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.