FBXO8

UniProt ID: Q9NRD0
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

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.

Existing Annotations Review

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

Core Functions

Substrate-recognition (F-box) subunit of an SCF (SKP1-CUL1-RBX1-F-box) / CRL1 E3 ubiquitin ligase complex that binds specific target proteins (e.g. GSTP1) via its substrate-binding region and, through F-box-SKP1 association, presents them for poly-ubiquitination by the complex and subsequent proteasomal degradation. FBXO8 confers substrate specificity rather than carrying catalytic ligase activity itself (the catalytic RING subunit is RBX1).

Molecular Function:
ubiquitin-like ligase-substrate adaptor activity
Directly Involved In:
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
In Complex:
SCF ubiquitin ligase complex
Supporting Evidence:
  • PMID:31024008
    F-box only protein 8 (FBX8), as a critical component of the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligases
  • PMID:31024008
    FBX8 directly targets GSTP1 for ubiquitin-mediated proteasome degradation in CRC.

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
PMID:10945468
cDNA cloning and expression analysis of new members of the mammalian F-box protein family.
  • FBS/FBXO8 is one of a family of mammalian F-box proteins; F-box proteins are components of the SCF ubiquitin-protein ligase complex and function in substrate recognition for ubiquitination and proteasomal degradation. FBS uniquely contains a Sec7 domain.
PMID:31024008
FBX8 degrades GSTP1 through ubiquitination to suppress colorectal cancer progression.
  • FBX8/FBXO8 is a critical component of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase and directly targets GSTP1 for ubiquitin-mediated proteasomal degradation; loss of FBX8 accelerates colon tumorigenesis and correlates with increased GSTP1 stability.
PMID:34445249
The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
  • The SCF complex comprises ~69 SKP1-CUL1-F-box E3 ubiquitin ligase complexes distinguished by variable F-box proteins (substrate specificity), which poly-ubiquitinate substrates for proteasomal degradation.
file:human/FBXO8/FBXO8-deep-research-falcon.md
Falcon deep research report for human FBXO8
  • FBXO8 is an F-box/SCF substrate receptor functionally tied to ARF6-associated membrane trafficking and invasion, reported to bind ARF6 via its Sec7 domain, localize to the plasma membrane, and mediate ARF6 ubiquitination.
    "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."
  • The available evidence supports a Sec7-like ARF6-binding/localization module rather than demonstrated Sec7 GEF catalysis for FBXO8; loss of FBXO8 confers resistance to the vesicular-transport inhibitor brefeldin A.
    "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."
  • FBXO8 acts as a tumor suppressor in hepatocellular carcinoma, where it is downregulated, predicts worse survival, and suppresses proliferation, migration, invasion and lung metastasis on re-expression.
    "FBXO8 acts as a suppressor of HCC proliferation, migration, invasion, tumor growth, and lung metastasis. FBXO8 was downregulated in HCC tissues/cell lines and was an independent prognostic factor for survival."

Suggested Questions for Experts

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?

Suggested Experiments

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.

Deep Research

Falcon

(FBXO8-deep-research-falcon.md)
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 19 citations 2 artifacts 2026-06-13T06:27:12.219625
Edison artifact artifact-00 (text/markdown)
## Context ID: pqac-00000009 The requested panels from Figure 2 and Figure 5 are provided. Figure 2 panels B, C, D, and E show FBX8 expression levels in various (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research report: Functional annotation of human FBXO8 (UniProt Q9NRD0)

0) Gene/protein identity verification (required)

The reviewed primary literature explicitly equates FBX8 with FBXO8 and describes it as an F-box protein containing an F-box domain plus a putative Sec7 domain, matching the target identity provided for human FBXO8 (UniProt Q9NRD0). (wang2013fbx8actsas pages 1-2)

1) Key concepts and definitions (current understanding)

1.1 F-box proteins and SCF E3 ubiquitin ligases

F-box proteins are generally understood as substrate-recognition subunits within SKP1–CUL1–F-box (SCF) Cullin-RING E3 ubiquitin ligase complexes, conferring specificity to ubiquitination reactions that can regulate protein stability and signaling. This framework is directly invoked in the HCC study’s background rationale for FBXO8/FBX8. (wang2013fbx8actsas pages 1-2)

1.2 Sec7 domains and ARF regulation (and what “Sec7-like” implies)

A Sec7 domain classically denotes a catalytic module found in ARF guanine nucleotide exchange factors (GEFs), but for FBXO8 the obtainable evidence is more consistent with a Sec7-like domain mediating ARF6 binding and trafficking-related phenotypes than with demonstrated GEF catalysis in the retrieved full texts. A secretory-pathway review summarizes that FBXO8 binds ARF6 via its Sec7 domain and can localize to the plasma membrane through its Sec7 and F-box domains. (lu2014acullinaryride pages 14-16)

2) Molecular function: what FBXO8 does (best-supported evidence)

