Affinage

FBXW2

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

Length
454 aa
Mass
51.5 kDa
Annotated
2026-04-28
20 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FBXW2 is the substrate-recognition subunit of an SCF-type (SKP1–CUL1–F-box) E3 ubiquitin ligase that targets a broad set of oncoproteins and signaling regulators for polyubiquitination and proteasomal degradation, thereby functioning as a tumor suppressor that restrains proliferation, invasion, stemness, and drug resistance. Working with the E2 conjugating enzyme UBE2D2, SCF(FBXW2) ubiquitinates substrates including GCM1, SKP2, β-catenin, MSX2, NF-κB p65, EGFR, Moesin, KSRP, and WASL, with substrate recognition typically governed by phosphorylation-dependent degron motifs — for example, AKT1-mediated Ser552 phosphorylation of β-catenin triggers FBXW2 binding, whereas AKT-mediated Thr558 phosphorylation of Moesin blocks it (PMID:30918250, PMID:37736741, PMID:35499593). FBXW2's own stability is controlled by β-TrCP1-mediated ubiquitination, establishing a β-TrCP1–FBXW2–SKP2 regulatory cascade, and substrate engagement is further modulated by competing interactors such as RACK1 and post-translational modifications such as p300-mediated acetylation of p65 (PMID:28090088, PMID:23651062, PMID:34465889). In macrophages, myeloid-specific FBXW2 knockout reduces proinflammatory responses through stabilization of KSRP, indicating a role in innate immune regulation beyond cancer biology (PMID:33101872).

Mechanistic history

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

    Establishing that FBXW2 assembles into an SCF ubiquitin ligase complex resolved how this WD-repeat/F-box protein connects to the ubiquitin-proteasome system.

    Evidence Co-immunoprecipitation showing mouse Fwd2 binds Skp1 via its F-box and recruits Cul1; immunofluorescence showing cytoplasmic localization

    PMID:10585767

    Open questions at the time
    • No substrate identified
    • Ubiquitin ligase activity not directly demonstrated
    • Only mouse ortholog tested
  2. 2005 High

    Identification of GCM1 as the first SCF(FBXW2) substrate demonstrated phosphorylation-dependent substrate recognition and established FBXW2 as an active E3 ligase controlling protein turnover.

    Evidence Co-immunoprecipitation, in vitro ubiquitination assay, RNAi knockdown with pulse-chase half-life analysis in placental cells

    PMID:15640526

    Open questions at the time
    • Identity of the kinase generating the phospho-degron on GCM1 not established
    • Cognate E2 enzyme not identified
  3. 2008 High

    Identification of UBE2D2 as the cognate E2 enzyme for SCF(FBXW2) completed the minimal enzymatic unit required for substrate ubiquitination.

    Evidence In vitro ubiquitination screen across E2 panel, co-immunoprecipitation of UBE2D2 with SCF(FBXW2), RNAi half-life analysis of GCM1

    PMID:18703417

    Open questions at the time
    • Whether UBE2D2 is the sole E2 for all FBXW2 substrates is unknown
    • Chain linkage type not determined
  4. 2013 Medium

    Discovery that RACK1 competes with GCM1 for FBXW2 binding revealed that substrate access to the E3 is regulated by competing WD-repeat-mediated interactions, adding a non-enzymatic layer of control.

    Evidence TAP-MS identification of RACK1 as FBXW2 interactor, competition co-IP, RNAi functional assays for placental cell migration

    PMID:23651062

    Open questions at the time
    • Whether RACK1 competition generalizes to other FBXW2 substrates is untested
    • Structural basis of the competition not resolved
  5. 2017 High

    Demonstrating that FBXW2 is itself ubiquitinated by β-TrCP1 while simultaneously targeting the oncoprotein SKP2 for degradation established a β-TrCP1–FBXW2–SKP2 cascade linking two F-box proteins in a hierarchical tumor-suppressor circuit.

    Evidence Reciprocal co-IPs, ubiquitination assays, half-life analysis, gain/loss-of-function studies including in vivo lung cancer models

    PMID:28090088

    Open questions at the time
    • Degron motif on FBXW2 recognized by β-TrCP1 not fully mapped
    • Upstream signals controlling β-TrCP1 activity toward FBXW2 not defined
  6. 2019 High

    Identification of β-catenin and MSX2 as FBXW2 substrates, each governed by distinct kinase inputs (AKT1 for β-catenin Ser552 phosphorylation; VRK2 for MSX2 under hypoxia), revealed how diverse upstream signals converge on SCF(FBXW2) to control Wnt signaling and cancer stemness.

    Evidence Phospho-site mutagenesis, co-IP, ubiquitination assays, in vivo lung cancer models for both substrates

    PMID:30918250 PMID:31548378

    Open questions at the time
    • Whether AKT1-Ser552 phosphorylation is the sole degron signal for β-catenin binding is not resolved
    • Structural basis for degron recognition by FBXW2 WD repeats remains unknown
  7. 2020 Medium

    Showing that myeloid-specific FBXW2 knockout dampens proinflammatory responses by stabilizing KSRP extended the functional scope of FBXW2 beyond cancer to innate immune regulation and metabolic inflammation.

