Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: Electronic transfer of cytoplasmic localization from the UniProt subcellular location; supported by IDA evidence. Reason: Correct localization, directly supported (IDA) in the SNAI1 study. Supporting Evidence: file:human/FBXL14/FBXL14-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:19955572}.
GO:0005515 protein binding	IPI PMID:25203322 PKD1 phosphorylation-dependent degradation of SNAIL by SCF-F...	KEEP AS NON CORE	Summary: Interaction with SNAI1 (O95863) reported in a study of SNAIL degradation by SCF-FBXO11/PKD1. Bare protein binding is uninformative. Reason: Records the functionally important FBXL14-SNAI1 substrate interaction, but bare protein binding is uninformative per curation guidelines; captured by the catabolic-process annotations. Supporting Evidence: file:human/FBXL14/FBXL14-uniprot.txt Q8N1E6; O95863: SNAI1; NbExp=2; IntAct=EBI-6425532, EBI-1045459;
GO:0005515 protein binding	IPI PMID:27705803 A High-Density Map for Navigating the Human Polycomb Complex...	KEEP AS NON CORE	Summary: Interaction with SKP1 (P63208) from a Polycomb complexome map. Bare protein binding is uninformative. Reason: Records the FBXL14-SKP1 association required for SCF assembly, but bare protein binding is uninformative. Supporting Evidence: file:human/FBXL14/FBXL14-uniprot.txt Q8N1E6; P63208: SKP1; NbExp=7; IntAct=EBI-6425532, EBI-307486;
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	KEEP AS NON CORE	Summary: Interaction with SKP1 (P63208) from a human-interactome architecture study. Bare protein binding is uninformative. Reason: High-throughput SKP1 interaction; bare protein binding is uninformative. Supporting Evidence: file:human/FBXL14/FBXL14-uniprot.txt Q8N1E6; P63208: SKP1; NbExp=7; IntAct=EBI-6425532, EBI-307486;
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: Interaction with SKP1 (P63208) from a binary interactome reference map. Bare protein binding is uninformative. Reason: High-throughput SKP1 interaction; bare protein binding is uninformative. Supporting Evidence: file:human/FBXL14/FBXL14-uniprot.txt Q8N1E6; P63208: SKP1; NbExp=7; IntAct=EBI-6425532, EBI-307486;
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: Interaction with SKP1 (P63208) from a cell-specific proteome-scale interactome. Bare protein binding is uninformative. Reason: High-throughput SKP1 interaction; bare protein binding is uninformative. Supporting Evidence: file:human/FBXL14/FBXL14-uniprot.txt Q8N1E6; P63208: SKP1; NbExp=7; IntAct=EBI-6425532, EBI-307486;
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	KEEP AS NON CORE	Summary: Interaction with SKP1 (P63208) from a multimodal cell-map genomics study. Bare protein binding is uninformative. Reason: High-throughput SKP1 interaction; bare protein binding is uninformative. Supporting Evidence: file:human/FBXL14/FBXL14-uniprot.txt Q8N1E6; P63208: SKP1; NbExp=7; IntAct=EBI-6425532, EBI-307486;
GO:0006355 regulation of DNA-templated transcription	NAS PMID:36372232 Identification of an E3 ligase that targets the catalytic su...	KEEP AS NON CORE	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. 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. Supporting Evidence: file:human/FBXL14/FBXL14-uniprot.txt The SCF(FBXL14) complex acts by mediating ubiquitination and subsequent degradation of SNAI1.
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: ComplexPortal author statement that FBXL14 functions in SCF-dependent proteasomal protein catabolism. Captures the core biological process. 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. Supporting Evidence: file:human/FBXL14/FBXL14-uniprot.txt The SCF(FBXL14) complex acts by mediating ubiquitination and subsequent degradation of SNAI1. file:human/FBXL14/FBXL14-deep-research-falcon.md 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).
GO:0005829 cytosol	TAS Reactome:R-HSA-8952618	KEEP AS NON CORE	Summary: Reactome cytosolic localization within generic CRL1/NEDD8-cycle reactions. Reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery rather than FBXL14-specific function. Supporting Evidence: file:human/FBXL14/FBXL14-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:19955572}.
GO:0005829 cytosol	TAS Reactome:R-HSA-8952620	KEEP AS NON CORE	Summary: Reactome cytosolic localization within a generic CRL1 NEDD8-binding reaction. Reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery. Supporting Evidence: file:human/FBXL14/FBXL14-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:19955572}.
GO:0005829 cytosol	TAS Reactome:R-HSA-8955241	KEEP AS NON CORE	Summary: Reactome cytosolic localization within a generic CAND1/CRL reaction. Reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery. Supporting Evidence: file:human/FBXL14/FBXL14-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:19955572}.
GO:0005829 cytosol	TAS Reactome:R-HSA-8955289	KEEP AS NON CORE	Summary: Reactome cytosolic localization within a generic COMMD/CAND1/CRL reaction. Reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery. Supporting Evidence: file:human/FBXL14/FBXL14-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:19955572}.
GO:0005829 cytosol	TAS Reactome:R-HSA-8956040	KEEP AS NON CORE	Summary: Reactome cytosolic localization within a generic COP9-signalosome deneddylation reaction. Reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery. Supporting Evidence: file:human/FBXL14/FBXL14-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:19955572}.
GO:0005829 cytosol	TAS Reactome:R-HSA-8956200	KEEP AS NON CORE	Summary: Reactome cytosolic localization within a generic DCUN1D3/CRL1 reaction. Reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery. Supporting Evidence: file:human/FBXL14/FBXL14-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:19955572}.
GO:0005829 cytosol	TAS Reactome:R-HSA-983140	KEEP AS NON CORE	Summary: Reactome cytosolic localization within a generic E2-to-substrate ubiquitin-transfer reaction. Reason: Generic ubiquitination pathway annotation; reflects shared cytosolic machinery. Supporting Evidence: file:human/FBXL14/FBXL14-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:19955572}.
GO:0005829 cytosol	TAS Reactome:R-HSA-983147	KEEP AS NON CORE	Summary: Reactome cytosolic localization within a generic E3-release reaction. Reason: Generic ubiquitination pathway annotation; reflects shared cytosolic machinery. Supporting Evidence: file:human/FBXL14/FBXL14-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:19955572}.
GO:0005829 cytosol	TAS Reactome:R-HSA-983156	KEEP AS NON CORE	Summary: Reactome cytosolic localization within a generic substrate-polyubiquitination reaction. Reason: Generic ubiquitination pathway annotation; reflects shared cytosolic machinery. Supporting Evidence: file:human/FBXL14/FBXL14-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:19955572}.
GO:0005829 cytosol	TAS Reactome:R-HSA-983157	KEEP AS NON CORE	Summary: Reactome cytosolic localization within a generic E3-substrate-E2 interaction reaction. Reason: Generic ubiquitination pathway annotation; reflects shared cytosolic machinery. Supporting Evidence: file:human/FBXL14/FBXL14-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:19955572}.
GO:0004842 ubiquitin-protein transferase activity	IDA PMID:19955572 The hypoxia-controlled FBXL14 ubiquitin ligase targets SNAIL...	MODIFY	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. 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 replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: file:human/FBXL14/FBXL14-uniprot.txt The SCF(FBXL14) complex acts by mediating ubiquitination and subsequent degradation of SNAI1.
GO:0005515 protein binding	IPI PMID:19955572 The hypoxia-controlled FBXL14 ubiquitin ligase targets SNAIL...	KEEP AS NON CORE	Summary: Interaction with SNAI1 (O95863), the FBXL14 substrate, requiring its destruction-motif serines. Bare protein binding is uninformative. Reason: Records the functionally important FBXL14-SNAI1 substrate interaction, but bare protein binding is uninformative; captured by the catabolic-process annotations. Supporting Evidence: file:human/FBXL14/FBXL14-uniprot.txt Q8N1E6; O95863: SNAI1; NbExp=2; IntAct=EBI-6425532, EBI-1045459;
GO:0005737 cytoplasm	IDA PMID:19955572 The hypoxia-controlled FBXL14 ubiquitin ligase targets SNAIL...	ACCEPT	Summary: Direct evidence for cytoplasmic localization from the SNAI1 study. Core localization. Reason: IDA-supported cytoplasmic localization, consistent with the UniProt subcellular location. Supporting Evidence: file:human/FBXL14/FBXL14-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:19955572}.
GO:0006511 ubiquitin-dependent protein catabolic process	IDA PMID:19955572 The hypoxia-controlled FBXL14 ubiquitin ligase targets SNAIL...	ACCEPT	Summary: Direct evidence that FBXL14 drives ubiquitin-dependent proteasomal degradation of SNAI1. A parent of the more specific SCF-dependent catabolic process. Reason: Core biological process directly supported by SNAI1 turnover; GO:0031146 (SCF-dependent) is the more specific term. Supporting Evidence: file:human/FBXL14/FBXL14-uniprot.txt The SCF(FBXL14) complex acts by mediating ubiquitination and subsequent degradation of SNAI1.
GO:1990756 ubiquitin-like ligase-substrate adaptor activity	IDA PMID:19955572 The hypoxia-controlled FBXL14 ubiquitin ligase targets SNAIL...	NEW	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. 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. Supporting Evidence: file:human/FBXL14/FBXL14-uniprot.txt Substrate-recognition component of some SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin-protein ligase complexes.

