FBXW4

UniProt ID: P57775
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

FBXW4 (dactylin; SHFM3) is a member of the F-box/WD40 (FBXW) family of proteins. Its 412-residue product contains an N-terminal F-box motif (approximately residues 25-71) and a C-terminal beta-propeller built from roughly six WD40 repeats. F-box proteins function as the interchangeable substrate-recognition subunits of SCF (SKP1-CUL1-F-box)-type cullin-RING E3 ubiquitin ligase complexes: the F-box motif docks the protein onto SKP1/CUL1, while the WD40 propeller recognizes (typically phosphorylated) substrate proteins and presents them for ubiquitination by the RBX1-bound E2, committing them to proteasomal degradation. Affinity-purification studies confirm that FBXW4 assembles, in an F-box-dependent manner, with the canonical SCF core subunits SKP1, CUL1 and RBX1 and with COP9 signalosome subunits (which deneddylate and regulate cullin-RING ligases), and that FBXW4 associates with ubiquitinated cellular proteins in a manner enhanced by proteasome inhibition - establishing it as a bona fide SCF substrate receptor engaged in ubiquitin-dependent turnover. Its physiological substrates, however, remain undefined. FBXW4 is broadly expressed (including brain, kidney, lung and liver) and is recurrently mutated, deleted, or under-expressed across human cancers, suggesting a candidate tumor-suppressor role. The human gene maps to chromosome 10q24.3 within the critical region for split-hand/foot malformation type 3 (SHFM3), and the orthologous gene is disrupted in the mouse dactylaplasia (Dac) mutant, which fails to maintain the apical ectodermal ridge and truncates the autopod. SHFM3 is most often associated with tandem/discontinuous genomic duplications at 10q24 that perturb a shared cis-regulatory neighborhood and alter expression of FBXW4 and several neighboring genes (e.g. BTRC, POLL, LBX1) rather than with coding mutations in FBXW4 itself, so FBXW4's precise contribution to limb development and its physiological ubiquitination substrates remain incompletely defined.

Proposed New Ontology Terms

ubiquitin-like ligase-substrate adaptor activity

Definition: Bridging a substrate to a ubiquitin-like protein ligase, as performed by an SCF F-box substrate-recognition subunit that binds both SKP1/the ligase scaffold and the substrate to facilitate the substrate's ubiquitination. This corresponds to the existing GO term GO:1990756, which is not currently in FBXW4's annotation set.

Justification: FBXW4 assembles with the SCF core (SKP1/CUL1/RBX1) and the COP9 signalosome in an F-box-dependent manner and associates with ubiquitinated proteins in a proteasome-inhibitor-dependent way, consistent with a substrate-adaptor molecular function rather than catalysis (which is RBX1's). Adding GO:1990756 would give FBXW4 an informative molecular-function term in place of the uninformative bare protein binding annotations.

Parent term: ubiquitin-like ligase-substrate adaptor activity

Supporting Evidence:

Existing Annotations Review

GO Term Evidence Action Reason
GO:0019005 SCF ubiquitin ligase complex
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic (PAN-GO) assignment of SCF complex membership, consistent with FBXW4's F-box motif that docks F-box proteins onto SKP1/CUL1. Now directly corroborated by FBXW4-specific affinity-purification data showing F-box-dependent assembly with SKP1, CUL1 and RBX1.
Reason: Core localization/assembly role for an F-box protein; supported by the F-box domain, the documented SKP1 interaction, and direct biochemical co-purification of FBXW4 with the SCF core (SKP1/CUL1/RBX1) and COP9 signalosome in an F-box-dependent manner.
Supporting Evidence:
file:human/FBXW4/FBXW4-uniprot.txt
Part of a SCF (SKP1-cullin-F-box) protein ligase complex
file:human/FBXW4/FBXW4-deep-research-falcon.md
FBXW4 co-purifies/interacts with **SKP1, CUL1, RBX1** and multiple **COP9 signalosome (COPS)** subunits, and these interactions are **F-box dependent**
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic assignment of involvement in SCF-dependent proteasomal degradation, the canonical process for F-box substrate-receptor proteins. FBXW4-specific data show it engages ubiquitinated proteins in a proteasome-inhibitor- and F-box-dependent manner, supporting genuine participation in ubiquitin-dependent turnover.
Reason: Core biological process for an F-box protein acting as an SCF substrate receptor; consistent with the UniProt function statement and with direct evidence that FBXW4 associates with ubiquitinated cellular proteins (increased by MG132) in an F-box-dependent manner.
Supporting Evidence:
file:human/FBXW4/FBXW4-uniprot.txt
Probably recognizes and binds to some phosphorylated proteins and promotes their ubiquitination and degradation
file:human/FBXW4/FBXW4-deep-research-falcon.md
FBXW4 interacts with **ubiquitinated cellular proteins**, and the interaction increases with **proteasome inhibition (MG132)** in an **F-box-dependent** manner, consistent with substrate engagement in ubiquitin-dependent turnover pathways
GO:0005515 protein binding
IPI
PMID:22632967
Cyclin F-mediated degradation of ribonucleotide reductase M2... 		KEEP AS NON CORE
Summary: IntAct interaction captured against SKP1 (UniProtKB:P63208) in a cyclin F/SCF study; records the functionally important FBXW4-SKP1 association. Bare protein binding is uninformative.
Reason: Records the real FBXW4-SKP1 interaction (the WITH/FROM target is P63208/SKP1), which underpins SCF assembly, but bare protein binding is uninformative per curation guidelines.
Supporting Evidence:
file:human/FBXW4/FBXW4-uniprot.txt
P57775; P63208: SKP1; NbExp=3; IntAct=EBI-2372268, EBI-307486
GO:0005515 protein binding
IPI
PMID:27705803
A High-Density Map for Navigating the Human Polycomb Complex... 		KEEP AS NON CORE
Summary: IntAct interaction against SKP1 (UniProtKB:P63208) from a Polycomb complexome map; supports FBXW4-SKP1 association. Bare protein binding is uninformative.
Reason: Records the FBXW4-SKP1 interaction (WITH/FROM P63208/SKP1) relevant to SCF assembly, but bare protein binding is uninformative.
Supporting Evidence:
file:human/FBXW4/FBXW4-uniprot.txt
P57775; P63208: SKP1; NbExp=3; IntAct=EBI-2372268, EBI-307486
GO:0005515 protein binding
IPI
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative ... 		KEEP AS NON CORE
Summary: High-throughput interactome interaction against PRKN/Parkin isoform (UniProtKB:O60260-5) from a neurodegenerative-disease interactome study. Bare protein binding is uninformative.
Reason: Records a high-throughput interaction (WITH/FROM O60260-5/PRKN); bare protein binding is uninformative and not a core function.
Supporting Evidence:
file:human/FBXW4/FBXW4-uniprot.txt
P57775; O60260-5: PRKN; NbExp=3; IntAct=EBI-2372268, EBI-21251460
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		KEEP AS NON CORE
Summary: IntAct interaction against SKP1 (UniProtKB:P63208) from a cell-specific interactome map; supports FBXW4-SKP1 association. Bare protein binding is uninformative.
Reason: Records the FBXW4-SKP1 interaction (WITH/FROM P63208/SKP1) relevant to SCF assembly, but bare protein binding is uninformative.
Supporting Evidence:
file:human/FBXW4/FBXW4-uniprot.txt
P57775; P63208: SKP1; NbExp=3; IntAct=EBI-2372268, EBI-307486
GO:0019005 SCF ubiquitin ligase complex
NAS
PMID:34445249
The SCF Complex Is Essential to Maintain Genome and Chromoso... 		ACCEPT
Summary: ComplexPortal (CPX-7761) curated assignment of FBXW4 to an SCF E3 ubiquitin ligase complex variant.
Reason: Correct core assembly annotation; FBXW4 is the substrate-receptor subunit of an SCF complex variant (ComplexPortal CPX-7761), consistent with SKP1 binding.
Supporting Evidence:
file:human/FBXW4/FBXW4-uniprot.txt
Part of a SCF (SKP1-cullin-F-box) protein ligase complex
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
NAS
PMID:34445249
The SCF Complex Is Essential to Maintain Genome and Chromoso... 		ACCEPT
Summary: ComplexPortal-derived assignment of involvement in SCF-dependent proteasomal degradation, the canonical process for an SCF substrate receptor.
Reason: Correct core biological process; redundant with the IBA assignment of the same term.
Supporting Evidence:
file:human/FBXW4/FBXW4-uniprot.txt
promotes their ubiquitination and degradation
GO:0060173 limb development
NAS
PMID:10471509
A novel member of the F-box/WD40 gene family, encoding dacty... 		KEEP AS NON CORE
Summary: Author-stated involvement in limb development, based on disruption of the orthologous gene (dactylin) in the mouse dactylaplasia mutant, which truncates the autopod via failure to maintain the apical ectodermal ridge.
Reason: Genetically well-supported developmental association (dactylaplasia mouse; SHFM3 locus) but the molecular mechanism and direct FBXW4 substrates in limb patterning are not established; this is a pleiotropic developmental role rather than a demonstrated direct molecular function.
Supporting Evidence:
PMID:10471509
this report demonstrates the importance of this gene family in vertebrate embryonic development
GO:0005829 cytosol
TAS
Reactome:R-HSA-8952618 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization for FBXW4 within generic CRL1/SCF neddylation and ubiquitination reactions.
Reason: Plausible cytosolic localization for an SCF subunit, but derived from generic CRL pathway reactions rather than FBXW4-specific localization data; the dactylin/SHFM3 literature implies action in developing tissues without resolving compartment.
Supporting Evidence:
file:human/FBXW4/FBXW4-uniprot.txt
Part of a SCF (SKP1-cullin-F-box) protein ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-8952620 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (NEDD8:AcM-UBE2M binds CRL1) propagated to FBXW4 as an SCF subunit.
Reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific.
Supporting Evidence:
file:human/FBXW4/FBXW4-uniprot.txt
Part of a SCF (SKP1-cullin-F-box) protein ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-8955241 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (CAND1 binds cytosolic CRL ligases) propagated to FBXW4.
Reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific.
Supporting Evidence:
file:human/FBXW4/FBXW4-uniprot.txt
Part of a SCF (SKP1-cullin-F-box) protein ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-8955289 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (COMMDs displace CAND1) propagated to FBXW4.
Reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific.
Supporting Evidence:
file:human/FBXW4/FBXW4-uniprot.txt
Part of a SCF (SKP1-cullin-F-box) protein ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-8956040 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (COP9 signalosome deneddylates CRLs) propagated to FBXW4.
Reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific.
Supporting Evidence:
file:human/FBXW4/FBXW4-uniprot.txt
Part of a SCF (SKP1-cullin-F-box) protein ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-8956200 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (MyrG-DCUN1D3 binds CRL1) propagated to FBXW4.
Reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific.
Supporting Evidence:
file:human/FBXW4/FBXW4-uniprot.txt
Part of a SCF (SKP1-cullin-F-box) protein ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-983140 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (transfer of Ub from E2 to substrate) propagated to FBXW4.
Reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific.
Supporting Evidence:
file:human/FBXW4/FBXW4-uniprot.txt
Part of a SCF (SKP1-cullin-F-box) protein ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-983147 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (release of E3 from polyubiquitinated substrate) propagated to FBXW4.
Reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific.
Supporting Evidence:
file:human/FBXW4/FBXW4-uniprot.txt
Part of a SCF (SKP1-cullin-F-box) protein ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-983156 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (polyubiquitination of substrate) propagated to FBXW4.
Reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific.
Supporting Evidence:
file:human/FBXW4/FBXW4-uniprot.txt
Part of a SCF (SKP1-cullin-F-box) protein ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-983157 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (interaction of E3 with substrate and E2-Ub complex) propagated to FBXW4.
Reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific.
Supporting Evidence:
file:human/FBXW4/FBXW4-uniprot.txt
Part of a SCF (SKP1-cullin-F-box) protein ligase complex
GO:0030326 embryonic limb morphogenesis
NAS
PMID:10405324
A novel human gene encoding an F-box/WD40 containing protein... 		KEEP AS NON CORE
Summary: Author-stated putative involvement in limb morphogenesis from the original cloning paper, based on FBXW4 mapping to the SHFM3 critical region at 10q24.3.
Reason: Reflects a candidate-gene/positional inference (SHFM3 critical region) rather than a demonstrated molecular mechanism; developmental role is non-core and the direct substrates in limb morphogenesis are unknown.
Supporting Evidence:
PMID:10405324
likely to be involved in key signaling pathways crucial for normal limb development, make it a promising candidate gene for SHFM3
GO:0000151 ubiquitin ligase complex
NAS
PMID:10945468
cDNA cloning and expression analysis of new members of the m... 		ACCEPT
Summary: Author-stated membership in a ubiquitin ligase complex, based on FBXW4 being an F-box/WD40 protein of the SCF family. A more general parent of the specific SCF complex term.
Reason: Correct but generic; subsumed by the more specific GO:0019005 (SCF ubiquitin ligase complex). Consistent with the F-box family role.
Supporting Evidence:
PMID:10945468
F-box proteins are critical components of the SCF ubiquitin-protein ligase complex and are involved in substrate recognition and recruitment for ubiquitination
GO:0006511 ubiquitin-dependent protein catabolic process
NAS
PMID:10945468
cDNA cloning and expression analysis of new members of the m... 		ACCEPT
Summary: Author-stated involvement in ubiquitin-dependent protein catabolism, a parent of the specific SCF-dependent proteasomal process.
Reason: Correct but generic; the more specific GO:0031146 better captures FBXW4's role as an SCF substrate receptor.
Supporting Evidence:
PMID:10945468
their distinct role in ubiquitin-dependent protein degradation

