Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005515 protein binding	IPI PMID:19159283 Array MAPPIT: high-throughput interactome analysis in mammal...	KEEP AS NON CORE	Summary: IntAct interaction against SKP1 (UniProtKB:P63208) from the Array MAPPIT high-throughput interactome screen (Lievens et al. 2009), validated by co-immunoprecipitation; supports FBXW9-SKP1 association underlying SCF assembly. Bare protein binding is uninformative. Reason: Records the functionally relevant FBXW9-SKP1 interaction (WITH/FROM P63208/SKP1), which underpins SCF assembly and is corroborated by co-IP validation, but bare protein binding is uninformative per curation guidelines; the substrate-adaptor molecular function (GO:1990756) better captures this role. Supporting Evidence: file:human/FBXW9/FBXW9-uniprot.txt Q5XUX1; P63208: SKP1; NbExp=8; IntAct=EBI-2322729, EBI-307486 file:human/FBXW9/FBXW9-deep-research-falcon.md FBXW9 was identified as a SKP1-interacting prey in a high-throughput array MAPPIT interactome screen and validated by co-immunoprecipitation in HEK293T cells
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 FBXW9-SKP1 association. Bare protein binding is uninformative. Reason: Records the FBXW9-SKP1 interaction (WITH/FROM P63208/SKP1) relevant to SCF assembly, but bare protein binding is uninformative. Supporting Evidence: file:human/FBXW9/FBXW9-uniprot.txt Q5XUX1; P63208: SKP1; NbExp=8; IntAct=EBI-2322729, EBI-307486
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 FBXW9-SKP1 association. Bare protein binding is uninformative. Reason: Records the FBXW9-SKP1 interaction (WITH/FROM P63208/SKP1) relevant to SCF assembly, but bare protein binding is uninformative. Supporting Evidence: file:human/FBXW9/FBXW9-uniprot.txt Q5XUX1; P63208: SKP1; NbExp=8; IntAct=EBI-2322729, EBI-307486
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	KEEP AS NON CORE	Summary: IntAct interaction against SKP1 (UniProtKB:P63208) from a multimodal cell-map study; supports FBXW9-SKP1 association. Bare protein binding is uninformative. Reason: Records the FBXW9-SKP1 interaction (WITH/FROM P63208/SKP1) relevant to SCF assembly, but bare protein binding is uninformative. Supporting Evidence: file:human/FBXW9/FBXW9-uniprot.txt Q5XUX1; P63208: SKP1; NbExp=8; IntAct=EBI-2322729, EBI-307486
GO:0019005 SCF ubiquitin ligase complex	NAS PMID:15520277 Systematic analysis and nomenclature of mammalian F-box prot...	ACCEPT	Summary: ComplexPortal/family-based assignment of SCF complex membership, consistent with FBXW9's F-box motif and experimentally documented SKP1 binding (array MAPPIT plus co-IP) and CUL1 co-purification (AP-MS); ComplexPortal CPX-7785 defines an SCF complex FBXW9 variant. Reason: Core assembly annotation for an F-box protein; supported by the F-box domain and direct experimental evidence that FBXW9 binds SKP1 and co-purifies with CUL1-containing SCF assemblies. Supporting Evidence: file:human/FBXW9/FBXW9-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex file:human/FBXW9/FBXW9-deep-research-falcon.md FBXW9 was identified as a SKP1-interacting prey in a high-throughput array MAPPIT interactome screen and validated by co-immunoprecipitation in HEK293T cells
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process	NAS PMID:15520277 Systematic analysis and nomenclature of mammalian F-box prot...	KEEP AS NON CORE	Summary: Family-based assignment of involvement in SCF-dependent proteasomal degradation, the canonical process for an SCF substrate receptor. FBXW9 assembles into SCF (SKP1/CUL1), but no FBXW9-specific substrate has been validated by direct ubiquitination/degradation assays; proposed substrates such as TP53 remain predictive. Reason: Plausible and consistent with the F-box family role and with experimental SCF assembly, but no FBXW9-specific substrate or degradation event has been demonstrated biochemically; cancer-context studies report transcriptional regulation and knockdown phenotypes rather than direct substrate degradation, so the process role still rests on family inference. Supporting Evidence: file:human/FBXW9/FBXW9-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex file:human/FBXW9/FBXW9-deep-research-falcon.md No directly validated endogenous ubiquitination substrate for human FBXW9 was recovered; no direct catalytic assay, no substrate degron definition
GO:0005829 cytosol	TAS Reactome:R-HSA-8952618	KEEP AS NON CORE	Summary: Reactome pathway-level cytosol localization (AcM-UBE2M transfers NEDD8 to CRL1) propagated to FBXW9 as an SCF subunit. Reason: Plausible cytosolic localization for an SCF subunit but derived from generic CRL pathway reactions, not FBXW9-specific localization data. Supporting Evidence: file:human/FBXW9/FBXW9-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9. Reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific. Supporting Evidence: file:human/FBXW9/FBXW9-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9. Reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific. Supporting Evidence: file:human/FBXW9/FBXW9-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9. Reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific. Supporting Evidence: file:human/FBXW9/FBXW9-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9. Reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific. Supporting Evidence: file:human/FBXW9/FBXW9-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9. Reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific. Supporting Evidence: file:human/FBXW9/FBXW9-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9. Reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific. Supporting Evidence: file:human/FBXW9/FBXW9-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9. Reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific. Supporting Evidence: file:human/FBXW9/FBXW9-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9. Reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific. Supporting Evidence: file:human/FBXW9/FBXW9-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9. Reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific. Supporting Evidence: file:human/FBXW9/FBXW9-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex

Core Functions

Substrate-recognition (substrate-adaptor) subunit of an SCF (SKP1-CUL1-F-box) cullin-RING E3 ubiquitin ligase complex; it docks via its F-box motif onto SKP1 (experimentally validated) and CUL1 (AP-MS), presenting a WD40 propeller for substrate recruitment. FBXW9 is non-catalytic (ubiquitin transfer is RBX1's), and its specific physiological substrates are not yet experimentally defined.

Cellular Locations:

cytosol

Supporting Evidence:

file:human/FBXW9/FBXW9-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
file:human/FBXW9/FBXW9-deep-research-falcon.md
FBXW9 was identified as a SKP1-interacting prey in a high-throughput **array MAPPIT** interactome screen and validated by **co-immunoprecipitation** in **HEK293T** cells

References

PMID:15520277

Systematic analysis and nomenclature of mammalian F-box proteins.

Systematic classification and nomenclature of mammalian F-box proteins into FBXL, FBXW and FBXO families; FBXW proteins are the WD40-repeat-containing substrate-recognition subunits of SCF ubiquitin ligase complexes.

PMID:19159283

Array MAPPIT: high-throughput interactome analysis in mammalian cells.

PMID:27705803

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

PMID:33961781

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

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

Reactome:R-HSA-983157

Interaction of E3 with substrate and E2-Ub complex

file:human/FBXW9/FBXW9-deep-research-falcon.md

Falcon deep research report for human FBXW9

FBXW9 binds SKP1 (array MAPPIT screen validated by co-immunoprecipitation in HEK293T) and co-purifies with CUL1 in AP-MS of SCF assemblies, providing direct experimental evidence that it is an SCF/CRL1 substrate-recognition adaptor rather than an enzyme.

"FBXW9 was identified as a SKP1-interacting prey in a high-throughput **array MAPPIT** interactome screen and validated by **co-immunoprecipitation** in **HEK293T** cells"
FBXW9 is a direct p53 transcriptional target (ChIP/luciferase/Nutlin-3 evidence) whose ectopic expression suppresses proliferation of p53-deficient cells, positioning it downstream of p53 tumor-suppressor signaling.

