FBXW8 (FBW8, FBX29) is an F-box/WD40-repeat protein that serves as the substrate-recognition subunit of a distinctive vertebrate-specific cullin-RING ubiquitin ligase. Unlike most F-box proteins, which assemble into the canonical SCF (SKP1-CUL1) ligase, FBXW8 is the exclusive F-box partner of CUL7, forming the CUL7-RING(FBXW8) (CRL7(FBXW8)) complex composed of CUL7, SKP1, RBX1 and FBXW8. Structural and biochemical work shows that CUL7 binds FBXW8 through an unusual F-box-independent mode and that, within CRL7(FBXW8), the RBX1 RING domain is held in an orientation incompatible with charging E2~ubiquitin/E2~NEDD8; the complex therefore lacks intrinsic catalytic activity and instead acts as a substrate receptor that couples, via SKP1-FBXW8, to a separately neddylated CUL1-RBX1 catalytic module that performs ubiquitin transfer. As an adaptor, FBXW8 selects substrates for polyubiquitination and proteasomal degradation. Documented substrates include insulin receptor substrate 1 (IRS1), recognized after S6-kinase phosphorylation in an mTOR-dependent manner (linking FBXW8 to insulin/IGF-1 signaling and cellular senescence); the Golgi stacking protein GORASP1/GRASP65, whose degradation, together with the scaffold OBSL1 that localizes CUL7(FBXW8) to the Golgi, controls Golgi morphology and dendrite patterning in neurons; the Ste20-family kinase MAP4K1/HPK1, recognized when autophosphorylated; phosphorylated cyclin D1 (CCND1), recognized after ERK/MAPK-dependent Thr286 phosphorylation and degraded in the cytoplasm during S phase; the chromatin-associated MRFAP1, degraded around anaphase-telophase; and adipose triglyceride lipase (ATGL/PNPLA2), K48-polyubiquitinated by a Golgi-localized CUL7-FBXW8 complex to restrain lipolysis. FBXW8 carries a polybasic N-terminal region that binds Golgi phosphatidylinositol 4-phosphate (PtdIns4P), coupling intracellular glucose status to recruitment of the CUL7-FBXW8 ligase to the Golgi. FBXW8 is also an associated component of the CUL7-OBSL1-CCDC8 "3M complex" implicated in microtubule and genome integrity and growth (3M syndrome), and is required in mouse models for placental development and fetal growth. FBXW8 is a cytoplasmic protein that also localizes to the perinuclear region and Golgi apparatus.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0060271 cilium assembly | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) assignment of cilium assembly involvement, inferred from the FBXW family. Human FBXW8 has no direct experimental evidence for ciliogenesis (that role is documented for its paralog FBXW5 via kinesin-13 degradation). Reason: Plausible family-level inference but unsupported by direct human FBXW8 evidence; the well-characterized functions are CUL7-dependent degradation of IRS1, GORASP1, HPK1 and cyclin D1. Supporting Evidence: file:human/FBXW8/FBXW8-uniprot.txt Substrate-recognition component of the Cul7-RING(FBXW8) ubiquitin ligase complex |
| GO:0016567 protein ubiquitination | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic assignment of protein ubiquitination, the general process FBXW8 participates in as a substrate-recognition adaptor of CRL7(FBXW8). Reason: Correct but generic; the SCF/CUL7-dependent proteasomal catabolic process annotations are more specific. Supporting Evidence: file:human/FBXW8/FBXW8-uniprot.txt mediates the ubiquitination and subsequent proteasomal degradation of target proteins |
| GO:0031467 Cul7-RING ubiquitin ligase complex | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of CUL7-RING complex membership, the core complex for FBXW8 as the exclusive F-box partner of CUL7. Reason: Core complex; FBXW8 is the substrate-recognition subunit of CRL7(FBXW8), supported by IDA and structural evidence. Supporting Evidence: file:human/FBXW8/FBXW8-uniprot.txt Component of the Cul7-RING(FBXW8) complex consisting of CUL7, RBX1, SKP1 and FBXW8 |
