FBXL18

UniProt ID: Q96ME1
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

FBXL18 (F-box/LRR-repeat protein 18, FBL18) is a member of the FBXL subfamily of F-box proteins, with an N-terminal F-box domain followed by an extensive C-terminal leucine-rich repeat (LRR) array. It serves as the substrate-recognition subunit of a Cullin-RING (SCF; SKP1-CUL1-F-box) E3 ubiquitin ligase, docking onto SKP1/CUL1 via its F-box domain and recruiting substrates through its LRRs. FBXL18 deploys two distinct ubiquitination modes. In a degradative (K48-linked) mode it targets another F-box protein, FBXL7, for polyubiquitination and proteasomal degradation, recognizing an N-terminal FQ motif in FBXL7 and conjugating ubiquitin onto FBXL7 Lys109; because FBXL7 is pro-apoptotic, this turnover limits apoptosis. SCF^FBXL18 (reconstituted with SKP1-CUL1-RBX1) also mediates K48-linked degradation of the TFIIH subunit XPB/ERCC3 in a drug-triggered, CDK7- and XPB-Ser90-dependent manner (spironolactone-induced), thereby impairing nucleotide-excision repair and transcription and sensitizing cells to platinum agents. In a second, non-degradative (K63-linked) mode FBXL18 ubiquitinates signaling proteins to modulate their activity rather than degrade them: it promotes K63-linked ubiquitination of AKT (driving AKT-FOXO3a-Bim survival signaling in glioma and ovarian cancer) and of PTEN (inhibiting PTEN and activating PI3K/AKT in non-small-cell lung cancer), and is frequently upregulated and pro-oncogenic in these tumors. Consistent with these roles, FBXL18 has been annotated in both the cytoplasm (AKT/PTEN signaling) and the nucleus (XPB/TFIIH). It is broadly expressed with enhancement in brain.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
IEA
GO_REF:0000002 		ACCEPT
Summary: InterPro/domain-based electronic assignment (FBXL18 F-box/LRR signature) that FBXL18 acts in SCF-dependent proteasomal degradation. This is the experimentally established core process (FBXL18 K48-polyubiquitinates and degrades FBXL7, and SCF^FBXL18 degrades the TFIIH subunit XPB/ERCC3).
Reason: Core biological process; directly supported by the experimental demonstration that FBXL18 polyubiquitinates and targets FBXL7 for proteasomal degradation, and by reconstituted SCF^FBXL18-mediated K48 degradation of XPB. Note FBXL18 also performs non-degradative K63 ubiquitination of AKT and PTEN, which this catabolic term does not capture.
Supporting Evidence:
PMID:25654763
an orphan F-box protein, Fbxl18, targets Fbxl7 for its polyubiquitylation and proteasomal degradation
file:human/FBXL18/FBXL18-deep-research-falcon.md
SCF^FBXL18 was biochemically reconstituted/purified (Cul1, Skp1, Rbx1, FBXL18) and shown to ubiquitinate XPB in vitro, supporting direct E3/substrate compatibility.
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
NAS
PMID:33234069
The FBXL family of F-box proteins: variations on a theme. 		ACCEPT
Summary: Family/ComplexPortal NAS assignment of the same core SCF-dependent degradation process, redundant with the experimentally supported IEA annotation.
Reason: Core biological process; supported experimentally (FBXL18 degrades FBXL7) and by family-level evidence.
Supporting Evidence:
PMID:25654763
an orphan F-box protein, Fbxl18, targets Fbxl7 for its polyubiquitylation and proteasomal degradation
GO:0042981 regulation of apoptotic process
NAS
PMID:25654763
F-box protein Fbxl18 mediates polyubiquitylation and proteas... 		KEEP AS NON CORE
Summary: FBXL18 regulates apoptosis by mediating the ubiquitin-dependent proteasomal degradation of the pro-apoptotic protein FBXL7; FBXL18 depletion accentuates FBXL7-induced apoptosis, and FBXL18 overexpression limits it.
Reason: Genuine biological consequence of FBXL18 activity, supported by the FBXL7 study, but it is an indirect, downstream outcome of the core SCF-dependent degradation function rather than a separate molecular role.
Supporting Evidence:
PMID:25654763
Fbxl18 regulates apoptosis by mediating ubiquitin-dependent proteasomal degradation of the pro-apoptotic protein Fbxl7
GO:0005829 cytosol
TAS
Reactome:R-HSA-8854051 		KEEP AS NON CORE
Summary: Reactome cytosol annotation tied to the curated reaction "SCF-FBXL18 ubiquitinates FBXL7", which reflects FBXL18's actual ligase reaction. The cytosol is a plausible compartment for this SCF activity.
Reason: Plausible localization linked to the bona fide FBXL18-FBXL7 reaction, but derived from Reactome pathway curation rather than direct FBXL18 localization data.
Supporting Evidence:
PMID:25654763
an orphan F-box protein, Fbxl18, targets Fbxl7 for its polyubiquitylation and proteasomal degradation
GO:0005829 cytosol
TAS
Reactome:R-HSA-8952618 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol annotation from the generic CRL1/neddylation reaction set.
Reason: Plausible but redundant generic-pathway localization; not FBXL18-specific.
Supporting Evidence:
file:human/FBXL18/FBXL18-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8952620 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol annotation from the generic CRL1 neddylation reaction set.
Reason: Plausible but redundant generic-pathway localization; not FBXL18-specific.
Supporting Evidence:
file:human/FBXL18/FBXL18-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8955241 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol annotation from the generic CRL (CAND1) reaction set.
Reason: Plausible but redundant generic-pathway localization; not FBXL18-specific.
Supporting Evidence:
file:human/FBXL18/FBXL18-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8955289 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol annotation from the generic CRL (COMMD/CAND1) reaction set.
Reason: Plausible but redundant generic-pathway localization; not FBXL18-specific.
Supporting Evidence:
file:human/FBXL18/FBXL18-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8956040 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol annotation from the generic CRL deneddylation (COP9) reaction set.
Reason: Plausible but redundant generic-pathway localization; not FBXL18-specific.
Supporting Evidence:
file:human/FBXL18/FBXL18-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8956200 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol annotation from the generic CRL1 (DCUN1D3) reaction set.
Reason: Plausible but redundant generic-pathway localization; not FBXL18-specific.
Supporting Evidence:
file:human/FBXL18/FBXL18-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
GO:0005829 cytosol
TAS
Reactome:R-HSA-983140 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol annotation from the generic ubiquitination reaction set (transfer of Ub from E2 to substrate).
Reason: Plausible but redundant generic-pathway localization; not FBXL18-specific.
Supporting Evidence:
file:human/FBXL18/FBXL18-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
GO:0005829 cytosol
TAS
Reactome:R-HSA-983147 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol annotation from the generic ubiquitination reaction set (release of E3 from substrate).
Reason: Plausible but redundant generic-pathway localization; not FBXL18-specific.
Supporting Evidence:
file:human/FBXL18/FBXL18-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
GO:0005829 cytosol
TAS
Reactome:R-HSA-983156 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol annotation from the generic ubiquitination reaction set (polyubiquitination of substrate).
Reason: Plausible but redundant generic-pathway localization; not FBXL18-specific.
Supporting Evidence:
file:human/FBXL18/FBXL18-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
GO:0005829 cytosol
TAS
Reactome:R-HSA-983157 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol annotation from the generic ubiquitination reaction set (interaction of E3 with substrate and E2-Ub).
Reason: Plausible but redundant generic-pathway localization; not FBXL18-specific.
Supporting Evidence:
file:human/FBXL18/FBXL18-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.

Core Functions

Substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase that targets substrates for K48-linked polyubiquitination and proteasomal degradation. It recognizes an FQ motif in the F-box protein FBXL7 and conjugates ubiquitin onto FBXL7 Lys109, controlling FBXL7 abundance and limiting FBXL7-driven apoptosis; reconstituted SCF^FBXL18 also degrades the TFIIH subunit XPB/ERCC3 (drug-triggered, CDK7/Ser90-dependent), affecting nucleotide-excision repair and transcription.

