FBXW5 (FBW5) is a 566-residue F-box/WD40-repeat protein that serves as a substrate-recognition subunit for cullin-RING E3 ubiquitin ligases. Through its N-terminal F-box domain (residues 3-49) it binds SKP1 and assembles into the canonical SCF (SKP1-CUL1-RBX1) ligase as the SCF(FBXW5) complex, while its seven WD40 repeats form the substrate-docking surface and additionally allow it to act as a DDB1-binding WD40 (DWD) protein that joins the DDB1-CUL4A/B-RBX1 (DCX/CRL4) ligase as the DCX(FBXW5) complex; deleting the F-box abolishes SKP1 binding yet preserves DDB1/CUL4A bridging, demonstrating that substrate recognition resides in the WD40 repeats while the F-box mediates SCF assembly. As an adaptor, FBXW5 does not itself catalyze ubiquitin transfer (the RING subunit RBX1 recruits the E2) but selects substrates for ubiquitination, most often K48-linked polyubiquitination and proteasomal degradation. Its best-defined substrates are the centriolar cartwheel protein SASS6/HsSAS-6, whose S-phase degradation by SCF(FBXW5) restrains centriole reduplication; the actin-regulator EPS8, degraded during G2 to permit mitotic cell-shape changes; the tumor suppressor TSC2, polyubiquitinated by the DCX(FBXW5)/CRL4 complex to control TSC1-TSC2 complex turnover and mTOR signaling; and the kinesin-13 microtubule depolymerases (MCAK/KIF2C, KIF2A, KIF2B), whose SCF(FBXW5)-mediated degradation in G2 lowers their levels at basal bodies and licenses ciliogenesis in the subsequent G1/G0. Additional substrates reported in cancer and metabolic-disease models include the Rho-GAP tumor suppressor DLC1 (degraded by CRL4A(FBXW5) in non-small-cell lung cancer), the Hippo-pathway kinase LATS1 (degraded in gastric cancer, leading to YAP1 activation), the aquaporin AQP3 (degraded by SCF(FBXW5), tuning PDPK1-AKT-mTOR signaling and autophagic cell death in hepatocellular carcinoma), and the stress kinase ASK1/MAP3K5, which FBXW5 modifies with non-degradative Lys63-linked polyubiquitin chains to activate JNK/p38 MAPK signaling in steatohepatitis. SCF(FBXW5) activity toward SASS6 is inhibited by PLK4 phosphorylation of FBXW5 at Ser151, and FBXW5 itself is a cell-cycle-regulated protein degraded by the APC/C during mitosis and G1 (via a D-box at residues 303-311) and reaccumulating at the G1/S transition. TNFAIP8L1 competes with TSC2 for FBXW5 binding, stabilizing TSC2. FBXW5 has also been reported as a negative regulator of MAP3K7/TAK1 in IL-1B signaling. It is a predominantly cytoplasmic protein.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer of cytoplasmic localization from UniProt subcellular location; consistent with the experimentally documented cytoplasmic localization. Reason: Correct localization; FBXW5 is documented as a cytoplasmic protein and acts on cytoplasmic/centrosomal substrates. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21725316}. |
| GO:0010564 regulation of cell cycle process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning assignment of regulation of a cell cycle process, a broad parent consistent with FBXW5's role in cell-cycle-coupled degradation of SASS6/EPS8. Reason: Correct but generic; the specific roles (regulation of centrosome duplication, SCF-dependent catabolism) better capture the function. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt mediates the ubiquitination and subsequent proteasomal degradation of SASS6 during S phase, leading to prevent centriole reduplication |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Combined automated assignment of protein ubiquitination, the general process in which FBXW5 participates as a substrate-recognition adaptor. Reason: Correct but generic; the SCF-dependent proteasomal catabolic process annotation is more specific and informative. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt PATHWAY: Protein modification; protein ubiquitination. |
| GO:0019005 SCF ubiquitin ligase complex | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of SCF complex membership, the core complex for FBXW5 as an F-box substrate receptor of SKP1-CUL1-RBX1. Reason: Core complex; FBXW5 is the substrate-recognition subunit of the SCF(FBXW5) complex, supported by IDA and UniProt subunit data. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXW5) composed of CUL1, SKP1, RBX1 and FBXW5 |
