Evidence: PMID:20802534 pVHL stably associated with Cdh1 and appeared to be a ubiquitylation substrate for APC/CCdh1 |
| GO:0005515 protein binding | IPI PMID:20802534 Hypoxia and cell cycle regulation of the von Hippel-Lindau t... | REMOVE | Summary: IPI with VHL (UniProtKB:P40337-3). Liu et al. found that pVHL stably associates with Cdh1 and 'appeared to be' an APC/C-Cdh1 ubiquitylation substrate during the cell cycle. Reason: Generic protein binding (GO:0005515) adds no information about what FZR1 does. The paper itself hedges on whether pVHL is a physiological APC/C-Cdh1 substrate and notes other ligases also target pVHL, so the interaction cannot confidently be promoted to substrate-adaptor activity; as a bare binding statement it is uninformative. Removal does not assert that the interaction is false; the biology is captured in the notes and in the specific MF/BP annotations. Supporting Evidence: PMID:20802534 pVHL stably associated with Cdh1 and appeared to be a ubiquitylation substrate for APC/CCdh1 |
| GO:0005515 protein binding | IPI PMID:21186364 Substrate binding on the APC/C occurs between the coactivato... | MODIFY | Summary: IPI with the APC/C core subunit CDC27 (ANAPC3). da Fonseca et al. mapped Cdh1 and Doc1 in the inner cavity of the APC/C and showed that substrates bind a bipartite receptor formed by the coactivator and Doc1/APC10. The informative molecular function behind this interaction is FZR1's docking onto the APC/C as its coactivator, i.e. anaphase-promoting complex binding. Reason: Generic protein binding carries no functional information. The CDC27 interaction is the coactivator-APC/C association through which FZR1 exerts every one of its functions (C-box/IR-tail docking onto APC3/APC8, structurally resolved in PMID:26083744 and PMID:27120157), so the row is better expressed as GO:0010997 anaphase-promoting complex binding, which the gene already carries by IBA/IEA. Proposed replacements: anaphase-promoting complex binding Supporting Evidence: PMID:21186364 Recognition of substrates by the APC/C depends on co–activator proteins, called Cdc20 and Cdh1, which promote substrate recruitment by interacting with both the APC/C and recognition motifs in substrates, called the destruction box (D box) and KEN box PMID:27120157 both coactivators associate with the APC/C through their common C-box and Ile-Arg tail motifs |
| GO:0005515 protein binding | IPI PMID:21241890 Nuclear PTEN regulates the APC-CDH1 tumor-suppressive comple... | MODIFY | Summary: IPI with the APC/C core subunit CDC27 (ANAPC3). Song et al. showed that nuclear PTEN promotes the association of CDH1 with the APC/C core. The informative molecular function behind this interaction is FZR1's docking onto the APC/C as its coactivator, i.e. anaphase-promoting complex binding. Reason: Generic protein binding carries no functional information. The CDC27 interaction is the coactivator-APC/C association through which FZR1 exerts every one of its functions (C-box/IR-tail docking onto APC3/APC8, structurally resolved in PMID:26083744 and PMID:27120157), so the row is better expressed as GO:0010997 anaphase-promoting complex binding, which the gene already carries by IBA/IEA. Proposed replacements: anaphase-promoting complex binding Supporting Evidence: PMID:21241890 nuclear PTEN interacts with APC/C, promotes APC/C association with CDH1, and thereby enhances the tumor-suppressive activity of the APC-CDH1 complex PMID:27120157 both coactivators associate with the APC/C through their common C-box and Ile-Arg tail motifs |
| GO:0005515 protein binding | IPI PMID:21596315 Deubiquitinase USP37 is activated by CDK2 to antagonize APC(... | REMOVE | Summary: IPI with USP37, a deubiquitinase that antagonises APC/C-Cdh1 in G1/S and becomes its substrate in mitosis. USP37 binds CDH1 and removes degradative polyubiquitin from cyclin A; in mitosis USP37 is itself K11-ubiquitinated by APC(CDH1). Reason: Generic protein binding (GO:0005515) adds no information about what FZR1 does. The interaction is regulatory (a DUB docking on the coactivator). USP37 substrate status is covered by the TAS K11-linked ubiquitination row; no additional FZR1 molecular function follows from generic binding. Removal does not assert that the interaction is false; the biology is captured in the notes and in the specific MF/BP annotations. Supporting Evidence: PMID:21596315 the deubiquitinase USP37 binds CDH1 and removes degradative polyubiquitin from cyclin A |
| GO:0005515 protein binding | IPI PMID:21986944 Male germ cell-associated kinase is overexpressed in prostat... | REMOVE | Summary: IPI with MAK, a kinase that binds (via the WD repeats) and phosphorylates CDH1. Wang and Kung showed a reciprocal MAK-CDH1 co-immunoprecipitation and MAK-dependent phosphorylation of CDH1 that deregulates APC/C-CDH1 in prostate cancer cells. Reason: Generic protein binding (GO:0005515) adds no information about what FZR1 does. FZR1 is the kinase's substrate here; the informative statement (protein kinase activity on CDH1) belongs to MAK. Removal does not assert that the interaction is false; the biology is captured in the notes and in the specific MF/BP annotations. Supporting Evidence: PMID:21986944 A reciprocal experiment of CDH1 immuoprecipitaion confirmed the MAK-CDH1 interaction PMID:21986944 In vitro kinase assays showed that CDH1 is indeed phosphorylated by wild-type MAK |
| GO:0005515 protein binding | IPI PMID:22014574 SIRT2 maintains genome integrity and suppresses tumorigenesi... | MODIFY | Summary: IPI with the APC/C core subunit CDC27 (ANAPC3). Kim et al. showed that SIRT2 deacetylation of CDH1 (Lys-69/Lys-159 per UniProt) enhances its binding to CDC27 and thereby APC/C activation. The informative molecular function behind this interaction is FZR1's docking onto the APC/C as its coactivator, i.e. anaphase-promoting complex binding. Reason: Generic protein binding carries no functional information. The CDC27 interaction is the coactivator-APC/C association through which FZR1 exerts every one of its functions (C-box/IR-tail docking onto APC3/APC8, structurally resolved in PMID:26083744 and PMID:27120157), so the row is better expressed as GO:0010997 anaphase-promoting complex binding, which the gene already carries by IBA/IEA. Proposed replacements: anaphase-promoting complex binding Supporting Evidence: PMID:22014574 SIRT2 regulates the anaphase-promoting complex/cyclosome activity through deacetylation of its coactivators, APC(CDH1) and CDC20 PMID:27120157 both coactivators associate with the APC/C through their common C-box and Ile-Arg tail motifs |
| GO:0005515 protein binding | IPI PMID:22014574 SIRT2 maintains genome integrity and suppresses tumorigenesi... | REMOVE | Summary: IPI with SIRT2, the deacetylase that removes acetyl groups from CDH1. SIRT2 deacetylates the APC/C coactivators CDH1 and CDC20 to sustain APC/C activity and genome integrity. Reason: Generic protein binding (GO:0005515) adds no information about what FZR1 does. FZR1 is the enzyme's substrate in this interaction; no FZR1 activity is described by the generic binding term. Removal does not assert that the interaction is false; the biology is captured in the notes and in the specific MF/BP annotations. Supporting Evidence: PMID:22014574 SIRT2 regulates the anaphase-promoting complex/cyclosome activity through deacetylation of its coactivators, APC(CDH1) and CDC20 |