Molecular Function:
ubiquitin-like ligase-substrate adaptor activity
Directly Involved In:
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
Cellular Locations:
cytosol
Supporting Evidence:
  • PMID:25654763
    an orphan F-box protein, Fbxl18, targets Fbxl7 for its polyubiquitylation and proteasomal degradation
  • file:human/FBXL18/FBXL18-deep-research-falcon.md
    SCF^FBXL18 was biochemically reconstituted/purified (Cul1, Skp1, Rbx1, FBXL18) and shown to ubiquitinate XPB in vitro, supporting direct E3/substrate compatibility.

In a second, non-degradative mode FBXL18 acts as an E3-ligase substrate adaptor that promotes K63-linked (non-degradative) ubiquitination of signaling proteins to modulate their activity, notably AKT (driving AKT-FOXO3a-Bim pro-survival signaling) and PTEN (inhibiting PTEN), thereby activating PI3K/AKT signaling and promoting proliferation/survival in glioma, ovarian and lung cancers.

Molecular Function:
ubiquitin-like ligase-substrate adaptor activity
Directly Involved In:
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
Cellular Locations:
cytosol
Supporting Evidence:
  • file:human/FBXL18/FBXL18-deep-research-falcon.md
    FBXL18 physically interacts with AKT and promotes **K63-linked ubiquitination** of AKT (with minimal effect on K48-linked ubiquitination), including reduced EGF-induced K63 ubiquitination upon FBXL18 knockdown.

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
PMID:25654763
F-box protein Fbxl18 mediates polyubiquitylation and proteasomal degradation of the pro-apoptotic SCF subunit Fbxl7.
  • FBXL18 targets FBXL7 for polyubiquitylation and proteasomal degradation, conjugating ubiquitin onto FBXL7 Lys109 and recognizing an FQ motif in FBXL7; this limits FBXL7-induced apoptosis (FBXL18 depletion accentuates, overexpression attenuates, FBXL7-driven apoptosis).
PMID:33234069
The FBXL family of F-box proteins: variations on a theme.
  • FBXL-family F-box proteins serve as substrate-recognition subunits of SCF E3 ubiquitin ligases, using their LRR domains for substrate binding and the F-box for SKP1/CUL1 recruitment.
file:human/FBXL18/FBXL18-deep-research-falcon.md
Falcon deep research report for human FBXL18
  • FBXL18 is an SCF substrate receptor that deploys two modes - degradative K48 polyubiquitination and non-degradative K63 ubiquitination.
    "FBXL18 (Q96ME1) is best annotated as an **SCF-family E3 ubiquitin ligase substrate receptor** that regulates cellular phenotypes by deploying **two mechanistic modes of ubiquitination**"
  • FBXL18 recognizes an N-terminal FQ motif in FBXL7 and uses Lys109 as the ubiquitin acceptor, degrading short-lived FBXL7 to restrain its pro-apoptotic activity.
    "Substrate recognition depends on an N-terminal **FQ docking motif** in FBXL7; mutation of that motif disrupts binding. **Lys109** in FBXL7 was identified as an essential ubiquitin acceptor for FBXL18-mediated ubiquitin conjugation."
  • SCF^FBXL18 mediates K48-linked degradation of the TFIIH subunit XPB/ERCC3 in a drug-triggered, CDK7- and XPB-Ser90-dependent manner, impairing NER.
    "Ueda et al. (Genes to Cells, 2019) established that spironolactone triggers proteasomal degradation of XPB (ERCC3) via **SCF^FBXL18**."
  • FBXL18 promotes non-degradative K63-linked ubiquitination of AKT, enhancing AKT-FOXO3a phosphorylation and suppressing apoptosis via Bim in glioma.
    "FBXL18 physically interacts with AKT and promotes **K63-linked ubiquitination** of AKT (with minimal effect on K48-linked ubiquitination), including reduced EGF-induced K63 ubiquitination upon FBXL18 knockdown."
  • FBXL18 promotes K63-linked ubiquitination of PTEN (non-proteolytic), inhibiting PTEN and activating PI3K/AKT signaling in NSCLC.
    "FBXL18 binds PTEN (mapping interaction to PTEN's **C-terminal region/C-tail and PDZ-binding domain**) and promotes **K63-linked ubiquitination** of PTEN in HEK293T and NSCLC models."
Reactome:R-HSA-8854051
SCF-FBXL18 ubiquitinates FBXL7
Reactome:R-HSA-8952618
AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex
Reactome:R-HSA-8952620
NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex
Reactome:R-HSA-8955241
CAND1 binds cytosolic CRL E3 ubiquitin ligases
Reactome:R-HSA-8955289
COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes
Reactome:R-HSA-8956040
COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes
Reactome:R-HSA-8956200
MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex
Reactome:R-HSA-983140
Transfer of Ub from E2 to substrate and release of E2
Reactome:R-HSA-983147
Release of E3 from polyubiquitinated substrate
Reactome:R-HSA-983156
Polyubiquitination of substrate
Reactome:R-HSA-983157
Interaction of E3 with substrate and E2-Ub complex

Suggested Questions for Experts

Q: What determines whether FBXL18 attaches degradative K48 chains (FBXL7, XPB) versus non-degradative K63 chains (AKT, PTEN) to a given substrate, and is this substrate-intrinsic or context-dependent?

Q: Beyond FBXL7, XPB, AKT and PTEN, what is the broader FBXL18 substrate repertoire, and how is FBXL18-FBXL7 cross-regulation balanced given both are SCF F-box receptors?

Q: How is FBXL18 activity and substrate selection regulated across tissues (notably brain), and do its multiple isoforms have distinct substrate specificities?

Suggested Experiments

Experiment: Reconstitute SCF-FBXL18 in vitro with FBXL7 and XPB to confirm direct K48-linked ubiquitination (FBXL7 Lys109, FQ-motif dependence) and contrast with K63-linked ubiquitination of AKT/PTEN, comparing wild-type FBXL18 to an F-box-deletion mutant.

Experiment: Identify endogenous FBXL18 substrates by AP-MS and by quantitative proteomics of FBXL18 knockout versus wild-type cells, classifying each by ubiquitin-chain linkage type, and test the apoptosis and PI3K/AKT-signaling phenotypes upon co-modulation of FBXL18 with FBXL7, AKT or PTEN.

Deep Research

Falcon

(FBXL18-deep-research-falcon.md)
Research report: Human **FBXL18** (UniProt: **Q96ME1**) functional annotation Falcon Edison Scientific Literature 14 citations 2 artifacts 2026-06-13T06:16:50.622762
Edison artifact artifact-00 (text/markdown)
## Context ID: pqac-00000019 Figure 5 demonstrates that FBXL18 promotes the K63-linked ubiquitination of Akt through various assays. Specifically, panel C shows (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: Human FBXL18 (UniProt: Q96ME1) functional annotation

0) Target verification (identity and scope)

The evidence summarized here pertains to the human gene FBXL18 encoding F-box/LRR-repeat protein 18 (UniProt Q96ME1), an F-box protein with leucine-rich repeats consistent with a substrate-recognition subunit of an SCF (Skp1–Cullin1–Rbx1–F-box) cullin-RING E3 ubiquitin ligase complex. Mechanistic studies explicitly describe SCF^FBXL18 complexes and test FBXL18 function by overexpression/knockdown in human cell lines and human tumor tissues, matching the requested target context. (liu2015fboxproteinfbxl18 pages 5-6, ueda2019spironolactone‐inducedxpbdegradation pages 2-3)

1) Key concepts and definitions (current understanding)

1.1 F-box/LRR proteins and SCF E3 ligases

F-box proteins are substrate receptors within SCF E3 ubiquitin ligases; the F-box domain binds Skp1, and additional domains (e.g., LRR) typically mediate substrate binding and specificity. FBXL18 is an FBXL-family F-box protein (F-box + LRR), and review syntheses classify FBXL proteins as key determinants of substrate selection in SCF complexes. (tekcham2020fboxproteinsand pages 4-6)

1.2 Ubiquitin chain topology as a functional “code”

FBXL18 has been reported to catalyze both:
- K48-linked polyubiquitination, which commonly targets proteins for proteasomal degradation (e.g., XPB/ERCC3 under spironolactone treatment). (ueda2019spironolactone‐inducedxpbdegradation pages 2-3, ueda2019spironolactone‐inducedxpbdegradation pages 6-8)
- K63-linked ubiquitination, a frequently non-degradative signal that can modulate protein activity, interactions, or signaling (e.g., AKT, PTEN in cancer signaling contexts). (zhang2017thef‐boxprotein pages 8-11, liu2024fbxl18promotescell pages 4-7)

2) Molecular function of FBXL18 (what it “does”)

2.1 Core biochemical role

Across mechanistic studies, FBXL18 functions as an E3 ubiquitin ligase substrate receptor in an SCF^FBXL18 complex, recruiting substrates for ubiquitination via its substrate-binding features, and coupling substrate to the cullin-RING catalytic core (Cul1–Rbx1). (ueda2019spironolactone‐inducedxpbdegradation pages 2-3, ueda2019spironolactone‐inducedxpbdegradation pages 3-5)

2.2 Experimentally supported direct substrates/targets

A concise evidence-backed substrate/target map is provided below, distinguishing degradative vs signaling ubiquitination.