Core Functions

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:

ubiquitin-like ligase-substrate adaptor activity

Directly Involved In:

SCF-dependent proteasomal ubiquitin-dependent protein catabolic process

Cellular Locations:

cytoplasm

Supporting Evidence:

file:human/FBXL14/FBXL14-uniprot.txt
The SCF(FBXL14) complex acts by mediating ubiquitination and subsequent degradation of SNAI1.

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:

ubiquitin-like ligase-substrate adaptor activity

Directly Involved In:

SCF-dependent proteasomal ubiquitin-dependent protein catabolic process

Cellular Locations:

cytoplasm

Supporting Evidence:

file:human/FBXL14/FBXL14-deep-research-falcon.md
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.

References

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

PMID:19955572

The hypoxia-controlled FBXL14 ubiquitin ligase targets SNAIL1 for proteasome degradation.

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.

PMID:25203322

PKD1 phosphorylation-dependent degradation of SNAIL by SCF-FBXO11 regulates epithelial-mesenchymal transition and metastasis.

PMID:27705803

A High-Density Map for Navigating the Human Polycomb Complexome.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:33234069

The FBXL family of F-box proteins: variations on a theme.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:36372232

Identification of an E3 ligase that targets the catalytic subunit of RNA Polymerase I upon transcription stress.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

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

file:human/FBXL14/FBXL14-deep-research-falcon.md

Falcon deep research report for human FBXL14

FBXL14 is an SCF (CRL1) substrate receptor that promotes ubiquitin-dependent proteasomal degradation of select transcriptional regulators, with validated direct substrates HES1 and SNAIL1.