| GO:0005515 protein binding | IPI PMID:22632967 Cyclin F-mediated degradation of ribonucleotide reductase M2... | MODIFY | Summary: IPI with RRM2 (ribonucleotide reductase M2). The cached abstract covers the cyclin F/G2 arm of RRM2 turnover; RRM2 is an established KEN-box APC/C-Cdh1 substrate in late mitosis/G1 (mouse R2), and the curator, who read the full text, recorded the FZR1-RRM2 interaction from this paper. The functional content of this interaction is degron-dependent substrate recruitment by the FZR1 WD40 propeller for APC/C-mediated ubiquitination. Reason: Generic protein binding is uninformative. The cited work documents RRM2 (ribonucleotide reductase M2) as an APC/C-Cdh1 substrate whose recognition by FZR1 leads to ubiquitination and proteasomal degradation, which is exactly the ubiquitin-like ligase-substrate adaptor activity (GO:1990756) that FZR1 already carries by IDA (PMID:14701726). Removing the generic term does not dispute the interaction. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:22632967 we identified RRM2 (the ribonucleotide reductase family member 2) as an interactor of the F-box protein cyclin F PMID:14701726 mouse ribonucleotide reductase R2 (mR2) protein is targeted to the APC/C-Cdh1 complex through KEN box-mediated binding and gets degraded in late mitosis |
| GO:0005515 protein binding | IPI PMID:22770219 Acetylation-dependent regulation of Skp2 function. | MODIFY | Summary: IPI with SKP2. Inuzuka et al. mapped the Cdh1-interaction motif of Skp2 (residues 46-90) and showed that p300 acetylation of K68/K71 within it blocks Cdh1 binding and stabilises Skp2; APC/C-Cdh1 is the established G1 ligase for Skp2. The functional content of this interaction is degron-dependent substrate recruitment by the FZR1 WD40 propeller for APC/C-mediated ubiquitination. Reason: Generic protein binding is uninformative. The cited work documents SKP2 as an APC/C-Cdh1 substrate whose recognition by FZR1 leads to ubiquitination and proteasomal degradation, which is exactly the ubiquitin-like ligase-substrate adaptor activity (GO:1990756) that FZR1 already carries by IDA (PMID:14701726). Removing the generic term does not dispute the interaction. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:22770219 We and others have identified APC/Cdh1 as the upstream E3 ligase that promotes Skp2 destruction PMID:22770219 a region within Skp2 between residues 46 and 90, which contains the Ser72 Akt phosphorylation site as well as the two acetylated lysines K68 and K71, is both necessary and sufficient for its interaction with Cdh1 |
| GO:0005515 protein binding | IPI PMID:23708001 Emi1 preferentially inhibits ubiquitin chain elongation by t... | REMOVE | Summary: IPI with FBXO5 (Emi1) in a kinetic study of APC inhibition. Wang and Kirschner showed that Emi1 inhibits both substrate binding and ubiquitin transfer/chain elongation on the APC. Reason: Generic protein binding (GO:0005515) adds no information about what FZR1 does. As in the other Emi1 rows, this is inhibitor binding to the coactivator; the FZR1-relevant activities (D-box receptor, APC/C activation) are annotated by specific terms. Removal does not assert that the interaction is false; the biology is captured in the notes and in the specific MF/BP annotations. Supporting Evidence: PMID:23708001 Emi1 inhibits ubiquitylation at both substrate binding and separately at the step of ubiquitin transfer to APC-bound substrates |
| GO:0005515 protein binding | IPI PMID:24163370 The HECT type ubiquitin ligase NEDL2 is degraded by anaphase... | MODIFY | Summary: IPI with HECW2 (NEDL2). Lu et al. showed that NEDL2 binds Cdh1 in vivo and in vitro and is degraded by APC/C-Cdh1 in a D-box-dependent manner during mitotic exit. The functional content of this interaction is degron-dependent substrate recruitment by the FZR1 WD40 propeller for APC/C-mediated ubiquitination. Reason: Generic protein binding is uninformative. The cited work documents HECW2 (NEDL2) as an APC/C-Cdh1 substrate whose recognition by FZR1 leads to ubiquitination and proteasomal degradation, which is exactly the ubiquitin-like ligase-substrate adaptor activity (GO:1990756) that FZR1 already carries by IDA (PMID:14701726). Removing the generic term does not dispute the interaction. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:24163370 NEDL2 was localized specifically on mitotic spindles and that its protein level reached a maximum in mitosis and was degraded by APC/C-Cdh1 in a D-box dependent manner during mitotic exit PMID:24163370 Cdh1 can interact with NEDL2 in vivo and in vitro |
| GO:0005515 protein binding | IPI PMID:27653696 APC/C and SCF(cyclin F) Constitute a Reciprocal Feedback Cir... | MODIFY | Summary: IPI with CCNF (cyclin F). Choudhury et al. showed that cyclin F is an APC/C substrate in G1 and, reciprocally, that SCF(cyclin F) ubiquitinates Cdh1 via an N-terminal D-box/Cy hybrid motif; the two ligases form a feedback circuit at S-phase entry. Because FZR1 is also cyclin F's substrate, only the APC/C-Cdh1 arm maps onto an FZR1 molecular function. The functional content of this interaction is degron-dependent substrate recruitment by the FZR1 WD40 propeller for APC/C-mediated ubiquitination. Reason: Generic protein binding is uninformative. The cited work documents CCNF (cyclin F) as an APC/C-Cdh1 substrate whose recognition by FZR1 leads to ubiquitination and proteasomal degradation, which is exactly the ubiquitin-like ligase-substrate adaptor activity (GO:1990756) that FZR1 already carries by IDA (PMID:14701726). Removing the generic term does not dispute the interaction. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:27653696 Cyclin F is an APC/C substrate PMID:27653696 Cdh1 is itself a substrate of SCF(cyclin F) |