Substrate/target Modification Key mechanistic details Model system Biological outcome/pathway Reference
FBXL7 Polyubiquitylation leading to proteasomal degradation; ubiquitin acceptor Lys109 on FBXL7 FBXL18 recognizes an N-terminal FQ motif in FBXL7; mutation of the FQ motif disrupts binding, and Lys109 is required as an acceptor site for ubiquitin conjugation Human HeLa cells; co-IP, peptide pull-down, CHX chase, shRNA depletion Limits FBXL7-driven apoptosis and affects cell-cycle-associated survival signaling Liu et al., 2015, Cell Death & Disease, https://doi.org/10.1038/cddis.2014.585 (liu2015fboxproteinfbxl18 pages 5-6)
AKT K63-linked ubiquitination of AKT; signaling activation rather than degradation FBXL18 interacts strongly with AKT; knockdown reduces EGF-induced K63 ubiquitination and decreases AKT and FOXO3a phosphorylation; increases BCL2L11/Bim expression Human glioma cell lines U251 and T98; co-IP, ubiquitin mutant assays, Annexin V/PI, soft agar Promotes glioma growth/survival through the AKT–FOXO3a–Bim axis and suppresses apoptosis Zhang et al., 2017, FEBS Letters, https://doi.org/10.1002/1873-3468.12521 (zhang2017thef‐boxprotein pages 11-14, zhang2017thef‐boxprotein pages 8-11, zhang2017thef‐boxprotein pages 14-18)
PTEN K63-linked ubiquitination of PTEN; reported inhibition of PTEN activity without marked degradation FBXL18 binds PTEN, with mapping to the PTEN C-terminal region/C-tail and PDZ-binding domain; CHX assays indicate no major shortening of PTEN half-life, consistent with non-proteolytic ubiquitination HEK293T biochemical assays; human NSCLC cell lines A549, H1299, H460, SPCA-1; 47 paired NSCLC and adjacent tissues Activates PI3K/AKT signaling, increases p-AKT, promotes NSCLC proliferation; high FBXL18 associated with poorer LUAD prognosis Liu et al., 2024 preprint, https://doi.org/10.21203/rs.3.rs-4980695/v1 (liu2024fbxl18promotescell pages 7-10, liu2024fbxl18promotescell pages 4-7, liu2024fbxl18promotescell pages 1-4, liu2024fbxl18promotescell pages 10-17)
XPB / ERCC3 K48-linked polyubiquitination leading to proteasomal degradation FBXL18 acts in SCF^FBXL18 (Skp1–Cul1–FBXL18–Rbx1); spironolactone-induced degradation requires CDK7 activity and XPB Ser90; MLN4924 and Cul1 depletion suppress the effect; in vitro ubiquitination supports SCF^FBXL18 specificity Human cells including HEK293T; siRNA screen of F-box proteins; in vitro ubiquitination; NER/transcription assays under spironolactone treatment Loss of XPB impairs NER and transcriptional functions of TFIIH; sensitizes cells to cisplatin/oxaliplatin and other DNA-damaging stress Ueda et al., 2019, Genes to Cells, https://doi.org/10.1111/gtc.12674 (ueda2019spironolactone‐inducedxpbdegradation pages 2-3, ueda2019spironolactone‐inducedxpbdegradation pages 1-2, ueda2019spironolactone‐inducedxpbdegradation pages 8-9, ueda2019spironolactone‐inducedxpbdegradation pages 5-6, ueda2019spironolactone‐inducedxpbdegradation pages 6-8, ueda2019spironolactone‐inducedxpbdegradation pages 3-5)
FBXL18 localization note Cytoplasm and nucleus Review table annotation for FBXL18 subcellular localization; not itself a substrate experiment, but consistent with roles in cytoplasmic AKT/PTEN signaling and nuclear XPB regulation Review synthesis of FBXL proteins Supports interpretation that FBXL18 can function in both signaling and nuclear quality-control/transcription-related contexts Tekcham et al., 2020, Theranostics, https://doi.org/10.7150/thno.42735 (tekcham2020fboxproteinsand pages 11-12)

Table: This table summarizes the main experimentally supported substrates, ubiquitin linkages, mechanistic details, and biological consequences reported for human FBXL18. It is useful for functional annotation because it distinguishes degradative versus non-degradative ubiquitination and links each target to specific pathways and disease contexts.

2.2.1 FBXL7: degradative ubiquitination controlling apoptosis

A 2015 Cell Death & Disease study identified FBXL7 as a direct target of FBXL18-mediated ubiquitination and proteasomal degradation. FBXL7 is short-lived (half-life ~1 hour) and is polyubiquitinated in an FBXL18-dependent fashion. Substrate recognition depends on an N-terminal FQ docking motif in FBXL7; mutation of that motif disrupts binding. Lys109 in FBXL7 was identified as an essential ubiquitin acceptor for FBXL18-mediated ubiquitin conjugation. Functionally, FBXL18 depletion increases apoptosis in a manner largely rescued by codepletion of FBXL7, consistent with FBXL18 restraining FBXL7 pro-apoptotic activity by degrading it. (liu2015fboxproteinfbxl18 pages 5-6)

2.2.2 AKT: K63-linked ubiquitination that promotes signaling and survival

In glioma cell models, FBXL18 physically interacts with AKT and promotes K63-linked ubiquitination of AKT (with minimal effect on K48-linked ubiquitination), including reduced EGF-induced K63 ubiquitination upon FBXL18 knockdown. Downstream, FBXL18 knockdown decreased AKT and FOXO3a phosphorylation and increased BCL2L11 (Bim) expression, linking FBXL18 to suppression of apoptosis via the AKT–FOXO3a–Bim axis. (zhang2017thef‐boxprotein pages 8-11, zhang2017thef‐boxprotein pages 14-18)

A key supporting ubiquitination panel is shown in the cropped figure region retrieved from the paper. (zhang2017thef‐boxprotein media 3f4bc9e0)

2.2.3 PTEN: K63-linked ubiquitination that correlates with PI3K/AKT activation (2024)

A 2024 preprint reported that FBXL18 binds PTEN (mapping interaction to PTEN’s C-terminal region/C-tail and PDZ-binding domain) and promotes K63-linked ubiquitination of PTEN in HEK293T and NSCLC models. Importantly, cycloheximide chase experiments were presented as consistent with non-proteolytic ubiquitination (i.e., PTEN stability not strongly reduced), while pathway readouts supported enhanced AKT phosphorylation (S473) and activation of PI3K/AKT signaling. (liu2024fbxl18promotescell pages 4-7)

2.2.4 XPB/ERCC3: CDK7-Ser90 phosphodegron and K48-linked degradation (drug-triggered)

Ueda et al. (Genes to Cells, 2019) established that spironolactone triggers proteasomal degradation of XPB (ERCC3) via SCF^FBXL18. A focused siRNA library screen identified FBXL18 as required for spironolactone-induced XPB degradation; Cul1 depletion and inhibition of cullin neddylation (MLN4924) suppressed XPB ubiquitination/degradation, supporting a cullin-RING ligase mechanism. (ueda2019spironolactone‐inducedxpbdegradation pages 3-5)

Mechanistically, CDK7 kinase activity is required and XPB Ser90 is essential: XPB(S90A) is resistant to spironolactone-induced degradation whereas XPB(S515A) is degraded like wild type. Ubiquitin linkage analysis supported K48-linked polyubiquitination of XPB under spironolactone exposure. SCF^FBXL18 was biochemically reconstituted/purified (Cul1, Skp1, Rbx1, FBXL18) and shown to ubiquitinate XPB in vitro, supporting direct E3/substrate compatibility. (ueda2019spironolactone‐inducedxpbdegradation pages 2-3, ueda2019spironolactone‐inducedxpbdegradation pages 5-6, ueda2019spironolactone‐inducedxpbdegradation pages 6-8)

