FBXO25

Summary

FBXO25 (F-box protein 25, HGNC:13596) is a protein-coding gene on chromosome 8p23.3, encoding F-box only protein 25 (Q8TCJ0). Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.

This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class. Three alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.

Source: NCBI Gene 26260 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 94 total — 1 pathogenic
• MANE Select transcript: NM_183420

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13596
Approved symbol	FBXO25
Name	F-box protein 25
Location	8p23.3
Locus type	gene with protein product
Status	Approved
Aliases	FBX25
Ensembl gene	ENSG00000147364
Ensembl biotype	protein_coding
OMIM	609098
Entrez	26260

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 22 protein_coding, 2 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000276326, ENST00000350302, ENST00000352684, ENST00000382824, ENST00000517464, ENST00000518240, ENST00000519274, ENST00000519376, ENST00000524015, ENST00000524125, ENST00000907984, ENST00000907985, ENST00000907986, ENST00000907987, ENST00000912191, ENST00000912192, ENST00000912193, ENST00000912194, ENST00000912195, ENST00000956411, ENST00000956412, ENST00000956413, ENST00000956414, ENST00000956415, ENST00000956416, ENST00000956417, ENST00000956418

RefSeq mRNA: 3 — MANE Select: NM_183420 NM_012173, NM_183420, NM_183421

CCDS: CCDS5952, CCDS5953, CCDS5954

Canonical transcript exons

ENST00000350302 — 10 exons

Exon	Start	End
ENSE00000000081	406958	407066
ENSE00001086462	451269	451453
ENSE00001743242	432886	432935
ENSE00003472937	431341	431444
ENSE00003508287	458369	458551
ENSE00003625255	413073	413213
ENSE00003629882	449990	450083
ENSE00003632971	463007	463150
ENSE00003682552	435615	435707
ENSE00003902662	468715	477967

Expression profiles

Bgee: expression breadth ubiquitous, 258 present calls, max score 97.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.7040 / max 155.1186, expressed in 1703 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
87134	11.0060	1689
87133	1.6980	968

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	97.83	gold quality
right testis	UBERON:0004534	97.53	gold quality
testis	UBERON:0000473	95.98	gold quality
sperm	CL:0000019	95.70	gold quality
tibialis anterior	UBERON:0001385	95.19	silver quality
adult organism	UBERON:0007023	94.59	gold quality
kidney epithelium	UBERON:0004819	94.19	gold quality
cardiac muscle of right atrium	UBERON:0003379	93.07	gold quality
upper arm skin	UBERON:0004263	93.01	gold quality
body of pancreas	UBERON:0001150	92.28	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.22	gold quality
left ventricle myocardium	UBERON:0006566	92.19	gold quality
epithelial cell of pancreas	CL:0000083	91.93	gold quality
deltoid	UBERON:0001476	91.91	gold quality
myocardium	UBERON:0002349	91.57	gold quality
right lobe of liver	UBERON:0001114	91.43	gold quality
pancreas	UBERON:0001264	91.25	gold quality
gastrocnemius	UBERON:0001388	90.82	gold quality
muscle of leg	UBERON:0001383	90.67	gold quality
islet of Langerhans	UBERON:0000006	90.64	gold quality
ileal mucosa	UBERON:0000331	90.26	gold quality
cortical plate	UBERON:0005343	90.09	gold quality
right adrenal gland	UBERON:0001233	90.01	gold quality
right adrenal gland cortex	UBERON:0035827	89.95	gold quality
calcaneal tendon	UBERON:0003701	89.92	gold quality
secondary oocyte	CL:0000655	89.83	gold quality
liver	UBERON:0002107	89.83	gold quality
skeletal muscle organ	UBERON:0014892	89.74	gold quality
heart left ventricle	UBERON:0002084	89.35	gold quality
rectum	UBERON:0001052	89.27	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	29.60
E-ANND-3	yes	9.82

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

58 targeting FBXO25, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-4502	99.65	66.99	1021
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-8064	99.45	66.92	875
HSA-MIR-1244	99.33	68.38	832

Literature-anchored findings (GeneRIF, showing 12)