| GO:0005515 protein binding | IPI PMID:31722219 CCDC84 Acetylation Oscillation Regulates Centrosome Duplicat... | MODIFY | Summary: IPI with SASS6 (HsSAS-6). Wang et al. showed that APC/C-Cdh1 degrades HsSAS-6 to limit centriole number and that acetylated CCDC84 enhances HsSAS-6 binding to Cdh1. The functional content of this interaction is degron-dependent substrate recruitment by the FZR1 WD40 propeller for APC/C-mediated ubiquitination. Reason: Generic protein binding is uninformative. The cited work documents SASS6 (HsSAS-6) as an APC/C-Cdh1 substrate whose recognition by FZR1 leads to ubiquitination and proteasomal degradation, which is exactly the ubiquitin-like ligase-substrate adaptor activity (GO:1990756) that FZR1 already carries by IDA (PMID:14701726). Removing the generic term does not dispute the interaction. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:31722219 CCDC84 constrains centriole number by modulating APC/CCdh1-mediated HsSAS-6 degradation PMID:31722219 acetylated CCDC84 promotes HsSAS-6 ubiquitination by enhancing the binding affinity of HsSAS-6 for Cdh1 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: IPI with UniProtKB:P30260 from the BioPlex 3.0 proteome-scale AP-MS network. High-throughput AP-MS interaction consistent with the low-throughput evidence (CDC27 = APC/C core; RRM2 and SKP2 = APC/C-Cdh1 substrates). Reason: Generic protein binding (GO:0005515) adds no information about what FZR1 does. Proteome-scale interactome rows record co-purification without characterising a molecular activity; the same partners are already captured by the specific MF rows derived from focused studies. Removal does not assert that the interaction is false; the biology is captured in the notes and in the specific MF/BP annotations. Supporting Evidence: PMID:33961781 Here we present BioPlex 3.0, the most complete model of the human interactome to date |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: IPI with UniProtKB:P31350 from the BioPlex 3.0 proteome-scale AP-MS network. High-throughput AP-MS interaction consistent with the low-throughput evidence (CDC27 = APC/C core; RRM2 and SKP2 = APC/C-Cdh1 substrates). Reason: Generic protein binding (GO:0005515) adds no information about what FZR1 does. Proteome-scale interactome rows record co-purification without characterising a molecular activity; the same partners are already captured by the specific MF rows derived from focused studies. Removal does not assert that the interaction is false; the biology is captured in the notes and in the specific MF/BP annotations. Supporting Evidence: PMID:33961781 Here we present BioPlex 3.0, the most complete model of the human interactome to date |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: IPI with UniProtKB:Q13309 from the BioPlex 3.0 proteome-scale AP-MS network. High-throughput AP-MS interaction consistent with the low-throughput evidence (CDC27 = APC/C core; RRM2 and SKP2 = APC/C-Cdh1 substrates). Reason: Generic protein binding (GO:0005515) adds no information about what FZR1 does. Proteome-scale interactome rows record co-purification without characterising a molecular activity; the same partners are already captured by the specific MF rows derived from focused studies. Removal does not assert that the interaction is false; the biology is captured in the notes and in the specific MF/BP annotations. Supporting Evidence: PMID:33961781 Here we present BioPlex 3.0, the most complete model of the human interactome to date |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: IPI with UniProtKB:P30260 from the U2OS multimodal cell-map AP-MS dataset. High-throughput AP-MS interaction (2,174 tagged baits, 36,842 interactions) consistent with the focused evidence for CDC27 (APC/C core) and the substrates RRM2, SKP2 and CLSPN. Reason: Generic protein binding (GO:0005515) adds no information about what FZR1 does. Proteome-scale co-purification does not by itself establish an FZR1 molecular function; the informative interactions are already represented by the specific MF rows. Removal does not assert that the interaction is false; the biology is captured in the notes and in the specific MF/BP annotations. Supporting Evidence: PMID:40205054 A total of 2,174 proteins were successfully tagged and isolated from U2OS whole-proteome extracts using affinity purification, and interacting partners were identified by tandem MS (AP–MS) to yield a total of 36,842 interactions among 7,543 proteins |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: IPI with UniProtKB:P31350 from the U2OS multimodal cell-map AP-MS dataset. High-throughput AP-MS interaction (2,174 tagged baits, 36,842 interactions) consistent with the focused evidence for CDC27 (APC/C core) and the substrates RRM2, SKP2 and CLSPN. Reason: Generic protein binding (GO:0005515) adds no information about what FZR1 does. Proteome-scale co-purification does not by itself establish an FZR1 molecular function; the informative interactions are already represented by the specific MF rows. Removal does not assert that the interaction is false; the biology is captured in the notes and in the specific MF/BP annotations. Supporting Evidence: PMID:40205054 A total of 2,174 proteins were successfully tagged and isolated from U2OS whole-proteome extracts using affinity purification, and interacting partners were identified by tandem MS (AP–MS) to yield a total of 36,842 interactions among 7,543 proteins |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: IPI with UniProtKB:Q13309 from the U2OS multimodal cell-map AP-MS dataset. High-throughput AP-MS interaction (2,174 tagged baits, 36,842 interactions) consistent with the focused evidence for CDC27 (APC/C core) and the substrates RRM2, SKP2 and CLSPN. Reason: Generic protein binding (GO:0005515) adds no information about what FZR1 does. Proteome-scale co-purification does not by itself establish an FZR1 molecular function; the informative interactions are already represented by the specific MF rows. Removal does not assert that the interaction is false; the biology is captured in the notes and in the specific MF/BP annotations. Supporting Evidence: PMID:40205054 A total of 2,174 proteins were successfully tagged and isolated from U2OS whole-proteome extracts using affinity purification, and interacting partners were identified by tandem MS (AP–MS) to yield a total of 36,842 interactions among 7,543 proteins |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: IPI with UniProtKB:Q9HAW4 from the U2OS multimodal cell-map AP-MS dataset. High-throughput AP-MS interaction (2,174 tagged baits, 36,842 interactions) consistent with the focused evidence for CDC27 (APC/C core) and the substrates RRM2, SKP2 and CLSPN. Reason: Generic protein binding (GO:0005515) adds no information about what FZR1 does. Proteome-scale co-purification does not by itself establish an FZR1 molecular function; the informative interactions are already represented by the specific MF rows. Removal does not assert that the interaction is false; the biology is captured in the notes and in the specific MF/BP annotations. Supporting Evidence: PMID:40205054 A total of 2,174 proteins were successfully tagged and isolated from U2OS whole-proteome extracts using affinity purification, and interacting partners were identified by tandem MS (AP–MS) to yield a total of 36,842 interactions among 7,543 proteins |