"ChIP-seq/ChIP-qPCR showed p53 occupancy near Fbxw9 promoter; p53 increased luciferase reporter activity; p53 knockdown reduced expression; Nutlin-3 induced Fbxw9 in p53-WT but not p53-null human cells"
In glioblastoma stem-like cells FBXW9 is a CREB-bound transcriptional target downstream of an IGFBP5-ROR1/HER2 axis, and FBXW9 knockdown reduces invasion, with high FBXW9 associated with worse survival.

"siRNA against FBXW9 significantly decreased invasion capacity in X01 and 448 GSC lines; high FBXW9 associated with worse glioma/LGG survival"
In breast cancer cells FBXW9 knockdown reduces proliferation and induces G0/G1 arrest with increased p21, but TP53 as an FBXW9 ubiquitination substrate remains predicted (UbiBrowser), not biochemically validated.

"TP53 as substrate remains predicted, not biochemically validated by ubiquitination/degradation assay"
No directly validated endogenous ubiquitination substrate for human FBXW9 has been established; the molecular substrate repertoire and degron remain unresolved.

"No directly validated endogenous ubiquitination substrate for human FBXW9 was recovered; no direct catalytic assay, no substrate degron definition"

Suggested Experiments

Experiment: Affinity purification of tagged FBXW9 with SKP1/CUL1/RBX1 followed by mass spectrometry to identify co-purifying and ubiquitinated substrate candidates, prioritizing cell types (breast cancer, glioblastoma stem-like cells) where knockdown phenotypes were reported.

Experiment: Reconstitute SCF(FBXW9) in vitro with SKP1, CUL1, RBX1 and an E2, and test ubiquitination of candidate substrates (e.g. TP53 predicted by UbiBrowser) comparing wild-type to F-box-deletion FBXW9.

Deep Research

Falcon

(FBXW9-deep-research-falcon.md)

Research Report: Human **FBXW9** (UniProt **Q5XUX1**) — Functional Annotation and Current Evidence (2023–2024 prioritized) Falcon Edison Scientific Literature 35 citations 2 artifacts 2026-06-13T07:17:03.215628

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000024 I have extracted the Kaplan–Meier survival plots and panels related to FBXW9 and its combination with IGFBP5. - **Kaplan–Meier (KM) (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 FBXW9 (UniProt Q5XUX1) — Functional Annotation and Current Evidence (2023–2024 prioritized)

Executive summary

FBXW9 (F-box/WD repeat-containing protein 9; gene FBXW9, synonym FBW9) is a human F-box/WD40 repeat protein that functions as a substrate-recognition component for cullin-RING E3 ubiquitin ligases (CRLs), most directly supported for SCF/CRL1 by physical interaction with SKP1 and proteomic association with CUL1. (lievens2009arraymappithighthroughput pages 6-8, lee2011thesteadystaterepertoire pages 6-7, lievens2009arraymappithighthroughput pages 5-6). Recent studies (2023–2024) implicate FBXW9 in (i) breast cancer cell-cycle/proliferation phenotypes (loss-of-function) and (ii) glioblastoma stem-like cell invasion downstream of an IGFBP5–ROR1/HER2–CREB axis, where FBXW9 is a CREB-bound transcriptional target and correlates with worse survival. (yu2023acomprehensiveanalysis pages 8-11, lin2023igfbp5isan pages 7-9, lin2023igfbp5isan pages 6-7, lin2023igfbp5isan media 2620dd74). A 2024 study additionally identifies FBXW9 as a direct p53 transcriptional target with anti-proliferative effects upon ectopic expression in p53-deficient settings. (shin2024apipelineto pages 1-3). Despite these functional links, direct biochemical substrates ubiquitinated by human FBXW9 remain largely unvalidated in the retrieved literature; several proposed substrates (e.g., TP53) are currently supported primarily by prediction and indirect transcriptional readouts. (yu2023acomprehensiveanalysis pages 5-8, yu2023acomprehensiveanalysis pages 8-11).

1) Key concepts and definitions (current understanding)

1.1 F-box proteins, FBXW subfamily, and SCF/CRL architecture

F-box proteins are adaptor/substrate-recognition proteins for SCF (SKP1–CUL1–F-box) E3 ubiquitin ligases, where the F-box domain mediates binding to SKP1 and additional domains (e.g., WD40 repeats) mediate substrate binding. In the FBXW subfamily, proteins contain an F-box domain and multiple WD40 domains. (yu2023acomprehensiveanalysis pages 1-2, yu2023acomprehensiveanalysis pages 2-5, jeong2023targetinge3ubiquitin pages 3-4).

The 2023 breast cancer-focused analysis explicitly states: “All members of FBXWs contain an F-box domain and multiple WD40 domains.” (yu2023acomprehensiveanalysis pages 1-2). The broader CRL framework is summarized in a 2023 review: CRL1/SCF consists of CUL1, SKP1, an F-box protein, and RBX1, with CUL1 as scaffold and RBX1 recruiting E2 enzymes to facilitate ubiquitin transfer. (jeong2023targetinge3ubiquitin pages 3-4).

1.2 What “functional annotation” means here

For FBXW9—a non-enzymatic adaptor—primary function is defined by:
1) complex membership (which CRL it binds),
2) substrate recognition (which proteins it recruits for ubiquitination), and
3) pathway placement (signaling or transcriptional circuits that control or are controlled by FBXW9).

2) Target identity verification (to avoid symbol ambiguity)

The research corpus consistently refers to human FBXW9 as “F-box and WD repeat domain containing 9” and situates it in the FBXW family of F-box/WD-repeat proteins. (huang2024pancanceranalysisof pages 2-4, yu2023acomprehensiveanalysis pages 1-2). Experimental assay design in a qPCR study used FBXW9 transcript accession NM_032301, consistent with the human gene. (dwivedi2020relativequantificationof pages 4-5). These sources align with the UniProt-provided identity (Q5XUX1: F-box/WD repeat-containing protein 9, human) and domain expectations (F-box + WD40 repeats). (yu2023acomprehensiveanalysis pages 1-2, yu2023acomprehensiveanalysis pages 2-5).

3) Molecular function, complexes, and localization

3.1 Complex membership: evidence for SCF/CRL1 association

SKP1 interaction (direct experimental evidence). FBXW9 was identified as a SKP1-interacting prey in a high-throughput array MAPPIT interactome screen and validated by co-immunoprecipitation in HEK293T cells (E-tagged SKP1 bait; Flag-tagged prey including FBXW9). (lievens2009arraymappithighthroughput pages 6-8, lievens2009arraymappithighthroughput pages 5-6).

CUL1 association (proteomics evidence). In affinity purification–mass spectrometry of tandem-tagged CUL1 complexes in HEK293-derived cells, FBXW9 was among the F-box proteins that co-purified with CUL1 (reported with substantial spectral counts), supporting its presence in the cellular repertoire of SCF assemblies. (lee2011thesteadystaterepertoire pages 6-7).

Together, these data support annotation of FBXW9 as a substrate receptor/adaptor in SCF/CRL1 E3 ligase complexes. (lievens2009arraymappithighthroughput pages 6-8, lee2011thesteadystaterepertoire pages 6-7).

3.2 Potential role in CRL7/CUL7: conflicting secondary-source statements

A 2023 review states: “unlike SCF, Fbxw9 is the only known substrate receptor for CRL7.” (jeong2023targetinge3ubiquitin pages 3-4). However, CUL7/CRL7-focused reviews from 2018 and 2020 emphasize FBXW8 (and sometimes FBXW11) as the F-box proteins shown to bind CUL7, listing multiple CRL7 substrates (e.g., cyclin D1, IRS1, GRASP65) in association with FBXW8—not FBXW9. (shi2020thefunctionalanalysis pages 1-2, jang2018chromatinboundcullinringligases pages 5-6).