| GO:0080008 Cul4-RING E3 ubiquitin ligase complex | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based assignment of CUL4-RING (CRL4/DCX) complex membership, consistent with FBXW5 acting as a DDB1-binding WD40 adaptor of the DDB1-CUL4-RBX1 ligase. F-box deletion abolishes SKP1 binding yet preserves DDB1-CUL4A bridging, demonstrating SCF-independent CRL4 assembly; in NSCLC the CRL4A(FBXW5) complex degrades the RhoGAP tumor suppressor DLC1. Reason: Correct second core complex; FBXW5 is a DWD adaptor of the DCX(FBXW5)/CRL4 complex that ubiquitinates TSC2 (and, in NSCLC, DLC1), supported by IDA evidence. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt Component of the DCX(FBXW5) E3 ubiquitin ligase complex, at least composed of (CUL4A or CUL4B), DDB1, FBXW5 and RBX1 file:human/FBXW5/FBXW5-deep-research-falcon.md Importantly, deletion of the F-box can abolish SKP1 binding yet retain the ability to bridge substrates to DDB1–CUL4A, demonstrating **SCF-independent CRL4 assembly**. |
| GO:0005515 protein binding | IPI PMID:15070733 M-phase kinases induce phospho-dependent ubiquitination of s... | KEEP AS NON CORE | Summary: IntAct interaction with SKP1 (P63208), the adaptor that links F-box proteins into the SCF complex. Bare protein binding is uninformative. Reason: Records the functionally meaningful FBXW5-SKP1 interaction but bare protein binding is uninformative; SCF membership is captured by GO:0019005. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt Q969U6; P63208: SKP1; NbExp=8; IntAct=EBI-741068, EBI-307486 |
| GO:0005515 protein binding | IPI PMID:19159283 Array MAPPIT: high-throughput interactome analysis in mammal... | KEEP AS NON CORE | Summary: Array MAPPIT high-throughput interaction with SKP1 (P63208). Bare protein binding is uninformative. Reason: Records FBXW5-SKP1 interaction from a high-throughput method; bare protein binding is uninformative and subsumed by SCF complex membership. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt Q969U6; P63208: SKP1; NbExp=8; IntAct=EBI-741068, EBI-307486 |
| GO:0005515 protein binding | IPI PMID:22632967 Cyclin F-mediated degradation of ribonucleotide reductase M2... | KEEP AS NON CORE | Summary: IntAct interaction with SKP1 (P63208) captured in a study primarily about cyclin F/RRM2. Bare protein binding is uninformative. Reason: Records the FBXW5-SKP1 association; bare protein binding is uninformative and subsumed by SCF complex membership. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt Q969U6; P63208: SKP1; NbExp=8; IntAct=EBI-741068, EBI-307486 |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Proteome-scale binary interactome capturing assorted FBXW5 partners (e.g. TRIM27, keratin-associated proteins). Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative and not a core function. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt Q969U6; P14373: TRIM27; NbExp=6; IntAct=EBI-741068, EBI-719493 |
| GO:0005515 protein binding | IPI PMID:27705803 A High-Density Map for Navigating the Human Polycomb Complex... | KEEP AS NON CORE | Summary: Polycomb complexome AP-MS map capturing an FBXW5-SKP1 (P63208) association. Bare protein binding is uninformative. Reason: High-throughput interaction (SKP1); bare protein binding is uninformative and subsumed by SCF complex membership. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt Q969U6; P63208: SKP1; NbExp=8; IntAct=EBI-741068, 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 capturing many FBXW5 partners, dominated by keratins and keratin-associated proteins. Bare protein binding is uninformative. Reason: High-throughput interactome (many likely sticky/keratin artifacts); bare protein binding is uninformative. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt Q969U6; Q15323: KRT31; NbExp=6; IntAct=EBI-741068, EBI-948001 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: Cell-specific interactome capturing an FBXW5-SKP1 (P63208) association. Bare protein binding is uninformative. Reason: High-throughput interaction (SKP1); bare protein binding is uninformative and subsumed by SCF complex membership. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt Q969U6; P63208: SKP1; NbExp=8; IntAct=EBI-741068, 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 study capturing an FBXW5-SKP1 (P63208) association. Bare protein binding is uninformative. Reason: High-throughput interaction (SKP1); bare protein binding is uninformative and subsumed by SCF complex membership. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt Q969U6; P63208: SKP1; NbExp=8; IntAct=EBI-741068, EBI-307486 |
