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, consistent with a cytosolic SCF substrate receptor. Reason: Correct localization for a cytosolic SCF F-box protein; consistent with the cytosolic Reactome annotations. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Cytoplasm {ECO:0000250}.
GO:0098793 presynapse	IEA GO_REF:0000108	KEEP AS NON CORE	Summary: Inter-ontology logical inference placing FBXL20 at the presynapse, consistent with the SCRAPPER ortholog's presynaptic role in regulating RIM1 and synaptic vesicle release. Reason: Plausible localization inferred from the mouse SCRAPPER ortholog's presynaptic function; not directly demonstrated for the human protein, and secondary to the core SCF substrate-receptor activity. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Role in neural transmission (By similarity).
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 FBXL20-SKP1 association required for SCF assembly, but bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Q96IG2; P63208: SKP1; NbExp=8; IntAct=EBI-8835647, 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/FBXL20/FBXL20-uniprot.txt Q96IG2; P63208: SKP1; NbExp=8; IntAct=EBI-8835647, 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/FBXL20/FBXL20-uniprot.txt Q96IG2; P63208: SKP1; NbExp=8; IntAct=EBI-8835647, EBI-307486;
GO:0005515 protein binding	IPI PMID:34731788 p53/FBXL20 axis negatively regulates the protein stability o...	KEEP AS NON CORE	Summary: Interaction with PPP2R2A/PR55alpha (P63151), the FBXL20 substrate identified in the p53/FBXL20/PR55alpha study. Bare protein binding is uninformative. Reason: Records the functionally important FBXL20-PR55alpha substrate interaction, but bare protein binding is uninformative; the relationship is captured by the catabolic-process context. Supporting Evidence: PMID:34731788 the protein-stability of PR55α via FBXL20, a p53-target gene that serves as a substrate recognition component of the SCF (Skp1_Cullin1_F-box) E3 ubiquitin ligase complex
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/FBXL20/FBXL20-uniprot.txt Q96IG2; P63208: SKP1; NbExp=8; IntAct=EBI-8835647, EBI-307486;
GO:0045202 synapse	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-based electronic assignment of synaptic activity, reflecting the mouse SCRAPPER ortholog's synaptic function. Reason: Plausible from the mouse ortholog (SCRAPPER), but not directly demonstrated for the human protein; secondary to the core SCF substrate-receptor activity. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Role in neural transmission (By similarity).
GO:0098685 Schaffer collateral - CA1 synapse	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-based electronic assignment of activity at the Schaffer collateral-CA1 synapse, from the mouse SCRAPPER ortholog. Reason: Highly specific synaptic localization inferred from the mouse ortholog; not demonstrated for the human protein and secondary to the core activity. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Role in neural transmission (By similarity).
GO:0098978 glutamatergic synapse	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-based electronic assignment of activity at glutamatergic synapses, from the mouse SCRAPPER ortholog. Reason: Plausible from the mouse ortholog; not directly demonstrated for the human protein and secondary to the core activity. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Role in neural transmission (By similarity).
GO:0099575 regulation of protein catabolic process at presynapse, modulating synaptic transmission	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-based electronic assignment of presynaptic protein-catabolism regulation, reflecting the SCRAPPER ortholog's ubiquitination of the active-zone protein RIM1 to control synaptic vesicle release. Reason: Plausible role inferred from the mouse SCRAPPER ortholog (RIM1 ubiquitination at the presynapse); not directly demonstrated for the human protein and a context-specific process distinct from the generic core activity. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Role in neural transmission (By similarity).
GO:2000300 regulation of synaptic vesicle exocytosis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-based electronic assignment of synaptic-vesicle-exocytosis regulation, reflecting the SCRAPPER ortholog's control of presynaptic release. Reason: Plausible role inferred from the mouse ortholog; not directly demonstrated for the human protein and downstream of the core SCF substrate-receptor activity. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Role in neural transmission (By similarity).
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 FBXL20 functions in SCF-dependent proteasomal protein catabolism. Captures the core biological process. Reason: Core biological process for an SCF F-box substrate receptor; supported by PR55alpha degradation (PMID:34731788) and the SCRAPPER ortholog's RIM1 turnover. Supporting Evidence: PMID:34731788 substrate recognition component of the SCF (Skp1_Cullin1_F-box) E3 ubiquitin ligase complex that promotes proteasomal degradation of its targeted proteins
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 FBXL20-specific function. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Cytoplasm {ECO:0000250}.
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/FBXL20/FBXL20-uniprot.txt Cytoplasm {ECO:0000250}.
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/FBXL20/FBXL20-uniprot.txt Cytoplasm {ECO:0000250}.
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/FBXL20/FBXL20-uniprot.txt Cytoplasm {ECO:0000250}.
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/FBXL20/FBXL20-uniprot.txt Cytoplasm {ECO:0000250}.
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/FBXL20/FBXL20-uniprot.txt Cytoplasm {ECO:0000250}.
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/FBXL20/FBXL20-uniprot.txt Cytoplasm {ECO:0000250}.
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/FBXL20/FBXL20-uniprot.txt Cytoplasm {ECO:0000250}.
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/FBXL20/FBXL20-uniprot.txt Cytoplasm {ECO:0000250}.
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/FBXL20/FBXL20-uniprot.txt Cytoplasm {ECO:0000250}.
GO:1990756 ubiquitin-like ligase-substrate adaptor activity	IDA PMID:34731788 p53/FBXL20 axis negatively regulates the protein stability o...	NEW	Summary: Proposed core molecular function. As the LRR substrate-recognition subunit of SCF(FBXL20), FBXL20 selects substrates (PR55alpha/PPP2R2A in human cells; RIM1 for the SCRAPPER ortholog) for SCF-dependent ubiquitination. This more informative MF term is not in the GOA. Reason: Captures the precise molecular function of FBXL20 as an SCF substrate-recognition adaptor, more informative than the bare protein binding annotations. Supporting Evidence: PMID:34731788 substrate recognition component of the SCF (Skp1_Cullin1_F-box) E3 ubiquitin ligase complex that promotes proteasomal degradation of its targeted proteins

Core Functions

Substrate-recognition subunit of an SCF (SKP1-CUL1-RBX1) E3 ubiquitin ligase complex that selects substrates for SCF-dependent polyubiquitination and proteasomal degradation; in human cells it targets PR55alpha/PPP2R2A (a PP2A regulatory subunit) downstream of p53.

Molecular Function:

ubiquitin-like ligase-substrate adaptor activity

Directly Involved In:

SCF-dependent proteasomal ubiquitin-dependent protein catabolic process

Cellular Locations:

cytoplasm

Supporting Evidence:

PMID:34731788
substrate recognition component of the SCF (Skp1_Cullin1_F-box) E3 ubiquitin ligase complex that promotes proteasomal degradation of its targeted proteins

As the SCF(FBXL20) substrate receptor, targets VPS34/PIK3C3 for phosphodegron-gated (VPS34 Thr159) ubiquitination and proteasomal degradation downstream of p53/DNA-damage signaling, lowering PtdIns3P output to negatively regulate autophagy and endosomal receptor (e.g. EGFR) trafficking.

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/FBXL20/FBXL20-deep-research-falcon.md
FBXL20 acts as the substrate-recognition component of an **SCF (SKP1-CUL1-FBXL20)** E3 ubiquitin ligase that promotes **ubiquitination and proteasomal degradation** of **VPS34 (PIK3C3)**, the catalytic subunit of class III PI3K complexes.

Membrane-associated presynaptic SCF substrate receptor (SCRAPPER ortholog), targeted to membranes via CAAX-motif isoprenylation, that regulates protein catabolism at the presynapse to modulate synaptic vesicle release and neurotransmission, via ubiquitination of active-zone substrates such as RIM1/RIMS1.

Molecular Function:

ubiquitin-like ligase-substrate adaptor activity

Directly Involved In:

regulation of protein catabolic process at presynapse, modulating synaptic transmission

Cellular Locations:

presynapse

Supporting Evidence:

file:human/FBXL20/FBXL20-uniprot.txt
Role in neural transmission (By similarity).
file:human/FBXL20/FBXL20-deep-research-falcon.md
FBXL20 contains a **CAAX motif** that is **isoprenylated**, directing FBXL20 to **membranes**; this localization is required for ubiquitylation-dependent degradation of **RIM1** (RAB3-interacting molecule 1)

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

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000108

Automatic assignment of GO terms using logical inference, based on on inter-ontology links

PMID:27705803

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

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:34731788

p53/FBXL20 axis negatively regulates the protein stability of PR55α, a regulatory subunit of PP2A Ser/Thr phosphatase.

FBXL20 is a p53-target gene whose product is the substrate-recognition component of an SCF E3 ligase that promotes ubiquitination and proteasomal degradation of PR55alpha/PPP2R2A; FBXL20 knockdown reduces PR55alpha ubiquitination and increases its stability.

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/FBXL20/FBXL20-deep-research-falcon.md

Falcon deep research report for human FBXL20

FBXL20 is the substrate-recognition subunit of an SCF (CUL1-SKP1-FBXL20) E3 ligase that promotes ubiquitination and proteasomal degradation of VPS34/PIK3C3, binding VPS34 through its C-terminal LRR region (VPS34 C2 domain).

