id: Q9UKT8
gene_symbol: FBXW2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FBXW2 (FBW2) is an F-box/WD40-repeat protein that serves as a
  substrate-recognition subunit of the canonical SCF (SKP1-CUL1-RBX1) E3
  ubiquitin ligase, forming the SCF(FBXW2) complex. Through its N-terminal F-box
  motif it binds SKP1 (which bridges to the CUL1-RBX1 catalytic core), while its
  five WD40 repeats provide a substrate-binding surface that recognizes
  (often phosphorylation-marked) target proteins and presents them for
  RBX1/RING-dependent polyubiquitination and proteasomal degradation; FBXW2
  itself does not catalyze ubiquitin transfer. Characterized substrates include
  the transcription factor GCM1 (glial cell missing 1), whose turnover FBXW2
  controls during placental cell migration and invasion (counter-regulated by
  RACK1, which competes with GCM1 for FBXW2 binding); the SCF receptor SKP2 (via
  a TSELLS-type degron) and
  β-catenin, whose FBXW2-mediated degradation suppresses proliferation and
  invasion of lung cancer cells; the kinase MAP3K7/TAK1, targeted for
  K48-linked polyubiquitination in hepatocellular carcinoma; NF-κB p65/RELA,
  ubiquitinated at K122 in a phosphorylation-dependent, p300-acetylation-antagonized
  manner to suppress breast cancer stemness and chemoresistance; the
  cytoskeletal effector Moesin, K48-polyubiquitinated unless protected by AKT
  phosphorylation at Thr558 (an AKT-Moesin-SKP2 axis); and EGFR (via a
  TSNNST-type degron). A non-oncologic role has also been reported in myeloid
  cells, where FBXW2 degrades KSRP and modulates obesity-associated
  inflammation. Across substrates FBXW2 acts largely as a tumor suppressor, and
  its substrate engagement is frequently conditional on substrate
  phosphorylation. FBXW2 is itself a
  substrate of SCF(β-TrCP1) (recognized via a phospho-dependent SSGART motif),
  placing it within a β-TrCP1-FBXW2-SKP2 regulatory
  axis. It is a predominantly cytoplasmic/cytosolic protein, though it can also
  ubiquitinate shuttling substrates such as p65 in the nucleus. As with other
  client proteins it associates transiently with the HSP90-CDC37 chaperone
  system during its own folding/maturation.
alternative_products:
- name: '1'
  id: Q9UKT8-1
- name: 2 (MD6b)
  id: Q9UKT8-2
  sequence_note: VSP_012983
existing_annotations:
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11238952
  qualifier: enables
  review:
    summary: IntAct interaction with SKP1 (P63208), the adaptor linking F-box proteins into the SCF complex. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the FBXW2-SKP1 interaction but bare protein binding is uninformative; SCF membership is captured by GO:0019005.
    supported_by:
    - reference_id: file:human/FBXW2/FBXW2-uniprot.txt
      supporting_text: 'Q9UKT8; P63208: SKP1; NbExp=8; IntAct=EBI-914727, EBI-307486'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15070733
  qualifier: enables
  review:
    summary: IntAct interaction with SKP1 (P63208). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the FBXW2-SKP1 interaction; bare protein binding is uninformative and subsumed by SCF complex membership.
    supported_by:
    - reference_id: file:human/FBXW2/FBXW2-uniprot.txt
      supporting_text: 'Q9UKT8; P63208: SKP1; NbExp=8; IntAct=EBI-914727, EBI-307486'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21145461
  qualifier: enables
  review:
    summary: CRL-network quantitative proteomics interaction with CUL1 (Q13616), the scaffold of the SCF(FBXW2) complex. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally meaningful FBXW2-CUL1 interaction but bare protein binding is uninformative; SCF membership is captured by GO:0019005.
    supported_by:
    - reference_id: file:human/FBXW2/FBXW2-uniprot.txt
      supporting_text: 'Q9UKT8; Q13616: CUL1; NbExp=5; IntAct=EBI-914727, EBI-359390'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22632967
  qualifier: enables
  review:
    summary: IntAct interaction with SKP1 (P63208) from a study about cyclin F/RRM2. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the FBXW2-SKP1 association; bare protein binding is uninformative and subsumed by SCF complex membership.