3) Subcellular localization and where FBXL18 acts

Direct localization experiments were not captured in the retrieved primary evidence excerpts; however, a cancer-focused review table annotates FBXL18 localization as cytoplasm and nucleus, consistent with:
- Cytoplasmic signaling substrates (AKT/PTEN)
- Nuclear targets/processes (XPB within TFIIH; transcription/NER) (tekcham2020fboxproteinsand pages 11-12)

4) Pathways and biological processes implicating FBXL18

4.1 PI3K/AKT signaling and apoptosis control

Multiple studies converge on FBXL18 as a positive regulator of AKT pathway activity through K63 ubiquitination of signaling proteins:
- In glioma models: FBXL18 promotes K63 ubiquitination of AKT and enhances AKT/FOXO3a phosphorylation, suppressing apoptosis via Bim repression. (zhang2017thef‐boxprotein pages 8-11, zhang2017thef‐boxprotein pages 14-18)
- In NSCLC models (2024 preprint): FBXL18 promotes K63 ubiquitination of PTEN and is reported to inhibit PTEN function, correlating with increased pAKT and PI3K/AKT pathway activation. (liu2024fbxl18promotescell pages 4-7, liu2024fbxl18promotescell pages 10-17)

4.2 Nucleotide excision repair (NER) and transcription initiation (TFIIH/XPB)

SCF^FBXL18 can mediate degradation of XPB (ERCC3), a TFIIH subunit essential for transcription initiation and NER. Spironolactone-induced XPB degradation was linked to attenuated repair of UV-induced 6-4 photoproducts (6-4PP) and broader impairment of NER/transcription-associated processes. (ueda2019spironolactone‐inducedxpbdegradation pages 1-2, ueda2019spironolactone‐inducedxpbdegradation pages 3-5)

5) Recent developments (prioritizing 2023–2024)

5.1 2024: PTEN K63 ubiquitination in NSCLC (preprint)

The 2024 report positions FBXL18 as an oncogenic driver in NSCLC by connecting FBXL18 upregulation to PTEN K63 ubiquitination and downstream PI3K/AKT activation, and provides both mechanistic assays and clinical association analyses (including paired tumor/adjacent tissues). This expands the substrate repertoire beyond AKT itself to upstream pathway suppressors (PTEN). (liu2024fbxl18promotescell pages 7-10, liu2024fbxl18promotescell pages 4-7, liu2024fbxl18promotescell pages 10-17)

5.2 2024: Ovarian cancer FBXL18/AKT axis

A 2024 translational study reports that FBXL18 supports ovarian cancer cell proliferation and migration and that it interacts with AKT and promotes K63-linked AKT ubiquitination to activate AKT signaling (with pharmacologic AKT inhibition reversing FBXL18-driven phenotypes). (zhuang2024fbxl18isrequired pages 12-13)

5.3 Evidence gap note (2023–2024 vs available full text)

A 2023 HCC mechanism paper (FBXL18–RPS15A–SMAD3) was identified at the abstract level in the retrieved corpus, but full-text evidence was not available in the captured text excerpts for extraction here; therefore, mechanistic and statistical details from that work cannot be reliably summarized in this report. (OpenTargets Search: -FBXL18)

6) Current applications and real-world implementations

6.1 Drug repurposing / combination therapy rationale: spironolactone → XPB degradation

A concrete translational application of FBXL18 biology is the observation that the approved drug spironolactone can trigger XPB degradation through a pathway requiring CDK7 activity and SCF^FBXL18, thereby inhibiting NER and potentiating cytotoxicity of platinum agents (cisplatin/oxaliplatin) in cancer cell contexts. This provides an actionable mechanistic basis for chemosensitization strategies that reduce DNA repair capacity. (ueda2019spironolactone‐inducedxpbdegradation pages 2-3, ueda2019spironolactone‐inducedxpbdegradation pages 8-9)

6.2 Biomarker/target rationale in oncology

Recent cancer studies report that FBXL18 is upregulated in tumors and that higher expression is associated with worse prognosis in certain datasets/cohorts, supporting evaluation as a biomarker candidate (e.g., in NSCLC analyses in 2024). (liu2024fbxl18promotescell pages 10-17)

7) Expert opinions and synthesis from authoritative sources

Reviews of F-box proteins emphasize that SCF substrate receptors are the specificity-determining modules of ubiquitin ligases and that dysregulated SCF components can be oncogenic or tumor suppressive depending on substrate network context. Within these syntheses, FBXL18 is cataloged as a cancer-relevant FBXL protein with cytoplasm/nucleus localization and with reported substrates including AKT and XPB. (tekcham2020fboxproteinsand pages 11-12, tekcham2020fboxproteinsand pages 4-6)

8) Relevant statistics and data points (from available evidence)

  • FBXL7 half-life ~1 hour (cycloheximide chase), supporting rapid proteasomal turnover regulated by FBXL18. (liu2015fboxproteinfbxl18 pages 5-6)
  • NSCLC cohort size: 47 paired NSCLC tumors and adjacent tissues were used to validate FBXL18 upregulation (2024 preprint). (liu2024fbxl18promotescell pages 7-10, liu2024fbxl18promotescell pages 10-17)
  • XPB phosphodegron requirement: XPB Ser90Ala mutation confers resistance to spironolactone-induced degradation (qualitative but mechanistically decisive). (ueda2019spironolactone‐inducedxpbdegradation pages 6-8)
  • Statistical reporting: glioma and NSCLC studies commonly report mean ± SD from replicated experiments and use p-value thresholds (e.g., P<0.05, *P<0.01), though effect sizes are not fully extractable from the limited excerpts. (zhang2017thef‐boxprotein pages 14-18, liu2024fbxl18promotescell pages 10-17)

9) Summary and functional annotation conclusion

FBXL18 (Q96ME1) is best annotated as an SCF-family E3 ubiquitin ligase substrate receptor that regulates cellular phenotypes by deploying two mechanistic modes of ubiquitination:
1) Degradative K48 polyubiquitination (e.g., XPB/ERCC3 under spironolactone; and FBXL7 via polyubiquitylation and proteasomal degradation), shaping DNA repair/transcription capacity and apoptotic thresholds. (ueda2019spironolactone‐inducedxpbdegradation pages 2-3, liu2015fboxproteinfbxl18 pages 5-6)
2) Non-degradative K63 ubiquitination of signaling proteins (AKT, PTEN), promoting PI3K/AKT signaling and pro-survival/proliferative outputs in multiple cancer contexts. (zhang2017thef‐boxprotein pages 8-11, liu2024fbxl18promotescell pages 4-7)

Key references (with URLs and publication dates)

  • Liu Y et al. 2015-02. “F-box protein Fbxl18 mediates polyubiquitylation and proteasomal degradation of the pro-apoptotic SCF subunit Fbxl7.” Cell Death & Disease. https://doi.org/10.1038/cddis.2014.585 (liu2015fboxproteinfbxl18 pages 5-6)
  • Zhang J et al. 2017-01. “The F-box protein FBXL18 promotes glioma progression by promoting K63-linked ubiquitination of Akt.” FEBS Letters. https://doi.org/10.1002/1873-3468.12521 (zhang2017thef‐boxprotein pages 8-11, zhang2017thef‐boxprotein media 3f4bc9e0)
  • Ueda M et al. 2019-04. “Spironolactone-induced XPB degradation depends on CDK7 kinase and SCF^FBXL18 E3 ligase.” Genes to Cells. https://doi.org/10.1111/gtc.12674 (ueda2019spironolactone‐inducedxpbdegradation pages 2-3)
  • Tekcham DS et al. 2020-03. “F-box proteins and cancer: an update…” Theranostics. https://doi.org/10.7150/thno.42735 (tekcham2020fboxproteinsand pages 11-12, tekcham2020fboxproteinsand pages 4-6)
  • Liu Y et al. 2024-10 (preprint). “FBXL18 promotes cell proliferation by inducing K63-linked ubiquitination of PTEN in NSCLC cells.” https://doi.org/10.21203/rs.3.rs-4980695/v1 (liu2024fbxl18promotescell pages 4-7, liu2024fbxl18promotescell pages 10-17)
  • Zhuang Y et al. 2024-01. “FBXL18 is required for ovarian cancer cell proliferation and migration through activating AKT signaling.” American Journal of Translational Research. https://doi.org/10.62347/hhxx8166 (zhuang2024fbxl18isrequired pages 12-13)

Appendix: disease-target association databases (contextual, not mechanistic)

Open Targets lists several FBXL18 disease associations (e.g., neurodegenerative disease, hypothyroidism) based on aggregated evidence; these associations may be hypothesis-generating but do not replace direct mechanistic validation. (OpenTargets Search: -FBXL18)

References

  1. (liu2015fboxproteinfbxl18 pages 5-6): Y. Liu, T. Lear, Y. Zhao, J. Zhao, C. Zou, B. Chen, and R. Mallampalli. F-box protein fbxl18 mediates polyubiquitylation and proteasomal degradation of the pro-apoptotic scf subunit fbxl7. Cell Death & Disease, 6:e1630-e1630, Feb 2015. URL: https://doi.org/10.1038/cddis.2014.585, doi:10.1038/cddis.2014.585. This article has 79 citations and is from a peer-reviewed journal.