"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)."
SCF(FBXL14) recognizes the conserved C-terminal WRPW motif of the Notch effector HES1, which is required for HES1 binding, ubiquitination, and degradation.

"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."
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.

"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)."
Hypoxia down-regulates FBXL14 mRNA in a TWIST1-dependent manner, stabilizing SNAIL1 protein without increasing SNAI1 mRNA and thereby supporting EMT.

"TWIST1 is required for this hypoxia response: Twist1 knockdown prevents hypoxia-induced FBXL14 down-modulation and prevents SNAIL1 stabilization."
FBXL14 is reported to ubiquitinate Thr58-phosphorylated c-MYC, promoting differentiation and suppressing glioma stem-cell tumorigenicity (review-summarized primary evidence).

"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."

Reactome:R-HSA-983157

Interaction of E3 with substrate and E2-Ub complex

Suggested Experiments

Experiment: 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.

Experiment: 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.

Deep Research

Falcon

(FBXL14-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 31 citations 2 artifacts 2026-06-13T06:12:03.557930

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000016 Figure 4 (on page 19) provides comprehensive data on HES1 binding to FBXL14 and the role of the WRPW motif: - **Binding and WRPW Re (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 FBXL14 (UniProt Q8N1E6) functional annotation

0) Target verification (mandatory)

FBXL14 (UniProt Q8N1E6) is the human F-box/LRR-repeat protein 14, an FBXL-class F-box protein (~418 aa) containing an N-terminal F-box (Skp1-binding) and ~11 leucine-rich repeats (LRRs) (substrate-binding), consistent across structural review and primary functional studies. (mason2020thefbxlfamily pages 3-4, mason2020thefbxlfamily pages 4-5, chen2017thee3ubiquitin pages 1-2)

1) Key concepts and definitions (current understanding)

1.1 SCF/CRL1 E3 ubiquitin ligases

FBXL14 functions as a substrate receptor in an SCF (also termed CRL1) Cullin–RING E3 ubiquitin ligase complex. Canonical SCF architecture comprises CUL1 (scaffold), RBX1 (RING), SKP1 (adaptor), and a variable F-box protein that confers substrate specificity. (chen2017thee3ubiquitin pages 1-2, tekcham2020fboxproteinsand pages 1-3, sato2010augmentationofthe pages 1-2)

Mechanistically, RBX1 recruits an E2~ubiquitin conjugate (for many SCF systems, classically CDC34 is emphasized), positioning ubiquitin for transfer to substrates brought in by the F-box receptor. (sato2010augmentationofthe pages 1-2, mason2020thefbxlfamily pages 2-3)

1.2 FBXL family structural principles (how FBXL14 likely recognizes substrates)

FBXL proteins are defined by an N-terminal F-box domain that binds Skp1 and a C-terminal array of LRRs that mediate substrate binding. (mason2020thefbxlfamily pages 3-4, mason2020thefbxlfamily pages 2-3, sato2010augmentationofthe pages 2-3)

The LRR domain forms a curved “horseshoe” solenoid; the concave surface is the dominant substrate-binding interface across structurally characterized FBXL members, providing a conceptual basis for FBXL14 substrate recognition. (mason2020thefbxlfamily pages 3-4, mason2020thefbxlfamily pages 5-6)

FBXL14 is repeatedly described as containing 11 LRRs (and being ~418 aa), a feature consistent with its classification and with substrate-recognition via an LRR surface. (mason2020thefbxlfamily pages 4-5, chen2017thee3ubiquitin pages 1-2)

2) Core molecular functions of FBXL14 (primary functional annotation)

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). (chen2017thee3ubiquitin pages 1-2, vinascastells2010thehypoxiacontrolledfbxl14 pages 1-2)

2.1 FBXL14 → HES1 (Notch pathway; neuronal differentiation)

A strong body of biochemical and functional evidence supports that SCF^FBXL14 targets HES1 for ubiquitin-dependent degradation:
- Knockdown of CRL1 components CUL1 or RBX1 increased HES1 abundance and prolonged HES1 half-life, implicating CRL1 machinery in HES1 turnover. (chen2017thee3ubiquitin pages 1-2)
- FBXL14 associates with HES1 and promotes HES1 ubiquitination and degradation; FBXL14 loss stabilizes HES1 and dampens oscillatory behavior. (chen2017thee3ubiquitin pages 18-20, chen2017thee3ubiquitin pages 16-18)
- Substrate recognition motif: 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. (chen2017thee3ubiquitin pages 18-20, chen2017thee3ubiquitin media 2535ebd1)
- SCF dependence: deleting the FBXL14 F-box (ΔF) reduces ubiquitination of HES1, consistent with the requirement for SCF complex assembly (Skp1/CUL1 engagement) to catalyze ubiquitin transfer. (chen2017thee3ubiquitin media 2535ebd1)

Functionally, this proteolysis promotes neuronal differentiation, positioning FBXL14 as a post-translational regulator of Notch/HES dynamics. (chen2017thee3ubiquitin pages 1-2)