Core Functions

Substrate-recognition (substrate-adaptor) subunit of an SCF (SKP1-CUL1-F-box) cullin-RING E3 ubiquitin ligase complex, docking via its F-box motif onto SKP1/CUL1 and using its WD40 propeller to recruit substrates and bridge them to the ligase for SCF-dependent proteasomal degradation. FBXW4 itself is not catalytic; the ubiquitin-transfer/RING activity resides on the RBX1 subunit of the assembled SCF complex. Direct physiological substrates of SCF(FBXW4) remain undefined.

Directly Involved In:
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
Cellular Locations:
cytosol
Supporting Evidence:
  • file:human/FBXW4/FBXW4-uniprot.txt
    Part of a SCF (SKP1-cullin-F-box) protein ligase complex
  • PMID:10945468
    F-box proteins are critical components of the SCF ubiquitin-protein ligase complex and are involved in substrate recognition and recruitment for ubiquitination
  • file:human/FBXW4/FBXW4-deep-research-falcon.md
    FBXW4 co-purifies/interacts with **SKP1, CUL1, RBX1** and multiple **COP9 signalosome (COPS)** subunits, and these interactions are **F-box dependent**

References

GO_REF:0000033
Annotation inferences using phylogenetic trees
PMID:10405324
A novel human gene encoding an F-box/WD40 containing protein maps in the SHFM3 critical region on 10q24.
  • Cloning of human Dactylin/FBXW4, an F-box/WD40 protein at 10q24.3 within the SHFM3 critical region; expressed in brain, kidney, lung and liver; proposed as a candidate gene for split hand/foot malformation acting via ubiquitination of signaling-pathway proteins in limb development.
PMID:10471509
A novel member of the F-box/WD40 gene family, encoding dactylin, is disrupted in the mouse dactylaplasia mutant.
  • Positional cloning of the mouse dactylaplasia (Dac) gene identifies dactylin (Fbxw4 ortholog); Dac disrupts maintenance of the apical ectodermal ridge and truncates the autopod, resembling human SHFM, demonstrating the importance of the F-box/WD40 family in vertebrate limb development.
PMID:10945468
cDNA cloning and expression analysis of new members of the mammalian F-box protein family.
  • Cloning of 10 mammalian F-box proteins including FBWD4 (FBXW4) which contains WD40-repeat domains; F-box proteins are substrate-recognition components of SCF ubiquitin-protein ligase complexes with distinct roles in ubiquitin-dependent degradation.
PMID:22632967
Cyclin F-mediated degradation of ribonucleotide reductase M2 controls genome integrity and DNA repair.
PMID:27705803
A High-Density Map for Navigating the Human Polycomb Complexome.
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:34445249
The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
  • Review of SCF (SKP1-CUL1-F-box) complex biology; provides the basis for ComplexPortal assignment of FBXW4 to an SCF E3 ubiquitin ligase complex variant and to SCF-dependent proteasomal degradation.
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
Reactome:R-HSA-983157
Interaction of E3 with substrate and E2-Ub complex
file:human/FBXW4/FBXW4-deep-research-falcon.md
Falcon deep research report for human FBXW4
  • FBXW4 assembles with the canonical SCF core (SKP1, CUL1, RBX1) and with COP9 signalosome subunits in an F-box-dependent manner, providing direct biochemical evidence (beyond family inference) that it is an SCF substrate-recognition subunit rather than an enzyme or transporter.
    "FBXW4 co-purifies/interacts with **SKP1, CUL1, RBX1** and multiple **COP9 signalosome (COPS)** subunits, and these interactions are **F-box dependent**"
  • FBXW4 associates with ubiquitinated cellular proteins, and this association increases upon proteasome inhibition in an F-box-dependent way, consistent with substrate engagement in ubiquitin-dependent turnover.
    "FBXW4 interacts with **ubiquitinated cellular proteins**, and the interaction increases with **proteasome inhibition (MG132)** in an **F-box-dependent** manner, consistent with substrate engagement in ubiquitin-dependent turnover pathways"
  • The endogenous substrate(s) of SCF(FBXW4) remain undefined; the primary biochemical study frames substrate identification as a future direction.
    "The specific endogenous **substrate(s)** targeted by SCF^FBXW4 remain insufficiently defined in the retrieved evidence; the 2013 study frames substrate identification as a future direction"
  • FBXW4 is recurrently mutated, lost, and under-expressed across human cancers, consistent with a possible tumor-suppressor role, though causal substrates/pathways are unclear.
    "FBXW4 is mutated, lost, and under-expressed in human cancers, and argue this pattern is consistent with a potential **tumor suppressor** role, though definitive causal substrates/pathways remain unclear"
  • SHFM3 at 10q24 is best explained as a cis-regulatory / multi-gene misexpression disorder; recurrent duplications include FBXW4 with neighboring genes, and enhancer perturbation in mouse alters Fbxw4 expression rather than acting through an FBXW4 coding mutation.
    "SVs likely perturb **cis-regulatory elements**, **3D chromatin architecture**, and/or coordinated expression of multiple genes in the region"

Suggested Questions for Experts

Q: What are the direct, phosphorylation-dependent ubiquitination substrates recognized by the FBXW4 WD40 propeller, and which signaling pathways (e.g. Wnt) do they belong to?

Q: Given that SHFM3 is associated with a tandem duplication at 10q24 rather than FBXW4 coding mutations, is the limb phenotype due to altered FBXW4 dosage, a neighboring gene, or a regulatory element, and what is FBXW4's direct molecular contribution?

Suggested Experiments

Experiment: Affinity purification of tagged FBXW4 with SKP1/CUL1/RBX1 followed by mass spectrometry of co-purifying and ubiquitinated proteins, in limb-bud-derived or epithelial cells, to identify physiological SCF(FBXW4) substrates.