2.1 Putative SCF substrate receptor; reported ubiquitination of ARF6

The strongest mechanistic theme across the obtainable sources is that FBXO8 functions as an F-box protein linked to SCF biology and has been reported (in prior primary studies cited by an accessible paper) to possess E3 ligase activity mediating ubiquitination of the small GTPase ARF6, with consequences for invasion. In the accessible HCC paper, this ARF6 ubiquitination is described as prior published evidence rather than newly demonstrated in that paper. (wang2013fbx8actsas pages 1-2)

A trafficking-focused review further frames this as: FBXO8 binds ARF6 through its Sec7 domain and associates with the plasma membrane via its Sec7 and F-box domains (review-level statement). (lu2014acullinaryride pages 14-16)

A large chemical-genetic CRISPR screen of the ubiquitin pathway reports that FBXO8 loss renders cells resistant to brefeldin A, a vesicular transport inhibitor; the authors interpret this as consistent with FBXO8 having a Sec7-like domain. This is indirect functional evidence connecting FBXO8 to membrane/ARF–Golgi pathways, but it does not by itself establish direct Sec7 catalytic (GEF) activity. (hundley2021acomprehensivephenotypic pages 1-4, OpenTargets Search: -FBXO8)

3) Subcellular localization (where FBXO8 acts)

Direct localization experiments were not available in the retrieved primary data excerpts. However, an authoritative review of cullin biology across the secretory pathway states that FBXO8 localizes to the plasma membrane via its Sec7 and F-box domains and binds ARF6 via its Sec7 domain. This supports a model in which FBXO8 functions at or near the cell cortex/plasma membrane to regulate ARF6-associated trafficking and signaling. (lu2014acullinaryride pages 14-16)

4) Biological roles and pathways (with emphasis on precise roles)

4.1 Cancer invasion/metastasis suppression in hepatocellular carcinoma (HCC)

A primary HCC study (PLoS ONE; published 2013-06-27) provides the most detailed experimental evidence available in this run. The study examined 120 paraffin-embedded HCC tissues, plus matched fresh tissues and HCC cell lines, and performed gain-/loss-of-function experiments.

Key findings:
- FBXO8 is downregulated in HCC tissues and cell lines, and low FBXO8 protein is associated with worse patient survival. (wang2013fbx8actsas pages 1-2, wang2013fbx8actsas pages 3-5)
- In vitro: FBXO8 overexpression reduced proliferation, motility, and invasion; FBXO8 knockdown had opposite effects. (wang2013fbx8actsas pages 3-5)
- In vivo: In a tail-vein metastasis model, lung metastasis incidence was 67% (4/6) in mock vs 17% (1/6) in FBXO8-overexpressing group, with fewer metastatic lung nodules reported (P<0.05). (wang2013fbx8actsas pages 3-5, wang2013fbx8actsas media 5f15fba2, wang2013fbx8actsas media 862ac157)

These results support a tumor-suppressive role for FBXO8 in HCC, plausibly connected to ARF6-regulated invasive behavior (as framed by prior mechanistic literature cited in the paper). (wang2013fbx8actsas pages 1-2)

4.2 EMT/dormancy: context-dependent interpretations in recent review literature

A 2023 review on metastatic dormancy includes FBXO8 among genes discussed in dormancy/EMT-related contexts (review-level claim). Because this contrasts with the HCC tumor-suppressor phenotype and the underlying primary source was not accessible here, this should be treated as hypothesis-generating rather than definitive functional annotation. (gelman2023thegenomicregulation pages 1-2)

5) Recent developments (prioritizing 2023–2024)

5.1 2023: FBXO8 in dormancy genomics review

Gelman (Cancer and Metastasis Reviews; final published form 2023-03) provides modern framing of dormancy pathways and includes FBXO8 in the discussion of dormancy-associated genomic programs (review-level mention). (gelman2023thegenomicregulation pages 1-2)

5.2 2024: Biomarker/clinical-correlation studies (identified but not fully retrievable)

A 2025 review of ubiquitination in acute lymphoblastic leukemia (ALL) cites two 2024 disease-focused studies proposing FBXO8 as a biomarker and functional regulator:
- Breast cancer: “FBXO8 is a novel prognostic biomarker in different molecular subtypes of breast cancer and suppresses breast cancer progression by targeting c-MYC” (Biochim Biophys Acta Gen Subj. 2024; DOI: 10.1016/j.bbagen.2024.130577; URL: https://doi.org/10.1016/j.bbagen.2024.130577). (xian2025ubiquitinationandall pages 13-14)
- Kidney renal clear cell carcinoma: “Diagnostic and prognostic potential of FBXO8 expression in kidney renal clear cell carcinoma and its regulation of renal adenocarcinoma cells” (Cancer Genet. 2024; DOI: 10.1016/j.cancergen.2024.11.004; URL: https://doi.org/10.1016/j.cancergen.2024.11.004). (xian2025ubiquitinationandall pages 13-14)

Because the full texts for these 2024 studies were not obtainable in this run, quantitative statistics (e.g., hazard ratios, multivariable models) and mechanistic details cannot be reliably extracted here. (xian2025ubiquitinationandall pages 13-14)