2.2 FBXL14 → SNAIL1 (EMT regulator; hypoxia/EMT coupling)

Primary data (JBC 2010) show that FBXL14 is a direct ubiquitin ligase for SNAIL1:
- FBXL14 interacts with SNAIL1 and promotes proteasome-dependent degradation; degradation is blocked by MG132 and requires an intact FBXL14 F-box (ΔF fails). (vinascastells2010thehypoxiacontrolledfbxl14 pages 4-6)
- FBXL14 is described to act independently of GSK-3 phosphorylation for SNAIL1 degradation, distinguishing it from the canonical GSK3β/β-TrCP axis. (vinascastells2010thehypoxiacontrolledfbxl14 pages 1-2)
- Subcellular localization: FBXL14 is reported as mainly cytoplasmic by immunofluorescence; in transfected cells it depletes nuclear SNAIL1, consistent with a model in which cytoplasmic ligase availability contributes to SNAIL1 turnover. (vinascastells2010thehypoxiacontrolledfbxl14 pages 4-6, vinascastells2010thehypoxiacontrolledfbxl14 pages 10-12)

Substrate determinants and ubiquitination sites were mapped:
- A minimal SNAIL1 region important for FBXL14-dependent degradation lies within aa 120–151 (including a hydrophobic segment), based on deletion mapping summarized across sources. (vinascastells2010thehypoxiacontrolledfbxl14 pages 10-12, castells2013ubiquitinligasesinvolved pages 97-100)
- 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). (vinascastells2010thehypoxiacontrolledfbxl14 pages 8-9, castells2013ubiquitinligasesinvolved pages 62-65)
- In CHX-chase experiments, depletion of FBXL14 increased exogenous SNAIL1 half-life from ~1 h to ~3 h, supporting FBXL14 as a key determinant of SNAIL1 proteostasis. (vinascastells2010thehypoxiacontrolledfbxl14 pages 8-9)

Hypoxia regulation linking microenvironment to EMT:
- Hypoxia down-regulates FBXL14 mRNA and stabilizes SNAIL1 protein without increasing Snail1 mRNA. (vinascastells2010thehypoxiacontrolledfbxl14 pages 1-2, vinascastells2010thehypoxiacontrolledfbxl14 pages 9-10)
- TWIST1 is required for this hypoxia response: Twist1 knockdown prevents hypoxia-induced FBXL14 down-modulation and prevents SNAIL1 stabilization. (vinascastells2010thehypoxiacontrolledfbxl14 pages 1-2, vinascastells2010thehypoxiacontrolledfbxl14 pages 9-10)

Together, these findings support FBXL14 as a mechanistic node coupling oxygen-sensing/transcriptional programs (HIF/TWIST) to EMT effector stability through ubiquitin-mediated proteolysis.

2.3 FBXL14 → c-Myc (glioma stemness/differentiation axis; review-supported)

Cancer-focused reviews summarize primary evidence that FBXL14 targets Thr58-phosphorylated c-Myc for ubiquitination, with functional consequences in glioma:
- 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. (yumimoto2020fboxproteinsand pages 7-10)
- Overexpression of FBXL14 promotes differentiation and suppresses glioma stem cell tumor-forming capacity; expression of degradation-resistant c-Myc(T58A) reverses these effects, supporting a Thr58-dependent mechanism. (yumimoto2020fboxproteinsand pages 7-10, yumimoto2020fboxproteinsand pages 10-12)
- The deubiquitinase USP13 is described (reviewing primary work) as antagonizing FBXL14-mediated Myc ubiquitination, thereby supporting glioblastoma stem cell maintenance. (tao2023rolesofubiquitin‑specific pages 8-9, tao2023rolesofubiquitin‑specific pages 5-6)

Because these points are largely review-derived within the retrieved corpus, they should be interpreted as strongly suggestive and motivated by primary literature (e.g., a cited J Exp Med 2017 study), but the underlying experimental details were not directly retrieved here. (tao2023rolesofubiquitin‑specific pages 8-9, tao2023rolesofubiquitin‑specific pages 5-6, yumimoto2020fboxproteinsand pages 7-10)

3) Subcellular localization and where FBXL14 acts

Across EMT-focused work and synthesis, FBXL14 is repeatedly described as predominantly cytoplasmic, consistent with:
- Cytoplasmic immunofluorescence localization and proposed targeting of newly synthesized/cytosolic SNAIL1. (vinascastells2010thehypoxiacontrolledfbxl14 pages 4-6, castells2013ubiquitinligasesinvolved pages 97-100)

In the Notch/HES1 study, subcellular localization of FBXL14 is not emphasized; however, SCF^FBXL14 activity requires CRL1 machinery (CUL1/RBX1), consistent with intracellular ubiquitin-proteasome regulation rather than extracellular action. (chen2017thee3ubiquitin pages 16-18, chen2017thee3ubiquitin pages 1-2)

4) Pathways and biological processes

4.1 Notch signaling dynamics and neuronal differentiation

By promoting HES1 turnover via an SCF complex, FBXL14 participates in the post-translational control of Notch effector abundance and thereby influences cell fate decisions (neuronal differentiation), consistent with HES1’s role as a proneural gene repressor. (chen2017thee3ubiquitin pages 1-2, chen2017thee3ubiquitin pages 18-20)

4.2 EMT regulation and tumor microenvironment (hypoxia)

FBXL14 destabilizes SNAIL1 and is described as a cytoplasmic Snail1 ubiquitin ligase; hypoxia-driven repression of FBXL14 stabilizes SNAIL1 and supports EMT. (vinascastells2010thehypoxiacontrolledfbxl14 pages 1-2, vinascastells2010thehypoxiacontrolledfbxl14 pages 9-10, vinascastells2010thehypoxiacontrolledfbxl14 pages 4-6)

5) Recent developments (prioritizing 2023–2024)

5.1 3D genome regulation (Nature 2023)

A 2023 Nature high-throughput Oligopaint-based screen identified FBXL14 as a validated hit in 3D genome regulation. In follow-up across 13 genome-wide domain-pair boundaries, depletion of FBXL14 significantly increased inter-TAD interactions at nearly all (≥12/13) boundaries tested, supporting a role as a general factor limiting inappropriate inter-domain contacts. (park2023highthroughputoligopaintscreen pages 4-6)

This finding is mechanistically orthogonal to the classical substrate-by-substrate SCF paradigm and suggests either (i) an as-yet-unknown chromatin substrate or (ii) indirect network effects via ubiquitin-proteasome control of genome-organization regulators.