"FBXL20 acts as the substrate-recognition component of an **SCF (SKP1-CUL1-FBXL20)** E3 ubiquitin ligase that promotes **ubiquitination and proteasomal degradation** of **VPS34 (PIK3C3)**, the catalytic subunit of class III PI3K complexes."
DNA damage drives a p53 to FBXL20 to VPS34 checkpoint in which CDK-dependent VPS34 Thr159 phosphorylation creates a phosphodegron required for FBXL20-mediated ubiquitination.

"phosphorylation at **T159** is required for efficient FBXL20-mediated ubiquitination and degradation. Specifically, VPS34 **T159A** (nonphosphorylatable) is largely resistant, whereas **T159E** (phosphomimetic) remains sensitive"
By lowering VPS34 and PtdIns3P output, FBXL20 acts as a negative regulator of autophagy under genotoxic stress and slows endosomal degradation of receptors such as EGFR.

"FBXL20 knockdown increases VPS34 and increases an autophagy marker readout (LC3-II ratio), whereas FBXL20 overexpression lowers VPS34; collectively this supports FBXL20 as a **negative regulator of autophagy** under genotoxic stress"
FBXL20 contains a CAAX motif that is isoprenylated, directing it to membranes, and this localization is required for ubiquitylation-dependent degradation of RIM1.

"FBXL20 contains a **CAAX motif** that is **isoprenylated**, directing FBXL20 to **membranes**; this localization is required for ubiquitylation-dependent degradation of **RIM1** (RAB3-interacting molecule 1)"

Reactome:R-HSA-983157

Interaction of E3 with substrate and E2-Ub complex

Suggested Experiments

Experiment: Reconstitute SCF(FBXL20)-mediated ubiquitination in vitro with purified SKP1-CUL1-RBX1-FBXL20, an E2, and candidate substrates (VPS34/PIK3C3 phosphorylated at Thr159, PR55alpha/PPP2R2A, RIM1) to confirm direct ubiquitination, test phosphodegron dependence, and map sites.

Experiment: Use FBXL20 knockout/knockdown (and CAAX-motif mutants) in human neurons and epithelial cells with quantitative ubiquitinome/proteome profiling and autophagy/PtdIns3P readouts to define the endogenous substrate repertoire, test the p53-FBXL20-VPS34 autophagy checkpoint, and assess conservation of the presynaptic role.

Deep Research

Falcon

(FBXL20-deep-research-falcon.md)

Research report: Human FBXL20 (UniProt Q96IG2) functional annotation Falcon Edison Scientific Literature 28 citations 2 artifacts 2026-06-13T06:18:15.126720

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000009 The document details the interaction and ubiquitination of Vps34 by FBXL20 in Figures 3 and 5. - **Interaction (Figure 3)**: Co-imm (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 FBXL20 (UniProt Q96IG2) functional annotation

0) Target verification (critical identity checks)

Target: Homo sapiens FBXL20 (UniProt Q96IG2), also referred to in the literature as SCRAPPER; an F-box protein with LRR (leucine-rich repeat) substrate-binding modules that functions as a substrate receptor in SCF ubiquitin ligases. The retrieved primary mechanistic paper explicitly studies human FBXL20 as an SCF adaptor that regulates VPS34/PIK3C3 stability, and multiple high-authority reviews cite the same human FBXL20→VPS34 axis. (xiao2015fbxl20mediatedvps34ubiquitination pages 1-2, xiao2015fbxl20mediatedvps34ubiquitination pages 4-6, mason2020thefbxlfamily pages 11-12)

Domain/function alignment with UniProt context: The literature describes FBXL20 as an F-box + LRR protein in the SCF (SKP1–CUL1–F-box) family, consistent with the UniProt domain architecture (F-box domain + LRRs). (xiao2015fbxl20mediatedvps34ubiquitination pages 1-2, xiao2015fbxl20mediatedvps34ubiquitination pages 4-6, mason2020thefbxlfamily pages 11-12)

1) Key concepts and definitions (current understanding)

1.1 SCF (SKP1–CUL1–F-box) ubiquitin ligases and FBXL proteins

SCF complexes are Cullin-RING E3 ubiquitin ligases (CRLs) in which CUL1 serves as a scaffold, SKP1 links CUL1 to an F-box protein, and the F-box protein provides substrate recognition (often via LRRs or WD40 repeats). A central concept is that F-box proteins impose spatiotemporal control by coupling substrate binding and localization to ubiquitin-dependent proteasomal degradation. (skaar2013mechanismsandfunction pages 4-5)

FBXL proteins (F-box + LRR proteins) are a subfamily of F-box proteins characterized by multiple LRRs that mediate substrate binding. A dedicated FBXL-family review highlights that FBXL members share similar folds but distinct interactomes, and specifically cites FBXL20’s mechanistic role in VPS34 regulation. (mason2020thefbxlfamily pages 11-12)

1.2 FBXL20 as a non-enzymatic adaptor (not a catalytic enzyme)

FBXL20 itself is not an enzyme; it is a substrate adaptor that determines which proteins are ubiquitinated by an associated E3 ligase complex (SCF). Therefore, FBXL20’s “primary function” is best defined as substrate recruitment to SCF^FBXL20, thereby controlling substrate ubiquitination and proteasomal turnover. (xiao2015fbxl20mediatedvps34ubiquitination pages 1-2, xiao2015fbxl20mediatedvps34ubiquitination pages 4-6)

2) Molecular function and mechanism of action

2.1 Core experimentally validated function: SCF adaptor that targets VPS34/PIK3C3

A seminal mechanistic study (Genes & Development, 2015-01; URL https://doi.org/10.1101/gad.252528.114) demonstrates that FBXL20 acts as the substrate-recognition component of an SCF (SKP1–CUL1–FBXL20) E3 ubiquitin ligase that promotes ubiquitination and proteasomal degradation of VPS34 (PIK3C3), the catalytic subunit of class III PI3K complexes. (xiao2015fbxl20mediatedvps34ubiquitination pages 1-2, xiao2015fbxl20mediatedvps34ubiquitination pages 4-6)

Mechanistic mapping of binding determinants:
- FBXL20 requires its C-terminal LRR region to bind VPS34.
- VPS34 uses its C2 domain for interaction with FBXL20. (xiao2015fbxl20mediatedvps34ubiquitination pages 4-6, xiao2015fbxl20mediatedvps34ubiquitination media 811f5268)

Direct E3 reconstitution evidence:
- In vitro, recombinant CUL1 + SKP1 + FBXL20 can mediate VPS34 ubiquitination in the presence of E1 and E2 (Ubc5c). (xiao2015fbxl20mediatedvps34ubiquitination pages 4-6, xiao2015fbxl20mediatedvps34ubiquitination media 811f5268)

Proteasome dependence:
- Proteasome inhibitor MG132 blocks FBXL20-driven VPS34 loss, supporting proteasome-dependent turnover. (xiao2015fbxl20mediatedvps34ubiquitination pages 1-2, xiao2015fbxl20mediatedvps34ubiquitination pages 4-6)

2.2 Upstream regulation: p53 transcriptional control and phosphorylation-dependent substrate recognition

p53-dependent FBXL20 induction after DNA damage. The 2015 study shows that FBXL20 is p53-inducible following DNA damage; p53 knockdown abolishes FBXL20 inducibility and disrupts the pathway linking DNA damage to VPS34 downregulation. (xiao2015fbxl20mediatedvps34ubiquitination pages 4-6, xiao2015fbxl20mediatedvps34ubiquitination pages 10-12)

Phosphodegron logic via VPS34 T159 phosphorylation. DNA damage-associated signaling activates CDK activity and promotes phosphorylation of VPS34; phosphorylation at T159 is required for efficient FBXL20-mediated ubiquitination and degradation. Specifically, VPS34 T159A (nonphosphorylatable) is largely resistant, whereas T159E (phosphomimetic) remains sensitive to DNA damage-associated reduction. (xiao2015fbxl20mediatedvps34ubiquitination pages 10-12, xiao2015fbxl20mediatedvps34ubiquitination pages 8-10)

miRNA regulation. FBXL20 is reported as a direct target negatively regulated by miR-3151 in the same mechanistic study, providing an additional post-transcriptional control layer. (xiao2015fbxl20mediatedvps34ubiquitination pages 10-12)

2.3 Subcellular localization signals and implications

A highly cited authoritative review (Nature Reviews Molecular Cell Biology, 2013-05; URL https://doi.org/10.1038/nrm3582) reports that FBXL20 contains a CAAX motif that is isoprenylated, directing FBXL20 to membranes; this localization is required for ubiquitylation-dependent degradation of RIM1 (RAB3-interacting molecule 1). This supports a model in which FBXL20’s functions are localization-dependent (membrane-associated contexts such as trafficking/endocytosis or synaptic membrane compartments). (skaar2013mechanismsandfunction pages 4-5)

In a cancer-focused review table, FBXL20 is annotated as cytoplasmic, consistent with a role in cytosol/membrane-proximal substrate control rather than nuclear transcription factor function. (tekcham2020fboxproteinsand pages 11-12)