| GO:0007088 regulation of mitotic nuclear division | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-based (mouse Q9QXW2) transfer of regulation of mitotic nuclear division, plausibly reflecting FBXW5's centrosome/mitotic-spindle role (overduplication causes multipolar spindles). Reason: Plausible but indirect; FBXW5's documented mitotic link is via centriole/centrosome duplication control rather than direct regulation of nuclear division. Supporting Evidence: PMID:21725316 Depletion of endogenous FBXW5 or overexpression of an F-box-deleted mutant version results in centrosome overduplication and formation of multipolar spindles |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated assignment of SCF-dependent proteasomal catabolism, the core biological process for FBXW5 as an SCF substrate receptor. Reason: Core biological process; FBXW5 directs substrates (SASS6, EPS8, kinesin-13s) to SCF-dependent proteasomal degradation, supported by IDA. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt mediates the ubiquitination and subsequent proteasomal degradation of SASS6 during S phase |
| GO:0019005 SCF ubiquitin ligase complex | NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... | ACCEPT | Summary: ComplexPortal non-traceable assertion of SCF complex membership, redundant with the experimentally supported core complex annotation. Reason: Core complex membership; corroborated by IDA and UniProt subunit composition. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXW5) composed of CUL1, SKP1, RBX1 and FBXW5 |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... | ACCEPT | Summary: ComplexPortal non-traceable assertion of SCF-dependent proteasomal catabolism, redundant with the experimentally supported core process. Reason: Core biological process; redundant with IDA evidence. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt mediates the ubiquitination and subsequent proteasomal degradation of SASS6 during S phase |
| GO:0051298 centrosome duplication | NAS PMID:34388369 Structure of the human signal peptidase complex reveals the ... | ACCEPT | Summary: ComplexPortal assertion of involvement in centrosome duplication; FBXW5 restrains centriole/centrosome reduplication by degrading SASS6. Reason: Well-supported core biological role; FBXW5 controls centrosome duplication via SASS6 degradation (IMP-supported in PMID:21725316). Supporting Evidence: PMID:21725316 centrosome duplication is regulated by the activity of an E3-ubiquitin ligase that employs the F-box protein FBXW5 |
| GO:0060271 cilium assembly | NAS PMID:34368969 SCF(Fbxw5) targets kinesin-13 proteins to facilitate cilioge... | ACCEPT | Summary: ComplexPortal assertion of involvement in cilium assembly, supported by the demonstration that SCF(FBXW5) degrades kinesin-13 proteins to facilitate ciliogenesis. Reason: Supported core biological role; loss of FBXW5 raises MCAK at basal bodies and impairs ciliogenesis, rescued by kinesin-13 knockdown. Supporting Evidence: PMID:34368969 loss of Fbxw5 leads to increased MCAK levels at basal bodies and impairs ciliogenesis in the following G1 /G0 , which can be rescued by concomitant knockdown of MCAK, Kif2a or Kif2b |
| GO:0010824 regulation of centrosome duplication | IMP PMID:21725316 The SCF-FBXW5 E3-ubiquitin ligase is regulated by PLK4 and t... | ACCEPT | Summary: Mutant-phenotype evidence that FBXW5 regulates centrosome duplication; depletion or F-box-deletion causes centrosome overduplication. Core biological process. Reason: Core biological process with direct experimental (IMP) support via SASS6 substrate control. Supporting Evidence: PMID:21725316 Depletion of endogenous FBXW5 or overexpression of an F-box-deleted mutant version results in centrosome overduplication and formation of multipolar spindles |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952618 | ACCEPT | Summary: Reactome curation of cytosolic localization within CRL neddylation reactions. Consistent with the documented cytoplasmic localization. Reason: Correct localization, consistent with experimental cytoplasmic localization; the CRL-cycle Reactome events are pathway-context annotations. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21725316}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952620 | ACCEPT | Summary: Reactome curation of cytosolic localization within CRL neddylation reactions. Consistent with documented cytoplasmic localization. Reason: Correct localization, redundant with other localization annotations. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21725316}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955241 | ACCEPT | Summary: Reactome curation of cytosolic localization (CAND1 binding to CRL). Consistent with documented cytoplasmic localization. Reason: Correct localization, redundant with other localization annotations. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21725316}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955289 | ACCEPT | Summary: Reactome curation of cytosolic localization (COMMD-CAND1 displacement). Consistent with documented cytoplasmic localization. Reason: Correct localization, redundant with other localization annotations. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21725316}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956040 | ACCEPT | Summary: Reactome curation of cytosolic localization (COP9 signalosome deneddylation). Consistent with documented cytoplasmic localization. Reason: Correct localization, redundant with other localization annotations. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21725316}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956200 | ACCEPT | Summary: Reactome curation of cytosolic localization (DCUN1D3 binding to CRL1). Consistent with documented cytoplasmic localization. Reason: Correct localization, redundant with other localization annotations. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21725316}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983140 | ACCEPT | Summary: Reactome curation of cytosolic localization (Ub transfer to substrate). Consistent with documented cytoplasmic localization. Reason: Correct localization, redundant with other localization annotations. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21725316}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983147 | ACCEPT | Summary: Reactome curation of cytosolic localization (E3 release from polyubiquitinated substrate). Consistent with documented cytoplasmic localization. Reason: Correct localization, redundant with other localization annotations. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21725316}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983156 | ACCEPT | Summary: Reactome curation of cytosolic localization (polyubiquitination of substrate). Consistent with documented cytoplasmic localization. Reason: Correct localization, redundant with other localization annotations. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21725316}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983157 | ACCEPT | Summary: Reactome curation of cytosolic localization (E3 interaction with substrate and E2-Ub). Consistent with documented cytoplasmic localization. Reason: Correct localization, redundant with other localization annotations. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21725316}. |
| GO:0005515 protein binding | IPI PMID:18381890 WD40 protein FBW5 promotes ubiquitination of tumor suppresso... | KEEP AS NON CORE | Summary: IntAct interactions with TSC2 (P49815) and TSC1 (Q92574), the substrate complex of the DCX(FBXW5) ligase. Bare protein binding is uninformative. Reason: Records the functionally important FBXW5-TSC2/TSC1 substrate interaction but bare protein binding is uninformative; substrate relationship is captured by the catabolic-process annotations. Supporting Evidence: PMID:18381890 TSC2 protein binds to FBW5, a DDB1-binding WD40 (DWD) protein, and is recruited by FBW5 to the DDB1-CUL4-ROC1 E3 ubiquitin ligase |
| GO:0005515 protein binding | IPI PMID:21725316 The SCF-FBXW5 E3-ubiquitin ligase is regulated by PLK4 and t... | KEEP AS NON CORE | Summary: IntAct interactions with CDC20 (Q12834) and SASS6 (Q6UVJ0); SASS6 is a key FBXW5 substrate. Bare protein binding is uninformative. Reason: Records the functionally important FBXW5-SASS6 substrate interaction (and CDC20) but bare protein binding is uninformative. Supporting Evidence: PMID:21725316 FBXW5 binds HsSAS-6 and promotes its ubiquitylation in vivo |
| GO:0005737 cytoplasm | IDA PMID:21725316 The SCF-FBXW5 E3-ubiquitin ligase is regulated by PLK4 and t... | ACCEPT | Summary: Direct experimental evidence (immunolocalization) for cytoplasmic localization of FBXW5. Reason: Core localization with direct experimental support. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21725316}. |
| GO:0016567 protein ubiquitination | IDA PMID:18381890 WD40 protein FBW5 promotes ubiquitination of tumor suppresso... | KEEP AS NON CORE | Summary: Direct evidence that FBXW5 (in the DCX/CRL4 ligase) promotes ubiquitination of TSC2. The general ubiquitination process. Reason: Correct but generic; FBXW5 acts as adaptor in TSC2 ubiquitination/degradation - better captured by the proteasomal catabolic-process annotations. Supporting Evidence: PMID:18381890 CUL4, DDB1, and FBW5 are required for the ubiquitination of TSC2 in vivo and in vitro |
| GO:0016567 protein ubiquitination | IDA PMID:21725316 The SCF-FBXW5 E3-ubiquitin ligase is regulated by PLK4 and t... | KEEP AS NON CORE | Summary: Direct evidence that FBXW5 (in SCF) promotes ubiquitination of SASS6/HsSAS-6. The general ubiquitination process. Reason: Correct but generic; the specific SCF-dependent proteasomal catabolic process annotation is more informative. Supporting Evidence: PMID:21725316 FBXW5 binds HsSAS-6 and promotes its ubiquitylation in vivo |