Interpretation: The strongest direct evidence assembled here supports FBXW9’s SCF/CRL1 role (SKP1 + CUL1 association). The CRL7 claim appears review-level and is not corroborated by the retrieved CUL7-specialist reviews; therefore, CRL7 assignment should be treated as uncertain pending primary data pinpointing a CUL7–FBXW9 complex in human cells. (jeong2023targetinge3ubiquitin pages 3-4, shi2020thefunctionalanalysis pages 1-2, jang2018chromatinboundcullinringligases pages 5-6).

3.3 Subcellular localization

A 2024 pan-cancer FBXW-family analysis compiling UniProt/GeneCards annotations reports FBXW9 localization as “Cytosol” and notes most FBXW members localize to cytoplasm/cytosol. (huang2024pancanceranalysisof pages 4-5). This supports a working localization annotation but is database-derived, not microscopy-based evidence specific to FBXW9. (huang2024pancanceranalysisof pages 4-5).

4) Pathways and biological roles: what is known (and what is inferred)

4.1 p53 regulatory axis (2024): FBXW9 as a direct p53 target gene

A 2024 study building a pipeline for p53 effector identification reports that p53 directly binds and transactivates Fbxw9:
- ChIP-seq/ChIP-qPCR evidence of p53 occupancy at the promoter region
- Promoter luciferase reporter activation by p53
- Reduced target expression upon p53 knockdown
- Nutlin-3 p53 activation induced targets in p53-WT but not p53-null human cells
- Tumors with wild-type p53 had higher target mRNA than p53-mutant tumors in TCGA analyses
- Overexpression of the targets (including Fbxw9) suppressed proliferation of p53-deficient MEFs
(shin2024apipelineto pages 1-3).

Functional implication: This positions FBXW9 downstream of p53 transcriptional programs; the study supports an anti-proliferative role when FBXW9 is ectopically expressed in p53-deficient settings, but does not define ubiquitination substrates. (shin2024apipelineto pages 1-3).

4.2 Glioblastoma invasion pathway (2023): IGFBP5–ROR1/HER2–CREB → FBXW9

A 2023 Nature Communications study reports FBXW9 as part of a CREB-driven transcriptional module downstream of IGFBP5 signaling through ROR1/HER2:
- FBXW9 is higher in invasive vs non-invasive glioma stem-like cells; IGFBP5 perturbation modulates FBXW9 expression. (lin2023igfbp5isan pages 6-7).
- ChIP-qPCR indicates CREB enrichment at the FBXW9 locus and reduced CREB binding at the FBXW9 TSS upon IGFBP5 knockdown (reported P = 0.002 for reduced binding). (lin2023igfbp5isan pages 7-9).
- siRNA against FBXW9 reduced invasion in GSC lines (X01, 448), supporting a causal contribution to invasion. (lin2023igfbp5isan pages 6-7).
- Survival associations: high FBXW9 correlated with worse patient survival in TCGA glioma/LGG analyses (text-reported P = 0.0005 for FBXW9; and P = 0.00004 for combined IGFBP5+FBXW9 stratification). (lin2023igfbp5isan pages 7-9).
- The paper includes Kaplan–Meier panels for FBXW9 and IGFBP5+FBXW9 survival stratification (figure evidence). (lin2023igfbp5isan media 2620dd74).

Interpretation: FBXW9 is experimentally supported as a downstream effector in an invasion-promoting transcriptional axis, but the molecular ubiquitination targets responsible for the invasion phenotype are not identified in the retrieved excerpts. (lin2023igfbp5isan pages 6-7).

4.3 Breast cancer phenotypes (2023): proliferation/cell cycle and inferred TP53–p21 connection

A 2023 integrative analysis in breast cancer reports:
- FBXW9 is frequently upregulated across cancer types and highlighted as a potential prognostic/immunologic biomarker. (yu2023acomprehensiveanalysis pages 1-2, yu2023acomprehensiveanalysis pages 2-5).
- In breast cancer cell lines (SUM159, MDA-MB-231), siRNA knockdown of FBXW9 reduced proliferation and colony formation and induced G0/G1 arrest (fewer S-phase cells). (yu2023acomprehensiveanalysis pages 8-11).
- Substrate prediction (UbiBrowser) suggested TP53 as a hub among candidate substrates; experimentally, FBXW9 knockdown increased p21 expression (a canonical TP53 target), and altered cyclins (CCNA2/CCNB1), consistent with activation of a cell-cycle arrest program. (yu2023acomprehensiveanalysis pages 5-8, yu2023acomprehensiveanalysis pages 8-11).
- FBXW9 repression of NECTIN2 was reported as an experimental regulatory relationship in breast cancer cells. (yu2023acomprehensiveanalysis pages 11-13).

Interpretation and limitation: While cell phenotypes and downstream transcriptional changes are experimentally shown, TP53 as an FBXW9 ubiquitination substrate remains predicted (not shown by direct ubiquitination/degradation assays in the retrieved text). (yu2023acomprehensiveanalysis pages 5-8).

5) Recent developments and “latest research” (prioritizing 2023–2024)

Key 2023–2024 advances for FBXW9 recovered here:
1) IGFBP5–ROR1/HER2–CREB axis in glioblastoma identifying FBXW9 as a CREB target and invasion mediator with survival associations (2023, high-impact primary study). (lin2023igfbp5isan pages 7-9, lin2023igfbp5isan pages 6-7, lin2023igfbp5isan media 2620dd74).
2) Breast cancer functional assays showing FBXW9 knockdown suppresses proliferation and affects cell cycle (2023). (yu2023acomprehensiveanalysis pages 8-11).
3) p53 effector pipeline demonstrating direct transcriptional regulation of FBXW9 by p53, positioning FBXW9 within canonical tumor suppressor signaling (2024). (shin2024apipelineto pages 1-3).
4) CRL architecture reviews explicitly discussing CRL composition and offering the (currently disputed) CRL7 receptor claim for FBXW9 (2023 review). (jeong2023targetinge3ubiquitin pages 3-4).

6) Current applications and real-world implementations

6.1 Biomarker research (cancer prognosis, immune context)

Multiple analyses position FBXW9 as a candidate biomarker in cancer (especially breast cancer), using TCGA/CPTAC and immune infiltration correlations; a 2024 family-level study similarly links FBXW members (including FBXW9) to prognosis and immune infiltration patterns. (yu2023acomprehensiveanalysis pages 2-5, yu2023acomprehensiveanalysis pages 11-13, huang2024pancanceranalysisof pages 2-4).

In glioma, FBXW9 expression stratifies survival and worsens prognosis in combination with IGFBP5 (shown in survival plots). (lin2023igfbp5isan pages 7-9, lin2023igfbp5isan media 2620dd74).

6.2 Assay design / clinical molecular diagnostics support role (reference gene)

A practical non-mechanistic application: a 2020 study identifying stable reference genes for BCL2 qPCR quantification across hematologic malignancy samples selected FBXW9 among the most stable genes and provides primer sequences targeting NM_032301. (dwivedi2020relativequantificationof pages 4-5, dwivedi2020relativequantificationof pages 5-7).

7) Relevant statistics and quantitative findings (recent studies)

Glioma survival association: FBXW9 high vs low expression associated with poorer survival in TCGA low-grade glioma analyses (P = 0.0005), and combined high IGFBP5+FBXW9 associated with worst survival (P = 0.00004). (lin2023igfbp5isan pages 7-9).
CREB binding regulation: Reduced CREB binding at the FBXW9 TSS upon IGFBP5 knockdown in ChIP-qPCR (P = 0.002). (lin2023igfbp5isan pages 7-9).
Therapeutic perturbation upstream of FBXW9 axis: CRISPR editing of IGFBP5 reduced invasion in GSCs (e.g., P = 0.0004 in one invasion assay comparison) and improved survival in mouse models (log-rank P = 0.001 for sgScramble vs sgIGFBP5; P = 0.0006 PBS vs sgIGFBP5). (lin2023igfbp5isan pages 9-11).