Experiment: Reconstitute SCF(FBXW4) in vitro with SKP1, CUL1, RBX1 and an E2 and test ubiquitination of candidate developmental-signaling substrates, comparing wild-type to F-box-deletion FBXW4 to confirm substrate-adaptor activity.

Deep Research

Falcon

(FBXW4-deep-research-falcon.md)
Research report: Human **FBXW4** (UniProt **P57775**) functional annotation Falcon Edison Scientific Literature 31 citations 2 artifacts 2026-06-13T06:57:19.910088
Edison artifact artifact-00 (text/markdown)
## Context ID: pqac-00000019 I have extracted Figure 4B, which shows gene expression changes for several genes including *Fbxw4* across different embryonic stag (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 FBXW4 (UniProt P57775) functional annotation

0. Target verification (gene/protein identity)

The literature retrieved for FBXW4 consistently refers to the human gene at the 10q24 locus historically connected to SHFM3 (split-hand/foot malformation type 3) and to the ortholog of mouse dactylin (Fbxw4). In particular, Lockwood et al. biochemically characterize FBXW4 as an F-box and WD40-repeat containing protein that forms an SCF-type E3 ubiquitin ligase complex, matching the provided UniProt description (F-box + WD-repeat domains; alias dactylin) and therefore supporting that the report is about the correct human FBXW4/P57775 target (Lockwood et al., 2013; https://doi.org/10.1371/journal.pone.0063610) (lockwood2013thenovelubiquitin pages 1-2, lockwood2013thenovelubiquitin pages 8-9).

1. Key concepts and definitions (current understanding)

1.1 FBXW4 as an F-box/WD-repeat substrate receptor in SCF E3 ubiquitin ligases

SCF (SKP1–CUL1–RBX1) complexes are multi-subunit E3 ubiquitin ligases in which F-box proteins provide substrate recognition: the F-box domain binds SKP1, coupling a variable substrate receptor to the CUL1–RBX1 catalytic core. WD40 repeats typically form a Ξ²-propeller scaffold that mediates protein–protein interactions, often contributing directly to substrate binding.

For FBXW4 specifically, biochemical evidence demonstrates it assembles with canonical SCF core components and regulatory machinery, strongly supporting its classification as an SCF substrate-recognition subunit (rather than an enzyme with an intrinsic catalytic reaction): FBXW4 co-purifies/interacts with SKP1, CUL1, RBX1 and multiple COP9 signalosome (COPS) subunits, and these interactions are F-box dependent (Lockwood et al., 2013; https://doi.org/10.1371/journal.pone.0063610) (lockwood2013thenovelubiquitin pages 1-2, lockwood2013thenovelubiquitin pages 2-3, lockwood2013thenovelubiquitin pages 3-4).

1.2 COP9 signalosome coupling

The COP9 signalosome (CSN) regulates cullin-RING ligases (including SCF complexes) via deneddylation and other mechanisms. FBXW4’s interaction with multiple CSN subunits is consistent with a regulated SCF ligase module and suggests FBXW4-containing SCF complexes are integrated into canonical ubiquitin–proteasome regulation (Lockwood et al., 2013) (lockwood2013thenovelubiquitin pages 1-2, lockwood2013thenovelubiquitin pages 2-3).

1.3 SHFM3/10q24 rearrangements as a β€œregulatory neighborhood” disorder

A major body of FBXW4-related human genetics concerns structural variants (SVs) at 10q24.31–10q24.32. Recurrent (and also nonrecurrent) duplications frequently include FBXW4 along with neighboring genes (e.g., LBX1, BTRC, POLL, DPCD, sometimes near FGF8 depending on breakpoint). Multiple papers argue the phenotype is not readily explained by a single coding mutation in FBXW4; rather, SVs likely perturb cis-regulatory elements, 3D chromatin architecture, and/or coordinated expression of multiple genes in the region (Lyle et al., 2006; Dimitrov et al., 2010; Dai et al., 2013; Li et al., 2015) (lyle2006split‐handsplit‐footmalformation3 pages 8-10, dimitrov2010distallimbdeficiencies pages 9-11, dai2013discontinuousmicroduplicationsat pages 3-5, li2015identificationofcritical pages 1-3).

2. Functional evidence for FBXW4

2.1 Molecular function: SCF complex assembly and ubiquitin-pathway engagement

Lockwood et al. provide direct biochemical support that FBXW4 operates in ubiquitin-mediated proteolysis as part of an SCF complex:
- FBXW4 associates with SKP1/CUL1/RBX1 and COP9 signalosome components, requiring an intact F-box (lockwood2013thenovelubiquitin pages 1-2, lockwood2013thenovelubiquitin pages 2-3, lockwood2013thenovelubiquitin pages 3-4).
- FBXW4 interacts with ubiquitinated cellular proteins, and the interaction increases with proteasome inhibition (MG132) in an F-box-dependent manner, consistent with substrate engagement in ubiquitin-dependent turnover pathways (lockwood2013thenovelubiquitin pages 4-6, lockwood2013thenovelubiquitin pages 3-4).

Key limitation: The specific endogenous substrate(s) targeted by SCF^FBXW4 remain insufficiently defined in the retrieved evidence; the 2013 study frames substrate identification as a future direction (lockwood2013thenovelubiquitin pages 8-8).

2.2 Domain architecture relevance

Cancer-associated truncating mutations described by Lockwood et al. include a frameshift predicted to remove the last ~2.5 WD-repeat motifs, and missense mutations predicted to disrupt function, implying the WD-repeat region is functionally important (e.g., for substrate binding or complex integrity) (lockwood2013thenovelubiquitin pages 6-8, lockwood2013thenovelubiquitin pages 4-6).

2.3 Subcellular localization

The retrieved primary sources do not provide a definitive, direct experimental statement of subcellular localization for endogenous human FBXW4 (e.g., nuclear vs cytosolic vs specific organelles). The functional contextβ€”assembly into SCF/COP9-regulated ubiquitin ligase machineryβ€”supports an intracellular role, but more targeted localization experiments (immunofluorescence, fractionation, proximity labeling) would be needed for a high-confidence localization claim from primary data in this corpus (lockwood2013thenovelubiquitin pages 1-2, lockwood2013thenovelubiquitin pages 2-3).

3. FBXW4 in pathways and biological processes

3.1 Ubiquitin–proteasome system (UPS)

FBXW4’s best-supported pathway placement is within the UPS as an SCF E3 ligase substrate receptor (lockwood2013thenovelubiquitin pages 1-2, lockwood2013thenovelubiquitin pages 2-3, lockwood2013thenovelubiquitin pages 3-4). Reviews on F-box proteins emphasize that substrate specificity is primarily controlled at the substrate-receptor (F-box protein) level, situating FBXW4 conceptually alongside other FBXW family members that direct degradation of key signaling and cell-cycle regulators (Sato & Yoshida, 2010; https://doi.org/10.3892/ijo_00000758) (sato2010augmentationofthe pages 3-5).

3.2 Developmental genetics: 10q24 SVs and limb development (SHFM3)

Although FBXW4 protein biochemistry points to the UPS, the clearest human phenotype link is via 10q24 duplications associated with SHFM3, where FBXW4 is frequently duplicated or partially duplicated, often with breakpoints in the gene.

Mechanistic themes supported in the literature include:
- Breakpoint clustering and recurrent interval: duplications commonly fall in the ~440–570 kb range, and distal breakpoints frequently lie within FBXW4 (5β€² UTR, introns 2 and 5 are repeatedly noted) (Li et al., 2015) (li2015identificationofcritical pages 1-3).
- Misexpression model: early work observed significant upregulation of BTRC and SUFU in patient lymphoblastoid cells, consistent with dosage/misexpression effects (Lyle et al., 2006) (lyle2006split‐handsplit‐footmalformation3 pages 8-10).
- Cis-regulatory element disruption: discontinuous duplications can separate or duplicate enhancer elements; Dai et al. describe a limb enhancer (hs326) located between two duplicated blocks and argue that partial duplication of FBXW4 plus regulatory perturbation supports a non-simple dosage model (Dai et al., 2013; https://doi.org/10.1186/1471-2350-14-45) (dai2013discontinuousmicroduplicationsat pages 3-5).
- 3D-regulatory neighborhood concept: Dimitrov et al. emphasize that phenotype severity does not map cleanly to duplication size and suggest disturbed interactions among multiple cis-acting regulatory elements and their target genes (Dimitrov et al., 2010; https://doi.org/10.1136/jmg.2008.065888) (dimitrov2010distallimbdeficiencies pages 9-11).

4. Recent developments (prioritizing 2023–2024)

4.1 2024: Family WGS confirmation of 10q24.32 duplication including FBXW4, with mosaic transmission

A 2024 Frontiers in Genetics case report used whole-genome sequencing to identify a 10q24.32 microduplication spanning BTRC, POLL, FBXW4, and LBX1 at coordinates chr10:102,934,495–103,496,555, validated in multiple family members and found to be mosaic in an unaffected grandmother, providing a clinically relevant example of variable expressivity and mosaic transmission (Akimova et al., 2024; https://doi.org/10.3389/fgene.2023.1303807) (singh2025uncoveringthegenetic pages 2-4).

A 2024 Human Molecular Genetics study deleted a conserved AIS-associated regulatory module (AIS-CRM) near Lbx1 in mice and measured expression of multiple genes in the local contact domain. Importantly, Fbxw4 mRNA increased ~1.8-fold vs WT at E15.5, while Poll increased ~1.7-fold; a gene outside the TAD (Npm3) showed no expression change, supporting a chromatin-domain constrained regulatory effect (McCallum-Loudeac et al., 2024; https://doi.org/10.1093/hmg/ddae011) (mccallumloudeac2024deletionofa pages 5-6, mccallumloudeac2024deletionofa pages 7-8).

