id: Q8N1E6 gene_symbol: FBXL14 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- FBXL14 (F-box/LRR-repeat protein 14; FBL14) is a substrate-recognition subunit of an SCF (SKP1-CUL1-RBX1) E3 ubiquitin ligase complex. Its F-box motif binds SKP1, linking it to the CUL1-RBX1 catalytic core, while its leucine-rich repeat domain provides substrate selectivity, directing substrate-specific polyubiquitination and proteasomal degradation. The best-characterized substrate is the EMT master transcription factor SNAI1/SNAIL1: SCF(FBXL14) binds (through a SNAI1 region around aa 120-151) and polyubiquitinates SNAI1 on lysines including K98, K137 and K146, promoting its proteasomal degradation in a manner independent of GSK-3beta phosphorylation, thereby controlling SNAI1 abundance during epithelial-to-mesenchymal transition. FBXL14 expression is down-regulated by hypoxia in a TWIST1-dependent manner, which stabilizes SNAI1 and supports EMT. FBXL14 also targets additional transcriptional regulators for degradation: it recognizes the conserved C-terminal WRPW motif of the Notch effector HES1 to promote its ubiquitination and turnover (affecting Notch signaling dynamics and neuronal differentiation), and it has been reported to ubiquitinate Thr58-phosphorylated c-MYC, promoting differentiation and suppressing glioma stem-cell tumorigenicity. FBXL14 is mainly cytoplasmic and acts in the cytoplasm/cytosol. existing_annotations: - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Electronic transfer of cytoplasmic localization from the UniProt subcellular location; supported by IDA evidence. action: ACCEPT reason: Correct localization, directly supported (IDA) in the SNAI1 study. supported_by: - reference_id: file:human/FBXL14/FBXL14-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:19955572}.' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25203322 qualifier: enables review: summary: Interaction with SNAI1 (O95863) reported in a study of SNAIL degradation by SCF-FBXO11/PKD1. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the functionally important FBXL14-SNAI1 substrate interaction, but bare protein binding is uninformative per curation guidelines; captured by the catabolic-process annotations. supported_by: - reference_id: file:human/FBXL14/FBXL14-uniprot.txt supporting_text: 'Q8N1E6; O95863: SNAI1; NbExp=2; IntAct=EBI-6425532, EBI-1045459;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27705803 qualifier: enables review: summary: Interaction with SKP1 (P63208) from a Polycomb complexome map. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the FBXL14-SKP1 association required for SCF assembly, but bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXL14/FBXL14-uniprot.txt supporting_text: 'Q8N1E6; P63208: SKP1; NbExp=7; IntAct=EBI-6425532, EBI-307486;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28514442 qualifier: enables review: summary: Interaction with SKP1 (P63208) from a human-interactome architecture study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput SKP1 interaction; bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXL14/FBXL14-uniprot.txt supporting_text: 'Q8N1E6; P63208: SKP1; NbExp=7; IntAct=EBI-6425532, EBI-307486;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: Interaction with SKP1 (P63208) from a binary interactome reference map. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput SKP1 interaction; bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXL14/FBXL14-uniprot.txt supporting_text: 'Q8N1E6; P63208: SKP1; NbExp=7; IntAct=EBI-6425532, EBI-307486;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: Interaction with SKP1 (P63208) from a cell-specific proteome-scale interactome. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput SKP1 interaction; bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXL14/FBXL14-uniprot.txt supporting_text: 'Q8N1E6; P63208: SKP1; NbExp=7; IntAct=EBI-6425532, EBI-307486;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:40205054 qualifier: enables review: summary: Interaction with SKP1 (P63208) from a multimodal cell-map genomics study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput SKP1 interaction; bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXL14/FBXL14-uniprot.txt supporting_text: 'Q8N1E6; P63208: SKP1; NbExp=7; IntAct=EBI-6425532, EBI-307486;' - term: id: GO:0006355 label: regulation of DNA-templated transcription evidence_type: NAS original_reference_id: PMID:36372232 qualifier: involved_in review: summary: ComplexPortal author statement linking an SCF(FBXL14)-containing complex to transcriptional regulation. The cited paper concerns an E3 ligase targeting the RNA Pol I catalytic subunit under transcription stress. action: KEEP_AS_NON_CORE reason: Plausible downstream regulatory role, but generic and indirect (transcription is regulated via degradation of transcription-associated substrates such as SNAI1); not the core substrate-receptor activity. supported_by: - reference_id: file:human/FBXL14/FBXL14-uniprot.txt supporting_text: The SCF(FBXL14) complex acts by mediating ubiquitination and subsequent degradation of SNAI1. - 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: ComplexPortal author statement that FBXL14 functions in SCF-dependent proteasomal protein catabolism. Captures the core