    supported_by:
    - reference_id: file:human/FBXW2/FBXW2-uniprot.txt
      supporting_text: 'Q9UKT8; P63208: SKP1; NbExp=8; IntAct=EBI-914727, EBI-307486'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22939624
  qualifier: enables
  review:
    summary: HSP90-client interaction study capturing FBXW2 binding to HSP90AB1 (P08238) and CDC37 (Q16543). Reflects chaperone-mediated folding of FBXW2, not a functional partnership. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records HSP90/CDC37 chaperone-client association (FBXW2 as client) but bare protein binding is uninformative and not a core function.
    supported_by:
    - reference_id: file:human/FBXW2/FBXW2-uniprot.txt
      supporting_text: 'Q9UKT8; P08238: HSP90AB1; NbExp=2; IntAct=EBI-914727, EBI-352572'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23108047
  qualifier: enables
  review:
    summary: IntAct interaction with CUL1 (Q13616) captured in a study about FBXW7/CCDC6. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the FBXW2-CUL1 interaction; bare protein binding is uninformative and subsumed by SCF complex membership.
    supported_by:
    - reference_id: file:human/FBXW2/FBXW2-uniprot.txt
      supporting_text: 'Q9UKT8; Q13616: CUL1; NbExp=5; IntAct=EBI-914727, EBI-359390'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23651062
  qualifier: enables
  review:
    summary: TAP-MS interactions with RACK1 (P63244) and GCM1 (Q9NP62); GCM1 is a substrate and RACK1 a competing regulator of FBXW2. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records functionally important FBXW2-GCM1 (substrate) and FBXW2-RACK1 (regulator) interactions but bare protein binding is uninformative.
    supported_by:
    - reference_id: PMID:23651062
      supporting_text: The F-box protein, FBW2 (F-box and WD-repeat domain-containing 2), which contains five WD (tryptophan-aspartate) repeats, recognizes GCM1 and mediates its ubiquitination via the SCFFBW2 E3 ligase complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25036637
  qualifier: enables
  review:
    summary: Chaperone-interaction network capturing FBXW2 binding to HSP90AB1 (P08238), CDC37 (Q16543) and NUDC (Q9Y266). Reflects chaperone-mediated folding. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records chaperone-client associations (FBXW2 as client) but bare protein binding is uninformative and not a core function.
    supported_by:
    - reference_id: file:human/FBXW2/FBXW2-uniprot.txt
      supporting_text: 'Q9UKT8; Q16543: CDC37; NbExp=2; IntAct=EBI-914727, EBI-295634'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27705803
  qualifier: enables
  review:
    summary: Polycomb complexome AP-MS map capturing an FBXW2-SKP1 (P63208) association. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction (SKP1); bare protein binding is uninformative and subsumed by SCF complex membership.
    supported_by:
    - reference_id: file:human/FBXW2/FBXW2-uniprot.txt
      supporting_text: 'Q9UKT8; P63208: SKP1; NbExp=8; IntAct=EBI-914727, EBI-307486'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31391242
  qualifier: enables
  review:
    summary: IntAct interaction with TRIM54 (Q9BYV2) from a DCAF8/MuRF1 muscle-atrophy study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXW2/FBXW2-uniprot.txt
      supporting_text: 'Q9UKT8; Q9BYV2: TRIM54; NbExp=2; IntAct=EBI-914727, EBI-2130429'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Binary interactome reference map capturing an FBXW2-CLVS2 (Q5SYC1) interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXW2/FBXW2-uniprot.txt
      supporting_text: 'Q9UKT8; Q5SYC1: CLVS2; NbExp=3; IntAct=EBI-914727, EBI-12357161'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Cell-specific interactome capturing an FBXW2-SKP1 (P63208) association. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction (SKP1); bare protein binding is uninformative and subsumed by SCF complex membership.
    supported_by:
    - reference_id: file:human/FBXW2/FBXW2-uniprot.txt
      supporting_text: 'Q9UKT8; P63208: SKP1; NbExp=8; IntAct=EBI-914727, EBI-307486'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-map study capturing an FBXW2-SKP1 (P63208) association. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction (SKP1); bare protein binding is uninformative and subsumed by SCF complex membership.
