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 Ξ²-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-ΞΊB 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(Ξ²-TrCP1) (recognized via a phospho-dependent SSGART motif), placing it within a Ξ²-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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:11238952 ATF4 degradation relies on a phosphorylation-dependent inter... | KEEP AS NON CORE | Summary: IntAct interaction with SKP1 (P63208), the adaptor linking F-box proteins into the SCF complex. Bare protein binding is uninformative. Reason: Records the FBXW2-SKP1 interaction but bare protein binding is uninformative; SCF membership is captured by GO:0019005. Supporting Evidence: file:human/FBXW2/FBXW2-uniprot.txt Q9UKT8; P63208: SKP1; NbExp=8; IntAct=EBI-914727, EBI-307486 |
| GO:0005515 protein binding | IPI PMID:15070733 M-phase kinases induce phospho-dependent ubiquitination of s... | KEEP AS NON CORE | Summary: IntAct interaction with SKP1 (P63208). Bare protein binding is uninformative. Reason: Records the FBXW2-SKP1 interaction; bare protein binding is uninformative and subsumed by SCF complex membership. Supporting Evidence: file:human/FBXW2/FBXW2-uniprot.txt Q9UKT8; P63208: SKP1; NbExp=8; IntAct=EBI-914727, EBI-307486 |
| GO:0005515 protein binding | IPI PMID:21145461 Dynamics of cullin-RING ubiquitin ligase network revealed by... | KEEP AS NON CORE | Summary: CRL-network quantitative proteomics interaction with CUL1 (Q13616), the scaffold of the SCF(FBXW2) complex. Bare protein binding is uninformative. Reason: Records the functionally meaningful FBXW2-CUL1 interaction but bare protein binding is uninformative; SCF membership is captured by GO:0019005. Supporting Evidence: file:human/FBXW2/FBXW2-uniprot.txt Q9UKT8; Q13616: CUL1; NbExp=5; IntAct=EBI-914727, EBI-359390 |
| GO:0005515 protein binding | IPI PMID:22632967 Cyclin F-mediated degradation of ribonucleotide reductase M2... | KEEP AS NON CORE | Summary: IntAct interaction with SKP1 (P63208) from a study about cyclin F/RRM2. Bare protein binding is uninformative. Reason: Records the FBXW2-SKP1 association; bare protein binding is uninformative and subsumed by SCF complex membership. Supporting Evidence: file:human/FBXW2/FBXW2-uniprot.txt Q9UKT8; P63208: SKP1; NbExp=8; IntAct=EBI-914727, EBI-307486 |
| GO:0005515 protein binding | IPI PMID:22939624 Quantitative analysis of HSP90-client interactions reveals p... | KEEP AS NON CORE | 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. Reason: Records HSP90/CDC37 chaperone-client association (FBXW2 as client) but bare protein binding is uninformative and not a core function. Supporting Evidence: file:human/FBXW2/FBXW2-uniprot.txt Q9UKT8; P08238: HSP90AB1; NbExp=2; IntAct=EBI-914727, EBI-352572 |
| GO:0005515 protein binding | IPI PMID:23108047 FBXW7-mediated degradation of CCDC6 is impaired by ATM durin... | KEEP AS NON CORE | Summary: IntAct interaction with CUL1 (Q13616) captured in a study about FBXW7/CCDC6. Bare protein binding is uninformative. Reason: Records the FBXW2-CUL1 interaction; bare protein binding is uninformative and subsumed by SCF complex membership. Supporting Evidence: file:human/FBXW2/FBXW2-uniprot.txt Q9UKT8; Q13616: CUL1; NbExp=5; IntAct=EBI-914727, EBI-359390 |
| GO:0005515 protein binding | IPI PMID:23651062 RACK1 (receptor for activated C-kinase 1) interacts with FBW... | KEEP AS NON CORE | 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. Reason: Records functionally important FBXW2-GCM1 (substrate) and FBXW2-RACK1 (regulator) interactions but bare protein binding is uninformative. Supporting Evidence: PMID:23651062 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 |
| GO:0005515 protein binding | IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc... | KEEP AS NON CORE | Summary: Chaperone-interaction network capturing FBXW2 binding to HSP90AB1 (P08238), CDC37 (Q16543) and NUDC (Q9Y266). Reflects chaperone-mediated folding. Bare protein binding is uninformative. Reason: Records chaperone-client associations (FBXW2 as client) but bare protein binding is uninformative and not a core function. Supporting Evidence: file:human/FBXW2/FBXW2-uniprot.txt Q9UKT8; Q16543: CDC37; NbExp=2; IntAct=EBI-914727, EBI-295634 |