| GO:0005814 centriole | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) assignment of centriolar localization/activity, inferred from family members. Human FBXW8 evidence places it in cytoplasm/perinuclear/Golgi; CUL7 (its partner) has reported centrosomal localization within the 3M complex. Reason: Family-level inference; centrosomal association is documented for the CUL7-OBSL1-CCDC8 3M complex but direct FBXW8 centriolar activity is not established in human. Supporting Evidence: PMID:24793695 regulate the level and centrosomal localization of CUL7 |
| GO:0036064 ciliary basal body | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic assignment of ciliary basal body activity, inferred from the family. Not directly supported for human FBXW8. Reason: Family-level inference without direct human FBXW8 evidence; documented FBXW8 localizations are cytoplasm, perinuclear region and Golgi. Supporting Evidence: file:human/FBXW8/FBXW8-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, perinuclear region {ECO:0000269|PubMed:21572988}. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of cytoplasmic localization, consistent with the experimentally documented cytoplasmic localization of FBXW8. Reason: Correct core localization with experimental support. Supporting Evidence: file:human/FBXW8/FBXW8-uniprot.txt Cytoplasm {ECO:0000269|PubMed:17205132}. |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer of Golgi localization from UniProt subcellular location, consistent with the experimentally documented Golgi localization where FBXW8 (CUL7) controls Golgi morphology. Reason: Correct localization; CUL7(FBXW8) localizes to the Golgi complex and regulates Golgi morphology, supported by IDA. Supporting Evidence: file:human/FBXW8/FBXW8-uniprot.txt Golgi apparatus {ECO:0000269|PubMed:21572988}. |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer of perinuclear localization from UniProt subcellular location, consistent with documented perinuclear/Golgi localization. Reason: Correct localization with experimental support. Supporting Evidence: file:human/FBXW8/FBXW8-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, perinuclear region {ECO:0000269|PubMed:21572988}. |
| 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 linking FBXW8 into the CRL7 complex. Bare protein binding is uninformative. Reason: Records the FBXW8-SKP1 interaction but bare protein binding is uninformative; complex membership is captured by the CUL7-RING/SCF complex annotations. Supporting Evidence: file:human/FBXW8/FBXW8-uniprot.txt Q8N3Y1; P63208: SKP1; NbExp=6; IntAct=EBI-914770, EBI-307486 |
| GO:0005515 protein binding | IPI PMID:17314511 Large-scale identification of c-MYC-associated proteins usin... | KEEP AS NON CORE | Summary: TAP/MudPIT interaction capturing FBXW8 association with MYC (P01106). Bare protein binding is uninformative. Reason: High-throughput interaction; bare protein binding is uninformative. Supporting Evidence: file:human/FBXW8/FBXW8-uniprot.txt Q8N3Y1; P01106: MYC; NbExp=3; IntAct=EBI-914770, EBI-447544 |
| 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 FBXW8 interaction. Bare protein binding is uninformative. Reason: High-throughput interaction; bare protein binding is uninformative. Supporting Evidence: file:human/FBXW8/FBXW8-uniprot.txt Q8N3Y1; P63208: SKP1; NbExp=6; IntAct=EBI-914770, EBI-307486 |
| 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 FBXW8 interaction. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/FBXW8/FBXW8-uniprot.txt Q8N3Y1; P63208: SKP1; NbExp=6; IntAct=EBI-914770, 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 FBXW8 interaction. Bare protein binding is uninformative. Reason: High-throughput interaction; bare protein binding is uninformative. Supporting Evidence: file:human/FBXW8/FBXW8-uniprot.txt Q8N3Y1; P63208: SKP1; NbExp=6; IntAct=EBI-914770, EBI-307486 |
| GO:0005829 cytosol | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog-based assignment of cytosolic site of action, consistent with the documented cytosolic localization (phospho-Ser85-dependent for IRS1 ubiquitination). Reason: Correct localization; FBXW8 acts in the cytosol/cytoplasm, consistent with experimental evidence. Supporting Evidence: file:human/FBXW8/FBXW8-uniprot.txt Note=Localizes to the cytosol when phosphorylated at Ser-85, promoting IRS1 ubiquitination. |