    supported_by:
    - reference_id: file:human/FBXW2/FBXW2-uniprot.txt
      supporting_text: 'Q9UKT8; P63208: SKP1; NbExp=8; IntAct=EBI-914727, EBI-307486'
- term:
    id: GO:0010564
    label: regulation of cell cycle process
  evidence_type: NAS
  original_reference_id: PMID:35414786
  qualifier: involved_in
  review:
    summary: Non-traceable assertion (review) of regulation of a cell cycle process, reflecting FBXW2's degradation of SKP2 and β-catenin to suppress proliferation, and its place in the β-TrCP1-FBXW2-SKP2 axis.
    action: KEEP_AS_NON_CORE
    reason: Supported as a downstream consequence of FBXW2 substrate degradation (SKP2/β-catenin) but generic; the SCF-dependent catabolic process is the core function.
    supported_by:
    - reference_id: PMID:35414786
      supporting_text: FBXW2 suppresses proliferation and invasion of lung cancer cells by targeting S phase kinase-associated protein 2 (SKP2) and β-catenin
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: part_of
  review:
    summary: ComplexPortal/NAS assertion of SCF complex membership, the core complex for FBXW2 as an F-box substrate receptor of SKP1-CUL1-RBX1.
    action: ACCEPT
    reason: Core complex; FBXW2 directly interacts with SKP1 and CUL1 and is the substrate-recognition subunit of SCF(FBXW2).
    supported_by:
    - reference_id: file:human/FBXW2/FBXW2-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: involved_in
  review:
    summary: ComplexPortal/NAS assertion of SCF-dependent proteasomal catabolism, the core biological process for FBXW2 as an SCF substrate receptor.
    action: ACCEPT
    reason: Core biological process; FBXW2 directs substrates (GCM1, SKP2, β-catenin, TAK1) to SCF-dependent proteasomal degradation.
    supported_by:
    - reference_id: PMID:23651062
      supporting_text: recognizes GCM1 and mediates its ubiquitination via the SCFFBW2 E3 ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952618
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization within CRL neddylation reactions. Consistent with the expected cytosolic localization of a SCF substrate receptor.
    action: ACCEPT
    reason: Correct localization; the CRL-cycle Reactome events are pathway-context annotations.
    supported_by:
    - reference_id: file:human/FBXW2/FBXW2-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 curation of cytosolic localization within CRL neddylation reactions.
    action: ACCEPT
    reason: Correct localization, redundant with other localization annotations.
    supported_by:
    - reference_id: file:human/FBXW2/FBXW2-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 curation of cytosolic localization (CAND1 binding to CRL).
    action: ACCEPT
    reason: Correct localization, redundant with other localization annotations.
    supported_by:
    - reference_id: file:human/FBXW2/FBXW2-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 curation of cytosolic localization (COMMD-CAND1 displacement).
    action: ACCEPT
    reason: Correct localization, redundant with other localization annotations.
    supported_by:
    - reference_id: file:human/FBXW2/FBXW2-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 curation of cytosolic localization (COP9 signalosome deneddylation).
    action: ACCEPT
    reason: Correct localization, redundant with other localization annotations.
    supported_by:
    - reference_id: file:human/FBXW2/FBXW2-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 curation of cytosolic localization (DCUN1D3 binding to CRL1).
    action: ACCEPT
    reason: Correct localization, redundant with other localization annotations.
    supported_by:
    - reference_id: file:human/FBXW2/FBXW2-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 curation of cytosolic localization (Ub transfer to substrate).
    action: ACCEPT
    reason: Correct localization, redundant with other localization annotations.
    supported_by:
    - reference_id: file:human/FBXW2/FBXW2-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 curation of cytosolic localization (E3 release from polyubiquitinated substrate).
    action: ACCEPT
    reason: Correct localization, redundant with other localization annotations.
    supported_by:
    - reference_id: file:human/FBXW2/FBXW2-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 curation of cytosolic localization (polyubiquitination of substrate).
    action: ACCEPT
    reason: Correct localization, redundant with other localization annotations.
    supported_by:
    - reference_id: file:human/FBXW2/FBXW2-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 curation of cytosolic localization (E3 interaction with substrate and E2-Ub).
    action: ACCEPT
    reason: Correct localization, redundant with other localization annotations.