The paper’s contact map and expression figure provide visual evidence that noncoding perturbations in the LBX1 neighborhood can alter expression of Fbxw4, reinforcing interpretations of 10q24 SVs (including SHFM3-associated duplications) as affecting a regulatory neighborhood rather than only a single gene’s coding sequence (mccallumloudeac2024deletionofa media 8cd1b654, mccallumloudeac2024deletionofa media 7c90f5c8).

5. Current applications and real-world implementations

5.1 Clinical genetics: CNV/SV testing for SHFM3 locus

Multiple studies highlight that array CGH, qPCR, and now WGS are used to detect 10q24 duplications/triplications and mosaicism relevant for SHFM3 diagnosis and genetic counseling (Dimitrov et al., 2010; Akimova et al., 2024) (dimitrov2010distallimbdeficiencies pages 11-14, singh2025uncoveringthegenetic pages 2-4).

5.2 Genetic counseling implications: mosaicism and variable expressivity

Somatic/gonadal mosaicism can explain unaffected carriers and recurrence risk:
- Dimitrov et al. report an apparently healthy mother with ~30% somatic mosaicism by FISH and a qPCR fold-difference ~1.25 consistent with mosaic duplication in blood, underscoring counseling complexity (dimitrov2010distallimbdeficiencies pages 11-14).
- Akimova et al. similarly report mosaic duplication in an unaffected grandmother detected by WGS validation across family members (singh2025uncoveringthegenetic pages 2-4).

5.3 Translational oncology hypothesis (research-stage)

Lockwood et al. report that FBXW4 is mutated, lost, and under-expressed in human cancers and argue this pattern is consistent with a potential tumor suppressor role, though definitive causal substrates/pathways remain unclear (Lockwood et al., 2013) (lockwood2013thenovelubiquitin pages 2-3, lockwood2013thenovelubiquitin pages 6-8).

6. Expert synthesis and interpretation (authoritative analyses)

6.1 What the evidence most strongly supports

  1. Primary molecular role: FBXW4 functions as an SCF-type E3 ubiquitin ligase substrate-recognition component interacting with SKP1/CUL1/RBX1 and the COP9 signalosome, and engaging ubiquitinated proteins in cells (lockwood2013thenovelubiquitin pages 1-2, lockwood2013thenovelubiquitin pages 2-3, lockwood2013thenovelubiquitin pages 3-4).
  2. Developmental genetics linkage: FBXW4 lies within a recurrently rearranged 10q24 interval associated with SHFM3 and related phenotypes, but multiple authors emphasize a cis-regulatory / multi-gene misexpression mechanism rather than a simple coding mutation effect of FBXW4 alone (dimitrov2010distallimbdeficiencies pages 9-11, dai2013discontinuousmicroduplicationsat pages 3-5, li2015identificationofcritical pages 1-3, lyle2006split‐handsplit‐footmalformation3 pages 8-10).

6.2 Key open questions

  • Endogenous substrates of SCF^FBXW4: not established in the retrieved biochemical literature, limiting precise pathway placement beyond β€œUPS/SCF biology” (lockwood2013thenovelubiquitin pages 8-8).
  • Which gene(s) drive SHFM3 phenotypes: breakpoint mapping suggests a shared interval often involving FBXW4, but at least one systematic review maps a critical region to BTRC exon 1, illustrating that FBXW4 may be a consistent bystander/participant in a broader regulatory syndrome (li2015identificationofcritical pages 1-3).

7. Quantitative statistics and data (recent/representative)

7.1 SHFM3 duplication sizes and coordinates

  • Common SHFM3 duplications often cluster around ~440–570 kb; specific reported examples include 514 kb (chr10:102,962,134–103,476,346; hg19) and others (li2015identificationofcritical pages 1-3).
  • A 2024 WGS-confirmed duplication spanning chr10:102,934,495–103,496,555 encompassed BTRC, POLL, FBXW4, LBX1 (singh2025uncoveringthegenetic pages 2-4).
  • Discontinuous duplications can include a ~247–260 kb centromeric block and a ~114–125 kb telomeric block partially duplicating FBXW4, with an enhancer coordinate reported at chr10:103,266,649–103,267,972 (Dai et al., 2013) (dai2013discontinuousmicroduplicationsat pages 3-5).

7.2 Mosaicism and triplication measurements

  • Dimitrov et al. report triplication in one individual (qPCR fold-difference ~2) and ~30% mosaic duplication in an unaffected mother (qPCR fold-difference ~1.25; FISH-confirmed mosaicism) (dimitrov2010distallimbdeficiencies pages 11-14).

7.3 Regulatory perturbation effect sizes on Fbxw4 expression (mouse)

  • AIS-CRM deletion produced ~1.8-fold upregulation of Fbxw4 at E15.5 (mccallumloudeac2024deletionofa pages 5-6), supported by the figure panel extracted (mccallumloudeac2024deletionofa media 8cd1b654, mccallumloudeac2024deletionofa media 7c90f5c8).

8. Disease associations (database-level summary)

Open Targets lists FBXW4 disease associations including split hand-foot malformation 3 and broader SHFM terms, alongside other associations (e.g., atrial fibrillation, uterine fibroid, neurodegenerative disease) with modest evidence scores; these should be interpreted as hypothesis-generating unless supported by focused mechanistic studies (Open Targets platform; evidence snapshot in this run) (OpenTargets Search: -FBXW4).

Evidence summary table

The following table consolidates biochemical, genetic, and regulatory evidence for FBXW4.

Area Key finding Evidence type Quantitative data Implication for FBXW4 function Source (paper + year + URL) and context citation id
Protein biochemistry Human/murine FBXW4 (dactylin) is an F-box/WD40 protein that assembles with core SCF ubiquitin ligase components and COP9 signalosome proteins in an F-box-dependent manner. FLAG co-IP, mass spectrometry, gel filtration, mutant analysis Fbxw4 reported to contain an F-box domain and five WD-40 motifs; deletion of the F-box abolished copurification with E3 ligase/COP9 components. Strongest direct evidence that FBXW4 functions as an SCF-type substrate-recognition subunit rather than an enzyme or transporter. Lockwood et al., 2013, https://doi.org/10.1371/journal.pone.0063610 (lockwood2013thenovelubiquitin pages 1-2, lockwood2013thenovelubiquitin pages 2-3, lockwood2013thenovelubiquitin pages 3-4)
Protein biochemistry FBXW4 associates with ubiquitinated cellular proteins, and this interaction increases after proteasome inhibition. IP/Western blot with MG132 treatment MG132 increased association of Fbxw4 with ubiquitinated proteins; effect required an intact F-box. Supports a role in ubiquitin-dependent substrate handling/proteolysis, consistent with SCF substrate recruitment. Lockwood et al., 2013, https://doi.org/10.1371/journal.pone.0063610 (lockwood2013thenovelubiquitin pages 4-6, lockwood2013thenovelubiquitin pages 3-4)
Protein biochemistry Cancer-associated truncating/missense alterations affect FBXW4 WD-repeat region; the locus is also reported lost/under-expressed in cancers. Mutation mapping, cancer genomic/expression analysis Frameshift E245fs* predicted to remove the last ~2.5 WD motifs; paper also reports frequent loss/under-expression in human cancers. WD repeats are likely functionally important for substrate recognition; data suggest possible tumor-suppressive relevance, though specific substrates remain unknown. Lockwood et al., 2013, https://doi.org/10.1371/journal.pone.0063610 (lockwood2013thenovelubiquitin pages 6-8, lockwood2013thenovelubiquitin pages 4-6)
Developmental genetics SHFM3-associated duplications at 10q24 commonly include FBXW4 together with nearby genes (e.g., LBX1, BTRC, POLL, DPCD), but the causal mechanism appears more regulatory than simple FBXW4 coding dosage. Literature synthesis, microarray breakpoint mapping Reported recurrent duplications cluster around ~440-570 kb; examples include 447 kb, 512 kb, and 514 kb (chr10:102,962,134-103,476,346; hg19). Distal breakpoints often fall within FBXW4 (5' UTR, intron 2, intron 5). FBXW4 is a consistent positional candidate at the SHFM3 locus, but evidence points to locus-level cis-regulatory disruption/misexpression rather than isolated FBXW4 coding mutation. Li et al., 2015, https://doi.org/10.3390/microarrays5010002 (li2015identificationofcritical pages 1-3)
Developmental genetics Early SHFM3 mapping identified duplications spanning the human ortholog of mouse dactylin/Fbxw4; expression data in patient lymphoblasts favored misexpression of neighboring genes. FISH, duplication mapping, expression assays Largest duplicated segment contained HUG1, TLX1, LBX1, BTRC, POLL, and SHFM3/FBXW4; minimal duplication ~325 kb; previous rearrangement ~500 kb in 7 families. BTRC and SUFU were significantly upregulated in lymphoblastoid cells. Supports a model in which FBXW4 sits within a pathogenic regulatory interval whose rearrangement perturbs multiple genes involved in limb development. Lyle et al., 2006, https://doi.org/10.1002/ajmg.a.31247 (lyle2006split‐handsplit‐footmalformation3 pages 8-10)
Developmental genetics A Chinese SHFM family carried two discontinuous 10q24 duplications, one partially duplicating FBXW4; authors favored altered regulatory architecture over simple gene overexpression. Array CGH, qPCR, family segregation Centromeric duplicated block ~247-260 kb; telomeric block ~114-125 kb including DPCD and part of FBXW4. Limb enhancer hs326 mapped to chr10:103,266,649-103,267,972 between the duplicated blocks. Partial FBXW4 duplication plus enhancer disruption is consistent with cis-regulatory misexpression affecting the locus during limb development. Dai et al., 2013, https://doi.org/10.1186/1471-2350-14-45 (dai2013discontinuousmicroduplicationsat pages 3-5)
Developmental genetics Syndromic and nonsyndromic SHFM3/related distal limb deficiency cases show variable 10q24 duplications including the whole FBXW4 gene; phenotype severity does not track cleanly with duplication size. Array CGH, FISH, qPCR Six patients had duplications roughly ~500-650 kb; one interval listed as 102,870,153-103,528,589 bp. One patient had triplication (qPCR fold difference ~2) and more severe defects. One unaffected mother showed ~30% somatic mosaicism in blood with qPCR fold difference ~1.25. Indicates dosage/regulatory complexity at the locus; FBXW4-containing rearrangements can be pathogenic, variably expressive, and modified by mosaicism/triplication. Dimitrov et al., 2010, https://doi.org/10.1136/jmg.2008.065888 (dimitrov2010distallimbdeficiencies pages 11-14, dimitrov2010distallimbdeficiencies pages 9-11)
Developmental genetics Recent family WGS further confirmed pathogenic 10q24.32 microduplication spanning FBXW4 with variable expressivity and mosaic transmission. Whole-genome sequencing, family validation Microduplication chr10:102,934,495-103,496,555 encompassing BTRC, POLL, FBXW4, and LBX1; mosaic duplication detected in unaffected paternal grandmother. Reinforces current clinical use of structural variant testing at the FBXW4-containing SHFM3 locus and the importance of mosaicism in counseling. Akimova et al., 2024, https://doi.org/10.3389/fgene.2023.1303807 (singh2025uncoveringthegenetic pages 2-4)
Regulatory genomics Deletion of a conserved AIS-associated enhancer region near Lbx1 in mice dysregulated several genes in the local contact domain, including Fbxw4. Mouse CRISPR enhancer deletion, RT-qPCR/expression analysis, chromatin contact mapping AIS-CRM located ~7.8 kb downstream of Lbx1. At E15.5, Fbxw4 mRNA increased to ~1.8-fold versus WT; Poll increased ~1.7-fold; Npm3 outside the TAD showed no change. Demonstrates that local noncoding regulatory elements can modulate Fbxw4 expression, supporting a broader regulatory-genomic model for the 10q24 neighborhood. McCallum-Loudeac et al., 2024, https://doi.org/10.1093/hmg/ddae011 (mccallumloudeac2024deletionofa pages 5-6, mccallumloudeac2024deletionofa pages 7-8)
Regulatory genomics The LBX1/AIS-CRM contact domain spans multiple neighboring genes, providing a structural explanation for why noncoding perturbations can alter Fbxw4 expression without FBXW4 coding mutation. Micro-C/contact map figure and staged expression profiling Long-range contacts extended ~550 kbp downstream from the LBX1-centered region; significant staged effects included E15.5 Fbxw4 upregulation (P < 0.05). Offers mechanistic support for interpreting SHFM3 and other 10q24 phenotypes as 3D-regulatory neighborhood disorders that include FBXW4 among the affected targets. McCallum-Loudeac et al., 2024, https://doi.org/10.1093/hmg/ddae011 (mccallumloudeac2024deletionofa pages 7-8, mccallumloudeac2024deletionofa media 8cd1b654, mccallumloudeac2024deletionofa media 7c90f5c8)