| GO:0005634 nucleus | IDA PMID:34788397 De novo FZR1 loss-of-function variants cause developmental a... | ACCEPT | Summary: Immunostaining of patient-derived and control cells showed FZR1 predominantly in the nucleus with weaker diffuse cytoplasmic signal. Nuclear localisation matches where APC/C-Cdh1 acts on most of its substrates (cyclins, PLK1, SKP2, geminin) and where Cdc14B activates it after DNA damage. Reason: Direct observation in human cells, concordant with UniProt (isoform 2: Nucleus), HPA nucleoplasm IDA, and the Reactome nucleoplasm events. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping (isoform 2: nucleus). Consistent with direct immunofluorescence (PMID:34788397) and with the nuclear site of most APC/C-Cdh1 substrate turnover. Reason: Electronic transfer of a curated UniProt location that agrees with the experimental nucleus IDA. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence places FZR1 in the nucleoplasm, in agreement with the literature nucleus IDA and the Reactome nucleoplasm assignments. Reason: Nucleoplasmic localisation is the expected compartment for the soluble APC/C-Cdh1 ligase acting on nuclear substrates during G1 and after DNA damage. Supporting Evidence: PMID:18662541 in response to genotoxic stress in G2, the phosphatase Cdc14B translocates from the nucleolus to the nucleoplasm and induces the activation of the ubiquitin ligase APC/C(Cdh1), with the consequent degradation of Plk1, a prominent mitotic kinase |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-174057 | ACCEPT | Summary: Reactome event 'Multiubiquitination of APC/C-associated Cdh1' (Reactome:R-HSA-174057) places FZR1 in the nucleoplasm, where APC/C-Cdh1 assembles, is regulated by CDK phosphorylation/dephosphorylation and Emi1, and ubiquitinates nuclear substrates (SKP2, geminin, EHMT1/2, cyclins). Reason: Pathway-curated location consistent with the nucleus IDA and HPA nucleoplasm IDA. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-174058 | ACCEPT | Summary: Reactome event 'Degradation of multiubiquitinated Cdh1' (Reactome:R-HSA-174058) places FZR1 in the nucleoplasm, where APC/C-Cdh1 assembles, is regulated by CDK phosphorylation/dephosphorylation and Emi1, and ubiquitinates nuclear substrates (SKP2, geminin, EHMT1/2, cyclins). Reason: Pathway-curated location consistent with the nucleus IDA and HPA nucleoplasm IDA. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-174079 | ACCEPT | Summary: Reactome event 'Phosphorylation of Cdh1 by Cyclin A:Cdk2' (Reactome:R-HSA-174079) places FZR1 in the nucleoplasm, where APC/C-Cdh1 assembles, is regulated by CDK phosphorylation/dephosphorylation and Emi1, and ubiquitinates nuclear substrates (SKP2, geminin, EHMT1/2, cyclins). Reason: Pathway-curated location consistent with the nucleus IDA and HPA nucleoplasm IDA. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-174097 | ACCEPT | Summary: Reactome event 'Association of Emi1 with Cdh1' (Reactome:R-HSA-174097) places FZR1 in the nucleoplasm, where APC/C-Cdh1 assembles, is regulated by CDK phosphorylation/dephosphorylation and Emi1, and ubiquitinates nuclear substrates (SKP2, geminin, EHMT1/2, cyclins). Reason: Pathway-curated location consistent with the nucleus IDA and HPA nucleoplasm IDA. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-174122 | ACCEPT | Summary: Reactome event 'Phosphorylation of the Emi1 DSGxxS degron by Cyclin B:Cdc2' (Reactome:R-HSA-174122) places FZR1 in the nucleoplasm, where APC/C-Cdh1 assembles, is regulated by CDK phosphorylation/dephosphorylation and Emi1, and ubiquitinates nuclear substrates (SKP2, geminin, EHMT1/2, cyclins). Reason: Pathway-curated location consistent with the nucleus IDA and HPA nucleoplasm IDA. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-174139 | ACCEPT | Summary: Reactome event 'Dissociation of phospho-Cdh1 from the APC/C complex' (Reactome:R-HSA-174139) places FZR1 in the nucleoplasm, where APC/C-Cdh1 assembles, is regulated by CDK phosphorylation/dephosphorylation and Emi1, and ubiquitinates nuclear substrates (SKP2, geminin, EHMT1/2, cyclins). Reason: Pathway-curated location consistent with the nucleus IDA and HPA nucleoplasm IDA. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-174174 | ACCEPT | Summary: Reactome event 'Phosphorylation of the Emi1 DSGxxS degron by Plk1' (Reactome:R-HSA-174174) places FZR1 in the nucleoplasm, where APC/C-Cdh1 assembles, is regulated by CDK phosphorylation/dephosphorylation and Emi1, and ubiquitinates nuclear substrates (SKP2, geminin, EHMT1/2, cyclins). Reason: Pathway-curated location consistent with the nucleus IDA and HPA nucleoplasm IDA. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-174251 | ACCEPT | Summary: Reactome event 'Phosphorylation of Cdh1 by Cyclin B1:Cdc2' (Reactome:R-HSA-174251) places FZR1 in the nucleoplasm, where APC/C-Cdh1 assembles, is regulated by CDK phosphorylation/dephosphorylation and Emi1, and ubiquitinates nuclear substrates (SKP2, geminin, EHMT1/2, cyclins). Reason: Pathway-curated location consistent with the nucleus IDA and HPA nucleoplasm IDA. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-187948 | ACCEPT | Summary: Reactome event 'Phosphorylation of proteins involved in the G1/S transition by Cyclin A:Cdk2' (Reactome:R-HSA-187948) places FZR1 in the nucleoplasm, where APC/C-Cdh1 assembles, is regulated by CDK phosphorylation/dephosphorylation and Emi1, and ubiquitinates nuclear substrates (SKP2, geminin, EHMT1/2, cyclins). Reason: Pathway-curated location consistent with the nucleus IDA and HPA nucleoplasm IDA. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-188191 | ACCEPT | Summary: Reactome event 'APC/C:Cdh1-mediated degradation of Skp2' (Reactome:R-HSA-188191) places FZR1 in the nucleoplasm, where APC/C-Cdh1 assembles, is regulated by CDK phosphorylation/dephosphorylation and Emi1, and ubiquitinates nuclear substrates (SKP2, geminin, EHMT1/2, cyclins). Reason: Pathway-curated location consistent with the nucleus IDA and HPA nucleoplasm IDA. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-188371 | ACCEPT | Summary: Reactome event 'Association of Cyclin A:Cdk2 with Cdh1' (Reactome:R-HSA-188371) places FZR1 in the nucleoplasm, where APC/C-Cdh1 assembles, is regulated by CDK phosphorylation/dephosphorylation and Emi1, and ubiquitinates nuclear substrates (SKP2, geminin, EHMT1/2, cyclins). Reason: Pathway-curated location consistent with the nucleus IDA and HPA nucleoplasm IDA. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-3788705 | ACCEPT | Summary: Reactome event 'CDKN1A (p21) prevents phosphorylation of Cdh1 by Cyclin A:Cdk2' (Reactome:R-HSA-3788705) places FZR1 in the nucleoplasm, where APC/C-Cdh1 assembles, is regulated by CDK phosphorylation/dephosphorylation and Emi1, and ubiquitinates nuclear substrates (SKP2, geminin, EHMT1/2, cyclins). Reason: Pathway-curated location consistent with the nucleus IDA and HPA nucleoplasm IDA. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-3788708 | ACCEPT | Summary: Reactome event 'CDKN1A (p21) prevents association of Cyclin A:Cdk2 with Cdh1' (Reactome:R-HSA-3788708) places FZR1 in the nucleoplasm, where APC/C-Cdh1 assembles, is regulated by CDK phosphorylation/dephosphorylation and Emi1, and ubiquitinates nuclear substrates (SKP2, geminin, EHMT1/2, cyclins). Reason: Pathway-curated location consistent with the nucleus IDA and HPA nucleoplasm IDA. