Affinage

FBXW2

F-box/WD repeat-containing protein 2 · UniProt Q9UKT8

Length
454 aa
Mass
51.5 kDa
Annotated
2026-06-09
19 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FBXW2 is the substrate-recognition subunit of an SCF(FBXW2) E3 ubiquitin ligase that assembles with SKP1 and CUL1 and directs ubiquitin-proteasomal degradation of a broad set of substrates, positioning it as a tumor suppressor across multiple cancer types (PMID:10585767, PMID:15640526, PMID:28090088). Substrate recognition is frequently gated by phosphorylation: it degrades GCM1/GCMa in a phosphorylation-dependent manner using UBE2D2 as the cognate E2 (PMID:15640526, PMID:18703417), engages β-catenin only after EGF-AKT1-driven Ser552 phosphorylation to block β-catenin-driven MMP transactivation and tumor cell invasion (PMID:30918250), and binds MSX2 in a manner facilitated by hypoxia-induced VRK2, thereby controlling a downstream SOX2/stemness program (PMID:31548378). FBXW2 also targets EGFR through a defined TSNNST degron (PMID:35499593), and degrades SKP2, NF-κB p65 (an activity blocked by p300-mediated p65 acetylation), Moesin (blocked by AKT-mediated Thr-558 phosphorylation), KSRP, and WASL, linking it to growth control, inflammation, and stemness (PMID:28090088, PMID:34465889, PMID:37736741, PMID:33101872, PMID:40721413). FBXW2 itself is regulated at the protein level by β-TrCP1-mediated ubiquitylation, forming a β-TrCP1–FBXW2–SKP2 cascade, and at the transcriptional level by FOXP2-mediated promoter repression (PMID:28090088, PMID:40721413). Its activity is further tuned by competitors such as RACK1, which displaces GCM1 from FBXW2 to stabilize it (PMID:23651062).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1999 Medium

    Established that the FBXW2 ortholog is a bona fide F-box protein that nucleates an SCF complex, defining its core biochemical identity before any substrate was known.

    Evidence Co-immunoprecipitation showing SKP1 (via F-box) and CUL1 (via SKP1) binding, with cytoplasmic immunofluorescence localization in mouse cells

    PMID:10585767

    Open questions at the time
    • No substrate identified at this stage
    • E2 enzyme and catalytic output not defined
  2. 2005 High

    Identified the first FBXW2 substrate, GCM1/GCMa, showing FBXW2 functions as a phosphorylation-dependent degradation receptor within the SCF complex.

    Evidence Co-IP, in vivo ubiquitination assay, and RNAi knockdown with pulse-chase stability assay in human cells

    PMID:15640526

    Open questions at the time
    • Specific phosphodegron residues on GCM1 not mapped
    • E2 enzyme not identified
  3. 2008 High

    Defined UBE2D2 as the E2 conjugating enzyme that powers SCF(FBXW2) ubiquitination, completing the enzymatic core of the ligase.

    Evidence In vitro ubiquitination with an E2 panel, RNAi knockdown, in vivo ubiquitination and half-life assays

    PMID:18703417

    Open questions at the time
    • Whether UBE2D2 serves all FBXW2 substrates not tested
    • Chain linkage type not characterized
  4. 2013 Medium

    Showed FBXW2 substrate targeting can be antagonized by competitive WD-repeat binding, revealing a layer of regulation over substrate access.

    Evidence TAP-MS, Co-IP, RNAi, ubiquitination and migration/invasion assays demonstrating RACK1 competes with GCM1 for FBXW2

    PMID:23651062

    Open questions at the time
    • Structural basis of RACK1-FBXW2 competition not resolved
    • Generality of competitive antagonism for other substrates unknown
  5. 2017 High

    Placed FBXW2 in a regulatory cascade, showing it is both a substrate of β-TrCP1 and an E3 ligase for the oncoprotein SKP2, establishing its tumor-suppressor role in lung cancer.

    Evidence Reciprocal Co-IP, ubiquitination assay, cycloheximide-chase half-life assay, and in vivo gain/loss-of-function lung cancer models

    PMID:28090088

    Open questions at the time
    • SKP2 degron on FBXW2 recognition not mapped
    • Inputs controlling β-TrCP1 targeting of FBXW2 unclear
  6. 2019 High

    Expanded the substrate repertoire to β-catenin and MSX2 and demonstrated that upstream kinases (AKT1, VRK2) gate substrate recognition, linking FBXW2 to invasion and stemness programs.