Table: This table consolidates the main biochemical, developmental-genetic, and regulatory-genomic evidence relevant to human FBXW4. It is useful for separating what is directly shown for the FBXW4 protein from what is inferred from 10q24 structural variation and enhancer perturbation studies.

Visual evidence (figures)

McCallum-Loudeac et al. (2024) Figure 4A–B provides a contact-domain view around LBX1/AIS-CRM and staged expression data showing Fbxw4 upregulation after enhancer deletion (mccallumloudeac2024deletionofa media 8cd1b654, mccallumloudeac2024deletionofa media 7c90f5c8).

References (URLs and publication dates)

  • Lockwood WW et al. May 2013. PLoS ONE. β€œThe Novel Ubiquitin Ligase Complex, SCF^Fbxw4, Interacts with the COP9 Signalosome…” https://doi.org/10.1371/journal.pone.0063610 (lockwood2013thenovelubiquitin pages 1-2)
  • Dimitrov B et al. Jul 2010. Journal of Medical Genetics. β€œDistal limb deficiencies… caused by chromosome 10q genomic rearrangements” https://doi.org/10.1136/jmg.2008.065888 (dimitrov2010distallimbdeficiencies pages 11-14)
  • Dai L et al. Apr 2013. BMC Medical Genetics. β€œDiscontinuous microduplications at chromosome 10q24.31…” https://doi.org/10.1186/1471-2350-14-45 (dai2013discontinuousmicroduplicationsat pages 3-5)
  • Lyle R et al. Jul 2006. American Journal of Medical Genetics A. β€œSplit-hand/split-foot malformation 3 (SHFM3) at 10q24…” https://doi.org/10.1002/ajmg.a.31247 (lyle2006split‐handsplit‐footmalformation3 pages 8-10)
  • Li CF et al. Dec 2015. Microarrays. β€œIdentification of Critical Region Responsible for SHFM3…” https://doi.org/10.3390/microarrays5010002 (li2015identificationofcritical pages 1-3)
  • Akimova D et al. Jan 2024. Frontiers in Genetics. β€œVariable clinical presentation… microduplication of 10q24.32” https://doi.org/10.3389/fgene.2023.1303807 (singh2025uncoveringthegenetic pages 2-4)
  • McCallum-Loudeac J et al. Jan 2024. Human Molecular Genetics. β€œDeletion of a conserved genomic region associated with AIS…” https://doi.org/10.1093/hmg/ddae011 (mccallumloudeac2024deletionofa pages 5-6)

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Artifacts

Citations

  1. lockwood2013thenovelubiquitin pages 8-8
  2. sato2010augmentationofthe pages 3-5
  3. li2015identificationofcritical pages 1-3
  4. dai2013discontinuousmicroduplicationsat pages 3-5
  5. dimitrov2010distallimbdeficiencies pages 9-11
  6. singh2025uncoveringthegenetic pages 2-4
  7. dimitrov2010distallimbdeficiencies pages 11-14
  8. mccallumloudeac2024deletionofa pages 5-6
  9. lockwood2013thenovelubiquitin pages 1-2
  10. lockwood2013thenovelubiquitin pages 8-9
  11. lockwood2013thenovelubiquitin pages 2-3
  12. lockwood2013thenovelubiquitin pages 3-4
  13. lockwood2013thenovelubiquitin pages 4-6
  14. lockwood2013thenovelubiquitin pages 6-8
  15. mccallumloudeac2024deletionofa pages 7-8
  16. https://doi.org/10.1371/journal.pone.0063610
  17. https://doi.org/10.3892/ijo_00000758
  18. https://doi.org/10.1186/1471-2350-14-45
  19. https://doi.org/10.1136/jmg.2008.065888
  20. https://doi.org/10.3389/fgene.2023.1303807
  21. https://doi.org/10.1093/hmg/ddae011
  22. https://doi.org/10.3390/microarrays5010002
  23. https://doi.org/10.1002/ajmg.a.31247
  24. https://doi.org/10.1371/journal.pone.0063610,
  25. https://doi.org/10.1002/ajmg.a.31247,
  26. https://doi.org/10.1136/jmg.2008.065888,
  27. https://doi.org/10.1186/1471-2350-14-45,
  28. https://doi.org/10.3390/microarrays5010002,
  29. https://doi.org/10.3892/ijo_00000758,
  30. https://doi.org/10.1055/s-0045-1814130,
  31. https://doi.org/10.1093/hmg/ddae011,

πŸ“š Additional Documentation

Pn Notes

(FBXW4-pn-notes.md)

FBXW4 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: P57775
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-13
  • Batch change status: added

Source Files Checked

Deep Research Files

AIGR Review Snapshot

  • Description: FBXW4 (dactylin; SHFM3) is a member of the F-box/WD40 (FBXW) family of proteins. Its 412-residue product contains an N-terminal F-box motif (approximately residues 25-71) and a C-terminal beta-propeller built from roughly six WD40 repeats. F-box proteins function as the interchangeable substrate-recognition subunits of SCF (SKP1-CUL1-F-box)-type cullin-RING E3 ubiquitin ligase complexes: the F-box motif docks the protein onto SKP1/CUL1, while the WD40 propeller recognizes (typically phosphorylated) substrate proteins and presents them for ubiquitination by the RBX1-bound E2, committing them to proteasomal degradation. Affinity-purification studies confirm that FBXW4 assembles, in an F-box-dependent manner, with the canonical SCF core subunits SKP1, CUL1 and RBX1 and with COP9 signalosome subunits (which deneddylate and regulate cullin-RING ligases), and that FBXW4 associates with ubiquitinated cellular proteins in a manner enhanced by proteasome inhibition - establishing it as a bona fide SCF substrate receptor engaged in ubiquitin-dependent turnover. Its physiological substrates, however, remain undefined. FBXW4 is broadly expressed (including brain, kidney, lung and liver) and is recurrently mutated, deleted, or under-expressed across human cancers, suggesting a candidate tumor-suppressor role. The human gene maps to chromosome 10q24.3 within the critical region for split-hand/foot malformation type 3 (SHFM3), and the orthologous gene is disrupted in the mouse dactylaplasia (Dac) mutant, which fails to maintain the apical ectodermal ridge and truncates the autopod. SHFM3 is most often associated with tandem/discontinuous genomic duplications at 10q24 that perturb a shared cis-regulatory neighborhood and alter expression of FBXW4 and several neighboring genes (e.g. BTRC, POLL, LBX1) rather than with coding mutations in FBXW4 itself, so FBXW4's precise contribution to limb development and its physiological ubiquitination substrates remain incompletely defined.
  • Existing/core annotation action counts: ACCEPT: 6; KEEP_AS_NON_CORE: 16