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-3788724 | ACCEPT | Summary: Reactome event 'Cdh1:APC/C ubiquitinates EHMT1 and EHMT2' (Reactome:R-HSA-3788724) places FZR1 in the nucleoplasm, where APC/C-Cdh1 assembles, is regulated by CDK phosphorylation/dephosphorylation and Emi1, and ubiquitinates nuclear substrates (SKP2, geminin, EHMT1/2, cyclins). Reason: Pathway-curated location consistent with the nucleus IDA and HPA nucleoplasm IDA. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-3788725 | ACCEPT | Summary: Reactome event 'Cdh1:APC/C complex binds EHMT1:EHMT2' (Reactome:R-HSA-3788725) places FZR1 in the nucleoplasm, where APC/C-Cdh1 assembles, is regulated by CDK phosphorylation/dephosphorylation and Emi1, and ubiquitinates nuclear substrates (SKP2, geminin, EHMT1/2, cyclins). Reason: Pathway-curated location consistent with the nucleus IDA and HPA nucleoplasm IDA. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-68712 | ACCEPT | Summary: Reactome event 'The geminin component of geminin:Cdt1 complexes is ubiquitinated, releasing Cdt1' (Reactome:R-HSA-68712) places FZR1 in the nucleoplasm, where APC/C-Cdh1 assembles, is regulated by CDK phosphorylation/dephosphorylation and Emi1, and ubiquitinates nuclear substrates (SKP2, geminin, EHMT1/2, cyclins). Reason: Pathway-curated location consistent with the nucleus IDA and HPA nucleoplasm IDA. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9686969 | ACCEPT | Summary: Reactome event 'APC/C:Cdh1 polyubiquitinates SKP2' (Reactome:R-HSA-9686969) places FZR1 in the nucleoplasm, where APC/C-Cdh1 assembles, is regulated by CDK phosphorylation/dephosphorylation and Emi1, and ubiquitinates nuclear substrates (SKP2, geminin, EHMT1/2, cyclins). Reason: Pathway-curated location consistent with the nucleus IDA and HPA nucleoplasm IDA. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9686980 | ACCEPT | Summary: Reactome event 'RB1 recruits APC/C:Cdh1 complex to SKP2' (Reactome:R-HSA-9686980) places FZR1 in the nucleoplasm, where APC/C-Cdh1 assembles, is regulated by CDK phosphorylation/dephosphorylation and Emi1, and ubiquitinates nuclear substrates (SKP2, geminin, EHMT1/2, cyclins). Reason: Pathway-curated location consistent with the nucleus IDA and HPA nucleoplasm IDA. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9687377 | ACCEPT | Summary: Reactome event 'Defective RB1 does not form a complex with SKP2 and FZR1' (Reactome:R-HSA-9687377) places FZR1 in the nucleoplasm, where APC/C-Cdh1 assembles, is regulated by CDK phosphorylation/dephosphorylation and Emi1, and ubiquitinates nuclear substrates (SKP2, geminin, EHMT1/2, cyclins). Reason: Pathway-curated location consistent with the nucleus IDA and HPA nucleoplasm IDA. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9929717 | ACCEPT | Summary: Reactome event 'CCNA:CDK1 phosphorylates FZR1' (Reactome:R-HSA-9929717) places FZR1 in the nucleoplasm, where APC/C-Cdh1 assembles, is regulated by CDK phosphorylation/dephosphorylation and Emi1, and ubiquitinates nuclear substrates (SKP2, geminin, EHMT1/2, cyclins). Reason: Pathway-curated location consistent with the nucleus IDA and HPA nucleoplasm IDA. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005680 anaphase-promoting complex | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT node PTN000460086 (Cdc20/Fizzy family) assigns APC/C membership to the coactivators. FZR1 is the transiently bound substrate-recognition coactivator rather than a constitutive core subunit; GO conventionally uses part_of APC/C for Cdc20-family activators (compare slp1, CDC20, yeast CDH1), and human FZR1 has been resolved bound to the APC/C by cryo-EM (PDB 4UI9). Reason: Phylogenetic inference agrees with direct structural and biochemical evidence that FZR1 assembles with the APC/C to form the active APC/C-Cdh1 ligase. Supporting Evidence: file:human/FZR1/FZR1-uniprot.txt STRUCTURE BY ELECTRON MICROSCOPY (3.60 ANGSTROMS) IN COMPLEX WITH APC/C PMID:27120157 both coactivators associate with the APC/C through their common C-box and Ile-Arg tail motifs |
| GO:0005680 anaphase-promoting complex | NAS PMID:27120157 Molecular mechanism of APC/C activation by mitotic phosphory... | ACCEPT | Summary: Cryo-EM analysis of human APC/C with its coactivators; the paper compares Cdh1 and Cdc20 N-terminal domain contacts with Apc1/Apc8 and shows Cdh1's higher APC/C affinity. Reason: Although coded NAS, the paper contains direct structural evidence that FZR1 is a component of the assembled APC/C-Cdh1 holoenzyme. Supporting Evidence: PMID:27120157 both coactivators associate with the APC/C through their common C-box and Ile-Arg tail motifs PMID:27120157 phosphorylation of Cdh1 prevents its association with the APC/C |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt records isoform 3 (CDH1beta) as cytoplasmic, and immunofluorescence shows a weaker diffuse cytoplasmic pool of FZR1. Cytoplasmic APC/C-Cdh1 acts on cytosolic substrates such as phosphorylated CDC6 (Reactome). Reason: A genuine but secondary pool; consistent with UniProt, the immunofluorescence data and Reactome cytosolic events. Supporting Evidence: file:human/FZR1/FZR1-uniprot.txt [Isoform 3]: Cytoplasm PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm file:human/FZR1/FZR1-deep-research-falcon.md Localization is best described as dynamic nuclear/chromatin and cytosolic activity rather than a single compartment |
| GO:0005829 cytosol | TAS Reactome:R-HSA-174070 | ACCEPT | Summary: Reactome event 'Association of Cdh1 with the APC/C' (Reactome:R-HSA-174070) places FZR1 in the cytosol, reflecting cytosolic APC/C-Cdh1 events (association with APC/C, Emi1 phosphorylation/degradation, ubiquitination of cytoplasmic CDC6 and other cell-cycle proteins). Reason: Pathway-curated location consistent with the diffuse cytoplasmic pool of FZR1 seen by immunofluorescence and with UniProt's cytoplasmic isoform 3. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-174088 | ACCEPT | Summary: Reactome event 'Association of cell cycle proteins with the APC/C:Cdh1 complex' (Reactome:R-HSA-174088) places FZR1 in the cytosol, reflecting cytosolic APC/C-Cdh1 events (association with APC/C, Emi1 phosphorylation/degradation, ubiquitination of cytoplasmic CDC6 and other cell-cycle proteins). Reason: Pathway-curated location consistent with the diffuse cytoplasmic pool of FZR1 seen by immunofluorescence and with UniProt's cytoplasmic isoform 3. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-174105 | ACCEPT | Summary: Reactome event 'Degradation of multiubiquitinated cell cycle proteins' (Reactome:R-HSA-174105) places FZR1 in the cytosol, reflecting cytosolic APC/C-Cdh1 events (association with APC/C, Emi1 phosphorylation/degradation, ubiquitination of cytoplasmic CDC6 and other cell-cycle proteins). Reason: Pathway-curated location consistent with the diffuse cytoplasmic pool of FZR1 seen by immunofluorescence and with UniProt's cytoplasmic isoform 3. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-174124 | ACCEPT | Summary: Reactome event 'Dephosphorylation of phospho-Cdh1' (Reactome:R-HSA-174124) places FZR1 in the cytosol, reflecting cytosolic APC/C-Cdh1 events (association with APC/C, Emi1 phosphorylation/degradation, ubiquitination of cytoplasmic CDC6 and other cell-cycle proteins). Reason: Pathway-curated location consistent with the diffuse cytoplasmic pool of FZR1 seen by immunofluorescence and with UniProt's cytoplasmic isoform 3. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-174159 | ACCEPT | Summary: Reactome event 'Ubiquitination of Emi1 by SCF-beta-TrCP' (Reactome:R-HSA-174159) places FZR1 in the cytosol, reflecting cytosolic APC/C-Cdh1 events (association with APC/C, Emi1 phosphorylation/degradation, ubiquitination of cytoplasmic CDC6 and other cell-cycle proteins). Reason: Pathway-curated location consistent with the diffuse cytoplasmic pool of FZR1 seen by immunofluorescence and with UniProt's cytoplasmic isoform 3. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-174195 | ACCEPT | Summary: Reactome event 'Ubiquitination of cell cycle proteins targeted by the APC/C:Cdh1complex' (Reactome:R-HSA-174195) places FZR1 in the cytosol, reflecting cytosolic APC/C-Cdh1 events (association with APC/C, Emi1 phosphorylation/degradation, ubiquitination of cytoplasmic CDC6 and other cell-cycle proteins). Reason: Pathway-curated location consistent with the diffuse cytoplasmic pool of FZR1 seen by immunofluorescence and with UniProt's cytoplasmic isoform 3. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-174203 | ACCEPT | Summary: Reactome event 'SCF-mediated degradation of Emi1' (Reactome:R-HSA-174203) places FZR1 in the cytosol, reflecting cytosolic APC/C-Cdh1 events (association with APC/C, Emi1 phosphorylation/degradation, ubiquitination of cytoplasmic CDC6 and other cell-cycle proteins). Reason: Pathway-curated location consistent with the diffuse cytoplasmic pool of FZR1 seen by immunofluorescence and with UniProt's cytoplasmic isoform 3. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-174209 | ACCEPT | Summary: Reactome event 'Phosphorylated Emi1 binds the beta-TrCP in the SCF complex' (Reactome:R-HSA-174209) places FZR1 in the cytosol, reflecting cytosolic APC/C-Cdh1 events (association with APC/C, Emi1 phosphorylation/degradation, ubiquitination of cytoplasmic CDC6 and other cell-cycle proteins). Reason: Pathway-curated location consistent with the diffuse cytoplasmic pool of FZR1 seen by immunofluorescence and with UniProt's cytoplasmic isoform 3. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-69015 | ACCEPT | Summary: Reactome event 'Cytoplasmic phosphorylated Cdc6 is ubiquitinated by the anaphase-promoting complex' (Reactome:R-HSA-69015) places FZR1 in the cytosol, reflecting cytosolic APC/C-Cdh1 events (association with APC/C, Emi1 phosphorylation/degradation, ubiquitination of cytoplasmic CDC6 and other cell-cycle proteins). Reason: Pathway-curated location consistent with the diffuse cytoplasmic pool of FZR1 seen by immunofluorescence and with UniProt's cytoplasmic isoform 3. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0007095 mitotic G2 DNA damage checkpoint signaling | IDA PMID:18662541 The Cdc14B-Cdh1-Plk1 axis controls the G2 DNA-damage-respons... | ACCEPT | Summary: After genotoxic stress in G2, Cdc14B dephosphorylates Cdh1, re-activating APC/C-Cdh1 to degrade PLK1; loss of PLK1 stabilises Claspin and Wee1 and enforces the G2 checkpoint. A constitutively active Cdh1(4xA) mutant bypasses the need for Cdc14B. FZR1 does the work of the step (substrate recognition of PLK1) rather than merely being required for it. Reason: Well-controlled IDA with full text cached; a specific, mechanistically defined checkpoint role of the FZR1-APC/C ligase, also reflected in UniProt's function annotation. Supporting Evidence: PMID:18662541 in response to genotoxic stress in G2, the phosphatase Cdc14B translocates from the nucleolus to the nucleoplasm and induces the activation of the ubiquitin ligase APC/C(Cdh1), with the consequent degradation of Plk1, a prominent mitotic kinase PMID:18662541 Cdh1-dependent degradation of Plk1 is required for an efficient DNA damage-induced G2 checkpoint |
| GO:0007346 regulation of mitotic cell cycle | NAS PMID:15678131 The anaphase-promoting complex: a key factor in the regulati... | MODIFY | Summary: Review-derived statement that APC/C-Cdh1 regulates the mitotic cell cycle. True but very general; the specific, well-evidenced cell-cycle role of FZR1 not otherwise captured is that APC/C-Cdh1 keeps cyclin A/SKP2/CDC6 and other S-phase promoters low during G1, so that Cdh1 overexpression imposes a G1 block and Cdh1 inactivation (CDK phosphorylation, Emi1) is required for S-phase entry. Reason: The generic term should be replaced by the more specific GO:2000134 negative regulation of G1/S transition of mitotic cell cycle, which the pombe ortholog srw1/ste9 already carries (IGI), and which is supported here by Cdh1-overexpression G1 arrest and by the requirement to inhibit APC/C-Cdh1 for S-phase entry. Proposed replacements: negative regulation of G1/S transition of mitotic cell cycle Supporting Evidence: PMID:11988738 hEmi1 overexpression accelerates S phase entry and can override a G1 block caused by overexpression of Cdh1 PMID:18662541 in late M, Cdc20 is replaced by Cdh1, the second activator of APC/C. During G1, APC/CCdh1 remains active to ensure that certain positive regulators of the cell cycle do not accumulate prematurely PMID:20802534 Cdh1-activated APC leads to the exit of mitosis and maintenance of a stable G1 phase |
| GO:0008284 positive regulation of cell population proliferation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfer of a mouse IMP (PMID:21241890) in which Cdh1 knockdown affected proliferation of Pten-deficient MEFs. The direct molecular role of APC/C-Cdh1 is to restrain cell-cycle entry (G1 maintenance, degradation of SKP2, cyclin A, CDC6); proliferation phenotypes in knockout cells arise indirectly through senescence, genome instability and checkpoint effects. Reason: A phenotype-level term that conflicts in direction with FZR1's direct cell-cycle function and rests on a single mouse genetic-interaction context; it should not be read as a core function of the human protein. Supporting Evidence: PMID:21241890 Pten -loss induced senescence is dependent on the Cdh1-Ets2-p16 pathway |
| GO:0010997 anaphase-promoting complex binding | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT node PTN000460086 assigns APC/C binding to the Cdc20/Cdh1 family. FZR1 binds the APC/C via its N-terminal C-box and C-terminal IR tail (Apc8/Apc3 sites), an interaction blocked by CDK phosphorylation and promoted by Cdc14B dephosphorylation, SIRT2 deacetylation and nuclear PTEN. Reason: Core molecular function, supported by cryo-EM of the human APC/C-Cdh1 complex and by many co-immunoprecipitation studies with CDC27. Supporting Evidence: PMID:27120157 both coactivators associate with the APC/C through their common C-box and Ile-Arg tail motifs PMID:10548110 Phosphorylation-deficient mutant Cdh1 or immunodepletion of cyclin A resulted in assembly of active Cdh1-APC even in S-phase cells |