6) Current applications and real-world implementations

  1. Prognostic biomarker candidate in HCC: FBXO8 immunohistochemistry and survival stratification in a clinical cohort supports potential use in prognosis, with in vivo functional support in mouse models. (wang2013fbx8actsas pages 1-2, wang2013fbx8actsas pages 3-5)
  2. Pathway-perturbation / chemical-genetics: FBXO8 appears as a hit conferring resistance to brefeldin A in a systematic chemical-genetic CRISPR screen across 41 conditions, suggesting utility for mapping ubiquitin-pathway dependencies in trafficking. (hundley2021acomprehensivephenotypic pages 1-4, OpenTargets Search: -FBXO8)
  3. Translational expansion to additional cancers (2024): Breast cancer and kidney RCC reports (identified via review citation) suggest expanding biomarker usage, but their quantitative/clinical validation metrics were not accessible here. (xian2025ubiquitinationandall pages 13-14)

7) Expert opinions and analysis (authoritative synthesis)

7.1 Most defensible “core function” model from accessible evidence

Across the strongest accessible sources, FBXO8 is most consistently supported as:
- an F-box protein likely acting as an SCF substrate receptor; (wang2013fbx8actsas pages 1-2)
- functionally tied to ARF6-associated membrane trafficking/invasion biology, via reported ARF6 ubiquitination and review-level ARF6 binding/localization; (wang2013fbx8actsas pages 1-2, lu2014acullinaryride pages 14-16)
- a context-dependent regulator of tumor phenotypes (tumor suppressor in HCC), with other contexts suggested by more recent reviews and secondary citations. (wang2013fbx8actsas pages 3-5, gelman2023thegenomicregulation pages 1-2, xian2025ubiquitinationandall pages 13-14)

7.2 Caution on Sec7 catalytic (GEF) interpretation

Although the Sec7 domain is classically catalytic in ARF-GEFs, the accessible evidence does not include direct biochemical demonstration of FBXO8 GEF activity. The most direct functional evidence available is a brefeldin A resistance phenotype and review-level ARF6 binding/localization statements, which are compatible with a Sec7-like interaction module but do not establish GEF catalysis. (OpenTargets Search: -FBXO8, lu2014acullinaryride pages 14-16)

8) Relevant statistics and data highlights (from recent/obtainable studies)

HCC clinical and in vivo statistics (Wang et al., 2013-06-27):
- In IHC-scored HCC tissues: 83/106 (78.3%) low FBXO8 expression; 23/106 (21.7%) high expression. (wang2013fbx8actsas pages 3-5)
- Overall survival: low FBXO8 associated with worse survival (Kaplan–Meier P=0.002). (wang2013fbx8actsas pages 3-5)
- Metastasis model: lung metastasis in 67% (4/6) mock vs 17% (1/6) FBXO8 overexpression group. (wang2013fbx8actsas pages 3-5, wang2013fbx8actsas media 5f15fba2, wang2013fbx8actsas media 862ac157)

Open Targets disease-association snapshot (evidence aggregation):
Open Targets lists low-to-moderate association scores and evidence counts linking FBXO8 (ENSG00000164117) to phenotypes/diseases such as neurodegenerative disease, cataract, pericarditis, actinic keratosis, with supporting literature including PMIDs 34031600 and 39024449 in the retrieved snapshot. (OpenTargets Search: -FBXO8)

9) Evidence table

The following table compiles the main obtainable sources, dates, models, quantitative highlights, and URLs/DOIs.