    supported_by:
    - reference_id: file:human/FBXW2/FBXW2-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: TAS
  original_reference_id: PMID:10531035
  qualifier: enables
  review:
    summary: Author-statement annotation from the F-box family identification paper attributing ligase/transferase activity to SCF complexes. FBXW2 is the substrate-recognition adaptor and does not itself catalyze ubiquitin transfer (that is RBX1/RING and the E2).
    action: MODIFY
    reason: The transferase activity is a property of the SCF catalytic core (RBX1/RING + E2), not of the F-box adaptor. The accurate molecular function for FBXW2 is substrate-adaptor activity.
    proposed_replacement_terms:
    - id: GO:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
    supported_by:
    - reference_id: file:human/FBXW2/FBXW2-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
- term:
    id: GO:0006508
    label: proteolysis
  evidence_type: TAS
  original_reference_id: PMID:10531035
  qualifier: involved_in
  review:
    summary: Author-statement annotation of proteolysis from the F-box family paper, reflecting the SCF role in controlled protein degradation. Very generic.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the SCF-dependent proteasomal ubiquitin-dependent catabolic process annotation is far more specific and informative.
    supported_by:
    - reference_id: PMID:10531035
      supporting_text: Some F-box proteins have been shown to be critical for the controlled degradation of cellular regulatory proteins
- term:
    id: GO:0036211
    label: protein modification process
  evidence_type: TAS
  original_reference_id: PMID:10531035
  qualifier: involved_in
  review:
    summary: Author-statement annotation of protein modification process, a very broad parent reflecting the ubiquitination role of SCF complexes.
    action: KEEP_AS_NON_CORE
    reason: Correct but extremely generic; the SCF-dependent proteasomal catabolic process annotation better captures the role.
    supported_by:
    - reference_id: PMID:10531035
      supporting_text: F-box proteins are one of the four subunits of ubiquitin protein ligases called SCFs
references:
- id: PMID:10531035
  title: Identification of a family of human F-box proteins.
  findings:
  - statement: F-box proteins (including the WD40-class Fbws such as FBW2/FBXW2) are substrate-recruiting subunits of SCF ubiquitin ligases composed of SKP1, a cullin (CUL1), ROC1/RBX1 and the F-box protein, bringing E2 enzymes to specifically recruited substrates.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Original identification of human F-box family including FBW2; abstract only. Source of the SCF subunit/proteolysis TAS annotations. The transferase-activity annotation conflates SCF-core catalysis with the adaptor role.
- id: PMID:11238952
  title: ATF4 degradation relies on a phosphorylation-dependent interaction with the SCF(betaTrCP) ubiquitin ligase.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Paper is about SCF(beta-TrCP)/ATF4; source of an FBXW2-SKP1 (P63208) generic SCF contact in IntAct.
- id: PMID:15070733
  title: M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFbeta-TrCP.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Paper about Wee1/beta-TrCP; source of an FBXW2-SKP1 (P63208) generic SCF contact.
- id: PMID:21145461
  title: Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: CRL-network proteomics; source of the FBXW2-CUL1 (Q13616) interaction confirming SCF assembly.
- id: PMID:22632967
  title: Cyclin F-mediated degradation of ribonucleotide reductase M2 controls genome integrity and DNA repair.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Paper about cyclin F/RRM2; source of an FBXW2-SKP1 (P63208) generic SCF contact.
- id: PMID:22939624
  title: Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: HSP90-client interactome; FBXW2 appears as an HSP90AB1/CDC37 client (folding), not a functional partner.
- id: PMID:23108047
  title: FBXW7-mediated degradation of CCDC6 is impaired by ATM during DNA damage response in lung cancer cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Paper about FBXW7/CCDC6; source of an FBXW2-CUL1 (Q13616) generic SCF contact.
- id: PMID:23651062
  title: 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.
  findings:
  - statement: FBW2/FBXW2 recognizes the transcription factor GCM1 (facilitated by GCM1 phosphorylation) and mediates its ubiquitination via the SCF(FBW2) complex; RACK1 competes with GCM1 for FBW2 binding, stabilizing GCM1 and promoting placental cell migration and invasion.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract only; establishes GCM1 as an SCF(FBXW2) substrate and RACK1 as a competing regulator. Most direct functional evidence for FBXW2 substrate recognition.