  2. (ueda2019spironolactone‐inducedxpbdegradation pages 2-3): Masanobu Ueda, Kenkyo Matsuura, Hidehiko Kawai, Mitsuo Wakasugi, and Tsukasa Matsunaga. Spironolactone‐induced xpb degradation depends on cdk7 kinase and scffbxl18 e3 ligase. Genes to Cells, 24:284-296, Apr 2019. URL: https://doi.org/10.1111/gtc.12674, doi:10.1111/gtc.12674. This article has 30 citations and is from a peer-reviewed journal.

  3. (tekcham2020fboxproteinsand pages 4-6): Dinesh Singh Tekcham, Di Chen, Yu Liu, Ting Ling, Yi Zhang, Huan Chen, Wen Wang, Wuxiyar Otkur, Huan Qi, Tian Xia, Xiaolong Liu, Hai-long Piao, and Hongxu Liu. F-box proteins and cancer: an update from functional and regulatory mechanism to therapeutic clinical prospects. Theranostics, 10:4150-4167, Mar 2020. URL: https://doi.org/10.7150/thno.42735, doi:10.7150/thno.42735. This article has 111 citations and is from a domain leading peer-reviewed journal.

  4. (ueda2019spironolactone‐inducedxpbdegradation pages 6-8): Masanobu Ueda, Kenkyo Matsuura, Hidehiko Kawai, Mitsuo Wakasugi, and Tsukasa Matsunaga. Spironolactone‐induced xpb degradation depends on cdk7 kinase and scffbxl18 e3 ligase. Genes to Cells, 24:284-296, Apr 2019. URL: https://doi.org/10.1111/gtc.12674, doi:10.1111/gtc.12674. This article has 30 citations and is from a peer-reviewed journal.

  5. (zhang2017thef‐boxprotein pages 8-11): Jindong Zhang, Zhifen Yang, Jiayu Ou, Xiaojun Xia, Feng Zhi, and Jun Cui. The f‐box protein fbxl18 promotes glioma progression by promoting k63‐linked ubiquitination of akt. FEBS Letters, 591:145-154, Jan 2017. URL: https://doi.org/10.1002/1873-3468.12521, doi:10.1002/1873-3468.12521. This article has 37 citations and is from a peer-reviewed journal.

  6. (liu2024fbxl18promotescell pages 4-7): Yu Liu, Xiaolong Liu, Hai-long Piao, and Hong-Xu Liu. Fbxl18 promotes cell proliferation by inducing k63-linked ubiquitination of pten in nsclc cells. Unknown journal, Oct 2024. URL: https://doi.org/10.21203/rs.3.rs-4980695/v1, doi:10.21203/rs.3.rs-4980695/v1.

  7. (ueda2019spironolactone‐inducedxpbdegradation pages 3-5): Masanobu Ueda, Kenkyo Matsuura, Hidehiko Kawai, Mitsuo Wakasugi, and Tsukasa Matsunaga. Spironolactone‐induced xpb degradation depends on cdk7 kinase and scffbxl18 e3 ligase. Genes to Cells, 24:284-296, Apr 2019. URL: https://doi.org/10.1111/gtc.12674, doi:10.1111/gtc.12674. This article has 30 citations and is from a peer-reviewed journal.

  8. (zhang2017thef‐boxprotein pages 11-14): Jindong Zhang, Zhifen Yang, Jiayu Ou, Xiaojun Xia, Feng Zhi, and Jun Cui. The f‐box protein fbxl18 promotes glioma progression by promoting k63‐linked ubiquitination of akt. FEBS Letters, 591:145-154, Jan 2017. URL: https://doi.org/10.1002/1873-3468.12521, doi:10.1002/1873-3468.12521. This article has 37 citations and is from a peer-reviewed journal.

  9. (zhang2017thef‐boxprotein pages 14-18): Jindong Zhang, Zhifen Yang, Jiayu Ou, Xiaojun Xia, Feng Zhi, and Jun Cui. The f‐box protein fbxl18 promotes glioma progression by promoting k63‐linked ubiquitination of akt. FEBS Letters, 591:145-154, Jan 2017. URL: https://doi.org/10.1002/1873-3468.12521, doi:10.1002/1873-3468.12521. This article has 37 citations and is from a peer-reviewed journal.

  10. (liu2024fbxl18promotescell pages 7-10): Yu Liu, Xiaolong Liu, Hai-long Piao, and Hong-Xu Liu. Fbxl18 promotes cell proliferation by inducing k63-linked ubiquitination of pten in nsclc cells. Unknown journal, Oct 2024. URL: https://doi.org/10.21203/rs.3.rs-4980695/v1, doi:10.21203/rs.3.rs-4980695/v1.

  11. (liu2024fbxl18promotescell pages 1-4): Yu Liu, Xiaolong Liu, Hai-long Piao, and Hong-Xu Liu. Fbxl18 promotes cell proliferation by inducing k63-linked ubiquitination of pten in nsclc cells. Unknown journal, Oct 2024. URL: https://doi.org/10.21203/rs.3.rs-4980695/v1, doi:10.21203/rs.3.rs-4980695/v1.

  12. (liu2024fbxl18promotescell pages 10-17): Yu Liu, Xiaolong Liu, Hai-long Piao, and Hong-Xu Liu. Fbxl18 promotes cell proliferation by inducing k63-linked ubiquitination of pten in nsclc cells. Unknown journal, Oct 2024. URL: https://doi.org/10.21203/rs.3.rs-4980695/v1, doi:10.21203/rs.3.rs-4980695/v1.

  13. (ueda2019spironolactone‐inducedxpbdegradation pages 1-2): Masanobu Ueda, Kenkyo Matsuura, Hidehiko Kawai, Mitsuo Wakasugi, and Tsukasa Matsunaga. Spironolactone‐induced xpb degradation depends on cdk7 kinase and scffbxl18 e3 ligase. Genes to Cells, 24:284-296, Apr 2019. URL: https://doi.org/10.1111/gtc.12674, doi:10.1111/gtc.12674. This article has 30 citations and is from a peer-reviewed journal.

  14. (ueda2019spironolactone‐inducedxpbdegradation pages 8-9): Masanobu Ueda, Kenkyo Matsuura, Hidehiko Kawai, Mitsuo Wakasugi, and Tsukasa Matsunaga. Spironolactone‐induced xpb degradation depends on cdk7 kinase and scffbxl18 e3 ligase. Genes to Cells, 24:284-296, Apr 2019. URL: https://doi.org/10.1111/gtc.12674, doi:10.1111/gtc.12674. This article has 30 citations and is from a peer-reviewed journal.

  15. (ueda2019spironolactone‐inducedxpbdegradation pages 5-6): Masanobu Ueda, Kenkyo Matsuura, Hidehiko Kawai, Mitsuo Wakasugi, and Tsukasa Matsunaga. Spironolactone‐induced xpb degradation depends on cdk7 kinase and scffbxl18 e3 ligase. Genes to Cells, 24:284-296, Apr 2019. URL: https://doi.org/10.1111/gtc.12674, doi:10.1111/gtc.12674. This article has 30 citations and is from a peer-reviewed journal.