Study (first author year) Publication date System/model Main finding about FBXO8 Quantitative/statistical highlights Relevance (molecular function/localization/disease) URL/DOI
Wang 2013 2013-06-27 Human hepatocellular carcinoma (HCC): 120 paraffin-embedded cases, 20 matched fresh tissues, 5 HCC cell lines, mouse xenograft/metastasis assays Verified identity as human FBX8/FBXO8, an F-box protein with a putative Sec7 domain; reports prior evidence that FBX8 is a Skp1-binding protein with E3 ligase activity toward ARF6, and experimentally shows FBXO8 acts as a suppressor of HCC proliferation, migration, invasion, tumor growth, and lung metastasis. FBXO8 was downregulated in HCC tissues/cell lines and was an independent prognostic factor for survival. (wang2013fbx8actsas pages 1-2, wang2013fbx8actsas pages 3-5) 83/106 HCC samples (78.3%) showed low FBX8 expression vs 23/106 (21.7%) high expression; lower FBX8 associated with worse 5-year survival (Kaplan-Meier, P=0.002); expression lower in HCC vs adjacent liver/cirrhotic liver (both P<0.001); correlation with differentiation (P=0.008) and serum AFP (P=0.005); in tail-vein metastasis model, lung metastasis in 67% (4/6) mock vs 17% (1/6) FBX8-overexpressing mice; fewer metastatic lung nodules and smaller tumors with FBX8 overexpression (P<0.05). (wang2013fbx8actsas pages 1-2, wang2013fbx8actsas pages 3-5, wang2013fbx8actsas media 5f15fba2, wang2013fbx8actsas media 862ac157) Disease evidence strongest in HCC; supports tumor-suppressive role. Also anchors molecular-function discussion by linking FBXO8 to SCF/Skp1 and prior ARF6 ubiquitination literature. https://doi.org/10.1371/journal.pone.0065495
Lu & Pfeffer 2014 2014-07 Review of secretory-pathway Cullin-RING ligases Review states that 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. (lu2014acullinaryride pages 14-16) Review-level statement; no primary numerical data in the retrieved excerpt. (lu2014acullinaryride pages 14-16) Key for inferred subcellular localization (plasma membrane) and mechanistic hypothesis that FBXO8 regulates ARF6-dependent trafficking/invasive behavior rather than acting as a canonical Sec7 GEF. https://doi.org/10.1016/j.tcb.2014.02.001
Hundley 2021 2021-03-18 Human HAP1 CRISPR-Cas9 ubiquitin-pathway screen across 41 compounds Genome-scale chemical-genetic screen found that 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. (OpenTargets Search: -FBXO8) Global screen uncovered 466 gene-compound interactions covering 25% of interrogated E3s/DUBs; FBXO8 signal was specifically highlighted as brefeldin A resistance in the tool-derived relevant snippet, but no FBXO8-specific effect size was provided in the retrieved text. (OpenTargets Search: -FBXO8, hundley2021acomprehensivephenotypic pages 1-4) Supports a trafficking-related role and compatibility of FBXO8 domain architecture with Golgi/ARF pathway biology; evidence is indirect and should not be overinterpreted as direct Sec7 catalytic activity. https://doi.org/10.1016/j.molcel.2021.01.014
Zhang 2022 2022-01-03 Public-database analysis of FBXO family in pancreatic ductal adenocarcinoma (PDAC) Establishes general context that FBXO proteins are substrate-recognition subunits of SCF E3 ligases involved in cancer pathways; notes that some FBXO members including FBXO8 have limited PDAC-focused study. In this paper, FBXO8 itself was not one of the six prioritized PDAC FBXOs. (zhang2022comprehensiveanalysisof pages 1-2) Six prioritized FBXOs showed >40% genetic alterations/mutations in PDAC and associations with prognosis/immune infiltration, but these quantitative results were not FBXO8-specific. (zhang2022comprehensiveanalysisof pages 1-2) Useful family-level context for current understanding of FBXO8 as an SCF-type substrate receptor; does not provide direct mechanistic FBXO8 evidence. https://doi.org/10.3389/fimmu.2021.774435
Gelman 2023 2023-03 Review of metastatic dormancy genomics Review-level claim states FBXO8 is an example of a protein that promotes dormancy by upregulating EMT and stem-like markers; this should be treated cautiously because it contrasts with the suppressor-of-invasion framing from HCC studies and the retrieved excerpt does not provide primary supporting data. (gelman2023thegenomicregulation pages 1-2, OpenTargets Search: -FBXO8) No quantitative FBXO8-specific statistics in the retrieved excerpt. (gelman2023thegenomicregulation pages 1-2) Potentially relevant to metastasis/dormancy biology, but currently lower-confidence than HCC experimental evidence; highlights context dependence and need to verify underlying primary source before strong annotation. https://doi.org/10.1007/s10555-022-10076-w
Open Targets summary Accessed from current Open Targets snapshot in tool output (date not stated in output) Curated disease-target evidence aggregation for human FBXO8/ENSG00000164117 Open Targets lists low-to-moderate evidence links between FBXO8 and several diseases/phenotypes, with supporting literature/study IDs rather than mechanistic annotation. Top listed associations in the retrieved output were actinic keratosis, neurodegenerative disease, pericarditis, precordial pain, and cataract. (OpenTargets Search: -FBXO8) Evidence sizes were 2 for each listed disease in the retrieved output; example association scores: neurodegenerative disease 0.231, precordial pain 0.171, cataract 0.167, pericarditis 0.128, actinic keratosis 0.127. Supporting literature IDs in the output included PMID 34031600 and PMID 39024449. (OpenTargets Search: -FBXO8) Helpful for disease landscape scanning, but evidence is indirect/aggregated and does not itself define molecular function or localization. https://platform.opentargets.org/target/ENSG00000164117

Table: This table compiles the most relevant retrieved evidence for human FBXO8/Q9NRD0, separating direct experimental findings from review-level or database-level inferences. It is useful for distinguishing well-supported roles in ARF6-related trafficking and cancer suppression from more tentative disease associations and recent contextual claims.