3) Biological processes and pathways

3.1 Autophagy regulation via VPS34 abundance and PtdIns3P output

VPS34 generates PtdIns3P, a lipid signal required for multiple trafficking steps including autophagy initiation and endosomal sorting. The 2015 mechanistic study shows that DNA damage induces an FBXL20-dependent reduction in VPS34, and correspondingly reduces a cellular PtdIns3P readout (FYVE reporter puncta), consistent with suppression of VPS34 complex output. (xiao2015fbxl20mediatedvps34ubiquitination pages 8-10)

Functionally, FBXL20 knockdown increases VPS34 and increases an autophagy marker readout (LC3-II ratio), whereas FBXL20 overexpression lowers VPS34; collectively this supports FBXL20 as a negative regulator of autophagy under genotoxic stress, acting through VPS34 proteasomal turnover. (xiao2015fbxl20mediatedvps34ubiquitination pages 1-2)

Recent review synthesis (2023–2024). Reviews on ubiquitination-dependent autophagy regulation in cancer continue to place VPS34 regulation by ubiquitin ligases as an important control node and cite the FBXL20–VPS34 degradation axis as part of the broader framework of UPS–autophagy crosstalk and potential intervention points. (2023-02: https://doi.org/10.3390/cancers15041112; 2024-10: https://doi.org/10.1186/s12967-024-05565-1) (xiao2015fbxl20mediatedvps34ubiquitination pages 8-10)

Note on novelty: Within the retrieved 2023–2024 sources, FBXL20 is primarily discussed as an established example rather than as the subject of new mechanistic discovery, suggesting that FBXL20-specific experimental advances in 2023–2024 may be comparatively limited or outside the retrieved corpus. (xiao2015fbxl20mediatedvps34ubiquitination pages 8-10)

3.2 Receptor trafficking and degradation (EGFR as a functional readout)

The 2015 study directly connects the p53→FBXL20→VPS34 axis to receptor degradation/endocytosis, using EGFR as a model receptor. FBXL20 knockdown increases VPS34 and accelerates EGF-stimulated EGFR degradation, while DNA damage conditions that reduce VPS34 correlate with reduced EGFR degradation; additionally, p53 knockdown in DNA-damaged cells significantly accelerates EGFR degradation, consistent with p53-mediated induction of FBXL20 acting upstream. (xiao2015fbxl20mediatedvps34ubiquitination pages 10-12)

This provides a specific pathway-level interpretation: DNA damage → p53 induction → FBXL20 upregulation → VPS34 downregulation → altered endosomal trafficking and receptor degradation. (xiao2015fbxl20mediatedvps34ubiquitination pages 1-2, xiao2015fbxl20mediatedvps34ubiquitination pages 10-12)

4) Visual mechanistic evidence from primary literature

Key primary-figure support was retrieved from the 2015 mechanistic study:
- FBXL20–VPS34 interaction by co-immunoprecipitation and the VPS34 domain schematic implicating the C2 domain in binding. (xiao2015fbxl20mediatedvps34ubiquitination media 811f5268)
- Evidence that a CUL1–SKP1–FBXL20 SCF complex mediates VPS34 ubiquitination, including in vitro reconstitution. (xiao2015fbxl20mediatedvps34ubiquitination media 83c73e8a)

5) Recent developments (prioritizing 2023–2024)

5.1 FBXL20 in the 2023–2024 “ubiquitin–autophagy–cancer” landscape

Two recent reviews (2023–2024) emphasize ubiquitination as a pervasive regulator of autophagy (including regulation of VPS34 complexes), and position ubiquitin-pathway manipulation as a therapeutic strategy in cancer; within that conceptual framework, the FBXL20→VPS34 degradation checkpoint remains a concrete mechanistic example linking DNA damage/p53 signaling to autophagy suppression. (2023-02: https://doi.org/10.3390/cancers15041112; 2024-10: https://doi.org/10.1186/s12967-024-05565-1) (xiao2015fbxl20mediatedvps34ubiquitination pages 8-10)

5.2 What remains unresolved or incomplete

The strongest mechanistic evidence for FBXL20 in human cells remains centered on VPS34 regulation and on localization-dependent degradation of RIM1 reported in an authoritative review. Additional substrates (e.g., E-cadherin) appear in review tables but were not supported by primary mechanistic evidence in the retrieved texts, so they should be treated as hypothesis-generating until confirmed by dedicated substrate validation studies. (tekcham2020fboxproteinsand pages 11-12, skaar2013mechanismsandfunction pages 4-5)

6) Current applications and real-world implementations

6.1 Biomarker/prognostic application in ovarian cancer (translational study)

A Translational Oncology study (2020-12; URL https://doi.org/10.1016/j.tranon.2020.100863) analyzed multi-omic and imaging cohorts (TCGA-OV, TCIA, CPTAC) and reported that FBXL20 CNV and expression levels are valuable prognostic markers for ovarian cancer survival outcomes:
- FBXL20 expression predicted overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) with reported P-values 0.0073, 0.0045, and 0.00475, respectively. (zheng2020agerelatedcopynumber pages 3-5)
- In CNV-based survival analysis (upper vs lower quartile), the study reports a hazard ratio (HR) of 7.115 for FBXL20. (zheng2020agerelatedcopynumber pages 3-5)
- The analysis also used median splits (FBXL20 High vs Low CNV) with n = 227 per group, and observed significant age distribution differences (P < 0.001). (zheng2020agerelatedcopynumber pages 3-5, zheng2020agerelatedcopynumber pages 2-3)
- Imaging association: tumor longest-dimension comparisons were performed with n = 190 (below-median FBXL20) and n = 191 (above-median FBXL20) groups, with a significant difference (P = 0.002). (zheng2020agerelatedcopynumber pages 5-8)

Mechanistic tie-in in this translational context: the authors cite VPS34 as “one well-studied substrate of FBXL20” and explicitly describe DDR-triggered VPS34 phosphorylation leading to FBXL20-mediated polyubiquitination and autophagy dampening. (zheng2020agerelatedcopynumber pages 5-8)

6.2 Therapeutic implication: targeting CRL activity (neddylation) rather than FBXL20 directly

The same ovarian cancer study discusses pevonedistat (a NEDD8 conjugation inhibitor) as a way to shut down SCF/CRL ubiquitin-conjugation activity, and suggests that inhibiting CRL activity could phenocopy lower FBXL20 activity in terms of clinical advantage (hypothesis-level translational framing). (zheng2020agerelatedcopynumber pages 8-8)

Interpretation: While this does not constitute FBXL20-specific drug development, it is a real-world translational implementation path: pharmacologic CRL inhibition as a way to modulate downstream proteostasis networks in cancer, potentially intersecting with SCF^FBXL20 function. (zheng2020agerelatedcopynumber pages 8-8)

7) Disease associations (Open Targets) and interpretation

Open Targets lists disease associations for FBXL20, including ovarian neoplasm, lower respiratory tract disease, asthma, and systemic lupus erythematosus, with multiple literature links (PubMed IDs) supporting these associations in the platform’s evidence framework. (OpenTargets Search: -FBXL20)

Interpretation caveat: Open Targets associations indicate a body of genetic/functional/omics evidence connecting a target to disease phenotypes, but do not by themselves establish a single causal mechanism; mechanistic interpretation should be anchored in primary experimental studies such as the VPS34/p53 checkpoint work. (OpenTargets Search: -FBXL20, xiao2015fbxl20mediatedvps34ubiquitination pages 1-2)

8) Expert synthesis and functional annotation summary

Primary molecular function (best-supported): FBXL20 is a substrate receptor in an SCF (CUL1–SKP1–FBXL20) E3 ubiquitin ligase that promotes ubiquitination and proteasomal degradation of VPS34/PIK3C3, thereby modulating PtdIns3P-dependent autophagy and receptor trafficking. (xiao2015fbxl20mediatedvps34ubiquitination pages 1-2, xiao2015fbxl20mediatedvps34ubiquitination pages 4-6, xiao2015fbxl20mediatedvps34ubiquitination pages 8-10)

Key upstream regulators:
- p53 transcriptional induction after DNA damage (checkpoint-like behavior). (xiao2015fbxl20mediatedvps34ubiquitination pages 4-6, xiao2015fbxl20mediatedvps34ubiquitination pages 10-12)
- CDK-dependent phosphorylation of VPS34 at T159 enabling recognition/ubiquitination. (xiao2015fbxl20mediatedvps34ubiquitination pages 10-12, xiao2015fbxl20mediatedvps34ubiquitination pages 8-10)
- miR-3151 negative regulation of FBXL20 (post-transcriptional). (xiao2015fbxl20mediatedvps34ubiquitination pages 10-12)
- CAAX motif isoprenylation driving membrane localization required for at least one substrate context (RIM1). (skaar2013mechanismsandfunction pages 4-5)

Where it acts in the cell: A combination of review and experimental pathway logic supports a cytoplasmic and membrane-associated functional space (endosomal/membrane trafficking; autophagy-related compartments), rather than a strictly nuclear role. (tekcham2020fboxproteinsand pages 11-12, skaar2013mechanismsandfunction pages 4-5)