| GO:0006511 ubiquitin-dependent protein catabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog-based assignment of ubiquitin-dependent catabolism, the core biological process for FBXW8 as a substrate receptor directing targets to degradation. Reason: Correct core biological process; FBXW8 directs substrates (IRS1, cyclin D1, HPK1) to ubiquitin-dependent degradation. The more specific proteasome-mediated/SCF-dependent catabolic process annotations are also present. Supporting Evidence: file:human/FBXW8/FBXW8-uniprot.txt mediates the ubiquitination and subsequent proteasomal degradation of target proteins |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Combined automated assignment of protein ubiquitination, redundant with the IBA/IDA ubiquitination annotations. Reason: Correct but generic; redundant with more specific catabolic-process annotations. Supporting Evidence: file:human/FBXW8/FBXW8-uniprot.txt PATHWAY: Protein modification; protein ubiquitination. |
| GO:0019005 SCF ubiquitin ligase complex | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-based assignment of SCF complex membership. FBXW8's defining complex is CRL7(FBXW8)/CUL7-RING; however, structural data show its catalytic coupling occurs via SKP1-FBXW8 to a CUL1-RBX1 module, so an SCF/CUL1 association is justified. Reason: The primary, well-defined complex is CUL7-RING(FBXW8); SCF/CUL1 membership reflects the catalytic-coupling partnership rather than the canonical receptor assembly. Supporting Evidence: PMID:35982156 CRL7 serves as a substrate receptor linked via SKP1-FBXW8 to a neddylated CUL1-RBX1 catalytic module mediating ubiquitination |
| GO:0031467 Cul7-RING ubiquitin ligase complex | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog-based assignment of CUL7-RING complex membership, the defining core complex of FBXW8. Reason: Core complex; redundant with IDA and structural evidence. Supporting Evidence: file:human/FBXW8/FBXW8-uniprot.txt Component of the Cul7-RING(FBXW8) complex consisting of CUL7, RBX1, SKP1 and FBXW8 |
| GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-based assignment of positive regulation of proteasomal catabolism, consistent with FBXW8 driving substrate degradation. Somewhat redundant with the direct catabolic-process annotations. Reason: Correct in spirit (FBXW8 promotes substrate degradation) but the direct proteasome-mediated catabolic process annotations are more accurate; FBXW8 directly mediates rather than regulates degradation. Supporting Evidence: file:human/FBXW8/FBXW8-uniprot.txt mediates the ubiquitination and subsequent proteasomal degradation of target proteins |
| GO:1990756 ubiquitin-like ligase-substrate adaptor activity | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog-based assignment of substrate-adaptor activity, the core molecular function of FBXW8 as the substrate-recognition subunit of CRL7(FBXW8). Reason: Core molecular function; FBXW8 is the substrate-specific adaptor that recognizes IRS1, GORASP1, HPK1 and cyclin D1, supported by IDA. Supporting Evidence: file:human/FBXW8/FBXW8-uniprot.txt Substrate-recognition component of the Cul7-RING(FBXW8) ubiquitin ligase complex |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence (HPA) evidence for cytosolic localization, consistent with the documented cytoplasmic/cytosolic localization. Reason: Correct localization with direct experimental support. Supporting Evidence: file:human/FBXW8/FBXW8-uniprot.txt Cytoplasm {ECO:0000269|PubMed:17205132}. |
| GO:0019005 SCF ubiquitin ligase complex | NAS PMID:35982156 Structure of CRL7(FBXW8) reveals coupling with CUL1-RBX1/ROC... | KEEP AS NON CORE | Summary: ComplexPortal/NAS assertion of SCF complex membership, reflecting the structural finding that CRL7(FBXW8) couples via SKP1-FBXW8 to a CUL1-RBX1 catalytic module. FBXW8 binds CUL1 through its F-box/SKP1 and CUL7 through F-box-independent regions, bridging a multi-cullin Rbx1-Cul1-Skp1-Fbxw8-Cul7-Rbx1 assembly. Reason: Justified by the catalytic-coupling partnership with CUL1-RBX1 but the primary receptor complex is CUL7-RING(FBXW8). FBXW8 is the substrate receptor; ubiquitin transfer is catalyzed by the neddylated CUL1-RBX1 module, consistent