| GO:0010997 anaphase-promoting complex binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro Cdc20/Fizzy family (IPR033010) mapping to APC/C binding; fully consistent with the structural and biochemical evidence. Reason: Family-level inference that matches the experimentally established coactivator role. Supporting Evidence: PMID:27120157 both coactivators associate with the APC/C through their common C-box and Ile-Arg tail motifs |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000041 | ACCEPT | Summary: UniPathway mapping to protein ubiquitination. FZR1 is not catalytic, but as the substrate receptor/activator it performs the recognition step of APC/C-mediated ubiquitination. Reason: Broad but correct; the specific process is captured by GO:0031145 and GO:0070979. Supporting Evidence: PMID:14701726 No ubiquitinylated ladders occurred if APC/C or Cdh1 was omitted in the reaction (lane 1 and 2), and complex containing Cdc20 did not support polyubiquitinylation of His-hTK1 |
| GO:0031145 anaphase-promoting complex-dependent catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT node PTN000460086; the target's own IDA (PMID:14701726) is among the descendant evidences. APC/C-Cdh1 directs ubiquitin-dependent proteasomal degradation of mitotic cyclins, PLK1, AURKA, CDC20, SKP2, geminin, TK1 and many others from anaphase through G1. Reason: Core process; the phylogenetic placement is correct and the human protein has direct experimental support. Supporting Evidence: PMID:14701726 hTK1 is targeted for degradation by the APC/C-Cdh1 ubiquitin ligase dependent on this KEN box motif |
| GO:0031145 anaphase-promoting complex-dependent catabolic process | IDA PMID:14701726 Mitotic degradation of human thymidine kinase 1 is dependent... | ACCEPT | Summary: Ke and Chang showed that human TK1 is degraded during mitotic exit by APC/C-Cdh1, that Cdh1 (not Cdc20) is rate-limiting, that a C-terminal KEN box is required for Cdh1 binding, and that reconstituted APC/C ubiquitinates TK1 only when Cdh1 is present. Reason: Direct, reconstituted evidence for FZR1-dependent APC/C-mediated proteolysis. Supporting Evidence: PMID:14701726 No ubiquitinylated ladders occurred if APC/C or Cdh1 was omitted in the reaction (lane 1 and 2), and complex containing Cdc20 did not support polyubiquitinylation of His-hTK1 PMID:14701726 hTK1 is targeted for degradation by the APC/C-Cdh1 ubiquitin ligase dependent on this KEN box motif |
| GO:0031145 anaphase-promoting complex-dependent catabolic process | IDA PMID:18662541 The Cdc14B-Cdh1-Plk1 axis controls the G2 DNA-damage-respons... | ACCEPT | Summary: APC/C-Cdh1 degrades PLK1 (D-box dependent) and Claspin; Claspin ubiquitination was reconstituted in vitro. Reason: Direct evidence for FZR1-dependent APC/C substrate degradation in G1 and in the G2 DNA-damage response. Supporting Evidence: PMID:18662541 Claspin, which we show to be an APC/C(Cdh1) substrate in G1, is targeted for degradation |
| GO:0031145 anaphase-promoting complex-dependent catabolic process | IDA PMID:21596315 Deubiquitinase USP37 is activated by CDK2 to antagonize APC(... | ACCEPT | Summary: Huang et al. showed that APC(CDH1) targets cyclin A (antagonised by USP37 in G1) and that USP37 itself becomes an APC(CDH1) substrate in mitosis. Reason: Direct evidence (abstract cached; curator read the full text) for FZR1-directed APC/C substrate ubiquitination. Supporting Evidence: PMID:21596315 it switched from an antagonist to a substrate of APC(CDH1) and was modified with degradative K11-linked polyubiquitin |
| GO:0031145 anaphase-promoting complex-dependent catabolic process | NAS PMID:15678131 The anaphase-promoting complex: a key factor in the regulati... | ACCEPT | Summary: Review of APC structure, regulation and substrate recognition; APC/C-Cdh1-dependent proteolysis is the central theme. Reason: NAS from an authoritative review, redundant with but consistent with the IDA and IBA rows. Supporting Evidence: PMID:15678131 Two different ubiquitin ligases play an important role in the cell cycle: the SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) |
| GO:0031965 nuclear membrane | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Human Protein Atlas antibody staining additionally reports a nuclear-membrane pattern. No functional study places APC/C-Cdh1 activity at the nuclear envelope, and the literature IDA describes nuclear plus weak diffuse cytoplasmic signal. Reason: The observation is retained because it is a direct antibody-based localisation, but it is not corroborated by orthogonal evidence and has no known functional counterpart; it should not be read as a site of FZR1 function. Supporting Evidence: PMID:34788397 FZR1 expression was detected in the nucleus, with a weaker diffuse signal in the cytoplasm |
| GO:0051445 regulation of meiotic cell cycle | NAS PMID:15678131 The anaphase-promoting complex: a key factor in the regulati... | KEEP AS NON CORE | Summary: Review-derived statement. Meiotic roles of Cdh1 (prophase I arrest and timing of meiosis I in mouse oocytes; Ime2-Cdh1 regulation in yeast) are documented in model organisms, but there is no direct evidence for human FZR1 in meiosis. Reason: Plausible by orthology and not contradicted, but it is a context-specific role outside the characterised somatic-cell function of the human protein. The deep-research synthesis likewise cautions that FZR1-only phenotypes cannot automatically be assigned to the APC/C ligase. Supporting Evidence: PMID:15678131 Two different ubiquitin ligases play an important role in the cell cycle: the SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) file:human/FZR1/FZR1-deep-research-falcon.md A 2024 study deleting the core subunit APC4 in neurons failed to validate several previously proposed neuronal APC/C substrates |
| GO:0070979 protein K11-linked ubiquitination | TAS PMID:21596315 Deubiquitinase USP37 is activated by CDK2 to antagonize APC(... | ACCEPT | Summary: APC/C-Cdh1 with UBE2C/UBE2S builds K11-linked polyubiquitin on its substrates; Huang et al. showed USP37 modified with degradative K11-linked chains as an APC(CDH1) substrate. Reason: FZR1 provides the substrate-recognition step of the K11-linked ubiquitination carried out by the APC/C-Cdh1 holoenzyme; consistent with the ANAPC2 review. Supporting Evidence: PMID:21596315 it switched from an antagonist to a substrate of APC(CDH1) and was modified with degradative K11-linked polyubiquitin |
| GO:0097027 ubiquitin-protein transferase activator activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro Cdc20/Fizzy family mapping to ubiquitin-protein transferase activator activity, the parent of the more specific ubiquitin ligase activator activity (GO:1990757) carried by IBA. Reason: Broader than the IBA term but correct: coactivator binding enhances APC/C affinity for its E2 and activates ubiquitin transfer. Supporting Evidence: PMID:27120157 Coactivators recognize substrate degrons, and enhance the affinity of the APC/C for its cognate E2 |
