FBXO8

FBXO8 is an F-box/Sec7 domain-containing substrate-recognition subunit of SCF E3 ubiquitin ligase complexes that acts as a tumor suppressor by directing ubiquitination of distinct substrates, with effects ranging from non-degradative inactivation to proteasomal degradation (PMID:18094045, PMID:27916606). Its founding activity is ubiquitination of the small GTPase Arf6: rather than triggering Arf6 degradation, this modification renders Arf6 refractory to activation, and both the F-box and Sec7 domains are required to suppress Arf6 activity and cell invasion (PMID:18094045). Through its Sec7 domain, FBXO8 also engages a panel of pro-proliferative substrates—mTOR, HIF-1α, CDK4, and c-Myc—targeting them for ubiquitin-mediated proteasomal degradation and thereby restraining cell cycle progression, proliferation, angiogenesis, and metastasis while promoting metastatic dormancy of colorectal cancer cells (PMID:27916606, PMID:32796813). FBXO8 likewise degrades GSTP1, and its loss stabilizes GSTP1 and accelerates colon tumorigenesis in knockout mice (PMID:31024008). This activity is itself regulated at multiple levels: c-Myc binds FBXO8 via its MBII domain to block FBXO8-dependent suppression of Arf6 and invasion (PMID:20848231), the lncRNA FENDRR scaffolds FBXO8 with GSTP1 to enhance GSTP1 degradation (PMID:38144314), and FBXO8 expression is suppressed by miR-223 downstream of MEF2A (PMID:27916606).

1. 2007 High

   Established FBXO8 as a functional E3 ligase component by showing it ubiquitinates Arf6 in a non-degradative manner that blocks Arf6 activation and cell invasion, defining both an enzymatic activity and a domain requirement.

   Evidence Ubiquitination assay, knockdown, F-box and Sec7 domain-deletion mutants, and invasion assays in breast tumor cell lines

   PMID:18094045

   Open questions at the time

   • Cullin/Skp1 scaffold composition of the FBXO8-containing SCF complex not biochemically defined
   • molecular basis for non-degradative outcome on Arf6 versus degradation of other substrates not resolved
2. 2010 Medium

   Identified c-Myc as a direct FBXO8 binding partner via its MBII domain that antagonizes FBXO8 function, showing FBXO8 activity is regulated by protein-protein interaction and subcellular relocalization.

   Evidence Tandem affinity purification, Co-IP, MBII domain mapping, localization and invasion assays

   PMID:20848231

   Open questions at the time

   • mechanism by which c-Myc binding alters FBXO8 localization unknown
   • whether c-Myc is also a substrate not addressed in this study
3. 2016 Medium

   Extended FBXO8 to degradative ubiquitination by identifying mTOR as a substrate and placed FBXO8 in a regulatory axis where miR-223/MEF2A suppress its expression in colorectal cancer.

   Evidence Ubiquitination/degradation assays, miRNA functional characterization, Co-IP, knockdown/overexpression with proliferation and invasion readouts, clinical validation

   PMID:27916606

   Open questions at the time

   • direct degron/recognition motif on mTOR not mapped
   • single-lab data without independent replication
4. 2019 High

   Provided in vivo tumor-suppressor evidence by showing FBXO8 degrades GSTP1 and that FBXO8 loss stabilizes GSTP1 and accelerates colon tumorigenesis in knockout mice.

   Evidence Reciprocal Co-IP, ubiquitination/degradation assays, FBX8 knockout mice, chemical-induced colon tumorigenesis model

   PMID:31024008

   Open questions at the time

   • contribution of GSTP1 stabilization relative to other substrates in the tumorigenesis phenotype not separated
5. 2020 Medium

   Broadened the FBXO8 substrate repertoire to HIF-1α, CDK4, and c-Myc through Sec7-domain binding, linking FBXO8 to cell cycle, angiogenesis, metastasis, and metastatic dormancy.

   Evidence GST pull-down, Co-IP, immunofluorescence, orthotopic liver metastasis mouse model, chemotherapy dormancy experiments, ubiquitination assays

   PMID:32796813

   Open questions at the time

   • specificity of a single Sec7 domain for multiple structurally distinct substrates not mechanistically explained
   • single-lab in vivo findings
6. 2023 Medium

   Identified a lncRNA-based regulatory layer in which FENDRR scaffolds FBXO8 with GSTP1 to enhance GSTP1 ubiquitination and degradation.

   Evidence RNA pull-down with mass spectrometry, RIP, Co-IP, immunofluorescence, rescue functional assays

   PMID:38144314

   Open questions at the time

   • whether FENDRR similarly modulates other FBXO8 substrates not tested
   • single-lab ternary-complex evidence

• The structural and biochemical basis for how a single Sec7-domain F-box protein selects such diverse substrates—and what determines degradative versus non-degradative ubiquitination outcomes—remains unresolved.
• no structure of FBXO8 or its substrate-bound complexes
• SCF complex composition not biochemically reconstituted
• rules governing degradative vs non-degradative ubiquitination unknown