5.2 FBXL14 as a candidate E3 for targeted protein degradation platforms (STTT 2024)

A 2024 Signal Transduction and Targeted Therapy article summarizing proteome-scale proximity-based screens reports FBXL14 among a small set of ligases that performed well across ten model substrates spanning different subcellular localizations, implying broad degradative capacity suitable for engineered proximity-inducing modalities (e.g., degrader design paradigms). (hermanns2024proximitydependentprotein(de)stabilization pages 1-2)

While this does not establish endogenous substrates, it is a key recent translationally oriented development: FBXL14 is highlighted as a potential E3 effector module beyond commonly used VHL/CRBN-centric approaches.

5.3 2023 synthesis of USP13–FBXL14–Myc axis in tumors

A 2023 review of USP13 notes that USP13 maintains glioblastoma stem cells by antagonizing FBXL14-mediated Myc ubiquitination, reinforcing interest in the FBXL14–Myc axis in cancer biology and potentially in therapeutic strategies that modulate ubiquitination/deubiquitination balance. (tao2023rolesofubiquitin‑specific pages 8-9, tao2023rolesofubiquitin‑specific pages 5-6)

6) Expert opinions and interpretive synthesis (authoritative sources)

6.1 Specificity challenges for targeting F-box proteins

Cancer reviews emphasize that F-box proteins can ubiquitinate both oncogenes and tumor suppressors; therefore non-specific inhibition risks side effects, and substrate-selective strategies (blocking specific F-box–substrate interfaces) are considered more plausible. This contextualizes FBXL14 therapeutics: manipulation would likely need to be pathway- and substrate-aware (e.g., EMT context vs neurodevelopmental context). (yumimoto2020fboxproteinsand pages 7-10)

6.2 Structural rationale for motif-driven substrate selection

The FBXL family review frames substrate recognition as primarily mediated by the concave LRR interface and highlights that LRR organization can enable high-affinity interactions. In FBXL14 specifically, this aligns with demonstrated recognition of short motifs (HES1 WRPW) and mapped substrate regions (SNAIL1 aa120–151) that plausibly engage an LRR surface. (mason2020thefbxlfamily pages 3-4, chen2017thee3ubiquitin media 2535ebd1, vinascastells2010thehypoxiacontrolledfbxl14 pages 10-12)

7) Relevant statistics and data highlights

Hypoxia/clinical tumor association (colon adenocarcinoma; n=33):
- CA9 present in 30/33 tumors; FBXL14 RNA decreased in 25/33 tumors vs normal mucosa. (vinascastells2010thehypoxiacontrolledfbxl14 pages 9-10)
- FBXL14 inversely correlated with CA9: r = −0.43, p = 0.013. (vinascastells2010thehypoxiacontrolledfbxl14 pages 9-10)
- TWIST1-positive tumors show lower FBXL14 (geometric average 0.3 vs 0.81, p = 0.046) and higher CA9 (geometric average 1.83 vs 0.09, p = 0.012). (vinascastells2010thehypoxiacontrolledfbxl14 pages 9-10)

SNAIL1 stability measurements (cell models):
- Exogenous SNAIL1 half-life increased from ~1 h to ~3 h upon FBXL14 depletion. (vinascastells2010thehypoxiacontrolledfbxl14 pages 8-9)
- A SNAIL1 triple-lysine mutant (K98R/K137R/K146R) is highly stable with ~80% remaining after 4 h CHX and shows reduced ubiquitination. (vinascastells2010thehypoxiacontrolledfbxl14 pages 8-9, castells2013ubiquitinligasesinvolved pages 62-65)

3D genome regulation validation statistic:
- FBXL14 depletion increased inter-TAD interactions at ≥12/13 boundaries tested. (park2023highthroughputoligopaintscreen pages 4-6)

8) Current applications and real-world implementations

8.1 Potential biomarker/prognostic use (evidence base still emerging)

The colon tumor dataset provides quantitative evidence that FBXL14 mRNA down-regulation associates with hypoxia (CA9) and TWIST1, consistent with an EMT-permissive program; this supports the plausibility of FBXL14 as a context-dependent biomarker of hypoxia/EMT state, although direct clinical implementation is not proposed in the source and would require validation. (vinascastells2010thehypoxiacontrolledfbxl14 pages 9-10)

8.2 Targeted protein degradation (TPD) engineering

FBXL14’s identification as a strong proximity-induced destabilizer across multiple substrate localizations supports its candidacy as an E3 ligase for engineered degrader systems (a translational research direction rather than a deployed clinical technology). (hermanns2024proximitydependentprotein(de)stabilization pages 1-2)

8.3 Drug discovery for chromatin architecture

By emerging as a “druggable” 3D genome regulator in a Nature screen, FBXL14 becomes a candidate node for chemical biology aimed at modulating chromatin folding; however, the mechanism and druggability at the protein-structure level remain to be established. (park2023highthroughputoligopaintscreen pages 4-6)

9) Evidence summary table

The following table consolidates direct substrates vs functional associations and highlights motifs, pathways, localization, and disease relevance.