(These quantify the pathway/clinical associations in which FBXW9 participates, even when FBXW9 itself is not the direct therapeutic target in that study.) (lin2023igfbp5isan pages 9-11).

8) Expert synthesis and consensus view (authoritative sources)

Consensus on molecular role: Across primary studies and reviews, FBXW9 is consistently categorized as an F-box/WD40 protein expected to function as a substrate recognition component in SCF-like CRLs, mediated by its F-box (complex assembly) and WD40 (substrate binding) architecture. (yu2023acomprehensiveanalysis pages 1-2, jeong2023targetinge3ubiquitin pages 3-4).
Consensus on knowledge gaps: Even in cancer-focused analyses, authors note that FBXW9 substrates and mechanisms are not well established compared with canonical FBXW members (e.g., FBXW7), and substrate lists are often predictive. (yu2023acomprehensiveanalysis pages 8-11, yu2023acomprehensiveanalysis pages 5-8).
CRL7 ambiguity: A 2023 review asserts a unique CRL7 substrate receptor role for FBXW9, but CUL7/CRL7-focused reviews emphasize FBXW8 (and FBXW11) as CUL7-binding F-box proteins. This discrepancy indicates that CRL7 assignment for FBXW9 is not settled in the retrieved evidence and should be treated cautiously. (jeong2023targetinge3ubiquitin pages 3-4, shi2020thefunctionalanalysis pages 1-2, jang2018chromatinboundcullinringligases pages 5-6).

9) Evidence map: what is experimentally supported vs inferred

Claim/topic	Evidence type	Key details/quantitative stats	Primary source	URL/DOI	Notes/limitations
FBXW9 identity as a human F-box/WD40 protein	Domain/family annotation supported by cancer-family analyses	FBXW9 is included among the 10 human FBXW proteins; FBXW family members contain an F-box domain plus multiple WD40 domains; FBXW9 length reported as 458 aa and localization as cytosol in UniProt/GeneCards-based family annotation (yu2023acomprehensiveanalysis pages 1-2, yu2023acomprehensiveanalysis pages 2-5, huang2024pancanceranalysisof pages 4-5)	Yu 2023, Int J Mol Sci; Huang 2024, Front Immunol	https://doi.org/10.3390/ijms24065262; https://doi.org/10.3389/fimmu.2022.1084339	Strong for family/domain assignment; not a direct biochemical assay on Q5XUX1 alone
FBXW9 binds SKP1	Experimental protein–protein interaction	Identified in array MAPPIT screen as a novel SKP1 interactor and validated by co-immunoprecipitation in HEK293T cells using E-tagged SKP1 bait and Flag-tagged FBXW9 prey (lievens2009arraymappithighthroughput pages 6-8, lievens2009arraymappithighthroughput pages 5-6)	Lievens 2009, J Proteome Res	https://doi.org/10.1021/pr8005167	Direct interaction evidence supports SCF-type adaptor behavior; does not by itself prove substrate specificity or ubiquitination activity
FBXW9 associates with CUL1-containing SCF assemblies	AP-MS proteomics	Tandem-tagged CUL1 affinity purification in HEK293-derived cells recovered FBXW9 among 42 CUL1-associated F-box proteins; FBXW9 reported with ~61 spectral counts (lee2011thesteadystaterepertoire pages 6-7)	Lee 2011, Mol Cell Proteomics	https://doi.org/10.1074/mcp.m110.006460	Co-purification is strong proteomic evidence for SCF association, but not an orthogonal FBXW9-specific co-IP
FBXW9 as a putative substrate receptor in CRL7	Review-level mechanistic claim	Review states: “However, unlike SCF, Fbxw9 is the only known substrate receptor for CRL7,” in context of cullin-RING ligase architecture (jeong2023targetinge3ubiquitin pages 3-4)	Jeong 2023, Exp Mol Med	https://doi.org/10.1038/s12276-023-01087-w	Useful expert summary, but secondary-source claim; underlying primary evidence was not recovered here. Note potential inconsistency within the review’s broader Cul7/Crl7 discussion (jeong2023targetinge3ubiquitin pages 2-3)
Subcellular localization	Database/family annotation	Family-level analyses cite FBXW9 localization as “cytosol”; most FBXW members localize to cytoplasm/cytosol (huang2024pancanceranalysisof pages 2-4, huang2024pancanceranalysisof pages 4-5)	Huang 2024, Front Immunol	https://doi.org/10.3389/fimmu.2022.1084339	Localization appears database-derived rather than from microscopy/fractionation experiments specific to FBXW9
FBXW9 is a direct p53 target gene	Experimental transcriptional regulation	ChIP-seq/ChIP-qPCR showed p53 occupancy near Fbxw9 promoter; p53 increased luciferase reporter activity; p53 knockdown reduced expression; Nutlin-3 induced Fbxw9 in p53-WT but not p53-null human cells; tumors with WT p53 had higher FBXW9 mRNA than p53-mutant tumors (shin2024apipelineto pages 1-3)	Shin 2024, Genes & Diseases	https://doi.org/10.1016/j.gendis.2023.03.009	Strong evidence that FBXW9 is p53-responsive; does not identify FBXW9 protein substrates
FBXW9 may regulate TP53/p21 axis in breast cancer	Mixed: prediction + perturbation experiment	UbiBrowser predicted 36 substrates with TP53 as hub; siRNA knockdown of FBXW9 in SUM159 and MDA-MB-231 cells increased p21 mRNA/protein and reduced CCNA2/CCNB1, consistent with G0/G1 arrest (yu2023acomprehensiveanalysis pages 5-8, yu2023acomprehensiveanalysis pages 8-11)	Yu 2023, Int J Mol Sci	https://doi.org/10.3390/ijms24065262	TP53 as substrate remains predicted, not biochemically validated by ubiquitination/degradation assay
FBXW9 promotes breast cancer cell proliferation/cell-cycle progression	Experimental cell biology	siRNA-mediated FBXW9 silencing in SUM159 and MDA-MB-231 reduced proliferation and colony formation and induced G0/G1 arrest with fewer S-phase cells (yu2023acomprehensiveanalysis pages 8-11)	Yu 2023, Int J Mol Sci	https://doi.org/10.3390/ijms24065262	Functional evidence in vitro; mechanism upstream/downstream of TP53 remains inferential
FBXW9 correlates with MYC activity, stemness, and immune features in breast cancer	Bioinformatic correlation + limited perturbation	FBXW9 positively correlated with MYC signaling and cancer stemness; knockdown repressed NECTIN2 and altered immune-related genes including CD274/PDCD1LG2; high FBXW9 associated with poorer outcome and poor prognosis under anti-PD1 treatment in analyzed cohorts (yu2023acomprehensiveanalysis pages 5-8, yu2023acomprehensiveanalysis pages 11-13)	Yu 2023, Int J Mol Sci	https://doi.org/10.3390/ijms24065262	Mostly correlative/transcriptomic; no direct mechanistic link to immune evasion established
FBXW9 is downstream of IGFBP5–ROR1/HER2–CREB signaling in glioblastoma stem-like cells	Experimental pathway mapping	FBXW9 expression higher in invasive vs non-invasive GSCs; IGFBP5 overexpression increased, and IGFBP5 knockdown decreased, FBXW9; CREB ChIP-qPCR showed enrichment at FBXW9 locus and reduced binding after shIGFBP5; CREB overexpression rescued invasion suppressed by IGFBP5/HER2/ROR1 knockdown (lin2023igfbp5isan pages 11-12, lin2023igfbp5isan pages 7-9, lin2023igfbp5isan pages 6-7)	Lin 2023, Nat Commun	https://doi.org/10.1038/s41467-023-37306-1	Strong pathway-position evidence, but does not show FBXW9 biochemical substrates
FBXW9 contributes to glioblastoma invasion	Experimental knockdown + clinical correlation	siRNA against FBXW9 significantly decreased invasion capacity in X01 and 448 GSC lines; high FBXW9 associated with worse glioma/LGG survival, including FBXW9 alone (P = 0.0005) and combined IGFBP5+FBXW9 signature (P = 0.00004) (lin2023igfbp5isan pages 7-9, lin2023igfbp5isan pages 6-7, lin2023igfbp5isan media 2620dd74)	Lin 2023, Nat Commun	https://doi.org/10.1038/s41467-023-37306-1	Invasion role is experimentally supported, but reported invasion quantification for direct FBXW9 knockdown is largely in supplementary figures
Upregulation and prognosis across cancers	Bioinformatic pan-cancer analysis	FBXW9 upregulated in many tumor types; family-level analyses implicate FBXW9 as detrimental in selected cancers and associated with immune infiltration/stromal features (huang2024pancanceranalysisof pages 2-4, yu2023acomprehensiveanalysis pages 2-5, yu2023acomprehensiveanalysis pages 11-13)	Yu 2023, Int J Mol Sci; Huang 2024, Front Immunol	https://doi.org/10.3390/ijms24065262; https://doi.org/10.3389/fimmu.2022.1084339	Important for hypothesis generation and biomarker studies, but not direct function
Disease-target associations in Open Targets	Database association	Open Targets lists low-score associations for FBXW9 with oral mucosa leukoplakia, familial isolated congenital asplenia, X-linked retinal dysplasia, central areolar choroidal dystrophy, and familial exudative vitreoretinopathy (OpenTargets Search: -FBXW9)	Open Targets Platform	https://platform.opentargets.org/target/ENSG00000132004	Evidence sizes were small and literature fields were empty in retrieved context; should not be overinterpreted
What is not yet established for human FBXW9	Negative/uncertain evidence summary	No directly validated endogenous ubiquitination substrate for human FBXW9 was recovered; no direct catalytic assay, no substrate degron definition, and no definitive microscopy-based localization were found in retrieved literature (yu2023acomprehensiveanalysis pages 8-11, yu2023acomprehensiveanalysis pages 5-8)	Synthesis from available sources	N/A	The literature supports FBXW9 as an F-box substrate-recognition protein with cancer-related functions, but its precise biochemical substrate repertoire remains largely unresolved
FBXW9 as a stable-expression reference gene in hematologic malignancy qPCR	Experimental application, not mechanism	In a qPCR normalization study across 78 samples, PTCD2, PPP1R3B, and FBXW9 were among the most stable low-variance genes selected as candidate reference genes; FBXW9 primer set targeted NM_032301 (dwivedi2020relativequantificationof pages 4-5, dwivedi2020relativequantificationof pages 5-7)	Dwivedi 2020, PLoS One	https://doi.org/10.1371/journal.pone.0236338	Useful real-world implementation for assay design; does not illuminate FBXW9 molecular function
Expert consensus framing	Review/expert analysis	Reviews describe FBXW proteins as substrate-recognition subunits of SCF E3 ligases that use F-box domains to assemble into SCF complexes and WD40 repeats to bind substrates; FBXW9 is repeatedly highlighted as poorly characterized compared with FBXW1/FBXW7 (yu2023acomprehensiveanalysis pages 1-2, yu2023acomprehensiveanalysis pages 8-11, jeong2023targetinge3ubiquitin pages 3-4)	Yu 2023, Int J Mol Sci; Jeong 2023, Exp Mol Med	https://doi.org/10.3390/ijms24065262; https://doi.org/10.1038/s12276-023-01087-w	Good high-level context; for FBXW9 specifically, many claims remain extrapolated from family behavior rather than direct primary evidence