| GO:1904668 positive regulation of ubiquitin protein ligase activity | IDA PMID:11459826 MAD2B is an inhibitor of the anaphase-promoting complex. | MODIFY | Summary: Chen and Fang used in vitro APC activation by CDH1 (and its inhibition by MAD2B) to show that CDH1 directly activates the APC ubiquitin ligase. Reason: The finding is correct, but direct activation by a bound coactivator is better represented by the molecular-function term ubiquitin ligase activator activity (GO:1990757, already carried by IBA) together with the process term positive regulation of anaphase-promoting complex-dependent catabolic process (GO:1905786); the generic 'positive regulation of ubiquitin protein ligase activity' process term is redundant and less specific. Proposed replacements: ubiquitin ligase activator activity positive regulation of anaphase-promoting complex-dependent catabolic process Supporting Evidence: PMID:11459826 The APC is activated in mitosis and G1 by CDC20 and CDH1, and inhibited by the checkpoint protein MAD2, a specific inhibitor of CDC20 PMID:27120157 Coactivators recognize substrate degrons, and enhance the affinity of the APC/C for its cognate E2 |
| GO:1905786 positive regulation of anaphase-promoting complex-dependent catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT node PTN000460086. As coactivator, FZR1 positively regulates APC/C-dependent proteolysis: Cdh1 addition activates purified APC/C, Cdh1 overexpression drives substrate degradation, and Cdh1 depletion stabilises substrates. Reason: Core process supported by direct human data (TK1, PLK1, Claspin, cyclin A). Supporting Evidence: PMID:14701726 No ubiquitinylated ladders occurred if APC/C or Cdh1 was omitted in the reaction (lane 1 and 2), and complex containing Cdc20 did not support polyubiquitinylation of His-hTK1 |
| GO:1990756 ubiquitin-like ligase-substrate adaptor activity | IDA PMID:14701726 Mitotic degradation of human thymidine kinase 1 is dependent... | ACCEPT | Summary: FZR1 binds TK1 through its KEN box and brings it to the APC/C for ubiquitination; KEN-box mutants neither bind Cdh1 nor are ubiquitinated. This is the defining substrate-adaptor activity of the coactivator WD40 propeller, which recognises D-box, KEN-box and ABBA degrons. Reason: Direct binding plus reconstituted ubiquitination; the core molecular function of FZR1. Supporting Evidence: PMID:14701726 data from these in vivo and in vitro experiments conclusively indicated that hTK1 directly interacts with Cdh1 via its KEN box signaling motif PMID:21186364 Recognition of substrates by the APC/C depends on co–activator proteins, called Cdc20 and Cdh1, which promote substrate recruitment by interacting with both the APC/C and recognition motifs in substrates, called the destruction box (D box) and KEN box |
| GO:1990757 ubiquitin ligase activator activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT node PTN000460086. Coactivator binding through the C-box/IR tail repositions the Apc2-Apc11 catalytic module and increases APC/C affinity for its E2; unphosphorylated Cdh1 activates the APC/C in late mitosis and G1. Reason: Core molecular function; consistent with the structural mechanism and with in vitro activation of purified APC/C by Cdh1. Supporting Evidence: PMID:27120157 Coactivators recognize substrate degrons, and enhance the affinity of the APC/C for its cognate E2 PMID:14701726 APC/C-mediated ubiquitinylation and degradation require two different activators, Cdc20 and Cdh1 |
| GO:2000773 negative regulation of cellular senescence | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of a mouse IMP (PMID:21241890): Pten-loss-induced senescence depends on a Cdh1-Ets2-p16 pathway, i.e. impaired APC/C-Cdh1 allows Ets2 accumulation and p16 induction. The human part of the same paper shows that PTEN promotes APC/C-CDH1 assembly and that impaired APC-CDH1 underlies the senescence response to acute PTEN loss. Reason: Supported in both mouse and human cells, but it is a context-dependent downstream consequence of APC/C-Cdh1 substrate turnover (Ets2) rather than a core function. Supporting Evidence: PMID:21241890 Pten -loss induced senescence is dependent on the Cdh1-Ets2-p16 pathway PMID:21241890 This nuclear function of PTEN provides a straightforward mechanistic explanation for the fail-safe cellular senescence response elicited by acute PTEN loss |
| GO:2000773 negative regulation of cellular senescence | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curated ISS from mouse Fzr1 (PMID:21241890) for negative regulation of cellular senescence via the Cdh1-Ets2-p16 pathway. Reason: Same evidence as the IEA row; a real but context-dependent, downstream role. Supporting Evidence: PMID:21241890 This nuclear function of PTEN provides a straightforward mechanistic explanation for the fail-safe cellular senescence response elicited by acute PTEN loss |
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Download this section (compressed HTML)Q: GO represents FZR1's activation of the APC/C both as a molecular function (GO:1990757 ubiquitin ligase activator activity, IBA) and as a process (GO:1904668 positive regulation of ubiquitin protein ligase activity, IDA). Should the process-level term be retired for direct coactivators in favour of the MF term plus GO:1905786, as proposed here?
Q: Several APC/C-Cdh1 substrates are recorded on FZR1 only as generic IPI protein-binding rows (PLK1, CLSPN, RAD17, RRM2, SKP2, HECW2, CCNF, SASS6). Would curators support converting these to GO:1990756 ubiquitin-like ligase-substrate adaptor activity with 'has input' extensions, so that the substrate relationships become machine-readable?
Q: The neuronal and post-mitotic roles of FZR1 (chromatin-protein clearance, neurodevelopment, DEE109) are documented mainly in mouse and Drosophila. Which, if any, should be annotated to human FZR1 given that some proposed neuronal substrates were not confirmed when the core subunit APC4 was deleted?
Experiment: Reconstitute human APC/C with wild-type and variant FZR1, measure APC/C binding (C-box/IR-tail dependent) and D-box/KEN-box peptide affinity, and quantify ubiquitination of PLK1, TK1 and INCENP with UBE2C/UBE2S; complement with rescue of FZR1-null cells for G1 length and mitotic-protein clearance.
Hypothesis: DEE109 missense variants (D187G/N, N333K) impair APC/C-Cdh1 substrate-adaptor and coactivator activity by disrupting the WD40 degron-binding surface or the APC/C-docking interface.
Type: in vitro reconstitution and mutational rescue
Experiment: Use degron-mutant FZR1 (N-terminal D-box/Cy motif) and non-degradable cyclin F in single-cell live imaging of APC/C-Cdh1 activity reporters to test whether disrupting either arm of the feedback advances or delays G1/S.
Hypothesis: The cyclin F/APC/C-Cdh1 reciprocal circuit sets the timing of S-phase entry in human cells.
Type: live-cell imaging with degron mutants
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