10) Limitations of this report (important for functional annotation)

  • Several key mechanistic primary papers on ARF6 ubiquitination by FBXO8 and c-Myc–FBXO8 regulation were not obtainable in this run; therefore, the report treats those mechanistic points as reported prior findings rather than extracting their experimental details (e.g., ubiquitin linkage types, ubiquitination sites, direct co-IP evidence). (wang2013fbx8actsas pages 1-2)
  • Recent 2024 biomarker studies in breast cancer and kidney RCC were identified by DOI via a 2025 review but were not available as full text here, so clinical effect sizes (HRs, AUCs) cannot be quoted. (xian2025ubiquitinationandall pages 13-14)

Key references (with dates and URLs)

  • Wang F. et al. 2013-06-27. PLoS ONE. https://doi.org/10.1371/journal.pone.0065495 (wang2013fbx8actsas pages 1-2, wang2013fbx8actsas pages 3-5)
  • Lu A., Pfeffer S.R. 2014-07. Trends in Cell Biology. https://doi.org/10.1016/j.tcb.2014.02.001 (lu2014acullinaryride pages 14-16)
  • Hundley F.V. et al. 2021-03-18. Molecular Cell. https://doi.org/10.1016/j.molcel.2021.01.014 (hundley2021acomprehensivephenotypic pages 1-4)
  • Gelman I.H. 2023-03. Cancer and Metastasis Reviews. https://doi.org/10.1007/s10555-022-10076-w (gelman2023thegenomicregulation pages 1-2)
  • Open Targets Platform entry for FBXO8 (ENSG00000164117): https://platform.opentargets.org/target/ENSG00000164117 (OpenTargets Search: -FBXO8)

References

  1. (wang2013fbx8actsas pages 1-2): Feifei Wang, Yudan Qiao, Jiang Yu, Xiaoli Ren, Jianmei Wang, Yi Ding, Xiaojing Zhang, Wenhui Ma, Yanqing Ding, and Li Liang. Fbx8 acts as an invasion and metastasis suppressor and correlates with poor survival in hepatocellular carcinoma. PLoS ONE, 8:e65495, Jun 2013. URL: https://doi.org/10.1371/journal.pone.0065495, doi:10.1371/journal.pone.0065495. This article has 25 citations and is from a peer-reviewed journal.

  2. (lu2014acullinaryride pages 14-16): Albert Lu and Suzanne R. Pfeffer. A cullinary ride across the secretory pathway: more than just secretion. Trends in cell biology, 24 7:389-99, Jul 2014. URL: https://doi.org/10.1016/j.tcb.2014.02.001, doi:10.1016/j.tcb.2014.02.001. This article has 35 citations and is from a domain leading peer-reviewed journal.

  3. (hundley2021acomprehensivephenotypic pages 1-4): Frances V. Hundley, Nerea Sanvisens Delgado, Harold C. Marin, Kaili L. Carr, Ruilin Tian, and David P. Toczyski. A comprehensive phenotypic crispr-cas9 screen of the ubiquitin pathway uncovers roles of ubiquitin ligases in mitosis. Molecular Cell, 81:1319-1336.e9, Mar 2021. URL: https://doi.org/10.1016/j.molcel.2021.01.014, doi:10.1016/j.molcel.2021.01.014. This article has 56 citations and is from a highest quality peer-reviewed journal.

  4. (OpenTargets Search: -FBXO8): Open Targets Query (-FBXO8, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  5. (wang2013fbx8actsas pages 3-5): Feifei Wang, Yudan Qiao, Jiang Yu, Xiaoli Ren, Jianmei Wang, Yi Ding, Xiaojing Zhang, Wenhui Ma, Yanqing Ding, and Li Liang. Fbx8 acts as an invasion and metastasis suppressor and correlates with poor survival in hepatocellular carcinoma. PLoS ONE, 8:e65495, Jun 2013. URL: https://doi.org/10.1371/journal.pone.0065495, doi:10.1371/journal.pone.0065495. This article has 25 citations and is from a peer-reviewed journal.

  6. (wang2013fbx8actsas media 5f15fba2): Feifei Wang, Yudan Qiao, Jiang Yu, Xiaoli Ren, Jianmei Wang, Yi Ding, Xiaojing Zhang, Wenhui Ma, Yanqing Ding, and Li Liang. Fbx8 acts as an invasion and metastasis suppressor and correlates with poor survival in hepatocellular carcinoma. PLoS ONE, 8:e65495, Jun 2013. URL: https://doi.org/10.1371/journal.pone.0065495, doi:10.1371/journal.pone.0065495. This article has 25 citations and is from a peer-reviewed journal.

  7. (wang2013fbx8actsas media 862ac157): Feifei Wang, Yudan Qiao, Jiang Yu, Xiaoli Ren, Jianmei Wang, Yi Ding, Xiaojing Zhang, Wenhui Ma, Yanqing Ding, and Li Liang. Fbx8 acts as an invasion and metastasis suppressor and correlates with poor survival in hepatocellular carcinoma. PLoS ONE, 8:e65495, Jun 2013. URL: https://doi.org/10.1371/journal.pone.0065495, doi:10.1371/journal.pone.0065495. This article has 25 citations and is from a peer-reviewed journal.