with the adaptor (not catalytic) nature of F-box proteins. Supporting Evidence: PMID:35982156 CRL7 serves as a substrate receptor linked via SKP1-FBXW8 to a neddylated CUL1-RBX1 catalytic module mediating ubiquitination file:human/FBXW8/FBXW8-deep-research-falcon.md CUL7 binds FBXW8 in an F-box-independent mode; CRL7^FBXW8 alone lacks auto-neddylation/ubiquitination activity; catalytic coupling occurs to CUL1-RBX1 |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | NAS PMID:35982156 Structure of CRL7(FBXW8) reveals coupling with CUL1-RBX1/ROC... | ACCEPT | Summary: ComplexPortal/NAS assertion of SCF-dependent proteasomal catabolism, consistent with FBXW8 directing substrates to degradation through a CUL1-coupled catalytic module. Reason: Core biological process; FBXW8 directs substrates to proteasomal degradation, with ubiquitin transfer catalyzed via a coupled CUL1-RBX1 module. Supporting Evidence: PMID:35982156 CRL7 serves as a substrate receptor linked via SKP1-FBXW8 to a neddylated CUL1-RBX1 catalytic module mediating ubiquitination |
| GO:0005737 cytoplasm | IDA PMID:18498745 The CUL7 E3 ubiquitin ligase targets insulin receptor substr... | ACCEPT | Summary: Direct evidence that FBXW8 (CUL7 complex) acts in the cytoplasm to target IRS1 for degradation. Reason: Correct cytoplasmic site of action with direct experimental support. Supporting Evidence: file:human/FBXW8/FBXW8-uniprot.txt Cytoplasm {ECO:0000269|PubMed:17205132}. |
| GO:0005737 cytoplasm | IDA PMID:17205132 A critical role for FBXW8 and MAPK in cyclin D1 degradation ... | ACCEPT | Summary: Direct evidence that the majority of FBXW8 is expressed in the cytoplasm where it mediates cyclin D1 degradation. Reason: Correct cytoplasmic site of action with direct experimental support. Supporting Evidence: PMID:17205132 The majority of FBXW8 is expressed in the cytoplasm during G1 and S phase |
| GO:0031467 Cul7-RING ubiquitin ligase complex | IDA PMID:17205132 A critical role for FBXW8 and MAPK in cyclin D1 degradation ... | ACCEPT | Summary: Direct evidence that FBXW8 is a component of the CUL7-RING E3 ligase that ubiquitinates cyclin D1. Core complex. Reason: Core complex membership with direct experimental support. Supporting Evidence: file:human/FBXW8/FBXW8-uniprot.txt Component of the Cul7-RING(FBXW8) complex consisting of CUL7, RBX1, SKP1 and FBXW8 |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:17205132 A critical role for FBXW8 and MAPK in cyclin D1 degradation ... | ACCEPT | Summary: Direct evidence that FBXW8 mediates cyclin D1 degradation via the proteasome. Core biological process. Reason: Core biological process with direct experimental support. Supporting Evidence: PMID:17205132 This is mediated by phosphorylation at Thr286 through the activity of the Ras/Raf/MEK/ERK cascade and the F-box protein FBXW8, which is an E3 ligase |
| GO:1990756 ubiquitin-like ligase-substrate adaptor activity | IDA PMID:17205132 A critical role for FBXW8 and MAPK in cyclin D1 degradation ... | ACCEPT | Summary: Direct evidence that FBXW8 functions as the substrate-recognition adaptor for cyclin D1. Core molecular function. Reason: Core molecular function with direct experimental support. Supporting Evidence: PMID:17205132 Increased cyclin D1 degradation is linked to association with FBXW8 in the cytoplasm |
| GO:1990756 ubiquitin-like ligase-substrate adaptor activity | IDA PMID:24362026 The CUL7/F-box and WD repeat domain containing 8 (CUL7/Fbxw8... | ACCEPT | Summary: Direct evidence that FBXW8 recognizes and binds autophosphorylated MAP4K1/HPK1 as a substrate adaptor. Core molecular function. Reason: Core molecular function with direct experimental support. Supporting Evidence: PMID:24362026 We found that the CUL7/Fbxw8 ubiquitin ligase targeted HPK1 for degradation via the 26 S proteasome. The ubiquitination of HPK1 required its kinase activity and autophosphorylation |