- id: PMID:25036637
  title: A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Chaperone interactome; FBXW2 appears as an HSP90/CDC37/NUDC client (folding), not a functional partner.
- id: PMID:27705803
  title: A High-Density Map for Navigating the Human Polycomb Complexome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: AP-MS complexome map; source of an FBXW2-SKP1 (P63208) interaction.
- id: PMID:31391242
  title: DCAF8, a novel MuRF1 interaction partner, promotes muscle atrophy.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Paper about DCAF8/MuRF1; source of an FBXW2-TRIM54 (Q9BYV2) bare protein binding annotation.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Binary interactome reference map; source of an FBXW2-CLVS2 bare protein binding annotation.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Cell-specific interactome; source of an FBXW2-SKP1 (P63208) interaction.
- id: PMID:34445249
  title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Review/ComplexPortal source supporting SCF complex membership and SCF-dependent catabolism for FBXW2.
- id: PMID:35414786
  title: The role of ubiquitination and deubiquitination in tumor invasion and metastasis.
  findings:
  - statement: FBXW2 is a substrate-recognition receptor of the SCF E3 ligase that suppresses proliferation and invasion of lung cancer cells by targeting SKP2 and β-catenin; it is itself a substrate of β-TrCP1 (forming the β-TrCP1-FBXW2-SKP2 axis), and in hepatocellular carcinoma targets TAK1 for K48-linked polyubiquitination and degradation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; review summarizing FBXW2's tumor-suppressive substrate repertoire (SKP2, β-catenin, TAK1) and the β-TrCP1-FBXW2-SKP2 axis.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Multimodal cell-map study; source of an FBXW2-SKP1 (P63208) interaction.
- id: file:human/FBXW2/FBXW2-deep-research-falcon.md
  title: Falcon deep research report for human FBXW2
  findings:
  - statement: FBXW2 functions as an SCF substrate adaptor that binds specific substrates (often phosphorylation-dependently) and promotes their polyubiquitination and proteasome-dependent degradation.
    supporting_text: FBXW2's primary biochemical function is as an **SCF substrate adaptor** that binds specific protein substrates (often in a phosphorylation-dependent manner) and promotes their **polyubiquitination** leading to **proteasome-dependent degradation**.
  - statement: FBXW2 is both a substrate of SCF(β-TrCP1) and an E3 substrate receptor for SKP2, forming a β-TrCP1-FBXW2-SKP2 F-box cascade in which β-TrCP1 recognizes FBXW2 via a conserved SSGART motif.
    supporting_text: 'β-TrCP1 recognition of FBXW2 involves a conserved motif (reported as **SSGART**) with phospho-dependent binding to the β-TrCP consensus'
  - statement: FBXW2 recognizes β-catenin after EGF-AKT1 phosphorylation at Ser552 via a TSXXXS-like degron, driving β-catenin ubiquitylation and proteasomal degradation and suppressing migration/invasion in lung cancer.
    supporting_text: '**EGF–AKT1 signaling** phosphorylates β-catenin at **Ser552**, enabling FBXW2 binding.'
  - statement: FBXW2 directly ubiquitinates NF-κB p65/RELA at K122 in a phosphorylation-dependent manner antagonized by p300-mediated acetylation, suppressing breast cancer stemness and paclitaxel resistance.
    supporting_text: The study identifies **p65 K122** as an FBXW2 ubiquitination site, and reports that **p300-mediated acetylation** inhibits FBXW2-induced p65 ubiquitination
  - statement: FBXW2 directs K48-linked polyubiquitination of Moesin, an interaction weakened by AKT phosphorylation of Moesin at Thr558, tying FBXW2 to an AKT-Moesin-SKP2 oncogenic axis.
    supporting_text: FBXW2 directs **Lys-48-linked polyubiquitination** of Moesin, consistent with proteasome-targeting chains.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: 'Falcon synthesis of FBXW2 primary literature; the SCF adaptor role, β-TrCP1-FBXW2-SKP2 axis, and GCM1/SKP2/β-catenin/TAK1 substrates cross-check against UniProt Q9UKT8 and cached PMID:23651062/PMID:35414786. Additional substrate leads (NF-κB p65, Moesin, EGFR, KSRP, WASL) are from single primary papers (Ren 2022, Barik 2023, Zhou 2022, Wang 2020, Lin 2025) not yet in GOA; treated as supporting context, not a basis to overrule curated annotations.'