PN Consistency Summary

  • Consistency: Row1 consistent β€” review treats FBXW4 (dactylin/SHFM3) as an SCF substrate receptor (GO:0019005 IBA/NAS ACCEPT, GO:0031146 ACCEPT, proposed_new_terms GO:1990756) with substrates UNDEFINED; deep research (Lockwood 2013) confirms F-box-dependent SKP1/CUL1/RBX1 + COP9 assembly and MG132-dependent association with ubiquitinated proteins. Row2 INCONSISTENT/over-reach: the PN "idiosyncratic Ub binding | E3 ligase" node projects GO:0061630 (catalytic ubiquitin protein ligase activity). PMID:21070969 (Pashkova 2010, Mol Cell, DOI) β€” per PubMed, "WD40 repeat propellers define a ubiquitin-binding domain that regulates turnover of F box proteins" β€” describes the WD40 propeller as a ubiquitin-BINDING module promoting F-box auto-ubiquitination/turnover, NOT ligase catalysis. F-box proteins are non-catalytic receptors (catalysis is RBX1 RING). Both the paper's content and the F-box pattern contradict GO:0061630.
  • PN story / NEW pressure: Row1 ADD GO:1990756 (verified real, new_to_goa) β€” defensible, already proposed by review. Row2 GO:0061630 over-reaches twice (wrong activity type AND wrong paper interpretation). If anything, PMID:21070969 supports GO:0043130 ubiquitin binding (verified real; molecular function), not ligase activity. Limb-development role (SHFM3, dactylaplasia) is correctly KEEP_AS_NON_CORE / positional, not a molecular function.
  • Evidence alignment: Row1 PN cites PMID:15340381 (family review). Review uses PMID:10405324/PMID:10471509 (SHFM3/dactylaplasia, HIGH), PMID:10945468, plus falcon (Lockwood 2013). Row2 PN's PMID:21070969 is NOT in the review and its claim (Ub-binding) is mischaracterized by the GO:0061630 mapping.
  • Verdict: Row1 CONSISTENT (ADD GO:1990756). Row2 PN node OVER-REACHES. Recommended edits: [MAP] change Row2 group Ubiquitin and UBL binding|E3 ligase projection for FBXW4 from GO:0061630 ubiquitin protein ligase activity to GO:0043130 ubiquitin binding, or set no_mapping β€” PMID:21070969 documents WD40 ubiquitin BINDING (regulating F-box turnover), not catalytic ligase activity; F-box proteins are non-catalytic.

Full Consistency Review

  • UniProt: P57775 Β· batch: proteostasis-batch-2026-06-13 Β· review status: COMPLETE
  • PN placement (2 rows): Row1 UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|WD40 (PMID:15340381); Row2 UPS|Ubiquitin and UBL binding|E3 ligase|CUL1 receptor|idiosyncratic Ub binding / WD40 (PMID:21070969). PN-node mapping: Row1 group=mapped GO:1990756; Row2 group=mapped GO:0061630 ubiquitin protein ligase activity (new_to_goa); both class nodes context_only/too_broad.
  • Consistency: Row1 consistent β€” review treats FBXW4 (dactylin/SHFM3) as an SCF substrate receptor (GO:0019005 IBA/NAS ACCEPT, GO:0031146 ACCEPT, proposed_new_terms GO:1990756) with substrates UNDEFINED; deep research (Lockwood 2013) confirms F-box-dependent SKP1/CUL1/RBX1 + COP9 assembly and MG132-dependent association with ubiquitinated proteins. Row2 INCONSISTENT/over-reach: the PN "idiosyncratic Ub binding | E3 ligase" node projects GO:0061630 (catalytic ubiquitin protein ligase activity). PMID:21070969 (Pashkova 2010, Mol Cell, DOI) β€” per PubMed, "WD40 repeat propellers define a ubiquitin-binding domain that regulates turnover of F box proteins" β€” describes the WD40 propeller as a ubiquitin-BINDING module promoting F-box auto-ubiquitination/turnover, NOT ligase catalysis. F-box proteins are non-catalytic receptors (catalysis is RBX1 RING). Both the paper's content and the F-box pattern contradict GO:0061630.
  • PN story / NEW pressure: Row1 ADD GO:1990756 (verified real, new_to_goa) β€” defensible, already proposed by review. Row2 GO:0061630 over-reaches twice (wrong activity type AND wrong paper interpretation). If anything, PMID:21070969 supports GO:0043130 ubiquitin binding (verified real; molecular function), not ligase activity. Limb-development role (SHFM3, dactylaplasia) is correctly KEEP_AS_NON_CORE / positional, not a molecular function.
  • Mapping strategy: Row1 correct. Row2 mapping is wrong: GO:0061630 should not be projected to F-box receptors from this Ub-binding paper. Recommend the Row2 node project GO:0043130 ubiquitin binding (if at all) or no_mapping β€” analogous to FBXW7's IBA ubiquitin-binding which the curator marked over-annotated.
  • Evidence alignment: Row1 PN cites PMID:15340381 (family review). Review uses PMID:10405324/PMID:10471509 (SHFM3/dactylaplasia, HIGH), PMID:10945468, plus falcon (Lockwood 2013). Row2 PN's PMID:21070969 is NOT in the review and its claim (Ub-binding) is mischaracterized by the GO:0061630 mapping.
  • Verdict: Row1 CONSISTENT (ADD GO:1990756). Row2 PN node OVER-REACHES. Recommended edits: [MAP] change Row2 group Ubiquitin and UBL binding|E3 ligase projection for FBXW4 from GO:0061630 ubiquitin protein ligase activity to GO:0043130 ubiquitin binding, or set no_mapping β€” PMID:21070969 documents WD40 ubiquitin BINDING (regulating F-box turnover), not catalytic ligase activity; F-box proteins are non-catalytic.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-13
  • review_yaml: genes/human/FBXW4/FBXW4-ai-review.yaml
  • PN workbook rows: 2

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul1 substrate receptor | F-box | WD40

  • UniProt: P57775
  • In branches: UPS
  • Signature domains: IPR001810
  • Auxiliary domains: IPR001680
  • 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|WD40
      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.

PN row 2: Ubiquitin Proteasome System | Ubiquitin and UBL binding | E3 ligase | CUL1 receptor | idiosyncratic Ub binding / WD40

  • UniProt: P57775
  • In branches: UPS
  • Signature domains: PMID: 21070969 (IPR001680)
  • Auxiliary domains: IPR001810
  • PN references (titles):
    • 21070969
  • PN-node mapping records (path + ancestors):
    • [subtype] Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase|CUL1 receptor|idiosyncratic Ub binding / WD40
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower enzyme-family, domain, or architecture subdivision already covered by a curated parent enzyme mapping. No additional direct GO mapping is needed at this node.
    • [type] Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase|CUL1 receptor
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower enzyme-family, domain, or architecture subdivision already covered by a curated parent enzyme mapping. No additional direct GO mapping is needed at this node.
    • [group] Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0061630 ubiquitin protein ligase activity]
      rationale: This PN group captures ubiquitin/UBL-binding factors that are E3 ligases. The shared molecular-function target is ubiquitin protein ligase activity.
    • [class] Ubiquitin Proteasome System|Ubiquitin and UBL binding
      status=context_only scope=too_broad_to_propagate GO=[GO:0140036 ubiquitin-modified protein reader activity]
      rationale: This class records ubiquitin/UBL-reader context, but the subtree mixes ubiquitin, SUMO, UBL-domain, domain-architecture, catalytic, signaling, trafficking, and nucleic-acid process buckets. It is useful context, not a safe direct propagation.
    • [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 (2)

  • 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
  • GO:0061630 ubiquitin protein ligase activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase

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.

