FBXL14

UniProt ID: Q8N1E6
Organism: Homo sapiens
Review Status: COMPLETE
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Gene 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 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.
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

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Suggested Questions for Experts

Q: 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?

Q: 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

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)

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📚 Additional Documentation

Pn Notes

(FBXL14-pn-notes.md)

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📄 View Raw YAML

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