Substrate/Process	Evidence type	Key recognition motif/degron	Pathway/biological context	Subcellular location notes	Disease relevance	Key citation (paper, year, DOI/URL)
HES1 (direct substrate)	siRNA knockdown of FBXL14, CUL1, RBX1; co-IP; in vivo ubiquitination assay; CHX chase; proteasome inhibition (MG132); neuronal differentiation assays in mES/F9 cells	C-terminal WRPW motif in HES1 required for FBXL14 binding and ubiquitination; FBXL14 F-box required for SCF activity; modeling supports WRPW interaction with FBXL14 LRR domain	Notch/HES1 oscillation and repression of proneural genes; SCF^FBXL14 promotes neuronal differentiation by destabilizing HES1	Specific FBXL14 localization not emphasized in this study; assays support action within SCF(CUL1-SKP1-RBX1)-FBXL14 complex	Functional relevance to development/neurogenesis; cited in relation to neurological phenotypes	Chen et al., 2017, J Biol Chem, doi:10.1074/jbc.M117.815001, https://doi.org/10.1074/jbc.M117.815001 (chen2017thee3ubiquitin pages 18-20, chen2017thee3ubiquitin pages 16-18, chen2017thee3ubiquitin pages 1-2, chen2017thee3ubiquitin media 2535ebd1)
SNAIL1 (direct substrate)	Interaction and ubiquitination/degradation assays summarized in review of primary work; shRNA inhibition stabilizes ectopic and endogenous SNAIL1; domain mapping of minimal region required for FBXL14-mediated degradation	Minimal SNAIL1 region for FBXL14-mediated degradation maps to aa 120-151; both phosphorylated and unphosphorylated SNAIL1 can be targeted	EMT regulation; hypoxia/HIF-1α/TWIST1 axis represses FBXL14, stabilizing SNAIL1	FBXL14 reported as cytoplasmic by immunofluorescence; proposed to act on newly synthesized cytoplasmic SNAIL1	Linked to tumor hypoxia, EMT, invasion, and poorer prognosis when FBXL14 is downregulated	Viñas-Castells et al., 2010, J Biol Chem, doi:10.1074/jbc.M109.065995, https://doi.org/10.1074/jbc.M109.065995; summarized with localization/mechanism in later review (castells2013ubiquitinligasesinvolveda pages 97-100, castells2013ubiquitinligasesinvolved pages 97-100)
c-Myc / Myc (direct substrate, supported mainly through cited primary studies and reviews)	Review-cited primary studies report FBXL14-mediated ubiquitination of Myc; overexpression promotes differentiation and suppresses glioma stem-cell growth/tumorigenicity; effects reversed by degradation-resistant c-Myc T58A mutant	Recognition linked to Thr58-phosphorylated c-Myc; USP13 antagonizes FBXL14-mediated Myc ubiquitination	Glioblastoma stem-cell maintenance/differentiation; FBXL14 acts opposite to USP13 on Myc stability	No firm FBXL14 localization detail extracted from recent review excerpts	Lower FBXL14 in glioma stem cells; FBXL14 overexpression suppresses tumor-forming capacity, while USP13 counteracts this axis	Tao et al., 2023, Oncol Lett, doi:10.3892/ol.2023.14191, https://doi.org/10.3892/ol.2023.14191; review cites primary glioblastoma studies including J Exp Med 2017. Supporting cancer review: Yumimoto et al., 2020, doi:10.3390/cancers12051249, https://doi.org/10.3390/cancers12051249 (tao2023rolesofubiquitin‑specific pages 8-9, tao2023rolesofubiquitin‑specific pages 9-10, tao2023rolesofubiquitin‑specific pages 5-6, yumimoto2020fboxproteinsand pages 7-10)
3D genome regulation / inter-TAD insulation (functional hit, not established direct substrate)	HiDRO/Oligopaint high-throughput depletion screen; validation across multiple genomic boundaries; knockdown increased inter-TAD interactions	No direct degron/substrate motif established for this phenotype	FBXL14 emerged as representative ubiquitin ligase-class regulator of chromatin folding/3D genome organization	No direct localization claim in excerpt; functional phenotype is genome-architecture associated	Identified as a potentially druggable 3D genome regulator; disease relevance indirect/technology-enabling rather than substrate-level	Park et al., 2023, Nature, doi:10.1038/s41586-023-06340-w, https://doi.org/10.1038/s41586-023-06340-w (park2023highthroughputoligopaintscreen pages 4-6)
Broad protein-destabilization capacity (functional association, not a specific substrate assignment)	Proteome-scale and proximity-dependent degradation-effector screens; activity tested against 10 model substrates with different localizations	No specific degron defined; screen measures proximity-induced destabilization	Positions FBXL14 as a candidate targeted protein degradation (TPD) effector / E3-recruitment module	Active across model substrates with varied subcellular localizations	Translational relevance for TPD/E3-ligase harnessing rather than endogenous biology alone	Hermanns & Hofmann, 2024, Signal Transduct Target Ther, doi:10.1038/s41392-024-01884-3, https://doi.org/10.1038/s41392-024-01884-3 (summarizing Poirson et al., 2024, Nature) (hermanns2024proximitydependentprotein(de)stabilization pages 1-2)

Table: This table summarizes the best-supported functions and reported substrates or associations for human FBXL14, distinguishing direct substrates from broader functional hits. It highlights the evidence base, recognition motifs, pathway context, localization clues, and disease relevance for rapid functional annotation.