| GO:0046627 negative regulation of insulin receptor signaling pathway | IDA PMID:18498745 The CUL7 E3 ubiquitin ligase targets insulin receptor substr... | ACCEPT | Summary: Direct evidence that FBXW8 (CUL7 complex) degrades IRS1, negatively regulating insulin/IGF-1 signaling. Reason: Supported core biological role; CUL7(FBXW8) targets IRS1 for degradation, dampening downstream AKT/MEK-ERK signaling. Supporting Evidence: PMID:18498745 we identified insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signaling, as a proteolytic target of the CUL7 E3 ligase |
| GO:0005829 cytosol | IDA PMID:18498745 The CUL7 E3 ubiquitin ligase targets insulin receptor substr... | ACCEPT | Summary: Direct evidence that FBXW8 acts in the cytosol for IRS1 ubiquitination. Reason: Correct cytosolic site of action with direct experimental support. Supporting Evidence: file:human/FBXW8/FBXW8-uniprot.txt Note=Localizes to the cytosol when phosphorylated at Ser-85, promoting IRS1 ubiquitination. |
| GO:0006511 ubiquitin-dependent protein catabolic process | IDA PMID:18498745 The CUL7 E3 ubiquitin ligase targets insulin receptor substr... | ACCEPT | Summary: Direct evidence that FBXW8 (CUL7 complex) targets IRS1 for ubiquitin-dependent degradation. Core biological process. Reason: Core biological process with direct experimental support. Supporting Evidence: PMID:18498745 a key role for the CUL7 E3 in targeting IRS-1 for degradation |
| GO:1990756 ubiquitin-like ligase-substrate adaptor activity | IDA PMID:18498745 The CUL7 E3 ubiquitin ligase targets insulin receptor substr... | ACCEPT | Summary: Direct evidence that FBXW8 is the substrate-targeting subunit recognizing IRS1. Core molecular function. Reason: Core molecular function with direct experimental support. Supporting Evidence: PMID:18498745 the Cullin 7 (CUL7) E3 ubiquitin ligase complex containing the Fbw8-substrate-targeting subunit |
| GO:0005515 protein binding | IPI PMID:18498745 The CUL7 E3 ubiquitin ligase targets insulin receptor substr... | KEEP AS NON CORE | Summary: IntAct interaction(s) from the IRS1 degradation study. Bare protein binding is uninformative. Reason: Records real complex/substrate interactions but bare protein binding is uninformative; substrate relationship captured by the catabolic-process annotations. Supporting Evidence: PMID:18498745 the Cullin 7 (CUL7) E3 ubiquitin ligase complex containing the Fbw8-substrate-targeting subunit |
| GO:0005515 protein binding | IPI PMID:24362026 The CUL7/F-box and WD repeat domain containing 8 (CUL7/Fbxw8... | KEEP AS NON CORE | Summary: IntAct interaction with MAP4K1/HPK1 from the HPK1 degradation study; a real substrate interaction. Bare protein binding is uninformative. Reason: Records the functionally meaningful FBXW8-HPK1 substrate interaction but bare protein binding is uninformative. Supporting Evidence: PMID:24362026 Wild-type protein phosphatase 4 (PP4), but not the phosphatase-dead PP4 mutant, PP4-RL, inhibits the interaction of Fbxw8 with HPK1 |
| GO:0008283 cell population proliferation | IDA PMID:24362026 The CUL7/F-box and WD repeat domain containing 8 (CUL7/Fbxw8... | KEEP AS NON CORE | Summary: Evidence that FBXW8-mediated HPK1 degradation promotes pancreatic cancer cell proliferation. Reason: A downstream physiological consequence of FBXW8 substrate degradation rather than a core molecular/biological function; relevant to cancer biology. Supporting Evidence: PMID:24362026 CUL7/Fbxw8 ubiquitin ligase promotes pancreatic cancer cell proliferation |
| GO:0016567 protein ubiquitination | IDA PMID:24362026 The CUL7/F-box and WD repeat domain containing 8 (CUL7/Fbxw8... | KEEP AS NON CORE | Summary: Direct evidence that FBXW8 promotes ubiquitination of HPK1. The general ubiquitination process. Reason: Correct but generic; the proteasome-mediated catabolic process annotation is more specific. Supporting Evidence: PMID:24362026 We found that the CUL7/Fbxw8 ubiquitin ligase targeted HPK1 for degradation via the 26 S proteasome |
| GO:0031467 Cul7-RING ubiquitin ligase complex | IDA PMID:18498745 The CUL7 E3 ubiquitin ligase targets insulin receptor substr... | ACCEPT | Summary: Direct evidence that FBXW8 is a component of the CUL7-RING ligase targeting IRS1. Core complex. Reason: Core complex membership with direct experimental support. Supporting Evidence: PMID:18498745 the Cullin 7 (CUL7) E3 ubiquitin ligase complex containing the Fbw8-substrate-targeting subunit, Skp1, and the ROC1 RING finger protein |