Table: This table separates experimentally supported findings from predictions and database associations for human FBXW9 (Q5XUX1). It is useful for quickly distinguishing what is known with direct evidence versus what remains inferred or weakly supported.

10) Conclusions and prioritized next steps for functional annotation

1) Highest-confidence functional annotation: FBXW9 is an F-box/WD40 substrate-recognition adaptor that binds SKP1 and associates with CUL1-based SCF assemblies; it is likely cytosolic/cytoplasmic. (lievens2009arraymappithighthroughput pages 6-8, lee2011thesteadystaterepertoire pages 6-7, huang2024pancanceranalysisof pages 4-5).
2) Most compelling 2023–2024 biology: FBXW9 is transcriptionally positioned downstream of CREB in glioblastoma invasion programs and downstream of p53 as a direct transcriptional target; in breast cancer cells, FBXW9 supports proliferation/cell-cycle progression. (lin2023igfbp5isan pages 7-9, shin2024apipelineto pages 1-3, yu2023acomprehensiveanalysis pages 8-11).
3) Main knowledge gap: Definitive endogenous protein substrates of FBXW9 (ubiquitination targets, degrons, linkage types, and whether degradation vs non-proteolytic ubiquitination) are not established in the retrieved primary evidence; TP53-centered models remain partly predictive. (yu2023acomprehensiveanalysis pages 5-8, yu2023acomprehensiveanalysis pages 8-11).

Key source list (URLs and publication dates)

Lievens et al. “Array MAPPIT: high-throughput interactome analysis in mammalian cells.” Journal of Proteome Research. 2009-01. https://doi.org/10.1021/pr8005167 (lievens2009arraymappithighthroughput pages 6-8)
Lee et al. “The Steady-State Repertoire of Human SCF Ubiquitin Ligase Complexes…” Molecular & Cellular Proteomics. 2011-05. https://doi.org/10.1074/mcp.m110.006460 (lee2011thesteadystaterepertoire pages 6-7)
Yu et al. “A Comprehensive Analysis Revealing FBXW9 as a Potential Prognostic and Immunological Biomarker in Breast Cancer.” International Journal of Molecular Sciences. 2023-03. https://doi.org/10.3390/ijms24065262 (yu2023acomprehensiveanalysis pages 1-2)
Lin et al. “IGFBP5 is an ROR1 ligand promoting glioblastoma invasion via ROR1/HER2-CREB signaling axis.” Nature Communications. 2023-03. https://doi.org/10.1038/s41467-023-37306-1 (lin2023igfbp5isan pages 7-9)
Jeong et al. “Targeting E3 ubiquitin ligases and their adaptors as a therapeutic strategy for metabolic diseases.” Experimental & Molecular Medicine. 2023-10. https://doi.org/10.1038/s12276-023-01087-w (jeong2023targetinge3ubiquitin pages 3-4)
Shin et al. “A pipeline to characterize p53 effectors…” Genes & Diseases. 2024-03. https://doi.org/10.1016/j.gendis.2023.03.009 (shin2024apipelineto pages 1-3)
Huang et al. “Pan-cancer analysis of FBXW family…” Frontiers in Immunology. 2024-12. https://doi.org/10.3389/fimmu.2022.1084339 (huang2024pancanceranalysisof pages 4-5)

Notes on scope and limitations

This report is constrained to the retrieved evidence in the tool context. Several claims in secondary reviews (e.g., CRL7 receptor assignment) could not be traced here to a specific underlying primary demonstration for FBXW9; therefore, they are explicitly presented as review-level claims with noted conflicts. (jeong2023targetinge3ubiquitin pages 3-4, shi2020thefunctionalanalysis pages 1-2).