10) Key figure evidence (visual)

Chen et al. (JBC 2017) Figure 4 provides direct visual evidence that the HES1 WRPW motif is required for FBXL14 binding/ubiquitination and that FBXL14 F-box deletion reduces HES1 polyubiquitination and degradation. (chen2017thee3ubiquitin media 2535ebd1, chen2017thee3ubiquitin media 2e33b0eb, chen2017thee3ubiquitin media a8a05436, chen2017thee3ubiquitin media f9d2cd0e)

11) Limitations of this synthesis

Some frequently cited FBXL14 substrates/phenotypes (e.g., CDCP1 in breast cancer; additional EMT factors such as TWIST/SLUG; developmental roles such as MKP3 in vertebrate axis formation) are referenced in reviews within the retrieved set but were not available here as directly retrieved primary full-text evidence. Accordingly, this report emphasizes HES1 and SNAIL1 as the most strongly supported direct substrates from primary mechanistic studies and treats additional claims as review-level context.

12) Primary references with dates and URLs (from retrieved corpus)

Viñas-Castells R. et al. 2010-02. J Biol Chem. “The Hypoxia-controlled FBXL14 Ubiquitin Ligase Targets SNAIL1 for Proteasome Degradation.” https://doi.org/10.1074/jbc.M109.065995 (vinascastells2010thehypoxiacontrolledfbxl14 pages 1-2, vinascastells2010thehypoxiacontrolledfbxl14 pages 8-9, vinascastells2010thehypoxiacontrolledfbxl14 pages 9-10, vinascastells2010thehypoxiacontrolledfbxl14 pages 4-6)
Chen F. et al. 2017-12. J Biol Chem. “The E3 ubiquitin ligase SCF^FBXL14 complex stimulates neuronal differentiation by targeting the Notch signaling factor HES1 for proteolysis.” https://doi.org/10.1074/jbc.M117.815001 (chen2017thee3ubiquitin pages 1-2, chen2017thee3ubiquitin pages 18-20, chen2017thee3ubiquitin media 2535ebd1)
Park D.S. et al. 2023-07. Nature. “High-throughput Oligopaint screen identifies druggable 3D genome regulators.” https://doi.org/10.1038/s41586-023-06340-w (park2023highthroughputoligopaintscreen pages 4-6)
Hermanns T., Hofmann K. 2024-07. Signal Transduction and Targeted Therapy. “Proximity-dependent protein (de)stabilization: screening the human ORFeome for protein degraders and stabilizers.” https://doi.org/10.1038/s41392-024-01884-3 (hermanns2024proximitydependentprotein(de)stabilization pages 1-2)
Tao Y. et al. 2023-12. Oncology Letters (Review). “Roles of ubiquitin-specific protease 13 in normal physiology and tumors.” https://doi.org/10.3892/ol.2023.14191 (tao2023rolesofubiquitin‑specific pages 8-9, tao2023rolesofubiquitin‑specific pages 5-6)
Mason B., Laman H. 2020-11. Open Biology (Review). “The FBXL family of F-box proteins: variations on a theme.” https://doi.org/10.1098/rsob.200319 (mason2020thefbxlfamily pages 3-4, mason2020thefbxlfamily pages 4-5)
Yumimoto K. et al. 2020-05. Cancers (Review). “F-Box Proteins and Cancer.” https://doi.org/10.3390/cancers12051249 (yumimoto2020fboxproteinsand pages 7-10, yumimoto2020fboxproteinsand pages 10-12)

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Artifacts

Edison artifact artifact-00

Citations

yumimoto2020fboxproteinsand pages 7-10
park2023highthroughputoligopaintscreen pages 4-6
mason2020thefbxlfamily pages 3-4
mason2020thefbxlfamily pages 4-5
tekcham2020fboxproteinsand pages 1-3
sato2010augmentationofthe pages 1-2
mason2020thefbxlfamily pages 2-3
sato2010augmentationofthe pages 2-3
mason2020thefbxlfamily pages 5-6
castells2013ubiquitinligasesinvolved pages 97-100
castells2013ubiquitinligasesinvolved pages 62-65
yumimoto2020fboxproteinsand pages 10-12
castells2013ubiquitinligasesinvolveda pages 97-100
https://doi.org/10.1074/jbc.M117.815001
https://doi.org/10.1074/jbc.M109.065995;
https://doi.org/10.3892/ol.2023.14191;
https://doi.org/10.3390/cancers12051249
https://doi.org/10.1038/s41586-023-06340-w
https://doi.org/10.1038/s41392-024-01884-3
https://doi.org/10.1074/jbc.M109.065995
https://doi.org/10.3892/ol.2023.14191
https://doi.org/10.1098/rsob.200319
https://doi.org/10.1098/rsob.200319,
https://doi.org/10.1074/jbc.m117.815001,
https://doi.org/10.7150/thno.42735,
https://doi.org/10.3892/ijo_00000758,
https://doi.org/10.1074/jbc.m109.065995,
https://doi.org/10.3390/cancers12051249,
https://doi.org/10.3892/ol.2023.14191,
https://doi.org/10.1038/s41586-023-06340-w,
https://doi.org/10.1038/s41392-024-01884-3,

📚 Additional Documentation

Pn Notes

(FBXL14-pn-notes.md)

FBXL14 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q8N1E6
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-13
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/FBXL14/FBXL14-ai-review.yaml
AIGR review HTML: missing - genes/human/FBXL14/FBXL14-ai-review.html
Gene notes: missing - genes/human/FBXL14/FBXL14-notes.md
GOA TSV: present - genes/human/FBXL14/FBXL14-goa.tsv
UniProt record: present - genes/human/FBXL14/FBXL14-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/FBXL14.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/FBXL14.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/FBXL14/FBXL14-deep-research-falcon.md