| GO:0031467 Cul7-RING ubiquitin ligase complex | IDA PMID:24362026 The CUL7/F-box and WD repeat domain containing 8 (CUL7/Fbxw8... | ACCEPT | Summary: Direct evidence that FBXW8 is a component of the CUL7-RING ligase targeting HPK1. Core complex. Reason: Core complex membership with direct experimental support. Supporting Evidence: PMID:24362026 We found that the CUL7/Fbxw8 ubiquitin ligase targeted HPK1 for degradation via the 26 S proteasome |
| GO:1990393 3M complex | IDA PMID:24793695 The 3M complex maintains microtubule and genome integrity. | ACCEPT | Summary: Evidence that FBXW8 is an associated component of the CUL7-OBSL1-CCDC8 3M complex implicated in microtubule and genome integrity. Reason: Supported; FBXW8 associates with the 3M complex (via CUL7), which functions in microtubule/genome integrity and growth (3M syndrome). Supporting Evidence: PMID:24793695 CUL7, OBSL1, and CCDC8 proteins form a 3M complex that functions in maintaining microtubule and genome integrity and normal development |
| GO:0005515 protein binding | IPI PMID:21572988 An OBSL1-Cul7Fbxw8 ubiquitin ligase signaling mechanism regu... | KEEP AS NON CORE | Summary: IntAct interactions from the OBSL1-CUL7(FBXW8) Golgi/dendrite study (e.g. OBSL1, GORASP1). Bare protein binding is uninformative. Reason: Records real complex/substrate interactions (OBSL1, GORASP1) but bare protein binding is uninformative. Supporting Evidence: PMID:21572988 OBSL1 forms a physical complex with the scaffold protein Cul7 and thereby localizes Cul7 at the Golgi apparatus |
| GO:0007030 Golgi organization | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of Golgi organization involvement, supported directly in human by the OBSL1-CUL7(FBXW8)/GORASP1 study. Reason: Supported core role; CUL7(FBXW8) regulates Golgi morphology via GORASP1 degradation (also IGI-supported in PMID:21572988). Supporting Evidence: PMID:21572988 Inhibition of Cul7(Fbxw8) also dramatically impairs the morphology of the Golgi complex, leading to deficient secretory trafficking in neurons |
| GO:0007030 Golgi organization | IGI PMID:21572988 An OBSL1-Cul7Fbxw8 ubiquitin ligase signaling mechanism regu... | ACCEPT | Summary: Genetic-interaction evidence (with OBSL1/GORASP1) that CUL7(FBXW8) controls Golgi morphology. Core biological role. Reason: Supported core biological role with genetic-interaction evidence. Supporting Evidence: PMID:21572988 Inhibition of Cul7(Fbxw8) also dramatically impairs the morphology of the Golgi complex, leading to deficient secretory trafficking in neurons |
| GO:0050775 positive regulation of dendrite morphogenesis | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of positive regulation of dendrite morphogenesis, supported directly in human/rat by the CUL7(FBXW8) neuronal study. Reason: Supported core role in neurons; CUL7(FBXW8) is selectively required for dendrite growth and elaboration. Supporting Evidence: PMID:21572988 Cul7(Fbxw8) is selectively required for the growth and elaboration of dendrites but not axons in primary neurons and in the developing rat cerebellum in vivo |
| GO:0050775 positive regulation of dendrite morphogenesis | IDA PMID:21572988 An OBSL1-Cul7Fbxw8 ubiquitin ligase signaling mechanism regu... | ACCEPT | Summary: Direct evidence that CUL7(FBXW8) promotes dendrite growth and elaboration in neurons. Reason: Supported core role in neuronal morphogenesis with direct experimental support. Supporting Evidence: PMID:21572988 Cul7(Fbxw8) is selectively required for the growth and elaboration of dendrites but not axons in primary neurons and in the developing rat cerebellum in vivo |
| GO:0005794 Golgi apparatus | IDA PMID:21572988 An OBSL1-Cul7Fbxw8 ubiquitin ligase signaling mechanism regu... | ACCEPT | Summary: Direct evidence that CUL7(FBXW8) localizes to the Golgi complex in brain neurons. Reason: Correct localization with direct experimental support. Supporting Evidence: PMID:21572988 the E3 ubiquitin ligase Cul7(Fbxw8) localizes to the Golgi complex in mammalian brain neurons |
