FBXO8 (F-box only protein 8; also FBS, FBX8, "F-box/SEC7 protein") is a 319 aa member of the F-box "other" (FBXO) family. Through its F-box domain (residues ~68-111) it binds SKP1 and serves as the substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) / CRL1 E3 ubiquitin-protein ligase complex, in which the catalytic RING subunit is RBX1; F-box proteins such as FBXO8 confer substrate specificity rather than carrying catalytic ligase activity themselves. As an SCF receptor, FBXO8 recruits target proteins for poly-ubiquitination and proteasomal degradation; documented/reported substrates include the detoxification enzyme GSTP1 (FBXO8-mediated degradation linked to suppression of colorectal cancer progression), the small GTPase ARF6 (reported ubiquitination, with consequences for cell invasion), and the oncogenic transcription factor MYC (reported in breast cancer). FBXO8 generally behaves as a tumor suppressor: it is downregulated in hepatocellular carcinoma where low expression predicts worse survival and its re-expression suppresses proliferation, migration, invasion and lung metastasis. Distinctively among F-box proteins, FBXO8 also contains a C-terminal SEC7 domain (residues ~146-276), the module that in canonical ARF guanine-nucleotide exchange factors catalyzes GDP-to-GTP exchange; for FBXO8 the available evidence is most consistent with a Sec7-like domain that mediates ARF6 binding and plasma-membrane localization rather than demonstrated GEF catalysis (loss of FBXO8 confers resistance to the trafficking inhibitor brefeldin A). Through these activities FBXO8 sits at the interface of SCF-type ubiquitination and ARF6-dependent membrane trafficking and invasion. FBXO8 is broadly expressed across human tissues.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005085 guanyl-nucleotide exchange factor activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro/SEC7-based electronic assignment of guanine-nucleotide exchange factor activity. FBXO8 carries a SEC7 domain (residues 146-276) and UniProt records a predicted ("Potential") ARF GEF activity, but this is not experimentally demonstrated, and the core, experimentally supported role of FBXO8 is as an SCF substrate-recognition subunit. Reason: Supported at the sequence level by a genuine SEC7 domain and a UniProt "Potential" GEF function, so not removed; however direct GEF catalysis has not been demonstrated. Falcon-sourced literature indicates the available functional evidence (ARF6 binding via the Sec7 domain, plasma-membrane localization, brefeldin A resistance on FBXO8 loss) is most consistent with a Sec7-like ARF6-interaction module rather than catalytic ARF guanine-nucleotide exchange. The activity therefore remains a predicted/unvalidated molecular function secondary to the documented SCF substrate-receptor role, and is kept as non-core rather than accepted as a core function. Supporting Evidence: file:human/FBXO8/FBXO8-uniprot.txt May promote guanine-nucleotide exchange on an ARF. Promotes the activation of ARF through replacement of GDP with GTP (Potential). file:human/FBXO8/FBXO8-deep-research-falcon.md loss of FBXO8 renders cells resistant to the vesicular transport inhibitor brefeldin A, a phenotype noted as consistent with FBXO8 containing a Sec7-like domain. This is functional-genetic, not direct biochemical proof of GEF activity. |
| GO:0032012 regulation of ARF protein signal transduction | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based electronic assignment of regulation of ARF protein signal transduction, derived from the SEC7 domain. Consistent with the predicted ARF-GEF activity of FBXO8 but, like that activity, sequence-inferred rather than experimentally established and peripheral to the core SCF role. Reason: Plausible given the SEC7 domain and predicted ARF-activating function. While the original GOA support is purely electronic, Falcon-sourced literature adds genuine functional context: FBXO8 is reported to bind ARF6 via its Sec7 domain, localize to the plasma membrane, mediate ARF6 ubiquitination, and its loss confers brefeldin A resistance. This strengthens a real link between FBXO8 and ARF6-dependent membrane trafficking/invasion, but the evidence is most consistent with a Sec7-like ARF6-binding module rather than demonstrated GEF catalysis, and it remains peripheral to the core SCF substrate-receptor role, so it is kept as non-core. Supporting Evidence: file:human/FBXO8/FBXO8-uniprot.txt May promote guanine-nucleotide exchange on an ARF. Promotes the activation of ARF through replacement of GDP with GTP (Potential). file:human/FBXO8/FBXO8-deep-research-falcon.md the SCF substrate receptor FBXO8 binds ARF6 via its Sec7 domain, localizes to the plasma membrane via its Sec7 and F-box domains, and mediates ARF6 ubiquitination; places FBXO8 at the interface of membrane trafficking and ubiquitin signaling. |
| GO:0005515 protein binding | IPI PMID:31024008 FBX8 degrades GSTP1 through ubiquitination to suppress color... | KEEP AS NON CORE | Summary: IntAct-curated physical interaction with GSTP1, the FBXO8 substrate ubiquitinated for proteasomal degradation in colorectal cancer. A real and functionally meaningful interaction, but the bare "protein binding" term is uninformative per curation guidelines. Reason: Records a genuine substrate interaction (FBXO8-GSTP1) underpinning the SCF degradation role, but bare protein binding does not convey the molecular function and is not a core annotation. Supporting Evidence: file:human/FBXO8/FBXO8-uniprot.txt Q9NRD0; P09211: GSTP1; NbExp=3; IntAct=EBI-11615366, EBI-353467; PMID:31024008 FBX8 directly targets GSTP1 for ubiquitin-mediated proteasome degradation in CRC. |