- id: Reactome:R-HSA-8952618
  title: AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8952620
  title: NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8955241
  title: CAND1 binds cytosolic CRL E3 ubiquitin ligases
  findings: []
- id: Reactome:R-HSA-8955289
  title: COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes
  findings: []
- id: Reactome:R-HSA-8956040
  title: COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes
  findings: []
- id: Reactome:R-HSA-8956200
  title: MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-983140
  title: Transfer of Ub from E2 to substrate and release of E2
  findings: []
- id: Reactome:R-HSA-983147
  title: Release of E3 from polyubiquitinated substrate
  findings: []
- id: Reactome:R-HSA-983156
  title: Polyubiquitination of substrate
  findings: []
- id: Reactome:R-HSA-983157
  title: Interaction of E3 with substrate and E2-Ub complex
  findings: []
core_functions:
- description: Substrate-recognition subunit of the SCF(FBXW2) (SKP1-CUL1-RBX1) E3 ubiquitin ligase that, via its WD40 repeats, recognizes target proteins (e.g. the transcription factor GCM1, in a phosphorylation-facilitated manner) and presents them for polyubiquitination and proteasomal degradation; substrate access is competitively regulated by RACK1.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:23651062
    supporting_text: recognizes GCM1 and mediates its ubiquitination via the SCFFBW2 E3 ligase complex
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
- description: Tumor-suppressive SCF(FBXW2) substrate receptor that targets the oncoprotein SKP2 and β-catenin (recognized after EGF-AKT1-dependent Ser552 phosphorylation) for ubiquitin-mediated degradation, along with TAK1 in hepatocellular carcinoma, NF-κB p65/RELA (K122) in breast cancer, Moesin (K48-linked) and EGFR; substrate engagement is frequently conditional on substrate phosphorylation. FBXW2 is itself degraded by SCF(β-TrCP1) within the β-TrCP1-FBXW2-SKP2 axis.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:35414786
    supporting_text: FBXW2 suppresses proliferation and invasion of lung cancer cells by targeting S phase kinase-associated protein 2 (SKP2) and β-catenin
  - reference_id: file:human/FBXW2/FBXW2-deep-research-falcon.md
    supporting_text: '**EGF–AKT1 signaling** phosphorylates β-catenin at **Ser552**, enabling FBXW2 binding.'
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
proposed_new_terms: []
suggested_questions:
- question: What sequence/phospho-degron features do FBXW2 WD40 repeats recognize across its substrates (GCM1, SKP2, β-catenin, TAK1, p65, Moesin, EGFR), given that reported degrons (TSXXXS on β-catenin, TSELLS on SKP2, TSNNST on EGFR) share a Thr-Ser pattern, and how general is competitive/PTM regulation (e.g. RACK1 competition, p300 acetylation of p65, AKT-Thr558 on Moesin)?
- question: How is the reciprocal β-TrCP1-FBXW2-SKP2 degradation axis balanced in normal versus tumor cells, and does FBXW2 loss drive tumorigenesis primarily through SKP2/β-catenin stabilization?
- question: Is FBXW2's reported non-oncologic, myeloid role (KSRP degradation in obesity-associated inflammation) mechanistically distinct from its tumor-suppressive substrate set, and does it reflect tissue-specific substrate availability?
suggested_experiments:
- description: Reconstitute SCF(FBXW2) in vitro with purified SKP1, CUL1, RBX1, an E2 and candidate substrates (GCM1, SKP2, β-catenin, TAK1, p65, Moesin, EGFR) to confirm direct, FBXW2-dependent ubiquitination and map degron requirements and chain linkages (e.g. K48 vs K63), which are unspecified for several substrates.
- description: Use FBXW2 knockout/knockdown with rescue (WT vs F-box-deletion vs WD40 mutants) combined with quantitative proteomics in lung, breast and hepatocellular carcinoma models to define the endogenous substrate repertoire and the contribution of each substrate to the anti-proliferative/anti-invasive phenotype.
- description: Test whether substrate PTM crosstalk (p300 acetylation of p65, AKT phosphorylation of Moesin Thr558 and β-catenin Ser552) governs FBXW2 substrate selection by combining phospho/acetyl-site mutants with FBXW2 binding and degradation assays.