References

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(dwivedi2020relativequantificationof pages 5-7): Nehanjali Dwivedi, Sreejeta Mondal, Smitha P. K., Sowmya T., Kartik Sachdeva, Christopher Bathula, Vishnupriyan K., Nataraj K. S., Sharat Damodar, Sujan K. Dhar, and Manjula Das. Relative quantification of bcl2 mrna for diagnostic usage needs stable uncontrolled genes as reference. PLoS ONE, 15:e0236338, Aug 2020. URL: https://doi.org/10.1371/journal.pone.0236338, doi:10.1371/journal.pone.0236338. This article has 5 citations and is from a peer-reviewed journal.
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(OpenTargets Search: -FBXW9): Open Targets Query (-FBXW9, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

Artifacts

Edison artifact artifact-00

Citations

shin2024apipelineto pages 1-3
yu2023acomprehensiveanalysis pages 1-2
dwivedi2020relativequantificationof pages 4-5
lee2011thesteadystaterepertoire pages 6-7
huang2024pancanceranalysisof pages 4-5
yu2023acomprehensiveanalysis pages 8-11
yu2023acomprehensiveanalysis pages 11-13
yu2023acomprehensiveanalysis pages 5-8
lievens2009arraymappithighthroughput pages 6-8
lievens2009arraymappithighthroughput pages 5-6
yu2023acomprehensiveanalysis pages 2-5
huang2024pancanceranalysisof pages 2-4
shi2020thefunctionalanalysis pages 1-2
jang2018chromatinboundcullinringligases pages 5-6
dwivedi2020relativequantificationof pages 5-7
https://doi.org/10.3390/ijms24065262;
https://doi.org/10.3389/fimmu.2022.1084339
https://doi.org/10.1021/pr8005167
https://doi.org/10.1074/mcp.m110.006460
https://doi.org/10.1038/s12276-023-01087-w
https://doi.org/10.1016/j.gendis.2023.03.009
https://doi.org/10.3390/ijms24065262
https://doi.org/10.1038/s41467-023-37306-1
https://platform.opentargets.org/target/ENSG00000132004
https://doi.org/10.1371/journal.pone.0236338
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https://doi.org/10.1074/mcp.m110.006460,
https://doi.org/10.3390/ijms24065262,
https://doi.org/10.1038/s41467-023-37306-1,
https://doi.org/10.1016/j.gendis.2023.03.009,
https://doi.org/10.1038/s12276-023-01087-w,
https://doi.org/10.3389/fimmu.2022.1084339,
https://doi.org/10.1371/journal.pone.0236338,
https://doi.org/10.1038/s41389-020-00276-w,
https://doi.org/10.3389/fmolb.2018.00019,

📚 Additional Documentation

Pn Notes

(FBXW9-pn-notes.md)

FBXW9 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q5XUX1
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-13
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/FBXW9/FBXW9-ai-review.yaml
AIGR review HTML: missing - genes/human/FBXW9/FBXW9-ai-review.html
Gene notes: missing - genes/human/FBXW9/FBXW9-notes.md
GOA TSV: present - genes/human/FBXW9/FBXW9-goa.tsv
UniProt record: present - genes/human/FBXW9/FBXW9-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/FBXW9.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/FBXW9.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/FBXW9/FBXW9-deep-research-falcon.md

AIGR Review Snapshot

Description: FBXW9 is a member of the F-box/WD40 (FBXW) family of proteins, containing an N-terminal F-box motif and a C-terminal beta-propeller built from seven WD40 repeats. F-box proteins serve as the interchangeable substrate-recognition subunits of SCF (SKP1-CUL1-F-box)-type cullin-RING E3 ubiquitin ligase complexes: the F-box motif binds SKP1 (which in turn bridges to CUL1 and the RBX1-bound catalytic RING), while the WD40 propeller engages substrate proteins and presents them for ubiquitination, marking them for proteasomal degradation. FBXW9 is itself non-catalytic: it acts as a substrate adaptor, with the ubiquitin-transfer (RING) activity contributed by RBX1 in the assembled SCF. FBXW9 has been shown experimentally to bind SKP1 (array MAPPIT screen with co-immunoprecipitation validation) and to co-purify with CUL1 in affinity purification-mass spectrometry of SCF assemblies, and ComplexPortal assigns it as the variable substrate-receptor subunit of an SCF complex variant. It is broadly expressed and undergoes N-terminal phosphorylation at several residues. FBXW9 remains poorly characterized at the level of direct biochemistry: no endogenous ubiquitination substrate has been validated by direct ubiquitination or degradation assays. Cancer-focused studies place FBXW9 transcription downstream of p53 (a direct p53 target gene) and of CREB in an IGFBP5-ROR1/HER2 signaling axis, and report cell-cycle/proliferation phenotypes on knockdown in breast cancer and invasion phenotypes in glioblastoma stem-like cells; however, candidate substrates such as TP53 remain predicted rather than biochemically demonstrated, so FBXW9's assigned molecular and process roles still rest largely on family-level inference.
Existing/core annotation action counts: ACCEPT: 1; KEEP_AS_NON_CORE: 15

PN Consistency Summary

Consistency: Consistent. Deep research (falcon), review YAML, PN annotation, and node mapping all treat FBXW9 as an SCF/CRL1 substrate adaptor whose specific substrate(s) are NOT experimentally defined (TP53 is UbiBrowser-predicted only). The review is appropriately cautious: SCF membership ACCEPT, but GO:0031146 catabolic process is KEEP_AS_NON_CORE because no substrate is biochemically validated. No contradictions.
PN story / NEW pressure: PN asserts the generic Cul1-receptor adaptor role. GOA currently lacks GO:1990756, so the projected term is correctly new_to_goa; the review proposes it under proposed_new_terms (GO:1990756, verified real via OLS). This is the flagged "member with NO validated substrate" case — adaptor activity is defensible from SKP1 binding (co-IP) + CUL1 AP-MS even without a known substrate. Conclusion: ADD GO:1990756 (already proposed by review); do not add any process/substrate term.
Evidence alignment: PN cites PMID:15340381 ("/ rev", SCF family review). Review anchors on PMID:15520277 (F-box nomenclature), PMID:19159283 (array MAPPIT SKP1 + co-IP), and falcon (CUL1 AP-MS). Different family-review citations but same adaptor conclusion; no conflict.
Verdict: CONSISTENT — no edits. Poorly-characterized but bona fide F-box receptor (no validated substrate); GO:1990756 ADD already proposed.

Full Consistency Review

UniProt: Q5XUX1 · batch: proteostasis-batch-2026-06-13 · review status: COMPLETE
PN placement: UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|WD40 ; PN-node mapping: group=mapped/ok_for_propagation_to_go GO:1990756; class=context_only/too_broad GO:0061630; subtype/type/branch=no_mapping
Consistency: Consistent. Deep research (falcon), review YAML, PN annotation, and node mapping all treat FBXW9 as an SCF/CRL1 substrate adaptor whose specific substrate(s) are NOT experimentally defined (TP53 is UbiBrowser-predicted only). The review is appropriately cautious: SCF membership ACCEPT, but GO:0031146 catabolic process is KEEP_AS_NON_CORE because no substrate is biochemically validated. No contradictions.
PN story / NEW pressure: PN asserts the generic Cul1-receptor adaptor role. GOA currently lacks GO:1990756, so the projected term is correctly new_to_goa; the review proposes it under proposed_new_terms (GO:1990756, verified real via OLS). This is the flagged "member with NO validated substrate" case — adaptor activity is defensible from SKP1 binding (co-IP) + CUL1 AP-MS even without a known substrate. Conclusion: ADD GO:1990756 (already proposed by review); do not add any process/substrate term.
Mapping strategy: Correct and conservative. Group-level GO:1990756 matches the review's proposed MF; not broader/narrower. Class-level GO:0061630 correctly too_broad. No node change.
Evidence alignment: PN cites PMID:15340381 ("/ rev", SCF family review). Review anchors on PMID:15520277 (F-box nomenclature), PMID:19159283 (array MAPPIT SKP1 + co-IP), and falcon (CUL1 AP-MS). Different family-review citations but same adaptor conclusion; no conflict.
Verdict: CONSISTENT — no edits. Poorly-characterized but bona fide F-box receptor (no validated substrate); GO:1990756 ADD already proposed.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-13
review_yaml: genes/human/FBXW9/FBXW9-ai-review.yaml
PN workbook rows: 1

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

UniProt: Q5XUX1
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.