Substrates with strongest support:
- VPS34/PIK3C3 (direct binding determinants and in vitro ubiquitination reconstitution). (xiao2015fbxl20mediatedvps34ubiquitination pages 4-6, xiao2015fbxl20mediatedvps34ubiquitination media 811f5268, xiao2015fbxl20mediatedvps34ubiquitination media 83c73e8a)
- RIM1 in the context of CAAX-dependent membrane localization (high-authority review synthesis). (skaar2013mechanismsandfunction pages 4-5)

9) Evidence summary table

Function/role	Molecular mechanism (SCF components, substrate recognition features)	Key substrates/interactors	Upstream regulation (p53, phosphorylation, miRNA, localization signals)	Pathways/biological processes affected	Experimental evidence type	Key quantitative/statistical notes	Primary sources (with DOI URLs, year)
Substrate receptor in an SCF E3 ubiquitin ligase that promotes VPS34 turnover	FBXL20 acts as the F-box substrate-recognition subunit of a CUL1-SKP1-FBXL20 SCF complex; the FBXL20 C-terminal LRR region is required to bind VPS34, and VPS34 uses its C2 domain for the interaction; SCF reconstitution with CUL1, SKP1, FBXL20, E1, and Ubc5c supports VPS34 ubiquitination in vitro (xiao2015fbxl20mediatedvps34ubiquitination pages 1-2, xiao2015fbxl20mediatedvps34ubiquitination pages 4-6, xiao2015fbxl20mediatedvps34ubiquitination media 811f5268)	VPS34/PIK3C3; SKP1; CUL1 (xiao2015fbxl20mediatedvps34ubiquitination pages 1-2, xiao2015fbxl20mediatedvps34ubiquitination pages 4-6, xiao2015fbxl20mediatedvps34ubiquitination media 811f5268)	FBXL20 expression is induced by p53 after DNA damage; transient p53 knockdown abolishes inducibility; FBXL20 is also reported as a miR-3151 target (xiao2015fbxl20mediatedvps34ubiquitination pages 4-6, xiao2015fbxl20mediatedvps34ubiquitination pages 10-12)	Autophagy control and receptor degradation/endocytosis via regulation of class III PI3K abundance (xiao2015fbxl20mediatedvps34ubiquitination pages 1-2, xiao2015fbxl20mediatedvps34ubiquitination pages 10-12, mason2020thefbxlfamily pages 11-12)	Co-immunoprecipitation, shRNA/siRNA knockdown, overexpression, in vitro ubiquitination reconstitution, proteasome inhibition with MG132 (xiao2015fbxl20mediatedvps34ubiquitination pages 1-2, xiao2015fbxl20mediatedvps34ubiquitination pages 4-6, xiao2015fbxl20mediatedvps34ubiquitination media 811f5268)	Quantification reported as mean ± SD from 3 independent experiments with significance thresholds P < 0.05 and P < 0.01; MG132 rescues FBXL20-driven VPS34 reduction (xiao2015fbxl20mediatedvps34ubiquitination pages 4-6)	Xiao et al., 2015, Genes and Development, DOI: https://doi.org/10.1101/gad.252528.114 (xiao2015fbxl20mediatedvps34ubiquitination pages 1-2, xiao2015fbxl20mediatedvps34ubiquitination pages 4-6)
DNA-damage-responsive checkpoint suppressing autophagy	DNA damage activates CDK-dependent phosphorylation of VPS34 at T159, creating a phospho-dependent signal for FBXL20 binding and ubiquitination; nonphosphorylatable VPS34 T159A is largely resistant, whereas phosphomimetic T159E remains sensitive to CPT-induced reduction (xiao2015fbxl20mediatedvps34ubiquitination pages 10-12, xiao2015fbxl20mediatedvps34ubiquitination pages 8-10)	VPS34/PIK3C3; CDK1 activity inferred from roscovitine sensitivity; FBXL20-SCF complex (xiao2015fbxl20mediatedvps34ubiquitination pages 10-12, xiao2015fbxl20mediatedvps34ubiquitination pages 8-10)	Upstream inputs include DNA damage, p53-dependent FBXL20 transcriptional induction, and CDK-mediated VPS34 phosphorylation; roscovitine suppresses the pathway (xiao2015fbxl20mediatedvps34ubiquitination pages 10-12, xiao2015fbxl20mediatedvps34ubiquitination pages 8-10)	Inhibition of autophagy under genotoxic stress through reduced PtdIns3P production and loss of VPS34 (xiao2015fbxl20mediatedvps34ubiquitination pages 1-2, xiao2015fbxl20mediatedvps34ubiquitination pages 8-10)	DNA-damage treatments with camptothecin, phosphomutant analysis, pharmacologic CDK inhibition, ubiquitination assays, PtdIns3P readout with FYVE reporters (xiao2015fbxl20mediatedvps34ubiquitination pages 8-10)	CPT treatment reduced FYVE-positive PtdIns3P puncta and these effects were reversed by FBXL20 knockdown; statistical significance reported qualitatively with P < 0.05 or P < 0.01 (xiao2015fbxl20mediatedvps34ubiquitination pages 8-10)	Xiao et al., 2015, Genes and Development, DOI: https://doi.org/10.1101/gad.252528.114 (xiao2015fbxl20mediatedvps34ubiquitination pages 10-12, xiao2015fbxl20mediatedvps34ubiquitination pages 8-10)
Negative regulator of receptor endocytosis and degradation through VPS34 depletion	By lowering VPS34, FBXL20 reduces endosomal PtdIns3P-dependent receptor trafficking; FBXL20 knockdown increases VPS34 and accelerates EGF-stimulated EGFR degradation, while CPT-induced FBXL20 and VPS34 regulation slows EGFR degradation (xiao2015fbxl20mediatedvps34ubiquitination pages 10-12, mason2020thefbxlfamily pages 11-12)	VPS34/PIK3C3; EGFR as downstream receptor-trafficking readout (xiao2015fbxl20mediatedvps34ubiquitination pages 10-12)	p53 knockdown in CPT-treated cells accelerates EGFR degradation, consistent with p53 to FBXL20 to VPS34 control; DNA damage is the main upstream trigger shown (xiao2015fbxl20mediatedvps34ubiquitination pages 10-12)	Receptor endocytosis and receptor degradation, especially EGFR trafficking (xiao2015fbxl20mediatedvps34ubiquitination pages 1-2, xiao2015fbxl20mediatedvps34ubiquitination pages 10-12, mason2020thefbxlfamily pages 11-12)	RNAi perturbation, DNA-damage treatment, receptor degradation assays with EGF stimulation (xiao2015fbxl20mediatedvps34ubiquitination pages 10-12)	ImageJ-based quantification from 2 independent experiments reported with P < 0.05 or P < 0.01 (xiao2015fbxl20mediatedvps34ubiquitination pages 10-12)	Xiao et al., 2015, Genes and Development, DOI: https://doi.org/10.1101/gad.252528.114; Mason and Laman, 2020, Open Biology, DOI: https://doi.org/10.1098/rsob.200319 (xiao2015fbxl20mediatedvps34ubiquitination pages 10-12, mason2020thefbxlfamily pages 11-12)
Membrane-localized FBXL adaptor with localization-dependent substrate control	High-authority review evidence states FBXL20 contains a CAAX motif that undergoes isoprenylation, directing FBXL20 to membranes; this membrane localization is required for ubiquitylation-dependent degradation of RIM1 (skaar2013mechanismsandfunction pages 4-5)	RIM1; membrane compartment; SCF context implied for FBXL proteins (skaar2013mechanismsandfunction pages 4-5)	CAAX motif-dependent isoprenylation controls localization and function (skaar2013mechanismsandfunction pages 4-5)	Spatial control of ubiquitylation; synaptic protein turnover in the cited review context (skaar2013mechanismsandfunction pages 4-5, sato2010augmentationofthe pages 2-3)	Review synthesis of prior mechanistic studies (skaar2013mechanismsandfunction pages 4-5, sato2010augmentationofthe pages 2-3)	No numerical effect sizes reported in the cited review excerpt (skaar2013mechanismsandfunction pages 4-5)	Skaar et al., 2013, Nature Reviews Molecular Cell Biology, DOI: https://doi.org/10.1038/nrm3582; Sato and Yoshida, 2010, International Journal of Oncology, DOI: https://doi.org/10.3892/ijo_00000758 (skaar2013mechanismsandfunction pages 4-5, sato2010augmentationofthe pages 2-3)
Cytoplasmic FBXL family member linked to oncogenic and Wnt/autophagy-related functions	Review table annotates FBXL20 as cytoplasmic and lists E-cadherin and VPS34 as substrate or pathway-linked targets; mechanistic depth is limited in this source, so these associations should be treated as curated review-level summaries rather than stand-alone primary proof (tekcham2020fboxproteinsand pages 11-12)	E-cadherin; VPS34 (tekcham2020fboxproteinsand pages 11-12)	Cytoplasmic localization annotated; no additional upstream regulators provided in the excerpt (tekcham2020fboxproteinsand pages 11-12)	Wnt signaling pathway and autophagy (tekcham2020fboxproteinsand pages 11-12)	Review table curation (tekcham2020fboxproteinsand pages 11-12)	No quantitative or statistical data in the cited table excerpt (tekcham2020fboxproteinsand pages 11-12)	Tekcham et al., 2020, Theranostics, DOI: https://doi.org/10.7150/thno.42735 (tekcham2020fboxproteinsand pages 11-12)
Current consensus role in autophagy literature	Multiple reviews summarize FBXL20 as a Cul1-based E3 adaptor that targets VPS34/PIK3C3 for ubiquitination and degradation, positioning FBXL20 as a negative regulator of autophagy initiation and execution by limiting VPS34 complex abundance (xiao2015fbxl20mediatedvps34ubiquitination pages 4-6, mason2020thefbxlfamily pages 11-12)	VPS34/PIK3C3; Cul1-SKP1-FBXL20 SCF machinery (xiao2015fbxl20mediatedvps34ubiquitination pages 4-6, mason2020thefbxlfamily pages 11-12)	p53 induction after DNA damage is the main upstream regulator repeatedly highlighted; VPS34 phosphorylation state determines recognition (xiao2015fbxl20mediatedvps34ubiquitination pages 4-6, xiao2015fbxl20mediatedvps34ubiquitination pages 8-10, mason2020thefbxlfamily pages 11-12)	Autophagy, proteostasis, receptor degradation; often discussed as part of Cullin-RING ligase and autophagy crosstalk (xiao2015fbxl20mediatedvps34ubiquitination pages 4-6, mason2020thefbxlfamily pages 11-12)	Review synthesis anchored in Xiao et al. 2015 primary data (xiao2015fbxl20mediatedvps34ubiquitination pages 4-6, mason2020thefbxlfamily pages 11-12)	No new quantitative values in reviews beyond citing the primary study; emphasis is on pathway placement and mechanistic interpretation (mason2020thefbxlfamily pages 11-12)	Mason and Laman, 2020, Open Biology, DOI: https://doi.org/10.1098/rsob.200319; Chen et al., 2019, Journal of Biomedical Science, DOI: https://doi.org/10.1186/s12929-019-0569-y; Lu et al., 2021, Trends in Cell Biology, DOI: https://doi.org/10.1016/j.tcb.2021.01.005; Jee and Cheong, 2023, Cancers, DOI: https://doi.org/10.3390/cancers15041112; Wu et al., 2024, Journal of Translational Medicine, DOI: https://doi.org/10.1186/s12967-024-05565-1 (mason2020thefbxlfamily pages 11-12, xiao2015fbxl20mediatedvps34ubiquitination pages 4-6, xiao2015fbxl20mediatedvps34ubiquitination pages 8-10)

