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.