| GO:0031467 Cul7-RING ubiquitin ligase complex | IDA PMID:21572988 An OBSL1-Cul7Fbxw8 ubiquitin ligase signaling mechanism regu... | ACCEPT | Summary: Direct evidence that FBXW8 is a component of the CUL7-RING ligase in the Golgi/dendrite study. Core complex. Reason: Core complex membership with direct experimental support. Supporting Evidence: file:human/FBXW8/FBXW8-uniprot.txt Component of the Cul7-RING(FBXW8) complex consisting of CUL7, RBX1, SKP1 and FBXW8 |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:21572988 An OBSL1-Cul7Fbxw8 ubiquitin ligase signaling mechanism regu... | ACCEPT | Summary: Direct evidence for perinuclear/Golgi localization of CUL7(FBXW8) in neurons. Reason: Correct localization with direct experimental support. Supporting Evidence: file:human/FBXW8/FBXW8-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, perinuclear region {ECO:0000269|PubMed:21572988}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952618 | ACCEPT | Summary: Reactome curation of cytosolic localization within CRL neddylation reactions. Consistent with documented cytoplasmic localization. Reason: Correct localization, consistent with experimental evidence; CRL-cycle Reactome events are pathway-context annotations. Supporting Evidence: file:human/FBXW8/FBXW8-uniprot.txt Cytoplasm {ECO:0000269|PubMed:17205132}. |
| 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/FBXW8/FBXW8-uniprot.txt Cytoplasm {ECO:0000269|PubMed:17205132}. |
| 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/FBXW8/FBXW8-uniprot.txt Cytoplasm {ECO:0000269|PubMed:17205132}. |
| 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/FBXW8/FBXW8-uniprot.txt Cytoplasm {ECO:0000269|PubMed:17205132}. |
| 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/FBXW8/FBXW8-uniprot.txt Cytoplasm {ECO:0000269|PubMed:17205132}. |
| 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/FBXW8/FBXW8-uniprot.txt Cytoplasm {ECO:0000269|PubMed:17205132}. |
| 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/FBXW8/FBXW8-uniprot.txt Cytoplasm {ECO:0000269|PubMed:17205132}. |
| 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/FBXW8/FBXW8-uniprot.txt Cytoplasm {ECO:0000269|PubMed:17205132}. |
| 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/FBXW8/FBXW8-uniprot.txt Cytoplasm {ECO:0000269|PubMed:17205132}. |
| 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/FBXW8/FBXW8-uniprot.txt Cytoplasm {ECO:0000269|PubMed:17205132}. |
Loading supporting content…
Download this section (compressed HTML)Q: Given that CRL7(FBXW8) lacks intrinsic catalytic activity and couples to a separate CUL1-RBX1 module, how is this two-cullin assembly regulated, and which substrates require the coupled module versus other catalytic partners?
Q: How do the phosphorylation states of substrates (IRS1, HPK1, cyclin D1) and of FBXW8 itself (Ser85 by mTORC2) coordinate the timing and subcellular site (cytosol vs Golgi) of FBXW8-dependent degradation?
Q: What determines whether an FBXW8-attached K48 polyubiquitin chain routes a substrate to proteasomal degradation (e.g. ATGL, cyclin D1) versus selective autophagy (as reported for viral nucleocapsid), and is PtdIns4P-dependent Golgi recruitment a general feature for membrane-proximal substrates?
Experiment: Reconstitute the full CRL7(FBXW8)-CUL1-RBX1 coupled ligase in vitro with neddylation machinery and phosphorylated substrates (IRS1, HPK1, cyclin D1, GORASP1, ATGL) to confirm the requirement for the CUL1-RBX1 catalytic module and map ubiquitination sites/chain linkages.
Experiment: Perform FBXW8 degron-depletion combined with quantitative phosphoproteomics and ubiquitinomics in neuronal, hepatocyte/adipocyte, and cancer cell models to define the endogenous substrate repertoire and dissect the Golgi/dendrite, lipolysis (ATGL/PtdIns4P), and insulin-signaling functions.
Experiment: Mutate the FBXW8 polybasic N-terminal region to abolish Golgi PtdIns4P binding and test, with cell fractionation and ubiquitination assays, whether Golgi recruitment is required selectively for ATGL/GORASP1 turnover but dispensable for cytosolic substrates (IRS1, HPK1, cyclin D1).
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)