| GO:0019005 SCF ubiquitin ligase complex | IDA PMID:21725316 The SCF-FBXW5 E3-ubiquitin ligase is regulated by PLK4 and t... | ACCEPT | Summary: Direct evidence that FBXW5 is the F-box receptor of an SCF complex (SCF-FBXW5) targeting HsSAS-6. Core complex. Reason: Core complex membership with direct experimental support. Supporting Evidence: PMID:21725316 centrosome duplication is regulated by the activity of an E3-ubiquitin ligase that employs the F-box protein FBXW5 |
| GO:0019901 protein kinase binding | IPI PMID:21725316 The SCF-FBXW5 E3-ubiquitin ligase is regulated by PLK4 and t... | KEEP AS NON CORE | Summary: IntAct interaction with the kinase PLK4 (O00444), which phosphorylates FBXW5 at Ser151 to inhibit its activity toward SASS6. A regulatory interaction. Reason: Records a real, functionally meaningful regulatory interaction with PLK4 but is subsidiary to the core adaptor/catabolic function. Supporting Evidence: PMID:21725316 negatively regulated by Polo-like kinase 4 (PLK4), which phosphorylates FBXW5 at Ser 151 to suppress its ability to ubiquitylate HsSAS-6 |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | IDA PMID:21725316 The SCF-FBXW5 E3-ubiquitin ligase is regulated by PLK4 and t... | ACCEPT | Summary: Direct evidence that FBXW5 directs SASS6 to SCF-dependent proteasomal degradation. Core biological process. Reason: Core biological process with direct experimental support. Supporting Evidence: file:human/FBXW5/FBXW5-uniprot.txt mediates the ubiquitination and subsequent proteasomal degradation of SASS6 during S phase, leading to prevent centriole reduplication |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:18381890 WD40 protein FBW5 promotes ubiquitination of tumor suppresso... | ACCEPT | Summary: Direct evidence that FBXW5 promotes proteasomal degradation of TSC2 via the DCX/CRL4 ligase. A parent of the SCF-specific catabolic process; here the relevant complex is CRL4. Reason: Correct core biological process; FBXW5 (DCX complex) drives proteasome-mediated degradation of TSC2. Supporting Evidence: PMID:18381890 Overexpression of FBW5 or CUL4A promotes TSC2 protein degradation |
| GO:0080008 Cul4-RING E3 ubiquitin ligase complex | IDA PMID:18381890 WD40 protein FBW5 promotes ubiquitination of tumor suppresso... | ACCEPT | Summary: Direct evidence that FBXW5 is a component (DWD adaptor) of the DDB1-CUL4-RBX1 (DCX/CRL4) E3 ligase that ubiquitinates TSC2. Core complex. Reason: Core complex membership with direct experimental support. Supporting Evidence: PMID:18381890 TSC2 protein binds to FBW5, a DDB1-binding WD40 (DWD) protein, and is recruited by FBW5 to the DDB1-CUL4-ROC1 E3 ubiquitin ligase |
| GO:1990756 ubiquitin-like ligase-substrate adaptor activity | IDA PMID:21725316 The SCF-FBXW5 E3-ubiquitin ligase is regulated by PLK4 and t... | NEW | Summary: FBXW5 functions as the substrate-recognition adaptor that bridges target proteins (SASS6, TSC2, EPS8, kinesin-13s) to the catalytic cullin-RING ligase core; this is its core molecular function and is more informative than the bare protein binding annotations. Not currently in GOA. Reason: Captures the actual molecular function of FBXW5 as an F-box/DWD substrate-specific adaptor of SCF/CRL4 ligases, replacing uninformative protein binding terms. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:21725316 FBXW5 binds HsSAS-6 and promotes its ubiquitylation in vivo PMID:18381890 TSC2 protein binds to FBW5, a DDB1-binding WD40 (DWD) protein, and is recruited by FBW5 to the DDB1-CUL4-ROC1 E3 ubiquitin ligase |
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Download this section (compressed HTML)Q: What determines partition of FBXW5 between the SCF(CUL1) and DCX(CRL4) ligases, and is substrate choice (SASS6/EPS8/kinesin-13 vs TSC2) dictated by which cullin scaffold FBXW5 engages?
Q: How is the cell-cycle timing of FBXW5 activity (G1/S reaccumulation, PLK4 inhibition, APC/C-mediated destruction) integrated to coordinate centriole duplication, mitotic cell-shape changes, and ciliogenesis?
Experiment: Reconstitute SCF(FBXW5) and DCX(FBXW5) ligases in vitro with purified components and candidate substrates (SASS6, EPS8, MCAK/KIF2C, TSC2) to determine which cullin scaffold each substrate requires and to map ubiquitination sites and chain linkages.
Experiment: Use degron/auxin-inducible depletion of FBXW5 combined with quantitative proteomics and ubiquitinomics across the cell cycle to define the endogenous substrate repertoire and the relative contributions of the CUL1 vs CUL4 complexes.
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