| GO:0000151 ubiquitin ligase complex | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-based (Ensembl Compara) electronic assignment of membership in a ubiquitin ligase complex, transferred from the mouse ortholog. Correct but generic; the specific SCF complex term (GO:0019005) better captures the localization. Reason: Accurate parent term (FBXO8 is part of an SCF/CRL1 E3 ligase complex) but subsumed by the more specific GO:0019005 SCF ubiquitin ligase complex annotation, which is the core localization. Supporting Evidence: PMID:31024008 F-box only protein 8 (FBX8), as a critical component of the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligases |
| GO:0019005 SCF ubiquitin ligase complex | NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... | ACCEPT | Summary: ComplexPortal-curated (NAS) assignment of FBXO8 as part of the SCF ubiquitin ligase complex (CPX-7921, "SCF E3 ubiquitin ligase complex, FBXO8 variant"). This is the core localization: FBXO8 is the F-box substrate-recognition subunit of an SCF/CRL1 complex. Reason: Core localization, well supported: FBXO8 contains an F-box domain, binds SKP1, and is a defined SCF complex variant in ComplexPortal; the literature describes it as a critical SCF component. Supporting Evidence: PMID:31024008 F-box only protein 8 (FBX8), as a critical component of the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligases file:human/FBXO8/FBXO8-uniprot.txt ComplexPortal; CPX-7921; SCF E3 ubiquitin ligase complex, FBXO8 variant. |
| 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-curated (NAS) assignment of involvement in SCF-dependent proteasomal ubiquitin-dependent protein catabolism. This is the core biological process: as the SCF substrate receptor, FBXO8 recruits targets (e.g. GSTP1) for SCF-mediated poly-ubiquitination and proteasomal degradation. Reason: Core biological process, supported by the demonstrated FBXO8-driven ubiquitin-mediated proteasomal degradation of GSTP1 and by FBXO8's defined role as an SCF substrate-recognition subunit. Supporting Evidence: PMID:31024008 FBX8 directly targets GSTP1 for ubiquitin-mediated proteasome degradation in CRC. PMID:34445249 SCF E3 ubiquitin ligase complexes that primarily modify protein substrates with poly-ubiquitin chains to target them for proteasomal degradation |
| GO:0000151 ubiquitin ligase complex | NAS PMID:10945468 cDNA cloning and expression analysis of new members of the m... | KEEP AS NON CORE | Summary: UniProt-curated (NAS) assignment from the original F-box family cloning paper, which describes F-box proteins as components of the SCF ubiquitin-protein ligase complex. Correct but generic relative to the specific SCF complex term. Reason: Accurate but generic parent term; subsumed by the more specific GO:0019005 SCF ubiquitin ligase complex annotation that captures the core localization. Supporting Evidence: PMID:10945468 F-box proteins are critical components of the SCF ubiquitin-protein ligase complex and are involved in substrate recognition and recruitment for ubiquitination and consequent degradation by the proteasome. |
| GO:0006511 ubiquitin-dependent protein catabolic process | NAS PMID:10945468 cDNA cloning and expression analysis of new members of the m... | KEEP AS NON CORE | Summary: UniProt-curated (NAS) assignment of involvement in ubiquitin-dependent protein catabolism, from the F-box family cloning paper. Correct but generic; the specific GO:0031146 (SCF-dependent proteasomal degradation) better captures the core role. Reason: Correct general process but redundant with and less precise than the specific SCF-dependent proteasomal catabolic process annotation, which is the core biological process. Supporting Evidence: PMID:10945468 involved in substrate recognition and recruitment for ubiquitination and consequent degradation by the proteasome |
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Download this section (compressed HTML)Q: Does the FBXO8 SEC7 domain catalyze ARF (ARF1/ARF6) guanine-nucleotide exchange, or does it act as a Sec7-like ARF6-binding/localization module that instead routes ARF6 for SCF-mediated ubiquitination? Resolving GEF catalysis versus ubiquitination is central to FBXO8's molecular function.
Q: Is ARF6 a bona fide direct SCF(FBXO8) ubiquitination substrate, and does FBXO8 thereby couple SCF-type ubiquitination to control of ARF6-dependent membrane trafficking, cell invasion, and metastasis suppression?
Q: Beyond GSTP1, ARF6 and the reported MYC, what is the full repertoire of FBXO8 SCF substrates, and what degrons or modifications govern FBXO8 substrate recognition given its non-canonical (Sec7-containing) architecture?
Experiment: Purify recombinant FBXO8 (or its isolated SEC7 domain) and assay ARF GDP/GTP exchange in vitro (e.g. fluorescent nucleotide-exchange assays with ARF1/ARF6) to directly test whether the predicted GEF activity is genuine; in parallel, map the FBXO8 Sec7-ARF6 interaction and assess ARF6 GTP-loading and trafficking (e.g. brefeldin A sensitivity, Golgi/plasma-membrane markers) upon FBXO8 depletion or overexpression.
Experiment: Reconstitute the FBXO8 SCF complex (SKP1-CUL1-RBX1-FBXO8) and perform in vitro ubiquitination of GSTP1 and ARF6, combined with cellular ubiquitinome/proteome profiling after FBXO8 knockout, to confirm direct adaptor function, test ARF6 as a substrate, and identify additional substrates such as MYC.
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