    Evidence Co-IP, ubiquitination, half-life assays, and in vivo models; phosphorylation-dependent binding (AKT1-Ser552 on β-catenin; hypoxia/VRK2 on MSX2)

    PMID:30918250 PMID:31548378

    Open questions at the time
    • Whether β-catenin and MSX2 degrons share a consensus motif unresolved
    • Cross-talk between the two cascades not examined
  7. 2020 Medium

    Extended FBXW2 function beyond cancer into innate immunity by identifying KSRP as a substrate driving proinflammatory macrophage responses.

    Evidence Co-IP, ubiquitination assay, and myeloid-specific knockout mouse models

    PMID:33101872

    Open questions at the time
    • KSRP degron not mapped
    • Reciprocal validation in human cells limited
  8. 2021 High

    Identified NF-κB p65 as an FBXW2 substrate and showed acetylation can override ubiquitination, revealing post-translational competition controlling stemness signaling.

    Evidence Reciprocal Co-IP, ubiquitination assay, FBXW2-knockout mice, and in vivo breast cancer tumor models; p300 acetylation blocks p65 ubiquitination

    PMID:34465889

    Open questions at the time
    • Which p65 lysines are acetyl/ubiquitin-competing not fully defined
    • Interplay with canonical NF-κB degradation pathways unclear
  9. 2022 Medium

    Defined an explicit TSNNST degron in EGFR recognized by FBXW2, providing the first sequence-level motif for FBXW2 substrate engagement.

    Evidence Co-IP, ubiquitination assay, cycloheximide-chase half-life assay, and dominant-negative FBXW2 mutant analysis in prostate cancer models

    PMID:35499593

    Open questions at the time
    • Whether the TSNNST motif is shared by other FBXW2 substrates not tested
    • Single-lab finding
  10. 2023 Medium

    Showed Moesin is an FBXW2 substrate whose AKT-phosphorylated form not only escapes degradation but feeds back to block FBXW2-mediated SKP2 turnover, defining an AKT-Moesin-SKP2 oncogenic axis.

    Evidence Co-IP, ubiquitination assay, kinase assay, and in vivo gain/loss-of-function studies; AKT Thr-558 phosphorylation weakens FBXW2-Moesin binding

    PMID:37736741

    Open questions at the time
    • Mechanism of Moesin-driven non-degradable SKP2 polyubiquitination not detailed
    • Single-lab finding
  11. 2025 Medium

    Identified WASL as a substrate and FOXP2 as a transcriptional repressor of FBXW2, adding transcriptional control to its regulation in gastric cancer.

    Evidence Label-free proteomics, Co-IP, ubiquitination assay, ChIP-PCR and DNA pull-down with in vivo models

    PMID:40721413

    Open questions at the time
    • WASL degron not mapped
    • Breadth of FOXP2-FBXW2 regulation beyond gastric cancer unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved whether the diverse FBXW2 substrates share a unifying degron logic and how the multiple phosphorylation/acetylation switches are coordinated within a cell.
  • No structural model of FBXW2 substrate recognition
  • No systematic comparison of degron motifs across substrates
  • Physiological substrate hierarchy in normal tissues undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016874 ligase activity 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 8 R-HSA-1643685 Disease 6
Partners
CTNNB1CUL1EGFRRACK1SKP1SKP2UBE2D2
Complex memberships
SCF(FBXW2) E3 ubiquitin ligase

