FBXW2

Summary

FBXW2 (F-box and WD repeat domain containing 2, HGNC:13608) is a protein-coding gene on chromosome 9q33.2, encoding F-box/WD repeat-containing protein 2 (Q9UKT8). Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.

F-box proteins are an expanding family of eukaryotic proteins characterized by an approximately 40 amino acid motif, the F box. Some F-box proteins have been shown to be critical for the ubiquitin-mediated degradation of cellular regulatory proteins. In fact, F-box proteins are one of the four subunits of ubiquitin protein ligases, called SCFs. SCF ligases bring ubiquitin conjugating enzymes to substrates that are specifically recruited by the different F-box proteins. Mammalian F-box proteins are classified into three groups based on the presence of either WD-40 repeats, leucine-rich repeats, or the presence or absence of other protein-protein interacting domains. This gene encodes the second identified member of the F-box gene family and contains multiple WD-40 repeats.

Source: NCBI Gene 26190 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 50 total
• MANE Select transcript: NM_012164

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13608
Approved symbol	FBXW2
Name	F-box and WD repeat domain containing 2
Location	9q33.2
Locus type	gene with protein product
Status	Approved
Aliases	FBW2, Md6, Fwd2
Ensembl gene	ENSG00000119402
Ensembl biotype	protein_coding
OMIM	609071
Entrez	26190

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 33 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000453291, ENST00000493559, ENST00000608872, ENST00000684001, ENST00000684047, ENST00000684405, ENST00000882759, ENST00000882760, ENST00000882761, ENST00000882762, ENST00000882763, ENST00000882764, ENST00000882765, ENST00000882766, ENST00000882767, ENST00000882768, ENST00000882769, ENST00000882770, ENST00000882771, ENST00000882772, ENST00000882773, ENST00000917243, ENST00000917245, ENST00000917247, ENST00000917248, ENST00000917249, ENST00000955468, ENST00000955469, ENST00000955470, ENST00000955471, ENST00000955472, ENST00000955473, ENST00000955474, ENST00000955475, ENST00000955476

RefSeq mRNA: 4 — MANE Select: NM_012164 NM_001375888, NM_001375889, NM_001375890, NM_012164

CCDS: CCDS43872, CCDS94471

Canonical transcript exons

ENST00000608872 — 8 exons

Exon	Start	End
ENSE00001016475	120793149	120793257
ENSE00001231662	120776093	120776226
ENSE00001413823	120793354	120793416
ENSE00003495122	120778351	120778545
ENSE00003557232	120772754	120772840
ENSE00003573729	120787769	120788278
ENSE00003667707	120771348	120771517
ENSE00003706883	120756974	120764847

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 95.50.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.6146 / max 297.4962, expressed in 1825 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
102303	32.0578	1821
102301	3.0843	1412
102302	2.4724	1351

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	95.50	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.05	gold quality
mammalian vulva	UBERON:0000997	94.83	gold quality
trabecular bone tissue	UBERON:0002483	94.81	gold quality
skin of hip	UBERON:0001554	94.80	gold quality
colonic mucosa	UBERON:0000317	94.23	gold quality
upper leg skin	UBERON:0004262	94.19	gold quality
lower lobe of lung	UBERON:0008949	94.13	gold quality
caput epididymis	UBERON:0004358	93.77	gold quality
penis	UBERON:0000989	93.60	gold quality
germinal epithelium of ovary	UBERON:0001304	93.52	gold quality
epithelium of nasopharynx	UBERON:0001951	93.43	gold quality
corpus epididymis	UBERON:0004359	93.27	gold quality
jejunal mucosa	UBERON:0000399	93.09	gold quality
bone marrow	UBERON:0002371	93.04	gold quality
cauda epididymis	UBERON:0004360	92.87	gold quality
urethra	UBERON:0000057	92.68	gold quality
stromal cell of endometrium	CL:0002255	92.49	gold quality
bone marrow cell	CL:0002092	92.45	gold quality
parietal pleura	UBERON:0002400	92.41	gold quality
secondary oocyte	CL:0000655	92.34	gold quality
mammary duct	UBERON:0001765	92.29	gold quality
visceral pleura	UBERON:0002401	92.29	gold quality
palpebral conjunctiva	UBERON:0001812	92.17	gold quality
pleura	UBERON:0000977	92.06	gold quality
sperm	CL:0000019	92.04	gold quality
epithelium of mammary gland	UBERON:0003244	91.97	gold quality
tibia	UBERON:0000979	91.96	gold quality
superficial temporal artery	UBERON:0001614	91.92	gold quality
thoracic mammary gland	UBERON:0005200	91.55	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.08