    Evidence Myeloid-conditional FBXW2 knockout mice, ubiquitination assay, dominant-negative fragment competition, in vivo metabolic disease models

    PMID:33101872

    Open questions at the time
    • Mechanism by which KSRP stabilization reduces inflammation not fully dissected
    • Whether other immune cell types depend on FBXW2 unknown
  8. 2021 High

    Demonstrating that p300-mediated acetylation of NF-κB p65 blocks FBXW2-induced ubiquitination revealed a post-translational switch that protects substrates from SCF(FBXW2) and connects acetylation signaling to the ubiquitin-proteasome pathway in stemness regulation.

    Evidence Co-IP, ubiquitination assay, acetylation blocking experiments, FBXW2-knockout mice, SOX2 stemness assays

    PMID:34465889

    Open questions at the time
    • Specific acetylation sites on p65 that block FBXW2 recognition not fully mapped
    • Whether other acetyltransferases can similarly regulate FBXW2-substrate interactions is untested
  9. 2022 Medium

    Identification of EGFR as a direct FBXW2 substrate via a consensus TSNNST degron motif provided the first defined degron sequence for FBXW2 and linked it to receptor tyrosine kinase turnover in prostate cancer.

    Evidence Co-IP, ubiquitination assay, degron motif mutagenesis, dominant-negative FBXW2 mutant, in vivo prostate cancer models

    PMID:35499593

    Open questions at the time
    • Whether the TSNNST degron is a general FBXW2 recognition motif across other substrates not tested
    • Single lab, awaits independent validation
  10. 2023 Medium

    Showing that AKT phosphorylation of Moesin at Thr558 blocks FBXW2 binding and that stabilized Moesin in turn shields SKP2 from FBXW2 revealed a substrate-level competition mechanism and an AKT–Moesin–SKP2 oncogenic axis.

    Evidence Co-IP, phospho-site mutagenesis, ubiquitination assay, half-life analysis, gain/loss-of-function in vitro and in vivo

    PMID:37736741

    Open questions at the time
    • Molecular mechanism by which Moesin shields SKP2 from FBXW2 not structurally resolved
    • Single lab, awaits independent confirmation
  11. 2025 Medium

    Identification of WASL as a FBXW2 substrate in gastric cancer expanded the substrate repertoire to actin-nucleation regulators and linked SCF(FBXW2) to suppression of cell motility and metastasis.

    Evidence Label-free quantitative proteomics, co-IP, ubiquitination assay, in vivo xenograft models, ChIP-PCR

    PMID:40721413

    Open questions at the time
    • Degron on WASL not mapped
    • Whether WASL degradation requires a specific kinase-generated phosphodegron is unknown
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unifying structural model of how the FBXW2 WD-repeat domain recognizes its diverse phospho-degron substrates is lacking, and no systematic, unbiased degron definition exists.
  • No crystal or cryo-EM structure of FBXW2 alone or in complex with any substrate
  • No consensus degron motif validated across multiple substrates
  • Ubiquitin chain linkage specificity not characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 10 R-HSA-1643685 Disease 6 R-HSA-162582 Signal Transduction 3
Partners
BTRCCTNNB1CUL1RACK1RELASKP1SKP2UBE2D2
Complex memberships
SCF(FBXW2) (SKP1-CUL1-FBXW2)