| GO:0005515 protein binding | IPI PMID:27705803 A High-Density Map for Navigating the Human Polycomb Complex... | KEEP AS NON CORE | Summary: Polycomb complexome AP-MS map capturing an FBXW2-SKP1 (P63208) association. Bare protein binding is uninformative. Reason: High-throughput interaction (SKP1); bare protein binding is uninformative and subsumed by SCF complex membership. Supporting Evidence: file:human/FBXW2/FBXW2-uniprot.txt Q9UKT8; P63208: SKP1; NbExp=8; IntAct=EBI-914727, EBI-307486 |
| GO:0005515 protein binding | IPI PMID:31391242 DCAF8, a novel MuRF1 interaction partner, promotes muscle at... | KEEP AS NON CORE | Summary: IntAct interaction with TRIM54 (Q9BYV2) from a DCAF8/MuRF1 muscle-atrophy study. Bare protein binding is uninformative. Reason: High-throughput interaction; bare protein binding is uninformative. Supporting Evidence: file:human/FBXW2/FBXW2-uniprot.txt Q9UKT8; Q9BYV2: TRIM54; NbExp=2; IntAct=EBI-914727, EBI-2130429 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Binary interactome reference map capturing an FBXW2-CLVS2 (Q5SYC1) interaction. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/FBXW2/FBXW2-uniprot.txt Q9UKT8; Q5SYC1: CLVS2; NbExp=3; IntAct=EBI-914727, EBI-12357161 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: Cell-specific interactome capturing an FBXW2-SKP1 (P63208) association. Bare protein binding is uninformative. Reason: High-throughput interaction (SKP1); bare protein binding is uninformative and subsumed by SCF complex membership. Supporting Evidence: file:human/FBXW2/FBXW2-uniprot.txt Q9UKT8; P63208: SKP1; NbExp=8; IntAct=EBI-914727, EBI-307486 |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | KEEP AS NON CORE | Summary: Multimodal cell-map study capturing an FBXW2-SKP1 (P63208) association. Bare protein binding is uninformative. Reason: High-throughput interaction (SKP1); bare protein binding is uninformative and subsumed by SCF complex membership. Supporting Evidence: file:human/FBXW2/FBXW2-uniprot.txt Q9UKT8; P63208: SKP1; NbExp=8; IntAct=EBI-914727, EBI-307486 |
| GO:0010564 regulation of cell cycle process | NAS PMID:35414786 The role of ubiquitination and deubiquitination in tumor inv... | KEEP AS NON CORE | Summary: Non-traceable assertion (review) of regulation of a cell cycle process, reflecting FBXW2's degradation of SKP2 and Ξ²-catenin to suppress proliferation, and its place in the Ξ²-TrCP1-FBXW2-SKP2 axis. Reason: Supported as a downstream consequence of FBXW2 substrate degradation (SKP2/Ξ²-catenin) but generic; the SCF-dependent catabolic process is the core function. Supporting Evidence: PMID:35414786 FBXW2 suppresses proliferation and invasion of lung cancer cells by targeting S phase kinase-associated protein 2 (SKP2) and Ξ²-catenin |
| GO:0019005 SCF ubiquitin ligase complex | NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... | ACCEPT | Summary: ComplexPortal/NAS assertion of SCF complex membership, the core complex for FBXW2 as an F-box substrate receptor of SKP1-CUL1-RBX1. Reason: Core complex; FBXW2 directly interacts with SKP1 and CUL1 and is the substrate-recognition subunit of SCF(FBXW2). Supporting Evidence: file:human/FBXW2/FBXW2-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... | ACCEPT | Summary: ComplexPortal/NAS assertion of SCF-dependent proteasomal catabolism, the core biological process for FBXW2 as an SCF substrate receptor. Reason: Core biological process; FBXW2 directs substrates (GCM1, SKP2, Ξ²-catenin, TAK1) to SCF-dependent proteasomal degradation. Supporting Evidence: PMID:23651062 recognizes GCM1 and mediates its ubiquitination via the SCFFBW2 E3 ligase complex |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952618 | ACCEPT | Summary: Reactome curation of cytosolic localization within CRL neddylation reactions. Consistent with the expected cytosolic localization of a SCF substrate receptor. Reason: Correct localization; the CRL-cycle Reactome events are pathway-context annotations. Supporting Evidence: file:human/FBXW2/FBXW2-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 | ACCEPT | Summary: Reactome curation of cytosolic localization within CRL neddylation reactions. Reason: Correct localization, redundant with other localization annotations. Supporting Evidence: file:human/FBXW2/FBXW2-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 | ACCEPT | Summary: Reactome curation of cytosolic localization (CAND1 binding to CRL). Reason: Correct localization, redundant with other localization annotations. Supporting Evidence: file:human/FBXW2/FBXW2-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 | ACCEPT | Summary: Reactome curation of cytosolic