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 9)

• the SCF(hFBW2) E3 complex has a key role in targeting hGCMa to the ubiquitin-proteasome degradation system (PMID:15640526)
• UBE2D2 is required for GCMa ubiquitination and for association with the SCF(FBXW2) complex. (PMID:18703417)
• RACK1 competes with GCM1 for FBW2 and thereby prevents GCM1 ubiquitination, which is also supported by the observation that GCM1 is destabilized in RACK1-knockdown BeWo placental cells (PMID:23651062)
• BTrCP-FBXW2-SKP2 axis forms an oncogene-tumour suppressor-oncogene cascade to control cancer cell growth with FBXW2 acting as a tumour suppressor by promoting SKP2 degradation. (PMID:28090088)
• Study demonstrates that FBXW2 inhibits tumor migration, invasion and metastasis in lung cancer cells by targeting beta-catenin for degradation. (PMID:30918250)
• High FBXW2 expression is associated with drug resistance in lung cancer. (PMID:31548378)
• TAK1 Is a Novel Target in Hepatocellular Carcinoma and Contributes to Sorafenib Resistance. (PMID:33962073)
• FBXW2 inhibits prostate cancer proliferation and metastasis via promoting EGFR ubiquitylation and degradation. (PMID:35499593)
• FBXW2 suppresses breast tumorigenesis by targeting AKT-Moesin-SKP2 axis. (PMID:37736741)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fbxw2	ENSDARG00000009745
mus_musculus	Fbxw2	ENSMUSG00000035949
rattus_norvegicus	Fbxw2	ENSRNOG00000018687

Protein

Protein identifiers

F-box/WD repeat-containing protein 2 — Q9UKT8 (reviewed: Q9UKT8)

Alternative names: F-box and WD-40 domain-containing protein 2, Protein MD6

All UniProt accessions (3): B4DT60, Q9UKT8, Q4VXH1

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.

Subunit / interactions. Directly interacts with SKP1 and CUL1.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UKT8-1	1	yes
Q9UKT8-2	2, MD6b

RefSeq proteins (4): NP_001362817, NP_001362818, NP_001362819, NP_036296* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR001810	F-box_dom	Domain
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR019775	WD40_repeat_CS	Conserved_site
IPR020472	WD40_PAC1	Repeat
IPR036047	F-box-like_dom_sf	Homologous_superfamily
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR042627	FBXW2	Family

Pfam: PF00400, PF12937

UniProt features (13 total): repeat 7, sequence conflict 2, chain 1, domain 1, splice variant 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UKT8-F1	89.04	0.64

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 298

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-390471	Association of TriC/CCT with target proteins during biosynthesis
R-HSA-8951664	Neddylation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 151 (showing top): WANG_CLIM2_TARGETS_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, LINDGREN_BLADDER_CANCER_CLUSTER_2A_DN, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, GOBP_REGULATION_OF_CELL_CYCLE, GOBP_SCF_DEPENDENT_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, BOYAULT_LIVER_CANCER_SUBCLASS_G12_UP

GO Biological Process (2): proteolysis (GO:0006508), protein modification process (GO:0036211)

GO Molecular Function (2): ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515)

GO Cellular Component (1): cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Chaperonin-mediated protein folding	1
Post-translational protein modification	1
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	2
macromolecule modification	1
ubiquitin-like protein transferase activity	1
binding	1
cytoplasm	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1570 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBXW2	SKP1	P34991	790
FBXW2	CUL1	Q13616	737
FBXW2	CUL2	Q13617	706
FBXW2	REV1	Q9UBZ9	670
FBXW2	LY86	O95711	660
FBXW2	FBXW4	P57775	612
FBXW2	FBXW5	Q969U6	556
FBXW2	FBXW8	Q8N3Y1	535
FBXW2	ZFP91	Q96JP5	528
FBXW2	REV3L	O60673	526
FBXW2	FBXO4	Q9UKT5	491
FBXW2	FBXL15	Q9H469	488
FBXW2	FBXW9	Q5XUX1	485
FBXW2	LY96	Q9Y6Y9	479
FBXW2	PSMD5	Q16401	471