  8. (gelman2023thegenomicregulation pages 1-2): Irwin H. Gelman. The genomic regulation of metastatic dormancy. Cancer and Metastasis Reviews, 42:255-276, Jan 2023. URL: https://doi.org/10.1007/s10555-022-10076-w, doi:10.1007/s10555-022-10076-w. This article has 7 citations and is from a peer-reviewed journal.

  9. (xian2025ubiquitinationandall pages 13-14): Wei Xian, Yinting Chen, Shuiqing Yu, Zhitao Ye, Yu Zhang, and Danlin Yao. Ubiquitination and all: identifying fbxo8 as a prognostic biomarker and therapeutic target. Frontiers in Immunology, May 2025. URL: https://doi.org/10.3389/fimmu.2025.1554231, doi:10.3389/fimmu.2025.1554231. This article has 1 citations and is from a peer-reviewed journal.

  10. (zhang2022comprehensiveanalysisof pages 1-2): Yalu Zhang, Qiaofei Liu, Ming Cui, Mengyi Wang, Surong Hua, Junyi Gao, and Quan Liao. Comprehensive analysis of expression, prognostic value, and immune infiltration for ubiquitination-related fbxos in pancreatic ductal adenocarcinoma. Frontiers in Immunology, Jan 2022. URL: https://doi.org/10.3389/fimmu.2021.774435, doi:10.3389/fimmu.2021.774435. This article has 19 citations and is from a peer-reviewed journal.

Artifacts

Citations

  1. lu2014acullinaryride pages 14-16
  2. gelman2023thegenomicregulation pages 1-2
  3. xian2025ubiquitinationandall pages 13-14
  4. zhang2022comprehensiveanalysisof pages 1-2
  5. hundley2021acomprehensivephenotypic pages 1-4
  6. https://doi.org/10.1016/j.bbagen.2024.130577
  7. https://doi.org/10.1016/j.cancergen.2024.11.004
  8. https://doi.org/10.1371/journal.pone.0065495
  9. https://doi.org/10.1016/j.tcb.2014.02.001
  10. https://doi.org/10.1016/j.molcel.2021.01.014
  11. https://doi.org/10.3389/fimmu.2021.774435
  12. https://doi.org/10.1007/s10555-022-10076-w
  13. https://platform.opentargets.org/target/ENSG00000164117
  14. https://doi.org/10.1371/journal.pone.0065495,
  15. https://doi.org/10.1016/j.tcb.2014.02.001,
  16. https://doi.org/10.1016/j.molcel.2021.01.014,
  17. https://doi.org/10.1007/s10555-022-10076-w,
  18. https://doi.org/10.3389/fimmu.2025.1554231,
  19. https://doi.org/10.3389/fimmu.2021.774435,

📚 Additional Documentation

Pn Notes

(FBXO8-pn-notes.md)

FBXO8 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q9NRD0
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-13
  • Batch change status: added

Source Files Checked

Deep Research Files

AIGR Review Snapshot

  • Description: 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.
  • Existing/core annotation action counts: ACCEPT: 2; KEEP_AS_NON_CORE: 6

PN Consistency Summary

  • Consistency: Consistent. DR ↔ YAML ↔ PN agree FBXO8 is an SCF/CRL1 F-box substrate receptor; review ACCEPTs the SCF complex (GO:0019005) and SCF-dependent catabolism (GO:0031146), and uses GO:1990756 as the core MF, matching the PN projection. No contradictions; the unusual SEC7/ARF6 angle is kept non-core (predicted GEF, not demonstrated).
  • PN story / NEW pressure: PN asserts only the family adaptor MF, which is the recurring correct call. GO:1990756 is verified real (def: "Usually mediated by F-box ... proteins"). It is NOT in GOA for FBXO8 (its only MF annotation is GO:0005085 GEF, IEA). So the adaptor MF is a defensible ADD, but note FBXO8 has NO existing catalytic ligase/transferase MF to MODIFY — GO:1990756 currently lives only in core_functions, not as a NEW existing_annotation. Validated protein substrate exists (GSTP1, PMID:31024008), so this is not a substrate-less F-box.
  • Evidence alignment: PN cites only 15340381 (family review). Review is far richer: PMID:31024008 (GSTP1 substrate), PMID:34445249 (SCF/ComplexPortal), PMID:10945468 (cloning), plus Falcon ARF6/Sec7 leads. Divergence is expansion, not conflict.
  • Verdict: Consistent; PN adaptor mapping (GO:1990756) appropriate and matches review core function.