Table: This table summarizes experimentally supported functions and regulatory mechanisms of human FBXL20/Q96IG2, emphasizing the primary Xiao et al. 2015 study and high-authority reviews. It separates direct primary evidence from review-level annotations to keep the functional claims evidence-based.

10) Key references (URLs and publication dates)

Xiao J. et al. “FBXL20-mediated Vps34 ubiquitination as a p53 controlled checkpoint in regulating autophagy and receptor degradation.” Genes & Development 2015-01. https://doi.org/10.1101/gad.252528.114 (xiao2015fbxl20mediatedvps34ubiquitination pages 1-2, xiao2015fbxl20mediatedvps34ubiquitination pages 4-6)
Skaar J.R. et al. “Mechanisms and function of substrate recruitment by F-box proteins.” Nature Reviews Molecular Cell Biology 2013-05. https://doi.org/10.1038/nrm3582 (skaar2013mechanismsandfunction pages 4-5)
Mason B., Laman H. “The FBXL family of F-box proteins: variations on a theme.” Open Biology 2020-11. https://doi.org/10.1098/rsob.200319 (mason2020thefbxlfamily pages 11-12)
Jee S.-C., Cheong H. “Autophagy/Mitophagy Regulated by Ubiquitination: A Promising Pathway in Cancer Therapeutics.” Cancers 2023-02. https://doi.org/10.3390/cancers15041112 (xiao2015fbxl20mediatedvps34ubiquitination pages 8-10)
Wu Y. et al. “Ubiquitination regulates autophagy in cancer: simple modifications, promising targets.” Journal of Translational Medicine 2024-10. https://doi.org/10.1186/s12967-024-05565-1 (xiao2015fbxl20mediatedvps34ubiquitination pages 8-10)
Zheng S., Fu Y. “Age-related copy number variations and expression levels of F-box protein FBXL20 predict ovarian cancer prognosis.” Translational Oncology 2020-12. https://doi.org/10.1016/j.tranon.2020.100863 (zheng2020agerelatedcopynumber pages 3-5, zheng2020agerelatedcopynumber pages 5-8)

References

(xiao2015fbxl20mediatedvps34ubiquitination pages 1-2): Juan Xiao, Tao Zhang, Daichao Xu, Huibing Wang, Yu Cai, Taijie Jin, Min Liu, Mingzhi Jin, Kejia Wu, and Junying Yuan. Fbxl20-mediated vps34 ubiquitination as a p53 controlled checkpoint in regulating autophagy and receptor degradation. Genes & Development, 29:184-196, Jan 2015. URL: https://doi.org/10.1101/gad.252528.114, doi:10.1101/gad.252528.114. This article has 89 citations and is from a highest quality peer-reviewed journal.
(xiao2015fbxl20mediatedvps34ubiquitination pages 4-6): Juan Xiao, Tao Zhang, Daichao Xu, Huibing Wang, Yu Cai, Taijie Jin, Min Liu, Mingzhi Jin, Kejia Wu, and Junying Yuan. Fbxl20-mediated vps34 ubiquitination as a p53 controlled checkpoint in regulating autophagy and receptor degradation. Genes & Development, 29:184-196, Jan 2015. URL: https://doi.org/10.1101/gad.252528.114, doi:10.1101/gad.252528.114. This article has 89 citations and is from a highest quality peer-reviewed journal.
(mason2020thefbxlfamily pages 11-12): Bethany Mason and Heike Laman. The fbxl family of f-box proteins: variations on a theme. Nov 2020. URL: https://doi.org/10.1098/rsob.200319, doi:10.1098/rsob.200319. This article has 51 citations and is from a peer-reviewed journal.
(skaar2013mechanismsandfunction pages 4-5): Jeffrey R. Skaar, Julia K. Pagan, and Michele Pagano. Mechanisms and function of substrate recruitment by f-box proteins. Nature Reviews Molecular Cell Biology, 14:369-381, May 2013. URL: https://doi.org/10.1038/nrm3582, doi:10.1038/nrm3582. This article has 818 citations and is from a domain leading peer-reviewed journal.
(xiao2015fbxl20mediatedvps34ubiquitination media 811f5268): Juan Xiao, Tao Zhang, Daichao Xu, Huibing Wang, Yu Cai, Taijie Jin, Min Liu, Mingzhi Jin, Kejia Wu, and Junying Yuan. Fbxl20-mediated vps34 ubiquitination as a p53 controlled checkpoint in regulating autophagy and receptor degradation. Genes & Development, 29:184-196, Jan 2015. URL: https://doi.org/10.1101/gad.252528.114, doi:10.1101/gad.252528.114. This article has 89 citations and is from a highest quality peer-reviewed journal.
(xiao2015fbxl20mediatedvps34ubiquitination pages 10-12): Juan Xiao, Tao Zhang, Daichao Xu, Huibing Wang, Yu Cai, Taijie Jin, Min Liu, Mingzhi Jin, Kejia Wu, and Junying Yuan. Fbxl20-mediated vps34 ubiquitination as a p53 controlled checkpoint in regulating autophagy and receptor degradation. Genes & Development, 29:184-196, Jan 2015. URL: https://doi.org/10.1101/gad.252528.114, doi:10.1101/gad.252528.114. This article has 89 citations and is from a highest quality peer-reviewed journal.
(xiao2015fbxl20mediatedvps34ubiquitination pages 8-10): Juan Xiao, Tao Zhang, Daichao Xu, Huibing Wang, Yu Cai, Taijie Jin, Min Liu, Mingzhi Jin, Kejia Wu, and Junying Yuan. Fbxl20-mediated vps34 ubiquitination as a p53 controlled checkpoint in regulating autophagy and receptor degradation. Genes & Development, 29:184-196, Jan 2015. URL: https://doi.org/10.1101/gad.252528.114, doi:10.1101/gad.252528.114. This article has 89 citations and is from a highest quality peer-reviewed journal.
(tekcham2020fboxproteinsand pages 11-12): Dinesh Singh Tekcham, Di Chen, Yu Liu, Ting Ling, Yi Zhang, Huan Chen, Wen Wang, Wuxiyar Otkur, Huan Qi, Tian Xia, Xiaolong Liu, Hai-long Piao, and Hongxu Liu. F-box proteins and cancer: an update from functional and regulatory mechanism to therapeutic clinical prospects. Theranostics, 10:4150-4167, Mar 2020. URL: https://doi.org/10.7150/thno.42735, doi:10.7150/thno.42735. This article has 111 citations and is from a domain leading peer-reviewed journal.
(xiao2015fbxl20mediatedvps34ubiquitination media 83c73e8a): Juan Xiao, Tao Zhang, Daichao Xu, Huibing Wang, Yu Cai, Taijie Jin, Min Liu, Mingzhi Jin, Kejia Wu, and Junying Yuan. Fbxl20-mediated vps34 ubiquitination as a p53 controlled checkpoint in regulating autophagy and receptor degradation. Genes & Development, 29:184-196, Jan 2015. URL: https://doi.org/10.1101/gad.252528.114, doi:10.1101/gad.252528.114. This article has 89 citations and is from a highest quality peer-reviewed journal.
(zheng2020agerelatedcopynumber pages 3-5): Shuhua Zheng and Yuejun Fu. Age-related copy number variations and expression levels of f-box protein fbxl20 predict ovarian cancer prognosis. Dec 2020. URL: https://doi.org/10.1016/j.tranon.2020.100863, doi:10.1016/j.tranon.2020.100863. This article has 9 citations and is from a peer-reviewed journal.
(zheng2020agerelatedcopynumber pages 2-3): Shuhua Zheng and Yuejun Fu. Age-related copy number variations and expression levels of f-box protein fbxl20 predict ovarian cancer prognosis. Dec 2020. URL: https://doi.org/10.1016/j.tranon.2020.100863, doi:10.1016/j.tranon.2020.100863. This article has 9 citations and is from a peer-reviewed journal.
(zheng2020agerelatedcopynumber pages 5-8): Shuhua Zheng and Yuejun Fu. Age-related copy number variations and expression levels of f-box protein fbxl20 predict ovarian cancer prognosis. Dec 2020. URL: https://doi.org/10.1016/j.tranon.2020.100863, doi:10.1016/j.tranon.2020.100863. This article has 9 citations and is from a peer-reviewed journal.
(zheng2020agerelatedcopynumber pages 8-8): Shuhua Zheng and Yuejun Fu. Age-related copy number variations and expression levels of f-box protein fbxl20 predict ovarian cancer prognosis. Dec 2020. URL: https://doi.org/10.1016/j.tranon.2020.100863, doi:10.1016/j.tranon.2020.100863. This article has 9 citations and is from a peer-reviewed journal.
(OpenTargets Search: -FBXL20): Open Targets Query (-FBXL20, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(sato2010augmentationofthe pages 2-3): Kazuyuki Sato and Kenichi Yoshida. Augmentation of the ubiquitin-mediated proteolytic system by f-box and additional motif-containing proteins (review). International journal of oncology, 37 5:1071-6, Nov 2010. URL: https://doi.org/10.3892/ijo_00000758, doi:10.3892/ijo_00000758. This article has 5 citations and is from a peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Citations