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Mouse Fwd2 (FBXW2 ortholog) assembles into an SCF-type ubiquitin ligase complex by interacting with Skp1 through its F-box domain and with Cul1 through Skp1, as demonstrated by co-immunoprecipitation. The protein localizes to the cytoplasm. Co-immunoprecipitation, immunofluorescence staining Genomics Medium 10585767
2005 FBXW2 serves as the substrate-recognition subunit of the SCF(FBXW2) E3 ligase complex, interacting with GCMa/hGCM1 in a phosphorylation-dependent manner and promoting its ubiquitination and proteasomal degradation. SKP1 and CUL1 associate with GCMa in vivo as part of this complex. Co-immunoprecipitation, in vitro ubiquitination assay, RNA interference knockdown with pulse-chase/half-life analysis The Journal of biological chemistry High 15640526
2008 UBE2D2 is the E2 ubiquitin-conjugating enzyme that works with the SCF(FBXW2) E3 complex to ubiquitinate GCM1. UBE2D2 enzymatic activity is required for GCM1 ubiquitination, UBE2D2 associates with the SCF(FBXW2) complex, and UBE2D2 knockdown reduces GCM1 ubiquitination and prolongs GCM1 half-life in vivo. In vitro ubiquitination assay with panel of E2 proteins, co-immunoprecipitation, RNA interference with half-life analysis Biology of reproduction High 18703417
2013 RACK1 interacts with FBW2 via WD repeats in both proteins, and competes with GCM1 for FBW2 binding, thereby preventing GCM1 ubiquitination and stabilizing GCM1. RACK1 knockdown destabilizes GCM1 and reduces expression of GCM1 target gene HTRA4, leading to decreased placental cell migration and invasion. Tandem-affinity purification coupled with MS, co-immunoprecipitation, RNA interference with functional assays (migration/invasion) The Biochemical journal Medium 23651062
2017 FBXW2 is a substrate of β-TrCP1 (which promotes FBXW2 ubiquitylation and shortens its half-life) and is itself an E3 ligase for SKP2 (promoting SKP2 ubiquitylation and degradation), forming a β-TrCP1–FBXW2–SKP2 oncogene–tumor suppressor–oncogene cascade that controls lung cancer cell growth. Co-immunoprecipitation, ubiquitination assay, half-life analysis, gain- and loss-of-function studies in vitro and in vivo Nature communications High 28090088
2019 FBXW2 is an E3 ligase for β-catenin. FBXW2 binds β-catenin upon EGF-AKT1-mediated phosphorylation on Ser552, promoting its ubiquitylation and proteasomal degradation, thereby reducing β-catenin transcriptional activity and suppressing MMP-driven lung cancer migration and invasion. Co-immunoprecipitation, ubiquitination assay, half-life analysis, phospho-mutant analysis, gain/loss-of-function in vitro and in vivo Nature communications High 30918250
2019 MSX2 is a substrate of FBXW2 E3 ligase. FBXW2 binds MSX2 and promotes its ubiquitylation and degradation, thereby de-repressing SOX2 expression. VRK2 kinase, induced by hypoxia, facilitates MSX2-FBXW2 binding and FBXW2-mediated MSX2 degradation, linking hypoxic stress to SOX2 induction and cancer stem cell properties. Co-immunoprecipitation, ubiquitination assay, half-life analysis, kinase identification, gain/loss-of-function in vitro and in vivo Proceedings of the National Academy of Sciences of the United States of America High 31548378
2020 FBXW2 promotes ubiquitination and degradation of KSRP (KH-type splicing regulatory protein) as a bona fide substrate of the SCF(FBXW2) complex in macrophages. Myeloid-specific FBXW2 knockout reduces proinflammatory responses; a C-terminal P3 fragment of FBXW2 competitively blocks KSRP degradation. Ubiquitination assay, genetic knockout (myeloid-specific), dominant-negative fragment competition, in vivo metabolic disease models Advanced science 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, providing a regulatory switch. This FBXW2-p65 axis controls SOX2-induced stemness, and FBXW2 knockout in mice confirms in vivo p65 regulation. Co-immunoprecipitation, ubiquitination assay, acetylation blocking experiments, FBXW2-knockout mice, in vitro and in vivo functional assays Cell death and differentiation High 34465889
2022 FBXW2 functions as an E3 ligase for EGFR in prostate cancer. FBXW2 binds EGFR via a consensus degron motif (TSNNST) on EGFR, ubiquitylates it, and promotes its degradation, repressing EGF downstream signaling. A dominant-negative FBXW2 mutant failed to degrade EGFR. Co-immunoprecipitation, ubiquitination assay, dominant-negative mutant, half-life analysis, gain/loss-of-function in vitro and in vivo Cellular and molecular life sciences : CMLS Medium 35499593
2023 Moesin is a substrate of FBXW2-mediated proteasomal degradation. AKT kinase phosphorylates Moesin at Thr-558, which weakens the FBXW2-Moesin association and protects Moesin from FBXW2-mediated degradation. Accumulated Moesin in turn prevents FBXW2-mediated degradation of SKP2, forming an AKT-Moesin-SKP2 oncogenic axis. Co-immunoprecipitation, ubiquitination assay, phospho-site mutagenesis, half-life analysis, gain/loss-of-function in vitro and in vivo Cell death & disease Medium 37736741
2025 WASL (WASP-like actin nucleation-promoting factor) is a direct downstream substrate of FBXW2. FBXW2 physically interacts with WASL and facilitates its ubiquitination-dependent proteasomal degradation, suppressing gastric cancer cell viability and metastatic potential. Label-free quantitative proteomics, co-immunoprecipitation, ubiquitination assay, gain/loss-of-function in vitro and in vivo xenograft models, ChIP-PCR Cell death discovery Medium 40721413

Source papers

Stage 0 corpus · 20 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 94 34465889
2019 FBXW2 suppresses migration and invasion of lung cancer cells via promoting β-catenin ubiquitylation and degradation. Nature communications 90 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 88 31548378
2017 The β-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor. Nature communications 75 28090088
2005 FBW2 targets GCMa to the ubiquitin-proteasome degradation system. The Journal of biological chemistry 45 15640526
2019 Gartanin is a novel NEDDylation inhibitor for induction of Skp2 degradation, FBXW2 expression, and autophagy. Molecular carcinogenesis 26 31782573
2022 FBXW2 inhibits prostate cancer proliferation and metastasis via promoting EGFR ubiquitylation and degradation. Cellular and molecular life sciences : CMLS 24 35499593
2022 The Arabidopsis F-box protein FBW2 targets AGO1 for degradation to prevent spurious loading of illegitimate small RNA. Cell reports 23 35417704
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 12 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