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: Q5XUX1
gene_symbol: FBXW9
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FBXW9 is a member of the F-box/WD40 (FBXW) family of proteins, containing an
  N-terminal F-box motif and a C-terminal beta-propeller built from seven WD40
  repeats. F-box proteins serve as the interchangeable substrate-recognition
  subunits of SCF (SKP1-CUL1-F-box)-type cullin-RING E3 ubiquitin ligase
  complexes: the F-box motif binds SKP1 (which in turn bridges to CUL1 and the
  RBX1-bound catalytic RING), while the WD40 propeller engages substrate proteins
  and presents them for ubiquitination, marking them for proteasomal degradation.
  FBXW9 is itself non-catalytic: it acts as a substrate adaptor, with the
  ubiquitin-transfer (RING) activity contributed by RBX1 in the assembled SCF.
  FBXW9 has been shown experimentally to bind SKP1 (array MAPPIT screen with
  co-immunoprecipitation validation) and to co-purify with CUL1 in affinity
  purification-mass spectrometry of SCF assemblies, and ComplexPortal assigns it
  as the variable substrate-receptor subunit of an SCF complex variant. It is
  broadly expressed and undergoes N-terminal phosphorylation at several residues.
  FBXW9 remains poorly characterized at the level of direct biochemistry: no
  endogenous ubiquitination substrate has been validated by direct ubiquitination
  or degradation assays. Cancer-focused studies place FBXW9 transcription
  downstream of p53 (a direct p53 target gene) and of CREB in an IGFBP5-ROR1/HER2
  signaling axis, and report cell-cycle/proliferation phenotypes on knockdown in
  breast cancer and invasion phenotypes in glioblastoma stem-like cells; however,
  candidate substrates such as TP53 remain predicted rather than biochemically
  demonstrated, so FBXW9's assigned molecular and process roles still rest largely
  on family-level inference.
existing_annotations:
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19159283
  qualifier: enables
  review:
    summary: IntAct interaction against SKP1 (UniProtKB:P63208) from the Array MAPPIT high-throughput interactome screen (Lievens et al. 2009), validated by co-immunoprecipitation; supports FBXW9-SKP1 association underlying SCF assembly. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally relevant FBXW9-SKP1 interaction (WITH/FROM P63208/SKP1), which underpins SCF assembly and is corroborated by co-IP validation, but bare protein binding is uninformative per curation guidelines; the substrate-adaptor molecular function (GO:1990756) better captures this role.
    additional_reference_ids:
    - file:human/FBXW9/FBXW9-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/FBXW9/FBXW9-uniprot.txt
      supporting_text: 'Q5XUX1; P63208: SKP1; NbExp=8; IntAct=EBI-2322729, EBI-307486'
    - reference_id: file:human/FBXW9/FBXW9-deep-research-falcon.md
      supporting_text: FBXW9 was identified as a SKP1-interacting prey in a high-throughput **array MAPPIT** interactome screen and validated by **co-immunoprecipitation** in **HEK293T** cells
- 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 FBXW9-SKP1 association. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the FBXW9-SKP1 interaction (WITH/FROM P63208/SKP1) relevant to SCF assembly, but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXW9/FBXW9-uniprot.txt
      supporting_text: 'Q5XUX1; P63208: SKP1; NbExp=8; IntAct=EBI-2322729, EBI-307486'
- 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 FBXW9-SKP1 association. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the FBXW9-SKP1 interaction (WITH/FROM P63208/SKP1) relevant to SCF assembly, but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXW9/FBXW9-uniprot.txt
      supporting_text: 'Q5XUX1; P63208: SKP1; NbExp=8; IntAct=EBI-2322729, EBI-307486'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: IntAct interaction against SKP1 (UniProtKB:P63208) from a multimodal cell-map study; supports FBXW9-SKP1 association. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the FBXW9-SKP1 interaction (WITH/FROM P63208/SKP1) relevant to SCF assembly, but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXW9/FBXW9-uniprot.txt
      supporting_text: 'Q5XUX1; P63208: SKP1; NbExp=8; IntAct=EBI-2322729, EBI-307486'
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:15520277
  qualifier: part_of
  review:
    summary: ComplexPortal/family-based assignment of SCF complex membership, consistent with FBXW9's F-box motif and experimentally documented SKP1 binding (array MAPPIT plus co-IP) and CUL1 co-purification (AP-MS); ComplexPortal CPX-7785 defines an SCF complex FBXW9 variant.
    action: ACCEPT
    reason: Core assembly annotation for an F-box protein; supported by the F-box domain and direct experimental evidence that FBXW9 binds SKP1 and co-purifies with CUL1-containing SCF assemblies.
    additional_reference_ids:
    - file:human/FBXW9/FBXW9-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/FBXW9/FBXW9-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
    - reference_id: file:human/FBXW9/FBXW9-deep-research-falcon.md
      supporting_text: FBXW9 was identified as a SKP1-interacting prey in a high-throughput **array MAPPIT** interactome screen and validated by **co-immunoprecipitation** in **HEK293T** cells
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:15520277
  qualifier: involved_in
  review:
    summary: Family-based assignment of involvement in SCF-dependent proteasomal degradation, the canonical process for an SCF substrate receptor. FBXW9 assembles into SCF (SKP1/CUL1), but no FBXW9-specific substrate has been validated by direct ubiquitination/degradation assays; proposed substrates such as TP53 remain predictive.
    action: KEEP_AS_NON_CORE
    reason: Plausible and consistent with the F-box family role and with experimental SCF assembly, but no FBXW9-specific substrate or degradation event has been demonstrated biochemically; cancer-context studies report transcriptional regulation and knockdown phenotypes rather than direct substrate degradation, so the process role still rests on family inference.
    additional_reference_ids:
    - file:human/FBXW9/FBXW9-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/FBXW9/FBXW9-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
    - reference_id: file:human/FBXW9/FBXW9-deep-research-falcon.md
      supporting_text: No directly validated endogenous ubiquitination substrate for human FBXW9 was recovered; no direct catalytic assay, no substrate degron definition
- 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 (AcM-UBE2M transfers NEDD8 to CRL1) propagated to FBXW9 as an SCF subunit.
    action: KEEP_AS_NON_CORE
    reason: Plausible cytosolic localization for an SCF subunit but derived from generic CRL pathway reactions, not FBXW9-specific localization data.
    supported_by:
    - reference_id: file:human/FBXW9/FBXW9-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific.
    supported_by:
    - reference_id: file:human/FBXW9/FBXW9-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific.
    supported_by:
    - reference_id: file:human/FBXW9/FBXW9-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific.
    supported_by:
    - reference_id: file:human/FBXW9/FBXW9-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific.
    supported_by:
    - reference_id: file:human/FBXW9/FBXW9-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific.
    supported_by:
    - reference_id: file:human/FBXW9/FBXW9-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific.
    supported_by:
    - reference_id: file:human/FBXW9/FBXW9-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific.
    supported_by:
    - reference_id: file:human/FBXW9/FBXW9-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific.
    supported_by:
    - reference_id: file:human/FBXW9/FBXW9-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin 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 FBXW9.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW9-specific.
    supported_by:
    - reference_id: file:human/FBXW9/FBXW9-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
references:
- id: PMID:15520277
  title: Systematic analysis and nomenclature of mammalian F-box proteins.
  findings:
  - statement: Systematic classification and nomenclature of mammalian F-box proteins into FBXL, FBXW and FBXO families; FBXW proteins are the WD40-repeat-containing substrate-recognition subunits of SCF ubiquitin ligase complexes.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified F-box nomenclature paper; basis for the family-level SCF complex and SCF-dependent catabolic process annotations for FBXW9.
- id: PMID:19159283
  title: 'Array MAPPIT: high-throughput interactome analysis in mammalian cells.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome method; FBXW9 annotation is an IntAct interaction against SKP1 (WITH/FROM P63208). Bare protein binding, non-core.
- 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; FBXW9 annotation is an IntAct interaction against SKP1 (WITH/FROM P63208).
- 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; FBXW9 annotation is an IntAct interaction against SKP1 (WITH/FROM P63208).
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Multimodal cell-map study; FBXW9 annotation is an IntAct interaction against SKP1 (WITH/FROM P63208).
- 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/FBXW9/FBXW9-deep-research-falcon.md
  title: Falcon deep research report for human FBXW9
  findings:
  - statement: FBXW9 binds SKP1 (array MAPPIT screen validated by co-immunoprecipitation in HEK293T) and co-purifies with CUL1 in AP-MS of SCF assemblies, providing direct experimental evidence that it is an SCF/CRL1 substrate-recognition adaptor rather than an enzyme.
    supporting_text: FBXW9 was identified as a SKP1-interacting prey in a high-throughput **array MAPPIT** interactome screen and validated by **co-immunoprecipitation** in **HEK293T** cells
  - statement: FBXW9 is a direct p53 transcriptional target (ChIP/luciferase/Nutlin-3 evidence) whose ectopic expression suppresses proliferation of p53-deficient cells, positioning it downstream of p53 tumor-suppressor signaling.
    supporting_text: ChIP-seq/ChIP-qPCR showed p53 occupancy near Fbxw9 promoter; p53 increased luciferase reporter activity; p53 knockdown reduced expression; Nutlin-3 induced Fbxw9 in p53-WT but not p53-null human cells
  - statement: In glioblastoma stem-like cells FBXW9 is a CREB-bound transcriptional target downstream of an IGFBP5-ROR1/HER2 axis, and FBXW9 knockdown reduces invasion, with high FBXW9 associated with worse survival.
    supporting_text: siRNA against FBXW9 significantly decreased invasion capacity in X01 and 448 GSC lines; high FBXW9 associated with worse glioma/LGG survival
  - statement: In breast cancer cells FBXW9 knockdown reduces proliferation and induces G0/G1 arrest with increased p21, but TP53 as an FBXW9 ubiquitination substrate remains predicted (UbiBrowser), not biochemically validated.
    supporting_text: TP53 as substrate remains predicted, not biochemically validated by ubiquitination/degradation assay
  - statement: No directly validated endogenous ubiquitination substrate for human FBXW9 has been established; the molecular substrate repertoire and degron remain unresolved.
    supporting_text: No directly validated endogenous ubiquitination substrate for human FBXW9 was recovered; no direct catalytic assay, no substrate degron definition
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Falcon synthesis grounded chiefly in Lievens et al. 2009 (J Proteome Res, doi:10.1021/pr8005167; array MAPPIT + co-IP SKP1 interaction) and Lee et al. 2011 (Mol Cell Proteomics, doi:10.1074/mcp.m110.006460; CUL1 AP-MS), which provide direct experimental support for SCF/CRL1 adaptor behavior. Cancer-context studies (Lin 2023 Nat Commun; Yu 2023 Int J Mol Sci; Shin 2024 Genes Dis) describe FBXW9 as a transcriptional target of CREB and p53 with knockdown phenotypes, but report no direct substrate ubiquitination; TP53 substrate is predictive only. The report explicitly flags the CRL7 receptor claim (Jeong 2023 review) as uncorroborated. Cross-checked against UniProt Q5XUX1 FUNCTION/SUBUNIT and ComplexPortal CPX-7785. No annotation action is changed on the basis of these correlative/transcriptional findings.
core_functions:
- description: Substrate-recognition (substrate-adaptor) subunit of an SCF (SKP1-CUL1-F-box) cullin-RING E3 ubiquitin ligase complex; it docks via its F-box motif onto SKP1 (experimentally validated) and CUL1 (AP-MS), presenting a WD40 propeller for substrate recruitment. FBXW9 is non-catalytic (ubiquitin transfer is RBX1's), and its specific physiological substrates are not yet experimentally defined.
  supported_by:
  - reference_id: file:human/FBXW9/FBXW9-uniprot.txt
    supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
  - reference_id: file:human/FBXW9/FBXW9-deep-research-falcon.md
    supporting_text: FBXW9 was identified as a SKP1-interacting prey in a high-throughput **array MAPPIT** interactome screen and validated by **co-immunoprecipitation** in **HEK293T** cells
  locations:
  - id: GO:0005829
    label: cytosol
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 FBXW9's annotation set.
  justification: FBXW9 binds SKP1 (validated by co-IP) and co-purifies with CUL1-containing SCF assemblies, consistent with a substrate-adaptor molecular function rather than catalysis (which is RBX1's). Adding GO:1990756 would give FBXW9 an informative molecular-function term in place of the uninformative bare protein binding annotations, even though its specific substrate is not yet defined.
  proposed_parent:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  supported_by:
  - reference_id: file:human/FBXW9/FBXW9-uniprot.txt
    supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
  - reference_id: file:human/FBXW9/FBXW9-deep-research-falcon.md
    supporting_text: FBXW9 was identified as a SKP1-interacting prey in a high-throughput **array MAPPIT** interactome screen and validated by **co-immunoprecipitation** in **HEK293T** cells
suggested_questions:
- question: What are the physiological ubiquitination substrates recognized by the FBXW9 WD40 propeller, and is substrate recognition phosphodegron-dependent? Is the predicted TP53 substrate directly ubiquitinated by SCF(FBXW9)?
- question: Do the p53- and CREB-driven transcriptional control of FBXW9 and the breast-cancer/glioblastoma knockdown phenotypes reflect a degradative SCF(FBXW9) substrate, or non-proteolytic/indirect mechanisms?
suggested_experiments:
- description: Affinity purification of tagged FBXW9 with SKP1/CUL1/RBX1 followed by mass spectrometry to identify co-purifying and ubiquitinated substrate candidates, prioritizing cell types (breast cancer, glioblastoma stem-like cells) where knockdown phenotypes were reported.
- description: Reconstitute SCF(FBXW9) in vitro with SKP1, CUL1, RBX1 and an E2, and test ubiquitination of candidate substrates (e.g. TP53 predicted by UbiBrowser) comparing wild-type to F-box-deletion FBXW9.