IntAct

69 interactions, top by confidence:

A	B	Type	Score
FBXO7	SKP1	psi-mi:“MI:0914”(association)	0.900
FBXW2	SKP1	psi-mi:“MI:0915”(physical association)	0.860
SKP1	FBXW2	psi-mi:“MI:0915”(physical association)	0.860
CUL1	FBXW2	psi-mi:“MI:0915”(physical association)	0.690
FBXW2	RACK1	psi-mi:“MI:0915”(physical association)	0.680
FBXW2	RACK1	psi-mi:“MI:0403”(colocalization)	0.680
FBXW2	RACK1	psi-mi:“MI:0914”(association)	0.680
SPANXN3	SUOX	psi-mi:“MI:0914”(association)	0.640
FBXW7	MYCBP2	psi-mi:“MI:0914”(association)	0.640
SKP1	MYCBP2	psi-mi:“MI:0914”(association)	0.640
GCM1	FBXW2	psi-mi:“MI:0915”(physical association)	0.610
CUL1	FBXO21	psi-mi:“MI:0914”(association)	0.600
CDC37	FBXW2	psi-mi:“MI:0915”(physical association)	0.590
CLVS2	FBXW2	psi-mi:“MI:0915”(physical association)	0.560
FBXW2	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (92): FBXW2 (Reconstituted Complex), EP300 (Affinity Capture-Western), FBXW2 (Affinity Capture-MS), FBXW2 (Affinity Capture-MS), CUL1 (Affinity Capture-Western), FBXW2 (Affinity Capture-MS), SKP1 (Affinity Capture-Western), BTRC (Affinity Capture-Western), FBXW2 (Affinity Capture-Western), FBXW2 (Biochemical Activity), SKP2 (Affinity Capture-Western), FBXW2 (Affinity Capture-Western), SKP2 (Biochemical Activity), CUL1 (Affinity Capture-Western), RBX1 (Affinity Capture-Western)

ESM2 similar proteins: A0JM23, A0JP70, B2RZ17, E1BVR9, O14727, O54927, O88879, O94952, P0CI65, Q08BB3, Q08DV6, Q13309, Q32KQ2, Q3U3W5, Q3U821, Q3UDP0, Q3UMR0, Q3UR70, Q58D00, Q5R5S1, Q5REW9, Q5XJS5, Q60584, Q68EI0, Q6AX81, Q6AZT7, Q6DFC6, Q6P1V3, Q6P2P2, Q6P2S7, Q6ZMY6, Q7T2F6, Q7TNH6, Q7Z494, Q8BHD1, Q8C5V5, Q8IWA0, Q8NA23, Q8VDH1, Q96NW4

Diamond homologs: B2RZ17, O14170, P0CS44, P0CS45, Q4P8R5, Q58D00, Q60584, Q9UKT8, A0JPH4, A1CBP8, A1DDL6, A2R3Z3, A2RRU4, A4RJV3, A6QM06, A6ZMK5, A7ETB3, A7RM20, A7S338, A7TH19, A7TNS8, A8NEG8, A8PTE4, B2B766, B4N0L0, C4Q0P6, E3LB80, O18640, O42937, P25387, P38262, P40217, P87060, P97260, Q01369, Q09855, Q0CJD8, Q0U2T3, Q12770, Q1DIW7

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
FBXW2	“down-regulates quantity”	GCM1	binding
FBXW2	“form complex”	SCF-FBW2	binding
FBXW2	“down-regulates quantity by destabilization”	MSX2	binding
FBXW2	“up-regulates activity”	“Cullin 1-RBX1-Skp1”	binding
VRK2	“down-regulates activity”	FBXW2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 44 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Neddylation	9	11.8×	4e-06
Antigen processing: Ubiquitination & Proteasome degradation	11	11.4×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process	7	62.4×	5e-09
regulation of protein localization	5	24.5×	1e-04
protein K48-linked ubiquitination	6	24.1×	2e-05
protein polyubiquitination	6	16.5×	1e-04
protein folding	5	12.3×	2e-03
protein ubiquitination	11	10.8×	5e-07
ubiquitin-dependent protein catabolic process	6	10.6×	8e-04
proteasome-mediated ubiquitin-dependent protein catabolic process	8	9.9×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

50 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	37
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1517 predictions. Top by Δscore:

Variant	Effect	Δscore
9:120771513:CAAAT:C	acceptor_gain	1.0000
9:120771517:TC:T	acceptor_loss	1.0000
9:120771518:C:CA	acceptor_loss	1.0000
9:120771518:C:CC	acceptor_gain	1.0000
9:120771519:T:A	acceptor_loss	1.0000
9:120772749:CTCA:C	donor_loss	1.0000
9:120772750:TCAC:T	donor_loss	1.0000
9:120772751:CACCT:C	donor_loss	1.0000
9:120772752:A:AC	donor_gain	1.0000
9:120772752:ACCT:A	donor_loss	1.0000
9:120772753:C:CC	donor_gain	1.0000
9:120772753:C:CG	donor_loss	1.0000
9:120772837:CTAC:C	acceptor_gain	1.0000
9:120778381:T:TA	donor_gain	1.0000
9:120778397:C:CA	donor_gain	1.0000
9:120778402:C:A	donor_gain	1.0000
9:120771341:ACATT:A	donor_loss	0.9900
9:120771342:CATTA:C	donor_loss	0.9900
9:120771343:ATTAC:A	donor_loss	0.9900
9:120771344:TTA:T	donor_loss	0.9900
9:120771345:TACC:T	donor_loss	0.9900
9:120771346:ACC:A	donor_loss	0.9900
9:120771347:C:A	donor_loss	0.9900
9:120771362:A:C	donor_gain	0.9900
9:120771514:AAAT:A	acceptor_gain	0.9900
9:120771515:AAT:A	acceptor_gain	0.9900
9:120771516:AT:A	acceptor_gain	0.9900
9:120772838:TAC:T	acceptor_gain	0.9900
9:120772847:A:C	acceptor_gain	0.9900
9:120776227:C:CC	acceptor_gain	0.9900

AlphaMissense

2997 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:120764607:G:C	S439R	1.000
9:120764607:G:T	S439R	1.000
9:120764609:T:G	S439R	1.000
9:120764614:G:T	A437D	1.000
9:120764620:A:T	V435D	1.000
9:120772775:A:C	S295R	1.000
9:120772775:A:T	S295R	1.000
9:120772777:T:G	S295R	1.000
9:120776102:C:A	W270C	1.000
9:120776102:C:G	W270C	1.000
9:120776104:A:G	W270R	1.000
9:120776104:A:T	W270R	1.000
9:120776155:A:G	W253R	1.000
9:120776155:A:T	W253R	1.000
9:120776181:C:T	G244D	1.000
9:120776183:G:C	S243R	1.000
9:120776183:G:T	S243R	1.000
9:120776185:T:G	S243R	1.000
9:120776222:A:C	F230L	1.000
9:120776222:A:T	F230L	1.000
9:120776224:A:G	F230L	1.000
9:120778403:C:A	W211C	1.000
9:120778403:C:G	W211C	1.000
9:120778405:A:G	W211R	1.000
9:120778405:A:T	W211R	1.000
9:120778422:T:A	D205V	1.000
9:120778424:A:C	F204L	1.000
9:120778424:A:T	F204L	1.000
9:120778425:A:C	F204C	1.000
9:120778425:A:G	F204S	1.000

dbSNP variants (sampled 300 via entrez): RS1000019735 (9:120781690 A>G), RS1000062259 (9:120767659 A>G), RS1000132193 (9:120766419 G>T), RS1000201372 (9:120785241 C>A,T), RS1000266940 (9:120762911 C>T), RS1000319516 (9:120763230 C>T), RS1000478774 (9:120791437 A>C), RS1000530565 (9:120786443 G>A,T), RS1000569913 (9:120786343 T>C), RS1000621205 (9:120756823 A>G), RS1000767688 (9:120791120 G>A,T), RS1000923462 (9:120774076 C>T), RS1001062248 (9:120773941 A>G), RS1001077534 (9:120780572 G>A,T), RS1001134074 (9:120792580 ATTTT>A,ATTT,ATTTTT)

Disease associations

OMIM: gene MIM:609071 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST004067_36	Hip circumference adjusted for BMI	6.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	4
nickel chloride	decreases expression	2
butyraldehyde	decreases expression	1
pentanal	decreases expression	1
abrine	decreases expression	1
Resveratrol	increases expression, affects cotreatment	1
Arsenic	affects methylation	1
Benzene	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Indomethacin	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Testosterone	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Vitamin E	increases expression	1
Cyclosporine	decreases expression	1
Phenol	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.