  16. (tekcham2020fboxproteinsand pages 11-12): Dinesh Singh Tekcham, Di Chen, Yu Liu, Ting Ling, Yi Zhang, Huan Chen, Wen Wang, Wuxiyar Otkur, Huan Qi, Tian Xia, Xiaolong Liu, Hai-long Piao, and Hongxu Liu. F-box proteins and cancer: an update from functional and regulatory mechanism to therapeutic clinical prospects. Theranostics, 10:4150-4167, Mar 2020. URL: https://doi.org/10.7150/thno.42735, doi:10.7150/thno.42735. This article has 111 citations and is from a domain leading peer-reviewed journal.

  17. (zhang2017thef‐boxprotein media 3f4bc9e0): Jindong Zhang, Zhifen Yang, Jiayu Ou, Xiaojun Xia, Feng Zhi, and Jun Cui. The f‐box protein fbxl18 promotes glioma progression by promoting k63‐linked ubiquitination of akt. FEBS Letters, 591:145-154, Jan 2017. URL: https://doi.org/10.1002/1873-3468.12521, doi:10.1002/1873-3468.12521. This article has 37 citations and is from a peer-reviewed journal.

  18. (zhuang2024fbxl18isrequired pages 12-13): Yanyan Zhuang, Jiajia Xue, Xiya Qiu, Yue Zhu, Jinxing Lv, and Fei Xia. Fbxl18 is required for ovarian cancer cell proliferation and migration through activating akt signaling. American journal of translational research, 16 5:1977-1990, Jan 2024. URL: https://doi.org/10.62347/hhxx8166, doi:10.62347/hhxx8166. This article has 2 citations and is from a peer-reviewed journal.

  19. (OpenTargets Search: -FBXL18): Open Targets Query (-FBXL18, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

Artifacts

Citations

  1. tekcham2020fboxproteinsand pages 4-6
  2. tekcham2020fboxproteinsand pages 11-12
  3. https://doi.org/10.1038/cddis.2014.585
  4. https://doi.org/10.1002/1873-3468.12521
  5. https://doi.org/10.21203/rs.3.rs-4980695/v1
  6. https://doi.org/10.1111/gtc.12674
  7. https://doi.org/10.7150/thno.42735
  8. https://doi.org/10.62347/hhxx8166
  9. https://doi.org/10.1038/cddis.2014.585,
  10. https://doi.org/10.1111/gtc.12674,
  11. https://doi.org/10.7150/thno.42735,
  12. https://doi.org/10.1002/1873-3468.12521,
  13. https://doi.org/10.21203/rs.3.rs-4980695/v1,
  14. https://doi.org/10.62347/hhxx8166,

📚 Additional Documentation

Pn Notes

(FBXL18-pn-notes.md)

FBXL18 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q96ME1
  • 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: FBXL18 (F-box/LRR-repeat protein 18, FBL18) is a member of the FBXL subfamily of F-box proteins, with an N-terminal F-box domain followed by an extensive C-terminal leucine-rich repeat (LRR) array. It serves as the substrate-recognition subunit of a Cullin-RING (SCF; SKP1-CUL1-F-box) E3 ubiquitin ligase, docking onto SKP1/CUL1 via its F-box domain and recruiting substrates through its LRRs. FBXL18 deploys two distinct ubiquitination modes. In a degradative (K48-linked) mode it targets another F-box protein, FBXL7, for polyubiquitination and proteasomal degradation, recognizing an N-terminal FQ motif in FBXL7 and conjugating ubiquitin onto FBXL7 Lys109; because FBXL7 is pro-apoptotic, this turnover limits apoptosis. SCF^FBXL18 (reconstituted with SKP1-CUL1-RBX1) also mediates K48-linked degradation of the TFIIH subunit XPB/ERCC3 in a drug-triggered, CDK7- and XPB-Ser90-dependent manner (spironolactone-induced), thereby impairing nucleotide-excision repair and transcription and sensitizing cells to platinum agents. In a second, non-degradative (K63-linked) mode FBXL18 ubiquitinates signaling proteins to modulate their activity rather than degrade them: it promotes K63-linked ubiquitination of AKT (driving AKT-FOXO3a-Bim survival signaling in glioma and ovarian cancer) and of PTEN (inhibiting PTEN and activating PI3K/AKT in non-small-cell lung cancer), and is frequently upregulated and pro-oncogenic in these tumors. Consistent with these roles, FBXL18 has been annotated in both the cytoplasm (AKT/PTEN signaling) and the nucleus (XPB/TFIIH). It is broadly expressed with enhancement in brain.
  • Existing/core annotation action counts: ACCEPT: 2; KEEP_AS_NON_CORE: 12

PN Consistency Summary

  • Consistency: Strong. Falcon, review YAML, and PN mapping agree FBXL18 is the SCF(FBXL18) substrate receptor. Cache-verified core: K48-degradation of fellow F-box protein FBXL7 (FQ motif, Lys109; limits apoptosis — PMID:25654763, full text). Falcon adds K48 degradation of XPB/ERCC3 (reconstituted SCF^FBXL18) and a non-degradative K63 mode on AKT and PTEN (activating PI3K/AKT) — flagged UNVERIFIED (DOI-only leads, PTEN is a 2024 preprint). Dual-mode framing is internally consistent.
  • PN story / NEW pressure: PN asserts generic adaptor MF (GO:1990756, verified real); GOA carries NO MF term at all (only BP/CC). Review uses GO:1990756 in core_functions (no MF to MODIFY). Correct. The K63 non-degradative mode is genuine NEW pressure not captured by GO:0031146/catabolic terms; the review handles it via a second core_function (MF still GO:1990756; BP GO:0051897 positive regulation of PI3K/AKT, verified real) rather than proposing an unverified MF — conservative and acceptable. No defensible additional real NEW GO term identified.
  • Evidence alignment: PN reference only "15340381/rev" (placeholder); review does not cite it. Review uses PMID:25654763 (verified) + 33234069 (family) + falcon. Benign divergence; K63-mode primary papers not PubMed-verified in cache.
  • Verdict: CONSISTENT / ACCEPT mapping. No edits required; adaptor-MF pattern correctly applied; degradative substrate (FBXL7) validated; K63 non-degradative mode noted but appropriately not over-asserted.

Full Consistency Review

  • UniProt: Q96ME1 · batch: proteostasis-batch-2026-06-13 · review status: COMPLETE
  • PN placement: UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|LRR ; PN-node mapping: group-level mapped / ok_for_propagation_to_go / GO:1990756; F-box+LRR subtype/type no_mapping; class context_only / too_broad / GO:0061630; branch no_mapping. NB only IPR032675 auxiliary domain listed (no IPR001611), but IPR001810 F-box signature present.
  • Consistency: Strong. Falcon, review YAML, and PN mapping agree FBXL18 is the SCF(FBXL18) substrate receptor. Cache-verified core: K48-degradation of fellow F-box protein FBXL7 (FQ motif, Lys109; limits apoptosis — PMID:25654763, full text). Falcon adds K48 degradation of XPB/ERCC3 (reconstituted SCF^FBXL18) and a non-degradative K63 mode on AKT and PTEN (activating PI3K/AKT) — flagged UNVERIFIED (DOI-only leads, PTEN is a 2024 preprint). Dual-mode framing is internally consistent.
  • PN story / NEW pressure: PN asserts generic adaptor MF (GO:1990756, verified real); GOA carries NO MF term at all (only BP/CC). Review uses GO:1990756 in core_functions (no MF to MODIFY). Correct. The K63 non-degradative mode is genuine NEW pressure not captured by GO:0031146/catabolic terms; the review handles it via a second core_function (MF still GO:1990756; BP GO:0051897 positive regulation of PI3K/AKT, verified real) rather than proposing an unverified MF — conservative and acceptable. No defensible additional real NEW GO term identified.
  • Mapping strategy: Gene does not change the node. FBXL7 (and XPB) are validated K48 substrates → degradative adaptor MF grounded, not orphan. The K63 mode rests on unverified leads; group GO:1990756 still applies (substrate adaptor regardless of chain type). Catalysis correctly excluded from sub-nodes (RBX1 RING). Canonical SCF (reconstituted with CUL1/SKP1/RBX1) — no non-canonical flag.
  • Evidence alignment: PN reference only "15340381/rev" (placeholder); review does not cite it. Review uses PMID:25654763 (verified) + 33234069 (family) + falcon. Benign divergence; K63-mode primary papers not PubMed-verified in cache.
  • Verdict: CONSISTENT / ACCEPT mapping. No edits required; adaptor-MF pattern correctly applied; degradative substrate (FBXL7) validated; K63 non-degradative mode noted but appropriately not over-asserted.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-13
  • review_yaml: genes/human/FBXL18/FBXL18-ai-review.yaml
  • PN workbook rows: 1