skaar2013mechanismsandfunction pages 4-5
mason2020thefbxlfamily pages 11-12
tekcham2020fboxproteinsand pages 11-12
zheng2020agerelatedcopynumber pages 3-5
zheng2020agerelatedcopynumber pages 5-8
zheng2020agerelatedcopynumber pages 8-8
zheng2020agerelatedcopynumber pages 2-3
sato2010augmentationofthe pages 2-3
https://doi.org/10.1101/gad.252528.114
https://doi.org/10.1038/nrm3582
https://doi.org/10.3390/cancers15041112;
https://doi.org/10.1186/s12967-024-05565-1
https://doi.org/10.1016/j.tranon.2020.100863
https://doi.org/10.1101/gad.252528.114;
https://doi.org/10.1098/rsob.200319
https://doi.org/10.1038/nrm3582;
https://doi.org/10.3892/ijo_00000758
https://doi.org/10.7150/thno.42735
https://doi.org/10.1098/rsob.200319;
https://doi.org/10.1186/s12929-019-0569-y;
https://doi.org/10.1016/j.tcb.2021.01.005;
https://doi.org/10.3390/cancers15041112
https://doi.org/10.1101/gad.252528.114,
https://doi.org/10.1098/rsob.200319,
https://doi.org/10.1038/nrm3582,
https://doi.org/10.7150/thno.42735,
https://doi.org/10.1016/j.tranon.2020.100863,
https://doi.org/10.3892/ijo_00000758,

📚 Additional Documentation

Pn Notes

(FBXL20-pn-notes.md)

FBXL20 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q96IG2
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-13
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/FBXL20/FBXL20-ai-review.yaml
AIGR review HTML: missing - genes/human/FBXL20/FBXL20-ai-review.html
Gene notes: missing - genes/human/FBXL20/FBXL20-notes.md
GOA TSV: present - genes/human/FBXL20/FBXL20-goa.tsv
UniProt record: present - genes/human/FBXL20/FBXL20-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/FBXL20.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/FBXL20.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/FBXL20/FBXL20-deep-research-falcon.md

AIGR Review Snapshot

Description: FBXL20 (F-box/LRR-repeat protein 20; FBL2; the mouse ortholog is named SCRAPPER) 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. FBXL20 carries a C-terminal CAAX motif that is isoprenylated, targeting it to membranes, and its localization governs which substrates it engages. A well-characterized human substrate is VPS34/PIK3C3, the catalytic subunit of class III PI3K: FBXL20 binds VPS34 through its C-terminal LRR region (engaging the VPS34 C2 domain) and, downstream of DNA damage, promotes CDK-dependent (VPS34 Thr159) phosphodegron-gated ubiquitination and proteasomal degradation of VPS34. FBXL20 is itself a p53-inducible gene (and a miR-3151 target), so the p53 to FBXL20 to VPS34 axis lowers PtdIns3P output, dampening autophagy and slowing endosomal receptor (e.g. EGFR) degradation under genotoxic stress. FBXL20 also promotes ubiquitination and degradation of PR55alpha/PPP2R2A, a regulatory B subunit of the PP2A serine/threonine phosphatase. In the nervous system the SCRAPPER/FBXL20 ortholog is a membrane-associated presynaptic regulator that ubiquitinates the active-zone protein RIM1/RIMS1, controlling synaptic vesicle release and neurotransmission; accordingly the protein has documented roles at the presynapse and at glutamatergic synapses (largely inferred from the mouse ortholog). FBXL20 acts in the cytoplasm/cytosol and at membranes.
Existing/core annotation action counts: ACCEPT: 2; KEEP_AS_NON_CORE: 21; NEW: 1

PN Consistency Summary

Consistency: Fully consistent. Falcon DR (VPS34/PIK3C3 phosphodegron axis; CAAX-isoprenylation/RIM1; PR55alpha), the review YAML, the PN F-box LRR substrate-receptor placement, and the GO:1990756 group mapping all converge. No contradictions.
PN story / NEW pressure: PN projects GO:1990756 (verified real, OLS: "binding...brings together a ubiquitin-like ligase and its substrate. Usually mediated by F-box...proteins") as new_to_goa. Review independently ADDS GO:1990756 as action: NEW (IDA, PMID:34731788), replacing five bare protein binding (SKP1/PR55alpha) IPI annotations. Matches PN projection exactly. Conclude: ADD — warranted and concordant.
Evidence alignment: PN reference is only "15340381 / rev" (Jin et al. F-box family review), not directly in the review's PMID set; review anchors on the human PR55alpha study PMID:34731788 (HIGH/VERIFIED) plus FBXL family review PMID:33234069 and Falcon DR for the VPS34 axis. Divergence is benign — PN uses a generic family review; review uses gene-specific primary literature.
Verdict: Consistent; GO:1990756 NEW warranted and matches PN (new_to_goa). No over-reach.