AIGR Review Snapshot

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/core annotation action counts: ACCEPT: 4; KEEP_AS_NON_CORE: 18; MODIFY: 1; NEW: 1

PN Consistency Summary

Consistency: Strong. Falcon, review YAML, and PN mapping agree FBXL14 is the SCF(FBXL14) substrate receptor degrading SNAI1/SNAIL1 (PMID:19955572, IDA), with falcon adding HES1 (WRPW motif) and Thr58-phospho-c-MYC substrate axes. No contradictions.
PN story / NEW pressure: PN asserts the generic adaptor MF (GO:1990756, verified real). GOA carries catalytic GO:0004842 ubiquitin-protein transferase activity (IDA) — the classic F-box mis-attribution of RBX1-RING catalysis to the receptor. The review correctly MODIFY's GO:0004842 → GO:1990756 AND adds GO:1990756 as a NEW IDA annotation. Bare protein binding (SNAI1, SKP1; 6 IPI rows) kept non-core. This is the canonical correct call. No unmet UPS NEW-term gap (SNAI1/HES1 degradation captured by GO:0031146/GO:0006511).
Evidence alignment: PN reference only "15340381/rev" (placeholder); review does not cite it. Review PMIDs (19955572 primary; 33234069 family; plus high-throughput SKP1 interactome PMIDs) are gene-specific. Benign divergence.
Verdict: CONSISTENT / ACCEPT mapping. No edits required; MODIFY(GO:0004842→GO:1990756) + NEW pattern correctly applied; substrate validated.

Full Consistency Review

UniProt: Q8N1E6 · 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.
Consistency: Strong. Falcon, review YAML, and PN mapping agree FBXL14 is the SCF(FBXL14) substrate receptor degrading SNAI1/SNAIL1 (PMID:19955572, IDA), with falcon adding HES1 (WRPW motif) and Thr58-phospho-c-MYC substrate axes. No contradictions.
PN story / NEW pressure: PN asserts the generic adaptor MF (GO:1990756, verified real). GOA carries catalytic GO:0004842 ubiquitin-protein transferase activity (IDA) — the classic F-box mis-attribution of RBX1-RING catalysis to the receptor. The review correctly MODIFY's GO:0004842 → GO:1990756 AND adds GO:1990756 as a NEW IDA annotation. Bare protein binding (SNAI1, SKP1; 6 IPI rows) kept non-core. This is the canonical correct call. No unmet UPS NEW-term gap (SNAI1/HES1 degradation captured by GO:0031146/GO:0006511).
Mapping strategy: Gene does not change the node. Status/scope right; catalysis excluded from sub-nodes. SNAI1 (and HES1) are validated substrates → adaptor MF experimentally grounded, not orphan/inferred-only. PN-projected GO:1990756 matches review core_functions MF exactly.
Evidence alignment: PN reference only "15340381/rev" (placeholder); review does not cite it. Review PMIDs (19955572 primary; 33234069 family; plus high-throughput SKP1 interactome PMIDs) are gene-specific. Benign divergence.
Verdict: CONSISTENT / ACCEPT mapping. No edits required; MODIFY(GO:0004842→GO:1990756) + NEW pattern correctly applied; substrate validated.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-13
review_yaml: genes/human/FBXL14/FBXL14-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: Q8N1E6
In branches: UPS
Signature domains: IPR001810
Auxiliary domains: IPR001611, 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: 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.

FBXL14

Gene Description

Existing Annotations Review

Core Functions

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.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research report: Human FBXL14 (UniProt Q8N1E6) functional annotation

0) Target verification (mandatory)

1) Key concepts and definitions (current understanding)

1.1 SCF/CRL1 E3 ubiquitin ligases

1.2 FBXL family structural principles (how FBXL14 likely recognizes substrates)

2) Core molecular functions of FBXL14 (primary functional annotation)

2.1 FBXL14 → HES1 (Notch pathway; neuronal differentiation)

2.2 FBXL14 → SNAIL1 (EMT regulator; hypoxia/EMT coupling)

2.3 FBXL14 → c-Myc (glioma stemness/differentiation axis; review-supported)

3) Subcellular localization and where FBXL14 acts

4) Pathways and biological processes

4.1 Notch signaling dynamics and neuronal differentiation

4.2 EMT regulation and tumor microenvironment (hypoxia)

5) Recent developments (prioritizing 2023–2024)

5.1 3D genome regulation (Nature 2023)

5.2 FBXL14 as a candidate E3 for targeted protein degradation platforms (STTT 2024)

5.3 2023 synthesis of USP13–FBXL14–Myc axis in tumors

6) Expert opinions and interpretive synthesis (authoritative sources)

6.1 Specificity challenges for targeting F-box proteins

6.2 Structural rationale for motif-driven substrate selection

7) Relevant statistics and data highlights

8) Current applications and real-world implementations

8.1 Potential biomarker/prognostic use (evidence base still emerging)

8.2 Targeted protein degradation (TPD) engineering

8.3 Drug discovery for chromatin architecture

9) Evidence summary table

10) Key figure evidence (visual)

11) Limitations of this synthesis

12) Primary references with dates and URLs (from retrieved corpus)

Artifacts

Citations

📚 Additional Documentation

Pn Notes

FBXL14 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

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

Projected GO annotations (1)

Note

📄 View Raw YAML