πŸ“„ View Raw YAML

 
id: P57775
gene_symbol: FBXW4
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FBXW4 (dactylin; SHFM3) is a member of the F-box/WD40 (FBXW) family of proteins.
  Its 412-residue product contains an N-terminal F-box motif (approximately residues
  25-71) and a C-terminal beta-propeller built from roughly six WD40 repeats. F-box
  proteins function as the interchangeable substrate-recognition subunits of SCF
  (SKP1-CUL1-F-box)-type cullin-RING E3 ubiquitin ligase complexes: the F-box motif
  docks the protein onto SKP1/CUL1, while the WD40 propeller recognizes (typically
  phosphorylated) substrate proteins and presents them for ubiquitination by the
  RBX1-bound E2, committing them to proteasomal degradation. Affinity-purification
  studies confirm that FBXW4 assembles, in an F-box-dependent manner, with the
  canonical SCF core subunits SKP1, CUL1 and RBX1 and with COP9 signalosome
  subunits (which deneddylate and regulate cullin-RING ligases), and that FBXW4
  associates with ubiquitinated cellular proteins in a manner enhanced by
  proteasome inhibition - establishing it as a bona fide SCF substrate receptor
  engaged in ubiquitin-dependent turnover. Its physiological substrates, however,
  remain undefined. FBXW4 is broadly expressed (including brain, kidney, lung and
  liver) and is recurrently mutated, deleted, or under-expressed across human
  cancers, suggesting a candidate tumor-suppressor role. The human gene maps to
  chromosome 10q24.3 within the critical region for split-hand/foot malformation
  type 3 (SHFM3), and the orthologous gene is disrupted in the mouse dactylaplasia
  (Dac) mutant, which fails to maintain the apical ectodermal ridge and truncates
  the autopod. SHFM3 is most often associated with tandem/discontinuous genomic
  duplications at 10q24 that perturb a shared cis-regulatory neighborhood and alter
  expression of FBXW4 and several neighboring genes (e.g. BTRC, POLL, LBX1) rather
  than with coding mutations in FBXW4 itself, so FBXW4's precise contribution to
  limb development and its physiological ubiquitination substrates remain
  incompletely defined.
existing_annotations:
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Phylogenetic (PAN-GO) assignment of SCF complex membership, consistent with FBXW4's F-box motif that docks F-box proteins onto SKP1/CUL1. Now directly corroborated by FBXW4-specific affinity-purification data showing F-box-dependent assembly with SKP1, CUL1 and RBX1.
    action: ACCEPT
    reason: Core localization/assembly role for an F-box protein; supported by the F-box domain, the documented SKP1 interaction, and direct biochemical co-purification of FBXW4 with the SCF core (SKP1/CUL1/RBX1) and COP9 signalosome in an F-box-dependent manner.
    additional_reference_ids:
    - file:human/FBXW4/FBXW4-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/FBXW4/FBXW4-uniprot.txt
      supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex
    - reference_id: file:human/FBXW4/FBXW4-deep-research-falcon.md
      supporting_text: FBXW4 co-purifies/interacts with **SKP1, CUL1, RBX1** and multiple **COP9 signalosome (COPS)** subunits, and these interactions are **F-box dependent**
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment of involvement in SCF-dependent proteasomal degradation, the canonical process for F-box substrate-receptor proteins. FBXW4-specific data show it engages ubiquitinated proteins in a proteasome-inhibitor- and F-box-dependent manner, supporting genuine participation in ubiquitin-dependent turnover.
    action: ACCEPT
    reason: Core biological process for an F-box protein acting as an SCF substrate receptor; consistent with the UniProt function statement and with direct evidence that FBXW4 associates with ubiquitinated cellular proteins (increased by MG132) in an F-box-dependent manner.
    additional_reference_ids:
    - file:human/FBXW4/FBXW4-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/FBXW4/FBXW4-uniprot.txt
      supporting_text: Probably recognizes and binds to some phosphorylated proteins and promotes their ubiquitination and degradation
    - reference_id: file:human/FBXW4/FBXW4-deep-research-falcon.md
      supporting_text: FBXW4 interacts with **ubiquitinated cellular proteins**, and the interaction increases with **proteasome inhibition (MG132)** in an **F-box-dependent** manner, consistent with substrate engagement in ubiquitin-dependent turnover pathways
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22632967
  qualifier: enables
  review:
    summary: IntAct interaction captured against SKP1 (UniProtKB:P63208) in a cyclin F/SCF study; records the functionally important FBXW4-SKP1 association. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the real FBXW4-SKP1 interaction (the WITH/FROM target is P63208/SKP1), which underpins SCF assembly, but bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/FBXW4/FBXW4-uniprot.txt
      supporting_text: 'P57775; P63208: SKP1; NbExp=3; IntAct=EBI-2372268, EBI-307486'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27705803
  qualifier: enables
  review:
    summary: IntAct interaction against SKP1 (UniProtKB:P63208) from a Polycomb complexome map; supports FBXW4-SKP1 association. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the FBXW4-SKP1 interaction (WITH/FROM P63208/SKP1) relevant to SCF assembly, but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXW4/FBXW4-uniprot.txt
      supporting_text: 'P57775; P63208: SKP1; NbExp=3; IntAct=EBI-2372268, EBI-307486'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: High-throughput interactome interaction against PRKN/Parkin isoform (UniProtKB:O60260-5) from a neurodegenerative-disease interactome study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a high-throughput interaction (WITH/FROM O60260-5/PRKN); bare protein binding is uninformative and not a core function.
    supported_by:
    - reference_id: file:human/FBXW4/FBXW4-uniprot.txt
      supporting_text: 'P57775; O60260-5: PRKN; NbExp=3; IntAct=EBI-2372268, EBI-21251460'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: IntAct interaction against SKP1 (UniProtKB:P63208) from a cell-specific interactome map; supports FBXW4-SKP1 association. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the FBXW4-SKP1 interaction (WITH/FROM P63208/SKP1) relevant to SCF assembly, but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXW4/FBXW4-uniprot.txt
      supporting_text: 'P57775; P63208: SKP1; NbExp=3; IntAct=EBI-2372268, EBI-307486'
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: part_of
  review:
    summary: ComplexPortal (CPX-7761) curated assignment of FBXW4 to an SCF E3 ubiquitin ligase complex variant.
    action: ACCEPT
    reason: Correct core assembly annotation; FBXW4 is the substrate-receptor subunit of an SCF complex variant (ComplexPortal CPX-7761), consistent with SKP1 binding.
    supported_by:
    - reference_id: file:human/FBXW4/FBXW4-uniprot.txt
      supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: involved_in
  review:
    summary: ComplexPortal-derived assignment of involvement in SCF-dependent proteasomal degradation, the canonical process for an SCF substrate receptor.
    action: ACCEPT
    reason: Correct core biological process; redundant with the IBA assignment of the same term.
    supported_by:
    - reference_id: file:human/FBXW4/FBXW4-uniprot.txt
      supporting_text: promotes their ubiquitination and degradation
- term:
    id: GO:0060173
    label: limb development
  evidence_type: NAS
  original_reference_id: PMID:10471509
  qualifier: involved_in
  review:
    summary: Author-stated involvement in limb development, based on disruption of the orthologous gene (dactylin) in the mouse dactylaplasia mutant, which truncates the autopod via failure to maintain the apical ectodermal ridge.
    action: KEEP_AS_NON_CORE
    reason: Genetically well-supported developmental association (dactylaplasia mouse; SHFM3 locus) but the molecular mechanism and direct FBXW4 substrates in limb patterning are not established; this is a pleiotropic developmental role rather than a demonstrated direct molecular function.
    supported_by:
    - reference_id: PMID:10471509
      supporting_text: this report demonstrates the importance of this gene family in vertebrate embryonic development
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952618
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization for FBXW4 within generic CRL1/SCF neddylation and ubiquitination reactions.
    action: KEEP_AS_NON_CORE
    reason: Plausible cytosolic localization for an SCF subunit, but derived from generic CRL pathway reactions rather than FBXW4-specific localization data; the dactylin/SHFM3 literature implies action in developing tissues without resolving compartment.
    supported_by:
    - reference_id: file:human/FBXW4/FBXW4-uniprot.txt
      supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952620
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (NEDD8:AcM-UBE2M binds CRL1) propagated to FBXW4 as an SCF subunit.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific.
    supported_by:
    - reference_id: file:human/FBXW4/FBXW4-uniprot.txt
      supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955241
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (CAND1 binds cytosolic CRL ligases) propagated to FBXW4.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific.
    supported_by:
    - reference_id: file:human/FBXW4/FBXW4-uniprot.txt
      supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955289
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (COMMDs displace CAND1) propagated to FBXW4.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific.
    supported_by:
    - reference_id: file:human/FBXW4/FBXW4-uniprot.txt
      supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956040
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (COP9 signalosome deneddylates CRLs) propagated to FBXW4.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific.
    supported_by:
    - reference_id: file:human/FBXW4/FBXW4-uniprot.txt
      supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956200
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (MyrG-DCUN1D3 binds CRL1) propagated to FBXW4.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific.
    supported_by:
    - reference_id: file:human/FBXW4/FBXW4-uniprot.txt
      supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983140
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (transfer of Ub from E2 to substrate) propagated to FBXW4.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific.
    supported_by:
    - reference_id: file:human/FBXW4/FBXW4-uniprot.txt
      supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983147
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (release of E3 from polyubiquitinated substrate) propagated to FBXW4.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific.
    supported_by:
    - reference_id: file:human/FBXW4/FBXW4-uniprot.txt
      supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983156
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (polyubiquitination of substrate) propagated to FBXW4.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific.
    supported_by:
    - reference_id: file:human/FBXW4/FBXW4-uniprot.txt
      supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983157
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (interaction of E3 with substrate and E2-Ub complex) propagated to FBXW4.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW4-specific.
    supported_by:
    - reference_id: file:human/FBXW4/FBXW4-uniprot.txt
      supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex
- term:
    id: GO:0030326
    label: embryonic limb morphogenesis
  evidence_type: NAS
  original_reference_id: PMID:10405324
  qualifier: involved_in
  review:
    summary: Author-stated putative involvement in limb morphogenesis from the original cloning paper, based on FBXW4 mapping to the SHFM3 critical region at 10q24.3.
    action: KEEP_AS_NON_CORE