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

  • UniProt: Q96ME1
  • In branches: UPS
  • Signature domains: IPR001810
  • Auxiliary domains: IPR032675
  • 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|LRR
      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: Q96ME1
gene_symbol: FBXL18
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FBXL18 (F-box/LRR-repeat protein 18, FBL18) is a member of the FBXL subfamily
  of F-box proteins, with an N-terminal F-box domain followed by an extensive
  C-terminal leucine-rich repeat (LRR) array. It serves as the
  substrate-recognition subunit of a Cullin-RING (SCF; SKP1-CUL1-F-box) E3
  ubiquitin ligase, docking onto SKP1/CUL1 via its F-box domain and recruiting
  substrates through its LRRs. FBXL18 deploys two distinct ubiquitination modes.
  In a degradative (K48-linked) mode it targets another F-box protein, FBXL7, for
  polyubiquitination and proteasomal degradation, recognizing an N-terminal FQ
  motif in FBXL7 and conjugating ubiquitin onto FBXL7 Lys109; because FBXL7 is
  pro-apoptotic, this turnover limits apoptosis. SCF^FBXL18 (reconstituted with
  SKP1-CUL1-RBX1) also mediates K48-linked degradation of the TFIIH subunit
  XPB/ERCC3 in a drug-triggered, CDK7- and XPB-Ser90-dependent manner
  (spironolactone-induced), thereby impairing nucleotide-excision repair and
  transcription and sensitizing cells to platinum agents. In a second,
  non-degradative (K63-linked) mode FBXL18 ubiquitinates signaling proteins to
  modulate their activity rather than degrade them: it promotes K63-linked
  ubiquitination of AKT (driving AKT-FOXO3a-Bim survival signaling in glioma and
  ovarian cancer) and of PTEN (inhibiting PTEN and activating PI3K/AKT in
  non-small-cell lung cancer), and is frequently upregulated and pro-oncogenic in
  these tumors. Consistent with these roles, FBXL18 has been annotated in both the
  cytoplasm (AKT/PTEN signaling) and the nucleus (XPB/TFIIH). It is broadly
  expressed with enhancement in brain.
alternative_products:
- name: '4'
  id: Q96ME1-4
- name: '1'
  id: Q96ME1-1
  sequence_note: VSP_061756
- name: '2'
  id: Q96ME1-2
  sequence_note: VSP_061758, VSP_061759
- name: '3'
  id: Q96ME1-3
  sequence_note: VSP_061754, VSP_061755
- name: '5'
  id: Q96ME1-5
  sequence_note: VSP_061757
existing_annotations:
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro/domain-based electronic assignment (FBXL18 F-box/LRR signature) that FBXL18 acts in SCF-dependent proteasomal degradation. This is the experimentally established core process (FBXL18 K48-polyubiquitinates and degrades FBXL7, and SCF^FBXL18 degrades the TFIIH subunit XPB/ERCC3).
    action: ACCEPT
    reason: Core biological process; directly supported by the experimental demonstration that FBXL18 polyubiquitinates and targets FBXL7 for proteasomal degradation, and by reconstituted SCF^FBXL18-mediated K48 degradation of XPB. Note FBXL18 also performs non-degradative K63 ubiquitination of AKT and PTEN, which this catabolic term does not capture.
    additional_reference_ids:
    - file:human/FBXL18/FBXL18-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:25654763
      supporting_text: an orphan F-box protein, Fbxl18, targets Fbxl7 for its polyubiquitylation and proteasomal degradation
    - reference_id: file:human/FBXL18/FBXL18-deep-research-falcon.md
      supporting_text: "SCF^FBXL18 was biochemically reconstituted/purified (Cul1, Skp1, Rbx1, FBXL18) and shown to ubiquitinate XPB in vitro, supporting direct E3/substrate compatibility."
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:33234069
  qualifier: involved_in
  review:
    summary: Family/ComplexPortal NAS assignment of the same core SCF-dependent degradation process, redundant with the experimentally supported IEA annotation.
    action: ACCEPT
    reason: Core biological process; supported experimentally (FBXL18 degrades FBXL7) and by family-level evidence.
    supported_by:
    - reference_id: PMID:25654763
      supporting_text: an orphan F-box protein, Fbxl18, targets Fbxl7 for its polyubiquitylation and proteasomal degradation
- term:
    id: GO:0042981
    label: regulation of apoptotic process
  evidence_type: NAS
  original_reference_id: PMID:25654763
  qualifier: involved_in
  review:
    summary: FBXL18 regulates apoptosis by mediating the ubiquitin-dependent proteasomal degradation of the pro-apoptotic protein FBXL7; FBXL18 depletion accentuates FBXL7-induced apoptosis, and FBXL18 overexpression limits it.
    action: KEEP_AS_NON_CORE
    reason: Genuine biological consequence of FBXL18 activity, supported by the FBXL7 study, but it is an indirect, downstream outcome of the core SCF-dependent degradation function rather than a separate molecular role.
    supported_by:
    - reference_id: PMID:25654763
      supporting_text: Fbxl18 regulates apoptosis by mediating ubiquitin-dependent proteasomal degradation of the pro-apoptotic protein Fbxl7
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8854051
  qualifier: located_in
  review:
    summary: Reactome cytosol annotation tied to the curated reaction "SCF-FBXL18 ubiquitinates FBXL7", which reflects FBXL18's actual ligase reaction. The cytosol is a plausible compartment for this SCF activity.
    action: KEEP_AS_NON_CORE
    reason: Plausible localization linked to the bona fide FBXL18-FBXL7 reaction, but derived from Reactome pathway curation rather than direct FBXL18 localization data.
    supported_by:
    - reference_id: PMID:25654763
      supporting_text: an orphan F-box protein, Fbxl18, targets Fbxl7 for its polyubiquitylation and proteasomal degradation
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952618
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol annotation from the generic CRL1/neddylation reaction set.
    action: KEEP_AS_NON_CORE
    reason: Plausible but redundant generic-pathway localization; not FBXL18-specific.
    supported_by:
    - reference_id: file:human/FBXL18/FBXL18-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952620
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol annotation from the generic CRL1 neddylation reaction set.
    action: KEEP_AS_NON_CORE
    reason: Plausible but redundant generic-pathway localization; not FBXL18-specific.
    supported_by:
    - reference_id: file:human/FBXL18/FBXL18-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955241
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol annotation from the generic CRL (CAND1) reaction set.
    action: KEEP_AS_NON_CORE
    reason: Plausible but redundant generic-pathway localization; not FBXL18-specific.
    supported_by:
    - reference_id: file:human/FBXL18/FBXL18-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955289
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol annotation from the generic CRL (COMMD/CAND1) reaction set.
    action: KEEP_AS_NON_CORE
    reason: Plausible but redundant generic-pathway localization; not FBXL18-specific.
    supported_by:
    - reference_id: file:human/FBXL18/FBXL18-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956040
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol annotation from the generic CRL deneddylation (COP9) reaction set.
    action: KEEP_AS_NON_CORE
    reason: Plausible but redundant generic-pathway localization; not FBXL18-specific.
    supported_by:
    - reference_id: file:human/FBXL18/FBXL18-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956200
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol annotation from the generic CRL1 (DCUN1D3) reaction set.
    action: KEEP_AS_NON_CORE
    reason: Plausible but redundant generic-pathway localization; not FBXL18-specific.
    supported_by:
    - reference_id: file:human/FBXL18/FBXL18-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983140
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol annotation from the generic ubiquitination reaction set (transfer of Ub from E2 to substrate).
    action: KEEP_AS_NON_CORE
    reason: Plausible but redundant generic-pathway localization; not FBXL18-specific.
    supported_by:
    - reference_id: file:human/FBXL18/FBXL18-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983147
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol annotation from the generic ubiquitination reaction set (release of E3 from substrate).
    action: KEEP_AS_NON_CORE
    reason: Plausible but redundant generic-pathway localization; not FBXL18-specific.
    supported_by:
    - reference_id: file:human/FBXL18/FBXL18-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983156