Full Consistency Review

UniProt: Q96IG2 (FBXL20/FBL2; mouse ortholog SCRAPPER) · batch: proteostasis-batch-2026-06-13 (Falcon DR) · review status: COMPLETE
PN placement: UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|LRR ; PN-node mapping: group Cul1 substrate receptor=mapped/ok_for_propagation→GO:1990756; F-box/LRR subtype+type=no_mapping; class=context_only/too_broad→GO:0061630.
Consistency: Fully consistent. Falcon DR (VPS34/PIK3C3 phosphodegron axis; CAAX-isoprenylation/RIM1; PR55alpha), the review YAML, the PN F-box LRR substrate-receptor placement, and the GO:1990756 group mapping all converge. No contradictions.
PN story / NEW pressure: PN projects GO:1990756 (verified real, OLS: "binding...brings together a ubiquitin-like ligase and its substrate. Usually mediated by F-box...proteins") as new_to_goa. Review independently ADDS GO:1990756 as action: NEW (IDA, PMID:34731788), replacing five bare protein binding (SKP1/PR55alpha) IPI annotations. Matches PN projection exactly. Conclude: ADD — warranted and concordant.
Mapping strategy: Gene supports, does not change, the node. KEY PATTERN holds: F-box = SCF substrate receptor, catalysis in RBX1; the correct shared MF is the GO:1990756 adaptor term at the receptor group, with the catalytic GO:0061630 correctly held at class level as too_broad. No PN-projected term is broader than the review (unlike TOMM20/HSPA8 precedent). Scopes correct.
Evidence alignment: PN reference is only "15340381 / rev" (Jin et al. F-box family review), not directly in the review's PMID set; review anchors on the human PR55alpha study PMID:34731788 (HIGH/VERIFIED) plus FBXL family review PMID:33234069 and Falcon DR for the VPS34 axis. Divergence is benign — PN uses a generic family review; review uses gene-specific primary literature.
Verdict: Consistent; GO:1990756 NEW warranted and matches PN (new_to_goa). No over-reach.
Recommended edits: none to FBXL20-ai-review.yaml; PN mappings sound as-is.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-13
review_yaml: genes/human/FBXL20/FBXL20-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: Q96IG2
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: Q96IG2
gene_symbol: FBXL20
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FBXL20 (F-box/LRR-repeat protein 20; FBL2; the mouse ortholog is named
  SCRAPPER) 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. FBXL20 carries a C-terminal CAAX motif that is
  isoprenylated, targeting it to membranes, and its localization governs which
  substrates it engages. A well-characterized human substrate is VPS34/PIK3C3,
  the catalytic subunit of class III PI3K: FBXL20 binds VPS34 through its
  C-terminal LRR region (engaging the VPS34 C2 domain) and, downstream of DNA
  damage, promotes CDK-dependent (VPS34 Thr159) phosphodegron-gated
  ubiquitination and proteasomal degradation of VPS34. FBXL20 is itself a
  p53-inducible gene (and a miR-3151 target), so the p53 to FBXL20 to VPS34 axis
  lowers PtdIns3P output, dampening autophagy and slowing endosomal receptor
  (e.g. EGFR) degradation under genotoxic stress. FBXL20 also promotes
  ubiquitination and degradation of PR55alpha/PPP2R2A, a regulatory B subunit of
  the PP2A serine/threonine phosphatase. In the nervous system the
  SCRAPPER/FBXL20 ortholog is a membrane-associated presynaptic regulator that
  ubiquitinates the active-zone protein RIM1/RIMS1, controlling synaptic vesicle
  release and neurotransmission; accordingly the protein has documented roles at
  the presynapse and at glutamatergic synapses (largely inferred from the mouse
  ortholog). FBXL20 acts in the cytoplasm/cytosol and at membranes.
alternative_products:
- name: '1'
  id: Q96IG2-1
- name: '2'
  id: Q96IG2-2
  sequence_note: VSP_030769
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, consistent with a cytosolic SCF substrate receptor.
    action: ACCEPT
    reason: Correct localization for a cytosolic SCF F-box protein; consistent with the cytosolic Reactome annotations.
    supported_by:
    - reference_id: file:human/FBXL20/FBXL20-uniprot.txt
      supporting_text: 'Cytoplasm {ECO:0000250}.'
- term:
    id: GO:0098793
    label: presynapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: located_in
  review:
    summary: Inter-ontology logical inference placing FBXL20 at the presynapse, consistent with the SCRAPPER ortholog's presynaptic role in regulating RIM1 and synaptic vesicle release.
    action: KEEP_AS_NON_CORE
    reason: Plausible localization inferred from the mouse SCRAPPER ortholog's presynaptic function; not directly demonstrated for the human protein, and secondary to the core SCF substrate-receptor activity.
    supported_by:
    - reference_id: file:human/FBXL20/FBXL20-uniprot.txt
      supporting_text: Role in neural transmission (By similarity).
- 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 FBXL20-SKP1 association required for SCF assembly, but bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/FBXL20/FBXL20-uniprot.txt
      supporting_text: 'Q96IG2; P63208: SKP1; NbExp=8; IntAct=EBI-8835647, 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/FBXL20/FBXL20-uniprot.txt
      supporting_text: 'Q96IG2; P63208: SKP1; NbExp=8; IntAct=EBI-8835647, 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/FBXL20/FBXL20-uniprot.txt
      supporting_text: 'Q96IG2; P63208: SKP1; NbExp=8; IntAct=EBI-8835647, EBI-307486;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34731788
  qualifier: enables
  review:
    summary: Interaction with PPP2R2A/PR55alpha (P63151), the FBXL20 substrate identified in the p53/FBXL20/PR55alpha study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally important FBXL20-PR55alpha substrate interaction, but bare protein binding is uninformative; the relationship is captured by the catabolic-process context.
    supported_by:
    - reference_id: PMID:34731788
      supporting_text: the protein-stability of PR55α via FBXL20, a p53-target gene that serves as a substrate recognition component of the SCF (Skp1_Cullin1_F-box) E3 ubiquitin ligase complex
- 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/FBXL20/FBXL20-uniprot.txt
      supporting_text: 'Q96IG2; P63208: SKP1; NbExp=8; IntAct=EBI-8835647, EBI-307486;'
- term:
    id: GO:0045202
    label: synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Ortholog-based electronic assignment of synaptic activity, reflecting the mouse SCRAPPER ortholog's synaptic function.
    action: KEEP_AS_NON_CORE
    reason: Plausible from the mouse ortholog (SCRAPPER), but not directly demonstrated for the human protein; secondary to the core SCF substrate-receptor activity.
    supported_by:
    - reference_id: file:human/FBXL20/FBXL20-uniprot.txt
      supporting_text: Role in neural transmission (By similarity).
- term:
    id: GO:0098685
    label: Schaffer collateral - CA1 synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Ortholog-based electronic assignment of activity at the Schaffer collateral-CA1 synapse, from the mouse SCRAPPER ortholog.
    action: KEEP_AS_NON_CORE
    reason: Highly specific synaptic localization inferred from the mouse ortholog; not demonstrated for the human protein and secondary to the core activity.
    supported_by:
    - reference_id: file:human/FBXL20/FBXL20-uniprot.txt
      supporting_text: Role in neural transmission (By similarity).
- term:
    id: GO:0098978
    label: glutamatergic synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Ortholog-based electronic assignment of activity at glutamatergic synapses, from the mouse SCRAPPER ortholog.
    action: KEEP_AS_NON_CORE
    reason: Plausible from the mouse ortholog; not directly demonstrated for the human protein and secondary to the core activity.
    supported_by:
    - reference_id: file:human/FBXL20/FBXL20-uniprot.txt
      supporting_text: Role in neural transmission (By similarity).
- term:
    id: GO:0099575
    label: regulation of protein catabolic process at presynapse, modulating synaptic
      transmission
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-based electronic assignment of presynaptic protein-catabolism regulation, reflecting the SCRAPPER ortholog's ubiquitination of the active-zone protein RIM1 to control synaptic vesicle release.
    action: KEEP_AS_NON_CORE
    reason: Plausible role inferred from the mouse SCRAPPER ortholog (RIM1 ubiquitination at the presynapse); not directly demonstrated for the human protein and a context-specific process distinct from the generic core activity.
    supported_by:
    - reference_id: file:human/FBXL20/FBXL20-uniprot.txt
      supporting_text: Role in neural transmission (By similarity).
- term:
    id: GO:2000300
    label: regulation of synaptic vesicle exocytosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-based electronic assignment of synaptic-vesicle-exocytosis regulation, reflecting the SCRAPPER ortholog's control of presynaptic release.
    action: KEEP_AS_NON_CORE
    reason: Plausible role inferred from the mouse ortholog; not directly demonstrated for the human protein and downstream of the core SCF substrate-receptor activity.
    supported_by:
    - reference_id: file:human/FBXL20/FBXL20-uniprot.txt
      supporting_text: Role in neural transmission (By similarity).
- 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 FBXL20 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; supported by PR55alpha degradation (PMID:34731788) and the SCRAPPER ortholog's RIM1 turnover.
    supported_by:
    - reference_id: PMID:34731788
      supporting_text: substrate recognition component of the SCF (Skp1_Cullin1_F-box) E3 ubiquitin ligase complex that promotes proteasomal degradation of its targeted proteins
- 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 FBXL20-specific function.
    supported_by:
    - reference_id: file:human/FBXL20/FBXL20-uniprot.txt
      supporting_text: 'Cytoplasm {ECO:0000250}.'
- 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/FBXL20/FBXL20-uniprot.txt
      supporting_text: 'Cytoplasm {ECO:0000250}.'
- 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/FBXL20/FBXL20-uniprot.txt
      supporting_text: 'Cytoplasm {ECO:0000250}.'
- 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/FBXL20/FBXL20-uniprot.txt
      supporting_text: 'Cytoplasm {ECO:0000250}.'
- 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/FBXL20/FBXL20-uniprot.txt
      supporting_text: 'Cytoplasm {ECO:0000250}.'
- 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/FBXL20/FBXL20-uniprot.txt
      supporting_text: 'Cytoplasm {ECO:0000250}.'
- 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/FBXL20/FBXL20-uniprot.txt
      supporting_text: 'Cytoplasm {ECO:0000250}.'
- 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/FBXL20/FBXL20-uniprot.txt
      supporting_text: 'Cytoplasm {ECO:0000250}.'
- 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/FBXL20/FBXL20-uniprot.txt
      supporting_text: 'Cytoplasm {ECO:0000250}.'
- 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/FBXL20/FBXL20-uniprot.txt
      supporting_text: 'Cytoplasm {ECO:0000250}.'
- term:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:34731788
  qualifier: enables
  review:
    summary: Proposed core molecular function. As the LRR substrate-recognition subunit of SCF(FBXL20), FBXL20 selects substrates (PR55alpha/PPP2R2A in human cells; RIM1 for the SCRAPPER ortholog) for SCF-dependent ubiquitination. This more informative MF term is not in the GOA.
    action: NEW
    reason: Captures the precise molecular function of FBXL20 as an SCF substrate-recognition adaptor, more informative than the bare protein binding annotations.
    supported_by:
    - reference_id: PMID:34731788
      supporting_text: substrate recognition component of the SCF (Skp1_Cullin1_F-box) E3 ubiquitin ligase complex that promotes proteasomal degradation of its targeted proteins
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: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- 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: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:34731788
  title: p53/FBXL20 axis negatively regulates the protein stability of PR55α, a regulatory
    subunit of PP2A Ser/Thr phosphatase.
  findings:
  - statement: FBXL20 is a p53-target gene whose product is the substrate-recognition component of an SCF E3 ligase that promotes ubiquitination and proteasomal degradation of PR55alpha/PPP2R2A; FBXL20 knockdown reduces PR55alpha ubiquitination and increases its stability.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (Neoplasia 2021), full text available; establishes PR55alpha/PPP2R2A as a human SCF(FBXL20) substrate and the p53 regulatory axis.
- 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/FBXL20/FBXL20-deep-research-falcon.md
  title: Falcon deep research report for human FBXL20
  findings:
  - statement: FBXL20 is the substrate-recognition subunit of an SCF (CUL1-SKP1-FBXL20) E3 ligase that promotes ubiquitination and proteasomal degradation of VPS34/PIK3C3, binding VPS34 through its C-terminal LRR region (VPS34 C2 domain).
    supporting_text: >-
      FBXL20 acts as the substrate-recognition component of an **SCF (SKP1-CUL1-FBXL20)**
      E3 ubiquitin ligase that promotes **ubiquitination and proteasomal degradation**
      of **VPS34 (PIK3C3)**, the catalytic subunit of class III PI3K complexes.
  - statement: DNA damage drives a p53 to FBXL20 to VPS34 checkpoint in which CDK-dependent VPS34 Thr159 phosphorylation creates a phosphodegron required for FBXL20-mediated ubiquitination.
    supporting_text: >-
      phosphorylation at **T159** is required for efficient FBXL20-mediated
      ubiquitination and degradation. Specifically, VPS34 **T159A** (nonphosphorylatable)
      is largely resistant, whereas **T159E** (phosphomimetic) remains sensitive
  - statement: By lowering VPS34 and PtdIns3P output, FBXL20 acts as a negative regulator of autophagy under genotoxic stress and slows endosomal degradation of receptors such as EGFR.
    supporting_text: >-
      FBXL20 knockdown increases VPS34 and increases an autophagy marker readout
      (LC3-II ratio), whereas FBXL20 overexpression lowers VPS34; collectively this
      supports FBXL20 as a **negative regulator of autophagy** under genotoxic stress
  - statement: FBXL20 contains a CAAX motif that is isoprenylated, directing it to membranes, and this localization is required for ubiquitylation-dependent degradation of RIM1.
    supporting_text: >-
      FBXL20 contains a **CAAX motif** that is **isoprenylated**, directing FBXL20 to
      **membranes**; this localization is required for ubiquitylation-dependent
      degradation of **RIM1** (RAB3-interacting molecule 1)
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Falcon adds the human VPS34/PIK3C3 substrate axis (Xiao et al. 2015 Genes &
      Dev, DOI 10.1101/gad.252528.114) and the CAAX-isoprenylation/membrane-localization
      requirement for RIM1 degradation (Skaar et al. 2013 Nat Rev Mol Cell Biol
      review). These are reported via author-year DOIs not in the PMID cache;
      cross-checked against UniProt and the existing PR55alpha study (PMID:34731788),
      and treated as well-supported leads rather than 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 substrates for SCF-dependent polyubiquitination and proteasomal degradation; in human cells it targets PR55alpha/PPP2R2A (a PP2A regulatory subunit) downstream of p53.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:34731788
    supporting_text: substrate recognition component of the SCF (Skp1_Cullin1_F-box) E3 ubiquitin ligase complex that promotes proteasomal degradation of its targeted proteins
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
- description: As the SCF(FBXL20) substrate receptor, targets VPS34/PIK3C3 for phosphodegron-gated (VPS34 Thr159) ubiquitination and proteasomal degradation downstream of p53/DNA-damage signaling, lowering PtdIns3P output to negatively regulate autophagy and endosomal receptor (e.g. EGFR) trafficking.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: file:human/FBXL20/FBXL20-deep-research-falcon.md
    supporting_text: >-
      FBXL20 acts as the substrate-recognition component of an **SCF (SKP1-CUL1-FBXL20)**
      E3 ubiquitin ligase that promotes **ubiquitination and proteasomal degradation**
      of **VPS34 (PIK3C3)**, the catalytic subunit of class III PI3K complexes.
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
- description: Membrane-associated presynaptic SCF substrate receptor (SCRAPPER ortholog), targeted to membranes via CAAX-motif isoprenylation, that regulates protein catabolism at the presynapse to modulate synaptic vesicle release and neurotransmission, via ubiquitination of active-zone substrates such as RIM1/RIMS1.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations:
  - id: GO:0098793
    label: presynapse
  supported_by:
  - reference_id: file:human/FBXL20/FBXL20-uniprot.txt
    supporting_text: Role in neural transmission (By similarity).
  - reference_id: file:human/FBXL20/FBXL20-deep-research-falcon.md
    supporting_text: >-
      FBXL20 contains a **CAAX motif** that is **isoprenylated**, directing FBXL20 to
      **membranes**; this localization is required for ubiquitylation-dependent
      degradation of **RIM1** (RAB3-interacting molecule 1)
  directly_involved_in:
  - id: GO:0099575
    label: regulation of protein catabolic process at presynapse, modulating synaptic
      transmission
proposed_new_terms: []
suggested_questions:
- question: Which of the FBXL20 functions established for the mouse SCRAPPER ortholog (RIM1 ubiquitination, regulation of synaptic vesicle release) are conserved and directly demonstrable for the human protein, and is CAAX isoprenylation required?
- question: How do the membrane/autophagy (VPS34/PIK3C3, p53-DNA-damage axis), synaptic (RIM1), and PP2A (PR55alpha) substrate-targeting activities of FBXL20 relate, and are they coordinated by CAAX-dependent localization or by distinct phosphodegrons?
suggested_experiments:
- description: Reconstitute SCF(FBXL20)-mediated ubiquitination in vitro with purified SKP1-CUL1-RBX1-FBXL20, an E2, and candidate substrates (VPS34/PIK3C3 phosphorylated at Thr159, PR55alpha/PPP2R2A, RIM1) to confirm direct ubiquitination, test phosphodegron dependence, and map sites.
- description: Use FBXL20 knockout/knockdown (and CAAX-motif mutants) in human neurons and epithelial cells with quantitative ubiquitinome/proteome profiling and autophagy/PtdIns3P readouts to define the endogenous substrate repertoire, test the p53-FBXL20-VPS34 autophagy checkpoint, and assess conservation of the presynaptic role.