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Mouse Fwd2 (FBXW2 ortholog) interacts with SKP1 through its F-box domain in vivo, and also interacts with CUL1 through SKP1, forming an SCF(Fwd2) ubiquitin ligase complex. FBXW2 localizes to the cytoplasm. Co-immunoprecipitation, immunofluorescence staining Genomics Medium 10585767
2005 FBXW2 (FBW2) is the substrate-recognition subunit of SCF(FBW2) E3 ligase that targets human GCMa (hGCMa/GCM1) for ubiquitin-proteasomal degradation in a phosphorylation-dependent manner. SKP1 and CUL1 associate with hGCMa in vivo. RNAi knockdown of FBW2 reduced hGCMa ubiquitination and increased its protein stability. Co-immunoprecipitation, in vivo ubiquitination assay, RNA interference knockdown with pulse-chase stability assay The Journal of biological chemistry High 15640526
2008 UBE2D2 is the E2 ubiquitin-conjugating enzyme required for SCF(FBXW2)-mediated ubiquitination of GCM1. UBE2D2 enzyme activity is required for GCM1 ubiquitination and for its association with the SCF(FBXW2) complex. Knockdown of UBE2D2 suppressed FBXW2-mediated GCM1 ubiquitination and prolonged GCM1 half-life. In vitro ubiquitination assay with a panel of E2 proteins, RNA interference knockdown, in vivo ubiquitination assay, protein half-life assay Biology of reproduction High 18703417
2013 RACK1 interacts with FBXW2 via WD repeats (in both proteins) and competes with GCM1 for FBXW2 binding, thereby preventing GCM1 ubiquitination and stabilizing GCM1. RACK1 knockdown destabilizes GCM1 and reduces expression of the GCM1 target gene HTRA4, leading to decreased placental cell migration and invasion. Tandem-affinity purification coupled with MS, Co-immunoprecipitation, RNA interference knockdown, ubiquitination assay, cell migration/invasion assays The Biochemical journal Medium 23651062
2017 FBXW2 is a substrate of β-TrCP1, which promotes FBXW2 ubiquitylation and shortens its half-life. FBXW2 in turn acts as an E3 ligase for SKP2, promoting SKP2 ubiquitylation and degradation. This forms a β-TrCP1-FBXW2-SKP2 oncogene–tumor suppressor–oncogene cascade controlling lung cancer cell growth. Co-immunoprecipitation, ubiquitination assay, protein half-life assay (cycloheximide chase), gain- and loss-of-function experiments in cell lines and in vivo Nature communications High 28090088
2019 FBXW2 is an E3 ligase for β-catenin. FBXW2 binds to β-catenin upon EGF-AKT1-mediated phosphorylation of β-catenin at Ser552, promoting its ubiquitylation and degradation. FBXW2 overexpression reduces β-catenin levels and protein half-life; FBXW2 knockdown increases them. Functionally, FBXW2 inhibits lung cancer cell migration and invasion by blocking β-catenin-driven MMP transactivation. Co-immunoprecipitation, ubiquitination assay, protein half-life assay (cycloheximide chase), gain- and loss-of-function in vitro and in vivo lung cancer models Nature communications High 30918250
2019 MSX2 is a substrate of FBXW2 E3 ligase. FBXW2 binds MSX2 and promotes its ubiquitylation and degradation, shortening its protein half-life. VRK2 kinase, induced by hypoxia, facilitates MSX2-FBXW2 binding and FBXW2-mediated MSX2 ubiquitylation and degradation, leading to SOX2 induction via derepression. This establishes a negative FBXW2-MSX2-SOX2 cascade regulating stem cell property and drug resistance. Co-immunoprecipitation, ubiquitination assay, protein half-life assay, gain- and loss-of-function in vitro and in vivo models, tumor sphere formation assay Proceedings of the National Academy of Sciences of the United States of America High 31548378
2020 KSRP (KH-type splicing regulatory protein) is a ubiquitin substrate of SCF(FBXW2). FBXW2 targets KSRP for degradation in macrophages, and the C-terminus (P3) of FBXW2 competitively inhibits this function. Myeloid-specific FBXW2 knockout reduces proinflammatory responses, implicating FBXW2 as a pro-inflammatory mediator through KSRP degradation. Co-immunoprecipitation, ubiquitination assay, myeloid-specific knockout mouse models, gain- and loss-of-function experiments Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 33101872
2021 NF-κB p65 is a substrate of FBXW2. FBXW2 directly binds p65 and promotes its ubiquitination and degradation. p300-mediated acetylation of p65 blocks FBXW2-induced p65 ubiquitination. FBXW2-p65 axis regulates SOX2-induced stemness in breast cancer, and FBXW2-induced p65 degradation was confirmed in FBXW2-knockout mice. Co-immunoprecipitation, ubiquitination assay, gain- and loss-of-function in vitro and in vivo, FBXW2-knockout mice Cell death and differentiation High 34465889
2022 FBXW2 is an E3 ligase for EGFR in prostate cancer. FBXW2 binds EGFR via its consensus degron motif (TSNNST), promoting EGFR ubiquitylation and degradation, shortening EGFR protein half-life. A dominant-negative FBXW2 mutant fails to degrade EGFR, confirming the mechanism. Co-immunoprecipitation, ubiquitination assay, protein half-life assay (cycloheximide chase), dominant-negative mutant analysis, gain- and loss-of-function in vitro and in vivo Cellular and molecular life sciences : CMLS Medium 35499593
2023 Moesin is a substrate of FBXW2 E3 ligase. FBXW2 promotes proteasomal degradation of Moesin. AKT phosphorylates Moesin at Thr-558, preventing FBXW2-mediated degradation by weakening the FBXW2-Moesin association. Accumulated Moesin in turn prevents FBXW2-mediated degradation of SKP2 by promoting non-degradable polyubiquitination of SKP2, establishing an AKT-Moesin-SKP2 oncogenic axis. Co-immunoprecipitation, ubiquitination assay, kinase assay, gain- and loss-of-function in vitro and in vivo Cell death & disease Medium 37736741
2025 WASL (WASP-like actin nucleation-promoting factor) is a direct substrate of FBXW2. FBXW2 physically interacts with WASL and promotes its ubiquitination-dependent proteasomal degradation in gastric cancer cells. Ectopic WASL expression abrogates FBXW2-mediated tumor suppression. FOXP2 transcription factor directly binds the FBXW2 promoter to repress its transcription. Label-free quantitative proteomics, Co-immunoprecipitation, ubiquitination assay, chromatin immunoprecipitation-PCR, DNA pull-down, gain- and loss-of-function in vitro and in vivo Cell death discovery Medium 40721413
2025 FBXW2 binds β-catenin and facilitates its ubiquitination in gastric cancer, leading to enhanced nuclear translocation of β-catenin upon FBXW2 knockdown. FBXW2 knockdown also reduced GSK3β and Axin2 levels. Co-immunoprecipitation, ubiquitination assay, Western blotting, shRNA knockdown International journal of medical sciences Low 40225854