FBXW9

Gene Description

Proposed New Ontology Terms

ubiquitin-like ligase-substrate adaptor activity

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research Report: Human FBXW9 (UniProt Q5XUX1) — Functional Annotation and Current Evidence (2023–2024 prioritized)

Executive summary

1) Key concepts and definitions (current understanding)

1.1 F-box proteins, FBXW subfamily, and SCF/CRL architecture

1.2 What “functional annotation” means here

2) Target identity verification (to avoid symbol ambiguity)

3) Molecular function, complexes, and localization

3.1 Complex membership: evidence for SCF/CRL1 association

3.2 Potential role in CRL7/CUL7: conflicting secondary-source statements

3.3 Subcellular localization

4) Pathways and biological roles: what is known (and what is inferred)

4.1 p53 regulatory axis (2024): FBXW9 as a direct p53 target gene

4.2 Glioblastoma invasion pathway (2023): IGFBP5–ROR1/HER2–CREB → FBXW9

4.3 Breast cancer phenotypes (2023): proliferation/cell cycle and inferred TP53–p21 connection

5) Recent developments and “latest research” (prioritizing 2023–2024)

6) Current applications and real-world implementations

6.1 Biomarker research (cancer prognosis, immune context)

6.2 Assay design / clinical molecular diagnostics support role (reference gene)

7) Relevant statistics and quantitative findings (recent studies)

8) Expert synthesis and consensus view (authoritative sources)

9) Evidence map: what is experimentally supported vs inferred

10) Conclusions and prioritized next steps for functional annotation

Key source list (URLs and publication dates)

Notes on scope and limitations

Artifacts

Citations

📚 Additional Documentation

Pn Notes

FBXW9 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 | WD40

Projected GO annotations (1)

Note

📄 View Raw YAML