FBXL20

Gene Description

Existing Annotations Review

Core Functions

Substrate-recognition subunit of an SCF (SKP1-CUL1-RBX1) E3 ubiquitin ligase complex that selects substrates for SCF-dependent polyubiquitination and proteasomal degradation; in human cells it targets PR55alpha/PPP2R2A (a PP2A regulatory subunit) downstream of p53.

As the SCF(FBXL20) substrate receptor, targets VPS34/PIK3C3 for phosphodegron-gated (VPS34 Thr159) ubiquitination and proteasomal degradation downstream of p53/DNA-damage signaling, lowering PtdIns3P output to negatively regulate autophagy and endosomal receptor (e.g. EGFR) trafficking.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research report: Human FBXL20 (UniProt Q96IG2) functional annotation

0) Target verification (critical identity checks)

1) Key concepts and definitions (current understanding)

1.1 SCF (SKP1–CUL1–F-box) ubiquitin ligases and FBXL proteins

1.2 FBXL20 as a non-enzymatic adaptor (not a catalytic enzyme)

2) Molecular function and mechanism of action

2.1 Core experimentally validated function: SCF adaptor that targets VPS34/PIK3C3

2.2 Upstream regulation: p53 transcriptional control and phosphorylation-dependent substrate recognition

2.3 Subcellular localization signals and implications

3) Biological processes and pathways

3.1 Autophagy regulation via VPS34 abundance and PtdIns3P output

3.2 Receptor trafficking and degradation (EGFR as a functional readout)

4) Visual mechanistic evidence from primary literature

5) Recent developments (prioritizing 2023–2024)

5.1 FBXL20 in the 2023–2024 “ubiquitin–autophagy–cancer” landscape

5.2 What remains unresolved or incomplete

6) Current applications and real-world implementations

6.1 Biomarker/prognostic application in ovarian cancer (translational study)

6.2 Therapeutic implication: targeting CRL activity (neddylation) rather than FBXL20 directly

7) Disease associations (Open Targets) and interpretation

8) Expert synthesis and functional annotation summary

9) Evidence summary table

10) Key references (URLs and publication dates)

Artifacts

Citations

📚 Additional Documentation

Pn Notes

FBXL20 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