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol annotation from the generic ubiquitination reaction set (polyubiquitination of substrate).
    action: KEEP_AS_NON_CORE
    reason: Plausible but redundant generic-pathway localization; not FBXL18-specific.
    supported_by:
    - reference_id: file:human/FBXL18/FBXL18-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983157
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol annotation from the generic ubiquitination reaction set (interaction of E3 with substrate and E2-Ub).
    action: KEEP_AS_NON_CORE
    reason: Plausible but redundant generic-pathway localization; not FBXL18-specific.
    supported_by:
    - reference_id: file:human/FBXL18/FBXL18-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: PMID:25654763
  title: F-box protein Fbxl18 mediates polyubiquitylation and proteasomal degradation
    of the pro-apoptotic SCF subunit Fbxl7.
  findings:
  - statement: FBXL18 targets FBXL7 for polyubiquitylation and proteasomal degradation, conjugating ubiquitin onto FBXL7 Lys109 and recognizing an FQ motif in FBXL7; this limits FBXL7-induced apoptosis (FBXL18 depletion accentuates, overexpression attenuates, FBXL7-driven apoptosis).
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; establishes the core FBXL18 substrate (FBXL7), the ubiquitin acceptor site (Lys109), the recognition motif (FQ), and the apoptosis-regulatory consequence.
- id: PMID:33234069
  title: 'The FBXL family of F-box proteins: variations on a theme.'
  findings:
  - statement: FBXL-family F-box proteins serve as substrate-recognition subunits of SCF E3 ubiquitin ligases, using their LRR domains for substrate binding and the F-box for SKP1/CUL1 recruitment.
    reference_section_type: LITERATURE_REVIEW
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Family-level review (full text available) supporting the general FBXL SCF substrate-receptor model.
- id: file:human/FBXL18/FBXL18-deep-research-falcon.md
  title: Falcon deep research report for human FBXL18
  findings:
  - statement: FBXL18 is an SCF substrate receptor that deploys two modes - degradative K48 polyubiquitination and non-degradative K63 ubiquitination.
    supporting_text: "FBXL18 (Q96ME1) is best annotated as an **SCF-family E3 ubiquitin ligase substrate receptor** that regulates cellular phenotypes by deploying **two mechanistic modes of ubiquitination**"
  - statement: FBXL18 recognizes an N-terminal FQ motif in FBXL7 and uses Lys109 as the ubiquitin acceptor, degrading short-lived FBXL7 to restrain its pro-apoptotic activity.
    supporting_text: "Substrate recognition depends on an N-terminal **FQ docking motif** in FBXL7; mutation of that motif disrupts binding. **Lys109** in FBXL7 was identified as an essential ubiquitin acceptor for FBXL18-mediated ubiquitin conjugation."
  - statement: SCF^FBXL18 mediates K48-linked degradation of the TFIIH subunit XPB/ERCC3 in a drug-triggered, CDK7- and XPB-Ser90-dependent manner, impairing NER.
    supporting_text: "Ueda et al. (Genes to Cells, 2019) established that spironolactone triggers proteasomal degradation of XPB (ERCC3) via **SCF^FBXL18**."
  - statement: FBXL18 promotes non-degradative K63-linked ubiquitination of AKT, enhancing AKT-FOXO3a phosphorylation and suppressing apoptosis via Bim in glioma.
    supporting_text: "FBXL18 physically interacts with AKT and promotes **K63-linked ubiquitination** of AKT (with minimal effect on K48-linked ubiquitination), including reduced EGF-induced K63 ubiquitination upon FBXL18 knockdown."
  - statement: FBXL18 promotes K63-linked ubiquitination of PTEN (non-proteolytic), inhibiting PTEN and activating PI3K/AKT signaling in NSCLC.
    supporting_text: "FBXL18 binds PTEN (mapping interaction to PTEN's **C-terminal region/C-tail and PDZ-binding domain**) and promotes **K63-linked ubiquitination** of PTEN in HEK293T and NSCLC models."
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: Falcon (Edison Scientific) deep research synthesis. Substantially expands FBXL18 from the FBXL7/apoptosis story (PMID:25654763) to a dual-mode SCF receptor - K48 degradation of FBXL7 and XPB/ERCC3 (Ueda et al. 2019, reconstituted SCF^FBXL18) and non-degradative K63 ubiquitination of AKT (Zhang et al. 2017; Zhuang et al. 2024) and PTEN (Liu et al. 2024 preprint), with cytoplasmic/nuclear localization. Primary leads cite DOIs not PMIDs and are not all in the local cache (the PTEN paper is a 2024 preprint); treated as leads informing the description and core functions, not overriding the experimental FBXL7 curation.
- id: Reactome:R-HSA-8854051
  title: SCF-FBXL18 ubiquitinates FBXL7
  findings: []
- id: Reactome:R-HSA-8952618
  title: AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8952620
  title: NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8955241
  title: CAND1 binds cytosolic CRL E3 ubiquitin ligases
  findings: []
- id: Reactome:R-HSA-8955289
  title: COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes
  findings: []
- id: Reactome:R-HSA-8956040
  title: COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes
  findings: []
- id: Reactome:R-HSA-8956200
  title: MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-983140
  title: Transfer of Ub from E2 to substrate and release of E2
  findings: []
- id: Reactome:R-HSA-983147
  title: Release of E3 from polyubiquitinated substrate
  findings: []
- id: Reactome:R-HSA-983156
  title: Polyubiquitination of substrate
  findings: []
- id: Reactome:R-HSA-983157
  title: Interaction of E3 with substrate and E2-Ub complex
  findings: []
core_functions:
- description: Substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase that targets substrates for K48-linked polyubiquitination and proteasomal degradation. It recognizes an FQ motif in the F-box protein FBXL7 and conjugates ubiquitin onto FBXL7 Lys109, controlling FBXL7 abundance and limiting FBXL7-driven apoptosis; reconstituted SCF^FBXL18 also degrades the TFIIH subunit XPB/ERCC3 (drug-triggered, CDK7/Ser90-dependent), affecting nucleotide-excision repair and transcription.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:25654763
    supporting_text: an orphan F-box protein, Fbxl18, targets Fbxl7 for its polyubiquitylation and proteasomal degradation
  - reference_id: file:human/FBXL18/FBXL18-deep-research-falcon.md
    supporting_text: "SCF^FBXL18 was biochemically reconstituted/purified (Cul1, Skp1, Rbx1, FBXL18) and shown to ubiquitinate XPB in vitro, supporting direct E3/substrate compatibility."
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
- description: In a second, non-degradative mode FBXL18 acts as an E3-ligase substrate adaptor that promotes K63-linked (non-degradative) ubiquitination of signaling proteins to modulate their activity, notably AKT (driving AKT-FOXO3a-Bim pro-survival signaling) and PTEN (inhibiting PTEN), thereby activating PI3K/AKT signaling and promoting proliferation/survival in glioma, ovarian and lung cancers.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/FBXL18/FBXL18-deep-research-falcon.md
    supporting_text: "FBXL18 physically interacts with AKT and promotes **K63-linked ubiquitination** of AKT (with minimal effect on K48-linked ubiquitination), including reduced EGF-induced K63 ubiquitination upon FBXL18 knockdown."
  directly_involved_in:
  - id: GO:0051897
    label: positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
proposed_new_terms: []
suggested_questions:
- question: What determines whether FBXL18 attaches degradative K48 chains (FBXL7, XPB) versus non-degradative K63 chains (AKT, PTEN) to a given substrate, and is this substrate-intrinsic or context-dependent?
- question: Beyond FBXL7, XPB, AKT and PTEN, what is the broader FBXL18 substrate repertoire, and how is FBXL18-FBXL7 cross-regulation balanced given both are SCF F-box receptors?
- question: How is FBXL18 activity and substrate selection regulated across tissues (notably brain), and do its multiple isoforms have distinct substrate specificities?
suggested_experiments:
- description: Reconstitute SCF-FBXL18 in vitro with FBXL7 and XPB to confirm direct K48-linked ubiquitination (FBXL7 Lys109, FQ-motif dependence) and contrast with K63-linked ubiquitination of AKT/PTEN, comparing wild-type FBXL18 to an F-box-deletion mutant.
- description: Identify endogenous FBXL18 substrates by AP-MS and by quantitative proteomics of FBXL18 knockout versus wild-type cells, classifying each by ubiquitin-chain linkage type, and test the apoptosis and PI3K/AKT-signaling phenotypes upon co-modulation of FBXL18 with FBXL7, AKT or PTEN.