    reason: Reflects a candidate-gene/positional inference (SHFM3 critical region) rather than a demonstrated molecular mechanism; developmental role is non-core and the direct substrates in limb morphogenesis are unknown.
    supported_by:
    - reference_id: PMID:10405324
      supporting_text: likely to be involved in key signaling pathways crucial for normal limb development, make it a promising candidate gene for SHFM3
- term:
    id: GO:0000151
    label: ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:10945468
  qualifier: part_of
  review:
    summary: Author-stated membership in a ubiquitin ligase complex, based on FBXW4 being an F-box/WD40 protein of the SCF family. A more general parent of the specific SCF complex term.
    action: ACCEPT
    reason: Correct but generic; subsumed by the more specific GO:0019005 (SCF ubiquitin ligase complex). Consistent with the F-box family role.
    supported_by:
    - reference_id: PMID:10945468
      supporting_text: F-box proteins are critical components of the SCF ubiquitin-protein ligase complex and are involved in substrate recognition and recruitment for ubiquitination
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:10945468
  qualifier: involved_in
  review:
    summary: Author-stated involvement in ubiquitin-dependent protein catabolism, a parent of the specific SCF-dependent proteasomal process.
    action: ACCEPT
    reason: Correct but generic; the more specific GO:0031146 better captures FBXW4's role as an SCF substrate receptor.
    supported_by:
    - reference_id: PMID:10945468
      supporting_text: their distinct role in ubiquitin-dependent protein degradation
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: PMID:10405324
  title: A novel human gene encoding an F-box/WD40 containing protein maps in the
    SHFM3 critical region on 10q24.
  findings:
  - statement: Cloning of human Dactylin/FBXW4, an F-box/WD40 protein at 10q24.3 within the SHFM3 critical region; expressed in brain, kidney, lung and liver; proposed as a candidate gene for split hand/foot malformation acting via ubiquitination of signaling-pathway proteins in limb development.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified original cloning; source of the SHFM3-locus and embryonic limb morphogenesis annotations. Limb role is positional/candidate-gene based, not a demonstrated molecular mechanism.
- id: PMID:10471509
  title: A novel member of the F-box/WD40 gene family, encoding dactylin, is disrupted
    in the mouse dactylaplasia mutant.
  findings:
  - statement: Positional cloning of the mouse dactylaplasia (Dac) gene identifies dactylin (Fbxw4 ortholog); Dac disrupts maintenance of the apical ectodermal ridge and truncates the autopod, resembling human SHFM, demonstrating the importance of the F-box/WD40 family in vertebrate limb development.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; genetic basis for the limb development annotation via the dactylaplasia mouse.
- id: PMID:10945468
  title: cDNA cloning and expression analysis of new members of the mammalian F-box
    protein family.
  findings:
  - statement: Cloning of 10 mammalian F-box proteins including FBWD4 (FBXW4) which contains WD40-repeat domains; F-box proteins are substrate-recognition components of SCF ubiquitin-protein ligase complexes with distinct roles in ubiquitin-dependent degradation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified family cloning paper; source of generic ubiquitin ligase complex and ubiquitin-dependent catabolic process annotations.
- id: PMID:22632967
  title: Cyclin F-mediated degradation of ribonucleotide reductase M2 controls genome
    integrity and DNA repair.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Study of SCF(cyclin F); the FBXW4 GOA annotation from this PMID is an IntAct interaction against SKP1 (WITH/FROM P63208), not a claim about cyclin F or RRM2. Source of a bare protein binding annotation.
- 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; FBXW4 annotation is an IntAct interaction against SKP1 (WITH/FROM P63208).
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; FBXW4 annotation is an interaction against a PRKN/Parkin isoform (WITH/FROM O60260-5). Bare protein binding, non-core.
- 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: Cell-specific interactome; FBXW4 annotation is an IntAct interaction against SKP1 (WITH/FROM P63208).
- id: PMID:34445249
  title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
  findings:
  - statement: Review of SCF (SKP1-CUL1-F-box) complex biology; provides the basis for ComplexPortal assignment of FBXW4 to an SCF E3 ubiquitin ligase complex variant and to SCF-dependent proteasomal degradation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified SCF review; basis for ComplexPortal SCF complex and SCF-dependent catabolic process annotations.
- id: Reactome:R-HSA-8952618
  title: AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8952620
  title: NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8955241
  title: CAND1 binds cytosolic CRL E3 ubiquitin ligases
  findings: []
- id: Reactome:R-HSA-8955289
  title: COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes
  findings: []
- id: Reactome:R-HSA-8956040
  title: COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes
  findings: []
- id: Reactome:R-HSA-8956200
  title: MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-983140
  title: Transfer of Ub from E2 to substrate and release of E2
  findings: []
- id: Reactome:R-HSA-983147
  title: Release of E3 from polyubiquitinated substrate
  findings: []
- id: Reactome:R-HSA-983156
  title: Polyubiquitination of substrate
  findings: []
- id: Reactome:R-HSA-983157
  title: Interaction of E3 with substrate and E2-Ub complex
  findings: []
- id: file:human/FBXW4/FBXW4-deep-research-falcon.md
  title: Falcon deep research report for human FBXW4
  findings:
  - statement: FBXW4 assembles with the canonical SCF core (SKP1, CUL1, RBX1) and with COP9 signalosome subunits in an F-box-dependent manner, providing direct biochemical evidence (beyond family inference) that it is an SCF substrate-recognition subunit rather than an enzyme or transporter.
    supporting_text: FBXW4 co-purifies/interacts with **SKP1, CUL1, RBX1** and multiple **COP9 signalosome (COPS)** subunits, and these interactions are **F-box dependent**
  - statement: FBXW4 associates with ubiquitinated cellular proteins, and this association increases upon proteasome inhibition in an F-box-dependent way, consistent with substrate engagement in ubiquitin-dependent turnover.
    supporting_text: FBXW4 interacts with **ubiquitinated cellular proteins**, and the interaction increases with **proteasome inhibition (MG132)** in an **F-box-dependent** manner, consistent with substrate engagement in ubiquitin-dependent turnover pathways
  - statement: The endogenous substrate(s) of SCF(FBXW4) remain undefined; the primary biochemical study frames substrate identification as a future direction.
    supporting_text: 'The specific endogenous **substrate(s)** targeted by SCF^FBXW4 remain insufficiently defined in the retrieved evidence; the 2013 study frames substrate identification as a future direction'
  - statement: FBXW4 is recurrently mutated, lost, and under-expressed across human cancers, consistent with a possible tumor-suppressor role, though causal substrates/pathways are unclear.
    supporting_text: FBXW4 is mutated, lost, and under-expressed in human cancers, and argue this pattern is consistent with a potential **tumor suppressor** role, though definitive causal substrates/pathways remain unclear
  - statement: SHFM3 at 10q24 is best explained as a cis-regulatory / multi-gene misexpression disorder; recurrent duplications include FBXW4 with neighboring genes, and enhancer perturbation in mouse alters Fbxw4 expression rather than acting through an FBXW4 coding mutation.
    supporting_text: SVs likely perturb **cis-regulatory elements**, **3D chromatin architecture**, and/or coordinated expression of multiple genes in the region
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Falcon synthesis grounded chiefly in Lockwood et al. 2013 (PLoS ONE, doi:10.1371/journal.pone.0063610), which provides the first direct biochemical evidence that FBXW4 is an SCF substrate receptor (F-box-dependent assembly with SKP1/CUL1/RBX1 and the COP9 signalosome; MG132-dependent association with ubiquitinated proteins). Cross-checked against UniProt P57775 SUBUNIT/FUNCTION statements and ComplexPortal CPX-7761. SHFM3 cis-regulatory-neighborhood model is consistent with the UniProt SHFM3 disease note and the prior SHFM3 cloning/mapping literature already cited in this review.
core_functions:
- description: Substrate-recognition (substrate-adaptor) subunit of an SCF (SKP1-CUL1-F-box) cullin-RING E3 ubiquitin ligase complex, docking via its F-box motif onto SKP1/CUL1 and using its WD40 propeller to recruit substrates and bridge them to the ligase for SCF-dependent proteasomal degradation. FBXW4 itself is not catalytic; the ubiquitin-transfer/RING activity resides on the RBX1 subunit of the assembled SCF complex. Direct physiological substrates of SCF(FBXW4) remain undefined.
  supported_by:
  - reference_id: file:human/FBXW4/FBXW4-uniprot.txt
    supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex
  - reference_id: PMID:10945468
    supporting_text: F-box proteins are critical components of the SCF ubiquitin-protein ligase complex and are involved in substrate recognition and recruitment for ubiquitination
  - reference_id: file:human/FBXW4/FBXW4-deep-research-falcon.md
    supporting_text: FBXW4 co-purifies/interacts with **SKP1, CUL1, RBX1** and multiple **COP9 signalosome (COPS)** subunits, and these interactions are **F-box dependent**
  locations:
  - id: GO:0005829
    label: cytosol
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
proposed_new_terms:
- proposed_name: ubiquitin-like ligase-substrate adaptor activity
  proposed_definition: Bridging a substrate to a ubiquitin-like protein ligase, as performed by an SCF F-box substrate-recognition subunit that binds both SKP1/the ligase scaffold and the substrate to facilitate the substrate's ubiquitination. This corresponds to the existing GO term GO:1990756, which is not currently in FBXW4's annotation set.
  justification: FBXW4 assembles with the SCF core (SKP1/CUL1/RBX1) and the COP9 signalosome in an F-box-dependent manner and associates with ubiquitinated proteins in a proteasome-inhibitor-dependent way, consistent with a substrate-adaptor molecular function rather than catalysis (which is RBX1's). Adding GO:1990756 would give FBXW4 an informative molecular-function term in place of the uninformative bare protein binding annotations.
  proposed_parent:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  supported_by:
  - reference_id: file:human/FBXW4/FBXW4-uniprot.txt
    supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex
  - reference_id: file:human/FBXW4/FBXW4-deep-research-falcon.md
    supporting_text: FBXW4 co-purifies/interacts with **SKP1, CUL1, RBX1** and multiple **COP9 signalosome (COPS)** subunits, and these interactions are **F-box dependent**
suggested_questions:
- question: What are the direct, phosphorylation-dependent ubiquitination substrates recognized by the FBXW4 WD40 propeller, and which signaling pathways (e.g. Wnt) do they belong to?
- question: Given that SHFM3 is associated with a tandem duplication at 10q24 rather than FBXW4 coding mutations, is the limb phenotype due to altered FBXW4 dosage, a neighboring gene, or a regulatory element, and what is FBXW4's direct molecular contribution?
suggested_experiments:
- description: Affinity purification of tagged FBXW4 with SKP1/CUL1/RBX1 followed by mass spectrometry of co-purifying and ubiquitinated proteins, in limb-bud-derived or epithelial cells, to identify physiological SCF(FBXW4) substrates.
- description: Reconstitute SCF(FBXW4) in vitro with SKP1, CUL1, RBX1 and an E2 and test ubiquitination of candidate developmental-signaling substrates, comparing wild-type to F-box-deletion FBXW4 to confirm substrate-adaptor activity.