Full Consistency Review

  • UniProt: Q9NRD0 · batch: proteostasis-batch-2026-06-13 (Falcon DR) · review status: COMPLETE
  • PN placement: UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|other ; PN-node mapping: subtype/type no_mapping; group Cul1 substrate receptor=mapped / ok_for_propagation_to_go → GO:1990756 ubiquitin-like ligase-substrate adaptor activity (new_to_goa); class context_only/too_broad (GO:0061630).
  • Consistency: Consistent. DR ↔ YAML ↔ PN agree FBXO8 is an SCF/CRL1 F-box substrate receptor; review ACCEPTs the SCF complex (GO:0019005) and SCF-dependent catabolism (GO:0031146), and uses GO:1990756 as the core MF, matching the PN projection. No contradictions; the unusual SEC7/ARF6 angle is kept non-core (predicted GEF, not demonstrated).
  • PN story / NEW pressure: PN asserts only the family adaptor MF, which is the recurring correct call. GO:1990756 is verified real (def: "Usually mediated by F-box ... proteins"). It is NOT in GOA for FBXO8 (its only MF annotation is GO:0005085 GEF, IEA). So the adaptor MF is a defensible ADD, but note FBXO8 has NO existing catalytic ligase/transferase MF to MODIFY — GO:1990756 currently lives only in core_functions, not as a NEW existing_annotation. Validated protein substrate exists (GSTP1, PMID:31024008), so this is not a substrate-less F-box.
  • Mapping strategy: Gene does not change the node; status/scope correct. PN-projected GO:1990756 is at the right altitude (matches review core MF). Class-level GO:0061630 correctly held as too_broad.
  • Evidence alignment: PN cites only 15340381 (family review). Review is far richer: PMID:31024008 (GSTP1 substrate), PMID:34445249 (SCF/ComplexPortal), PMID:10945468 (cloning), plus Falcon ARF6/Sec7 leads. Divergence is expansion, not conflict.
  • Verdict: Consistent; PN adaptor mapping (GO:1990756) appropriate and matches review core function.
  • Recommended edits: [YAML] consider adding GO:1990756 as a NEW existing_annotation (MF) to make the adaptor activity an explicit annotation, not only a core_functions entry (FBXO8 currently has no curated SCF-adaptor MF in GOA; the only MF is the IEA GEF term, kept non-core). [MAP] none.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-13
  • review_yaml: genes/human/FBXO8/FBXO8-ai-review.yaml
  • PN workbook rows: 1

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul1 substrate receptor | F-box | other

  • UniProt: Q9NRD0
  • In branches: UPS
  • Signature domains: IPR001810
  • Auxiliary domains: (none)
  • PN references (titles):
    • 15340381 / rev
  • PN-node mapping records (path + ancestors):
    • [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|other
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
    • [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
    • [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor
      status=mapped scope=ok_for_propagation_to_go GO=[GO:1990756 ubiquitin-like ligase-substrate adaptor activity]
      rationale: This PN group captures substrate receptors/adaptors for cullin/UBL ligase systems. The shared GO molecular-function target is ubiquitin-like ligase-substrate adaptor activity.
    • [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
      status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
      rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
    • [branch] Ubiquitin Proteasome System
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (1)

  • GO:1990756 ubiquitin-like ligase-substrate adaptor activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