localization (COMMD-CAND1 displacement). Reason: Correct localization, redundant with other localization annotations. Supporting Evidence: file:human/FBXW2/FBXW2-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 | ACCEPT | Summary: Reactome curation of cytosolic localization (COP9 signalosome deneddylation). Reason: Correct localization, redundant with other localization annotations. Supporting Evidence: file:human/FBXW2/FBXW2-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 | ACCEPT | Summary: Reactome curation of cytosolic localization (DCUN1D3 binding to CRL1). Reason: Correct localization, redundant with other localization annotations. Supporting Evidence: file:human/FBXW2/FBXW2-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 | ACCEPT | Summary: Reactome curation of cytosolic localization (Ub transfer to substrate). Reason: Correct localization, redundant with other localization annotations. Supporting Evidence: file:human/FBXW2/FBXW2-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 | ACCEPT | Summary: Reactome curation of cytosolic localization (E3 release from polyubiquitinated substrate). Reason: Correct localization, redundant with other localization annotations. Supporting Evidence: file:human/FBXW2/FBXW2-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 | ACCEPT | Summary: Reactome curation of cytosolic localization (polyubiquitination of substrate). Reason: Correct localization, redundant with other localization annotations. Supporting Evidence: file:human/FBXW2/FBXW2-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 | ACCEPT | Summary: Reactome curation of cytosolic localization (E3 interaction with substrate and E2-Ub). Reason: Correct localization, redundant with other localization annotations. Supporting Evidence: file:human/FBXW2/FBXW2-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. |
| GO:0004842 ubiquitin-protein transferase activity | TAS PMID:10531035 Identification of a family of human F-box proteins. | MODIFY | 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). 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 replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: file:human/FBXW2/FBXW2-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. |
| GO:0006508 proteolysis | TAS PMID:10531035 Identification of a family of human F-box proteins. | KEEP AS NON CORE | Summary: Author-statement annotation of proteolysis from the F-box family paper, reflecting the SCF role in controlled protein degradation. Very generic. Reason: Correct but generic; the SCF-dependent proteasomal ubiquitin-dependent catabolic process annotation is far more specific and informative. Supporting Evidence: PMID:10531035 Some F-box proteins have been shown to be critical for the controlled degradation of cellular regulatory proteins |
| GO:0036211 protein modification process | TAS PMID:10531035 Identification of a family of human F-box proteins. | KEEP AS NON CORE | Summary: Author-statement annotation of protein modification process, a very broad parent reflecting the ubiquitination role of SCF complexes. Reason: Correct but extremely generic; the SCF-dependent proteasomal catabolic process annotation better captures the role. Supporting Evidence: PMID:10531035 F-box proteins are one of the four subunits of ubiquitin protein ligases called SCFs |
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Download this section (compressed HTML)Q: What sequence/phospho-degron features do FBXW2 WD40 repeats recognize across its substrates (GCM1, SKP2, Ξ²-catenin, TAK1, p65, Moesin, EGFR), given that reported degrons (TSXXXS on Ξ²-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)?
Q: How is the reciprocal Ξ²-TrCP1-FBXW2-SKP2 degradation axis balanced in normal versus tumor cells, and does FBXW2 loss drive tumorigenesis primarily through SKP2/Ξ²-catenin stabilization?
Q: 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?
Experiment: Reconstitute SCF(FBXW2) in vitro with purified SKP1, CUL1, RBX1, an E2 and candidate substrates (GCM1, SKP2, Ξ²-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.
Experiment: 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.
Experiment: Test whether substrate PTM crosstalk (p300 acetylation of p65, AKT phosphorylation of Moesin Thr558 and Ξ²-catenin Ser552) governs FBXW2 substrate selection by combining phospho/acetyl-site mutants with FBXW2 binding and degradation assays.
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