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 Ubiquitination of NF-κB p65 by FBXW2 suppresses breast cancer stemness, tumorigenesis, and paclitaxel resistance. Cell death and differentiation 98 34465889
2019 FBXW2 suppresses migration and invasion of lung cancer cells via promoting β-catenin ubiquitylation and degradation. Nature communications 91 30918250
2019 The FBXW2-MSX2-SOX2 axis regulates stem cell property and drug resistance of cancer cells. Proceedings of the National Academy of Sciences of the United States of America 89 31548378
2017 The β-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor. Nature communications 76 28090088
2005 FBW2 targets GCMa to the ubiquitin-proteasome degradation system. The Journal of biological chemistry 45 15640526
2022 FBXW2 inhibits prostate cancer proliferation and metastasis via promoting EGFR ubiquitylation and degradation. Cellular and molecular life sciences : CMLS 26 35499593
2019 Gartanin is a novel NEDDylation inhibitor for induction of Skp2 degradation, FBXW2 expression, and autophagy. Molecular carcinogenesis 26 31782573
2008 Ubiquitin-conjugating enzyme UBE2D2 is responsible for FBXW2 (F-box and WD repeat domain containing 2)-mediated human GCM1 (glial cell missing homolog 1) ubiquitination and degradation. Biology of reproduction 23 18703417
1999 Structure and expression of the gene encoding mouse F-box protein, Fwd2. Genomics 22 10585767
2013 RACK1 (receptor for activated C-kinase 1) interacts with FBW2 (F-box and WD-repeat domain-containing 2) to up-regulate GCM1 (glial cell missing 1) stability and placental cell migration and invasion. The Biochemical journal 16 23651062
2023 FBXW2 suppresses breast tumorigenesis by targeting AKT-Moesin-SKP2 axis. Cell death & disease 13 37736741
2020 E3 Ligase FBXW2 Is a New Therapeutic Target in Obesity and Atherosclerosis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 12 33101872
2019 FBXW2 suppresses proliferation and invasion of lung cancer cells by targeting SKP2 and β-catenin. Molecular & cellular oncology 10 31211237
2018 FBXW2 localizes with osteocalcin in bovine periosteum on culture dishes as visualized by double immunostaining. Heliyon 5 30229138
2018 Characterization of the F-box Proteins FBXW2 and FBXL14 in the Initiation of Bone Regeneration in Transplants given to Nude Mice. The open biomedical engineering journal 5 30450135
2021 Role of FBXW2 in explant cultures of bovine periosteum-derived cells. BMC research notes 4 34736516
2025 LINC00908 Inactivates Wnt/β-Catenin Signaling Pathway to Inhibit Prostate Cancer Cell Stemness via Upregulating GSK3B and FBXW2. Cancer medicine 3 40344383
2025 FBXW2 inhibits the progression of gastric cancer via promoting β-catenin ubiquitylation. International journal of medical sciences 1 40225854
2025 FOXP2 suppresses gastric cancer progression by transcriptionally repressing FBXW2 via WASL degradation. Cell death discovery 0 40721413

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