 
id: Q9NRD0
gene_symbol: FBXO8
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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.
alternative_products:
- name: '1'
  id: Q9NRD0-1
- name: '2'
  id: Q9NRD0-2
  sequence_note: VSP_055885
existing_annotations:
- term:
    id: GO:0005085
    label: guanyl-nucleotide exchange factor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/FBXO8/FBXO8-uniprot.txt
      supporting_text: "May promote guanine-nucleotide exchange on an ARF. Promotes the activation of ARF through replacement of GDP with GTP (Potential)."
    - reference_id: file:human/FBXO8/FBXO8-deep-research-falcon.md
      supporting_text: 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.
- term:
    id: GO:0032012
    label: regulation of ARF protein signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/FBXO8/FBXO8-uniprot.txt
      supporting_text: "May promote guanine-nucleotide exchange on an ARF. Promotes the activation of ARF through replacement of GDP with GTP (Potential)."
    - reference_id: file:human/FBXO8/FBXO8-deep-research-falcon.md
      supporting_text: 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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31024008
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/FBXO8/FBXO8-uniprot.txt
      supporting_text: "Q9NRD0; P09211: GSTP1; NbExp=3; IntAct=EBI-11615366, EBI-353467;"
    - reference_id: PMID:31024008
      supporting_text: "FBX8 directly targets GSTP1 for ubiquitin-mediated proteasome degradation in CRC."
- term:
    id: GO:0000151
    label: ubiquitin ligase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:31024008
      supporting_text: "F-box only protein 8 (FBX8), as a critical component of the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligases"
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: part_of
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:31024008
      supporting_text: "F-box only protein 8 (FBX8), as a critical component of the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligases"
    - reference_id: file:human/FBXO8/FBXO8-uniprot.txt
      supporting_text: "ComplexPortal; CPX-7921; SCF E3 ubiquitin ligase complex, FBXO8 variant."
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:31024008
      supporting_text: "FBX8 directly targets GSTP1 for ubiquitin-mediated proteasome degradation in CRC."
    - reference_id: PMID:34445249
      supporting_text: "SCF E3 ubiquitin ligase complexes that primarily modify protein substrates with poly-ubiquitin chains to target them for proteasomal degradation"
- term:
    id: GO:0000151
    label: ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:10945468
  qualifier: part_of
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate but generic parent term; subsumed by the more specific GO:0019005
      SCF ubiquitin ligase complex annotation that captures the core localization.
    supported_by:
    - reference_id: PMID:10945468
      supporting_text: "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."
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:10945468
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:10945468
      supporting_text: "involved in substrate recognition and recruitment for ubiquitination and consequent degradation by the proteasome"
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: PMID:10945468
  title: cDNA cloning and expression analysis of new members of the mammalian F-box protein family.
  findings:
  - statement: FBS/FBXO8 is one of a family of mammalian F-box proteins; F-box proteins are components of the SCF ubiquitin-protein ligase complex and function in substrate recognition for ubiquitination and proteasomal degradation. FBS uniquely contains a Sec7 domain.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Abstract-only. Original cloning paper establishing FBXO8/FBS as an F-box
      family member with a Sec7 domain; source of the NAS ubiquitin ligase complex
      and ubiquitin-dependent catabolism annotations.
- id: PMID:31024008
  title: FBX8 degrades GSTP1 through ubiquitination to suppress colorectal cancer progression.
  findings:
  - statement: FBX8/FBXO8 is a critical component of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase and directly targets GSTP1 for ubiquitin-mediated proteasomal degradation; loss of FBX8 accelerates colon tumorigenesis and correlates with increased GSTP1 stability.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only (full_text_available: false). Establishes a specific FBXO8 SCF
      substrate (GSTP1) and the core SCF-dependent degradation function; source of
      the IntAct GSTP1 protein-binding annotation.
- id: PMID:34445249
  title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
  findings:
  - statement: The SCF complex comprises ~69 SKP1-CUL1-F-box E3 ubiquitin ligase complexes distinguished by variable F-box proteins (substrate specificity), which poly-ubiquitinate substrates for proteasomal degradation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Abstract-only review of SCF complex biology used by ComplexPortal as the NAS
      basis for the SCF complex and SCF-dependent catabolic process annotations.
- id: file:human/FBXO8/FBXO8-deep-research-falcon.md
  title: Falcon deep research report for human FBXO8
  findings:
  - statement: FBXO8 is an F-box/SCF substrate receptor functionally tied to ARF6-associated membrane trafficking and invasion, reported to bind ARF6 via its Sec7 domain, localize to the plasma membrane, and mediate ARF6 ubiquitination.
    supporting_text: 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.
  - statement: The available evidence supports a Sec7-like ARF6-binding/localization module rather than demonstrated Sec7 GEF catalysis for FBXO8; loss of FBXO8 confers resistance to the vesicular-transport inhibitor brefeldin A.
    supporting_text: 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.
  - statement: FBXO8 acts as a tumor suppressor in hepatocellular carcinoma, where it is downregulated, predicts worse survival, and suppresses proliferation, migration, invasion and lung metastasis on re-expression.
    supporting_text: FBXO8 acts as a suppressor of HCC proliferation, migration, invasion, tumor growth, and lung metastasis. FBXO8 was downregulated in HCC tissues/cell lines and was an independent prognostic factor for survival.
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: >-
      Falcon synthesis anchored on Wang et al. 2013 (PLoS ONE,
      doi:10.1371/journal.pone.0065495; HCC tumor suppression), Lu & Pfeffer 2014
      (Trends Cell Biol, doi:10.1016/j.tcb.2014.02.001; ARF6/Sec7/plasma-membrane
      review), and Hundley et al. 2021 (Mol Cell, doi:10.1016/j.molcel.2021.01.014;
      brefeldin A CRISPR screen). These independently corroborate the predicted
      SEC7/ARF link in UniProt and add functional context (ARF6 binding/
      ubiquitination, plasma-membrane localization, BFA resistance) beyond the
      GSTP1-centric experimental record (PMID:31024008). Falcon cites
      author-year/DOIs not PMIDs and the papers are not in the local cache; the
      ARF6/c-MYC substrate claims are reported (sometimes review-level) and treated
      as leads (UNVERIFIED) rather than independently verified.
core_functions:
- description: >-
    Substrate-recognition (F-box) subunit of an SCF (SKP1-CUL1-RBX1-F-box) / CRL1
    E3 ubiquitin ligase complex that binds specific target proteins (e.g. GSTP1)
    via its substrate-binding region and, through F-box-SKP1 association, presents
    them for poly-ubiquitination by the complex and subsequent proteasomal
    degradation. FBXO8 confers substrate specificity rather than carrying
    catalytic ligase activity itself (the catalytic RING subunit is RBX1).
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  in_complex:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  supported_by:
  - reference_id: PMID:31024008
    supporting_text: "F-box only protein 8 (FBX8), as a critical component of the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligases"
  - reference_id: PMID:31024008
    supporting_text: "FBX8 directly targets GSTP1 for ubiquitin-mediated proteasome degradation in CRC."
proposed_new_terms: []
suggested_questions:
- question: 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.
- question: 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?
- question: 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?
suggested_experiments:
- description: >-
    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.
- description: >-
    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.