biological process. action: ACCEPT reason: Core biological process for an SCF F-box substrate receptor; directly supported by SNAI1 degradation (PMID:19955572) and, per falcon synthesis, by HES1 turnover via the HES1 WRPW motif. supported_by: - reference_id: file:human/FBXL14/FBXL14-uniprot.txt supporting_text: The SCF(FBXL14) complex acts by mediating ubiquitination and subsequent degradation of SNAI1. - reference_id: file:human/FBXL14/FBXL14-deep-research-falcon.md supporting_text: >- FBXL14 is best supported as an **SCF (CRL1) E3 ubiquitin ligase substrate receptor** that promotes **ubiquitin-dependent proteasomal degradation** of select transcriptional regulators, with validated direct substrates including **HES1** (Notch signaling effector) and **SNAIL1** (EMT transcription factor). - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952618 qualifier: located_in review: summary: Reactome cytosolic localization within generic CRL1/NEDD8-cycle reactions. action: KEEP_AS_NON_CORE reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery rather than FBXL14-specific function. supported_by: - reference_id: file:human/FBXL14/FBXL14-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:19955572}.' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952620 qualifier: located_in review: summary: Reactome cytosolic localization within a generic CRL1 NEDD8-binding reaction. action: KEEP_AS_NON_CORE reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery. supported_by: - reference_id: file:human/FBXL14/FBXL14-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:19955572}.' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955241 qualifier: located_in review: summary: Reactome cytosolic localization within a generic CAND1/CRL reaction. action: KEEP_AS_NON_CORE reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery. supported_by: - reference_id: file:human/FBXL14/FBXL14-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:19955572}.' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955289 qualifier: located_in review: summary: Reactome cytosolic localization within a generic COMMD/CAND1/CRL reaction. action: KEEP_AS_NON_CORE reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery. supported_by: - reference_id: file:human/FBXL14/FBXL14-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:19955572}.' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956040 qualifier: located_in review: summary: Reactome cytosolic localization within a generic COP9-signalosome deneddylation reaction. action: KEEP_AS_NON_CORE reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery. supported_by: - reference_id: file:human/FBXL14/FBXL14-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:19955572}.' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956200 qualifier: located_in review: summary: Reactome cytosolic localization within a generic DCUN1D3/CRL1 reaction. action: KEEP_AS_NON_CORE reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery. supported_by: - reference_id: file:human/FBXL14/FBXL14-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:19955572}.' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983140 qualifier: located_in review: summary: Reactome cytosolic localization within a generic E2-to-substrate ubiquitin-transfer reaction. action: KEEP_AS_NON_CORE reason: Generic ubiquitination pathway annotation; reflects shared cytosolic machinery. supported_by: - reference_id: file:human/FBXL14/FBXL14-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:19955572}.' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983147 qualifier: located_in review: summary: Reactome cytosolic localization within a generic E3-release reaction. action: KEEP_AS_NON_CORE reason: Generic ubiquitination pathway annotation; reflects shared cytosolic machinery. supported_by: - reference_id: file:human/FBXL14/FBXL14-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:19955572}.' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983156 qualifier: located_in review: summary: Reactome cytosolic localization within a generic substrate-polyubiquitination reaction. action: KEEP_AS_NON_CORE reason: Generic ubiquitination pathway annotation; reflects shared cytosolic machinery. supported_by: - reference_id: file:human/FBXL14/FBXL14-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:19955572}.' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983157 qualifier: located_in review: summary: Reactome cytosolic localization within a generic E3-substrate-E2 interaction reaction. action: KEEP_AS_NON_CORE reason: Generic ubiquitination pathway annotation; reflects shared cytosolic machinery. supported_by: - reference_id: file:human/FBXL14/FBXL14-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:19955572}.' - term: id: GO:0004842 label: ubiquitin-protein transferase activity evidence_type: IDA original_reference_id: PMID:19955572 qualifier: enables review: summary: Direct evidence that FBXL14 promotes SNAI1 polyubiquitination within the SCF complex. As an F-box protein, FBXL14 is the substrate receptor; the transferase activity resides in the RBX1-recruited E2, so the more precise term is the substrate-adaptor activity. action: MODIFY reason: FBXL14 is the substrate-recognition subunit, not the catalytic transferase (catalysis is contributed by RBX1/E2 in the SCF). The ubiquitin-like ligase-substrate adaptor activity term more accurately captures its molecular function while preserving the experimentally supported role in substrate ubiquitination. proposed_replacement_terms: - id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity supported_by: - reference_id: file:human/FBXL14/FBXL14-uniprot.txt supporting_text: The SCF(FBXL14) complex acts by mediating ubiquitination and subsequent degradation of SNAI1. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19955572 qualifier: enables review: summary: Interaction with SNAI1 (O95863), the FBXL14 substrate, requiring its destruction-motif serines. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the functionally important FBXL14-SNAI1 substrate interaction, but bare protein binding is uninformative; captured by the catabolic-process annotations. supported_by: - reference_id: file:human/FBXL14/FBXL14-uniprot.txt supporting_text: 'Q8N1E6; O95863: SNAI1; NbExp=2; IntAct=EBI-6425532, EBI-1045459;' - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:19955572 qualifier: located_in review: summary: Direct evidence for cytoplasmic localization from the SNAI1 study. Core localization. action: ACCEPT reason: IDA-supported cytoplasmic localization, consistent with the UniProt subcellular location. supported_by: - reference_id: file:human/FBXL14/FBXL14-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:19955572}.' - term: id: GO:0006511 label: ubiquitin-dependent protein catabolic process evidence_type: IDA original_reference_id: PMID:19955572 qualifier: involved_in review: summary: Direct evidence that FBXL14 drives ubiquitin-dependent proteasomal degradation of SNAI1. A parent of the more specific SCF-dependent catabolic process. action: ACCEPT reason: Core biological process directly supported by SNAI1 turnover; GO:0031146 (SCF-dependent) is the more specific term. supported_by: - reference_id: file:human/FBXL14/FBXL14-uniprot.txt supporting_text: The SCF(FBXL14) complex acts by mediating ubiquitination and subsequent degradation of SNAI1. - term: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity evidence_type: IDA original_reference_id: PMID:19955572 qualifier: enables review: summary: Proposed core molecular function. As the LRR substrate-recognition subunit of SCF(FBXL14), FBXL14 selects SNAI1/SNAIL1 (via its D-S-G phosphodegron motif) for SCF-dependent ubiquitination. This is the precise replacement for the broader ubiquitin-protein transferase annotation. action: NEW reason: Captures the precise molecular function of FBXL14 as an SCF substrate-recognition adaptor, more informative than bare protein binding and more accurate than the generic transferase activity term. supported_by: - reference_id: file:human/FBXL14/FBXL14-uniprot.txt supporting_text: Substrate-recognition component of some SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin-protein ligase complexes. references: - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: PMID:19955572 title: The hypoxia-controlled FBXL14 ubiquitin ligase targets SNAIL1 for proteasome degradation. findings: - statement: SCF(FBXL14) binds and polyubiquitinates the EMT transcription factor SNAI1/SNAIL1 and promotes its proteasomal degradation independently of GSK-3beta phosphorylation; FBXL14 is down-regulated by hypoxia, stabilizing SNAI1. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: PubMed-verified (J Biol Chem 2010); establishes SNAI1 as the defining SCF(FBXL14) substrate and the hypoxia regulation. Abstract-only in cache; quotes for molecular detail drawn from the UniProt entry. - id: PMID:25203322 title: PKD1 phosphorylation-dependent degradation of SNAIL by SCF-FBXO11 regulates epithelial-mesenchymal transition and metastasis. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Concerns SNAIL degradation by SCF-FBXO11/PKD1; source of an FBXL14-SNAI1 interaction annotation. SNAI1 is a shared substrate context. - id: PMID:27705803 title: A High-Density Map for Navigating the Human Polycomb Complexome. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput complexome map; source of an SKP1 interaction (bare protein binding). - id: PMID:28514442 title: Architecture of the human interactome defines protein communities and disease networks. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput interactome; source of an SKP1 interaction (bare protein binding). - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Binary interactome reference map; source of an SKP1 interaction (bare protein binding). - id: PMID:33234069 title: 'The FBXL family of F-box proteins: variations on a theme.' findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Review of the FBXL family; basis for the ComplexPortal NAS SCF-catabolic-process annotation. - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput interactome; source of an SKP1 interaction (bare protein binding). - id: PMID:36372232 title: Identification of an E3 ligase that targets the catalytic subunit of RNA Polymerase I upon transcription stress. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Basis for the ComplexPortal NAS transcription-regulation annotation; relationship to FBXL14's direct function is indirect. - id: PMID:40205054 title: Multimodal cell maps as a foundation for structural and functional genomics. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput cell-map genomics; source of an SKP1 interaction (bare protein binding). - 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: file:human/FBXL14/FBXL14-deep-research-falcon.md title: Falcon deep research report for human FBXL14 findings: - statement: FBXL14 is an SCF (CRL1) substrate receptor that promotes ubiquitin-dependent proteasomal degradation of select transcriptional regulators, with validated direct substrates HES1 and SNAIL1. supporting_text: >- FBXL14 is best supported as an **SCF (CRL1) E3 ubiquitin ligase substrate receptor** that promotes **ubiquitin-dependent proteasomal degradation** of select transcriptional regulators, with validated direct substrates including **HES1** (Notch signaling effector) and **SNAIL1** (EMT transcription factor). - statement: SCF(FBXL14) recognizes the conserved C-terminal WRPW motif of the Notch effector HES1, which is required for HES1 binding, ubiquitination, and degradation. supporting_text: >- the conserved **C-terminal WRPW motif** in HES1 is required for FBXL14 binding and for SCF^FBXL14-mediated ubiquitination and degradation; deleting WRPW reduces co-IP with FBXL14, increases HES1 stability in CHX chase, and decreases polyubiquitination. - statement: SCF(FBXL14) ubiquitinates SNAIL1 on acceptor lysines K98, K137 and K146, with a triple K-to-R mutant strongly stabilized, and depletion of FBXL14 extends SNAIL1 half-life from about 1 h to about 3 h. supporting_text: >- Major SNAIL1 ubiquitination acceptor lysines include **K98, K137, K146**: a triple mutant shows reduced ubiquitination and is highly stable (e.g., ~80% remaining after 4 h CHX in cited experiments). - statement: Hypoxia down-regulates FBXL14 mRNA in a TWIST1-dependent manner, stabilizing SNAIL1 protein without increasing SNAI1 mRNA and thereby supporting EMT. supporting_text: >- TWIST1 is required for this hypoxia response: Twist1 knockdown prevents hypoxia-induced FBXL14 down-modulation and prevents SNAIL1 stabilization. - statement: FBXL14 is reported to ubiquitinate Thr58-phosphorylated c-MYC, promoting differentiation and suppressing glioma stem-cell tumorigenicity (review-summarized primary evidence). supporting_text: >- FBXL14 is reported to ubiquitylate **Thr58-phosphorylated c-Myc**; FBXL14 is low in glioma stem cells but higher in non-stem-like glioma cells/neural progenitors. reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- Falcon adds two substrate axes beyond SNAI1 - HES1 (Chen et al. 2017, via the HES1 WRPW motif) and Thr58-phospho-c-MYC (review-summarized, Yumimoto/Nakayama) - and refines SNAI1 degron/acceptor-lysine mapping (aa 120-151; K98/K137/K146) and TWIST1-dependent hypoxic repression. SNAI1 axis cross-checks the cached PMID:19955572; HES1/c-MYC axes are reported via author-year DOIs not in the PMID cache and are treated as well-supported leads, not added as new GOA terms. - 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-RBX1) E3 ubiquitin ligase complex that selects the EMT transcription factor SNAI1/SNAIL1 (binding a region around aa 120-151; acceptor lysines K98/K137/K146) for SCF-dependent polyubiquitination and proteasomal degradation, controlling SNAI1 abundance during epithelial-to-mesenchymal transition. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: file:human/FBXL14/FBXL14-uniprot.txt supporting_text: The SCF(FBXL14) complex acts by mediating ubiquitination and subsequent degradation of SNAI1. directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process - description: As the SCF(FBXL14) substrate receptor, recognizes the conserved C-terminal WRPW motif of the Notch effector HES1 to drive its ubiquitination and proteasomal turnover, contributing to Notch signaling dynamics and neuronal differentiation. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: file:human/FBXL14/FBXL14-deep-research-falcon.md supporting_text: >- the conserved **C-terminal WRPW motif** in HES1 is required for FBXL14 binding and for SCF^FBXL14-mediated ubiquitination and degradation; deleting WRPW reduces co-IP with FBXL14, increases HES1 stability in CHX chase, and decreases polyubiquitination. directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process proposed_new_terms: [] suggested_questions: - question: How does FBXL14 discriminate among its degron types - the phosphorylation-independent SNAI1 region (aa 120-151), the linear WRPW motif of HES1, and Thr58-phosphorylated c-MYC - using its single LRR concave surface? - question: How does hypoxic, TWIST1-dependent down-regulation of FBXL14 integrate with other SNAI1-targeting ligases (e.g. beta-TrCP, FBXO11) to control EMT in development and cancer, and is HES1/Notch turnover similarly hypoxia-regulated? suggested_experiments: - description: Reconstitute SCF(FBXL14)-mediated ubiquitination of SNAI1, HES1 (WRPW-dependent), and Thr58-phospho-c-MYC in vitro with purified SKP1-CUL1-RBX1-FBXL14 and an E2 to confirm direct ubiquitination, map sites, and define degron requirements. - description: Perform quantitative ubiquitinome/proteome profiling in FBXL14-knockout versus wild-type cells under normoxia and hypoxia (and in neural/glioma models) to define the endogenous substrate landscape and the EMT, Notch, and differentiation consequences.