• investigated hFBX25’s genomic organization and established hFBX25 as an FBP by verifying its interaction with Skp1 and Cul1 (PMID:16278047)
• The cellular distribution of FBXO25 and its colocalization with some nuclear proteins is investigated by using immunochemical and biochemical approaches. (PMID:18287534)
• Beta-actin, physically interacts through its N-terminus with FBXO25 and is enriched in the FBXO25 nuclear compartments. (PMID:20473970)
• Altogether, Fbxo25 acts as an ubiquitin E3 ligase to target cardiac transcription factors including Nkx2-5, Isl1, and Hand1, indicating that cardiac protein homeostasis through Fbxo25 has a pivotal impact on cardiac development. (PMID:21596019)
• FBXO25 mediates ELK-1 degradation through the ubiquitin proteasome system and thereby plays a role in regulating the activation of ELK-1 pathway in response to mitogens (PMID:23940030)
• FBXO25 functions as a haploinsufficient tumor suppressor in mantle cell lymphoma. (PMID:25419709)
• High FBXO25 expression is associated with non-small-cell lung cancer. (PMID:27596142)
• Taken together we show that FBXO25 functions as a negative regulator of MAPK signaling though the reduction of ERK1/2 activation. (PMID:28389297)
• LncRNA ODIR1 inhibits osteogenic differentiation of hUC-MSCs through the FBXO25/H2BK120ub/H3K4me3/OSX axis. (PMID:31827076)
• From man to fly - convergent evidence links FBXO25 to ADHD and comorbid psychiatric phenotypes. (PMID:31849056)
• FBXO25 Promotes Cutaneous Squamous Cell Carcinoma Growth and Metastasis through Cyclin D1. (PMID:32335130)
• ELK-1 ubiquitination status and transcriptional activity are modulated independently of F-Box protein FBXO25. (PMID:33428929)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	fbxo25	ENSDARG00000075172
mus_musculus	Fbxo25	ENSMUSG00000038365
rattus_norvegicus	Fbxo25	ENSRNOG00000042464
drosophila_melanogaster	CG11658	FBGN0036196
caenorhabditis_elegans	mfb-1	WBGENE00008439

Paralogs (1): FBXO32 (ENSG00000156804)

Protein

Protein identifiers

F-box only protein 25 — Q8TCJ0 (reviewed: Q8TCJ0)

All UniProt accessions (3): Q8TCJ0, E5RFH9, H0YBS4

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. May play a role in accumulation of expanded polyglutamine (polyQ) protein huntingtin (HTT).

Subunit / interactions. Part of a SCF (SKP1-cullin-F-box) protein ligase complex consisting of FBXO25, SKP1, CUL1 and RBX1. Interacts directly with SKP1 and CUL1. Interacts (via C-terminus) with beta-actin (via N-terminus).

Subcellular location. Nucleus.

Tissue specificity. Expressed in all brain tissue observed.

Disease relevance. A chromosomal aberration involving FBXO25 is a cause of X-linked intellectual disability (XLID). Translocation t(X;8)(p11.22;p23.3) with SHROOM4.

Domain organisation. The F-box is necessary for the interaction with SKP1.

Pathway. Protein modification; protein ubiquitination.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8TCJ0-1	1	yes
Q8TCJ0-2	2
Q8TCJ0-3	3

RefSeq proteins (3): NP_036305, NP_904356, NP_904357 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR036047	F-box-like_dom_sf	Homologous_superfamily
IPR040394	FBX25/32	Family

UniProt features (11 total): splice variant 3, sequence conflict 2, sequence variant 2, chain 1, domain 1, region of interest 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TCJ0-F1	76.03	0.37

Functional residue map

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

Mutagenesis-validated functional residues (1):

Position	Phenotype
244	loss of skp1-binding.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 113 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, BENPORATH_ES_WITH_H3K27ME3, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_5, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_SCF_DEPENDENT_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, DING_LUNG_CANCER_EXPRESSION_BY_COPY_NUMBER, GOMF_ACTIN_BINDING, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, GOBP_PROTEIN_CATABOLIC_PROCESS, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_DN, GOCC_SCF_UBIQUITIN_LIGASE_COMPLEX, GOCC_TRANSFERASE_COMPLEX, GOBP_PROTEOLYSIS

GO Biological Process (1): protein ubiquitination (GO:0016567)

GO Molecular Function (3): actin binding (GO:0003779), ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515)

GO Cellular Component (4): ubiquitin ligase complex (GO:0000151), nucleus (GO:0005634), cytoplasm (GO:0005737), SCF ubiquitin ligase complex (GO:0019005)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein modification by small protein conjugation	1
cytoskeletal protein binding	1
ubiquitin-like protein transferase activity	1
binding	1
intracellular protein-containing complex	1
transferase complex	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1
cullin-RING ubiquitin ligase complex	1

Protein interactions and networks

STRING

1018 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBXO25	SKP1	P34991	897
FBXO25	CUL1	Q13616	897
FBXO25	YIPF1	Q9Y548	775
FBXO25	TDRP	Q86YL5	696
FBXO25	FBXO33	Q7Z6M2	589
FBXO25	ZNF596	Q8TC21	583
FBXO25	ERICH1	Q86X53	570
FBXO25	RBX1	P62877	555
FBXO25	FBXO11	Q86XK2	507
FBXO25	FBXW5	Q969U6	495
FBXO25	FBXL14	Q8N1E6	492
FBXO25	FBXL7	Q9UJT9	491
FBXO25	Q8WV35	Q8WV35	485
FBXO25	FBXO45	P0C2W1	475
FBXO25	FBXO2	Q9UK22	474

IntAct

16 interactions, top by confidence:

A	B	Type	Score
FBXO25	CUL1	psi-mi:“MI:0403”(colocalization)	0.580
FBXO25	SKP1	psi-mi:“MI:0914”(association)	0.530
ACTB	FBXO25	psi-mi:“MI:0915”(physical association)	0.460
FBXO25	ACTB	psi-mi:“MI:0403”(colocalization)	0.460
HSP90AB1	FBXO25	psi-mi:“MI:0915”(physical association)	0.400
FKBP5	FBXO25	psi-mi:“MI:0915”(physical association)	0.400
	FBXO25	psi-mi:“MI:0915”(physical association)	0.400
FBXO25	HSP90AA1	psi-mi:“MI:0915”(physical association)	0.400
PPP5C	FBXO25	psi-mi:“MI:0915”(physical association)	0.400
FBXO25	ORC4	psi-mi:“MI:0915”(physical association)	0.370
EP300	FBXO25	psi-mi:“MI:0915”(physical association)	0.370
FBXO25	ARHGAP1	psi-mi:“MI:0914”(association)	0.350
CAND1	FBXO25	psi-mi:“MI:0914”(association)	0.350

BioGRID (220): NKX2-5 (Reconstituted Complex), FBXO25 (Reconstituted Complex), TBX5 (Reconstituted Complex), FBXO25 (Reconstituted Complex), UBE2E3 (Affinity Capture-MS), ARHGAP1 (Affinity Capture-MS), PNPO (Affinity Capture-MS), PNPO (Affinity Capture-MS), ARHGAP1 (Affinity Capture-MS), UBE2E3 (Affinity Capture-MS), FBXO25 (Synthetic Lethality), FBXO25 (Two-hybrid), HAX1 (Affinity Capture-Western), POU2F1 (Affinity Capture-Western), FBXO25 (Affinity Capture-Western)

ESM2 similar proteins: A1KXW8, A6QL50, E1BGQ2, H0Y354, O94955, P47224, Q08326, Q0IIH8, Q1JQA1, Q1RMS8, Q1RMZ1, Q2TBU5, Q3T1H6, Q4R372, Q4R528, Q4R9C4, Q5F480, Q5F4A1, Q5I0G3, Q5RCQ0, Q5RFG8, Q5TFE4, Q5TYM5, Q641X7, Q6L9T8, Q6PIP5, Q7L622, Q7Z6J8, Q7ZX59, Q86X60, Q8BFZ8, Q8BKW4, Q8BM85, Q8BX13, Q8CEL2, Q8N5C7, Q8N635, Q8NHU2, Q8TCF1, Q8TCJ0

Diamond homologs: Q1A730, Q1RMS8, Q2KHT6, Q2T9S7, Q4R372, Q641X7, Q8TCJ0, Q91Z62, Q969P5, Q9CPU7, Q9D2Y6

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
FBXO25	“down-regulates quantity by destabilization”	ELK1	binding
FBXO25	“up-regulates activity”	“Cullin 1-RBX1-Skp1”	binding
PRKCD	“up-regulates activity”	FBXO25	phosphorylation
FBXO25	“down-regulates quantity by destabilization”	HAX1	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	63
Likely benign	8
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
979227	GRCh37/hg19 8p23.3-23.2(chr8:158048-3476104)x1	Pathogenic

SpliceAI

1931 predictions. Top by Δscore:

Variant	Effect	Δscore
8:413210:GCAT:G	donor_gain	1.0000
8:413214:G:GG	donor_gain	1.0000
8:431336:TTCA:T	acceptor_loss	1.0000
8:431337:TCA:T	acceptor_loss	1.0000
8:431339:A:AG	acceptor_gain	1.0000
8:431339:A:AT	acceptor_loss	1.0000
8:431340:G:GC	acceptor_gain	1.0000
8:431340:GT:G	acceptor_gain	1.0000
8:431340:GTA:G	acceptor_gain	1.0000
8:431340:GTAT:G	acceptor_gain	1.0000
8:431340:GTATC:G	acceptor_gain	1.0000
8:431443:AA:A	donor_gain	1.0000
8:431444:AG:A	donor_loss	1.0000
8:431445:G:GG	donor_gain	1.0000
8:431446:T:TC	donor_loss	1.0000
8:432932:GGAA:G	donor_gain	1.0000
8:432933:G:GT	donor_gain	1.0000
8:432933:GAA:G	donor_gain	1.0000
8:432936:G:GG	donor_gain	1.0000
8:435610:TCCA:T	acceptor_loss	1.0000
8:435612:CA:C	acceptor_loss	1.0000
8:435613:A:AC	acceptor_loss	1.0000
8:435613:A:AG	acceptor_gain	1.0000
8:435613:AGAG:A	acceptor_gain	1.0000
8:435614:G:GC	acceptor_gain	1.0000
8:435614:GA:G	acceptor_gain	1.0000
8:435614:GAGG:G	acceptor_gain	1.0000
8:435614:GAGGC:G	acceptor_gain	1.0000
8:435703:TCA:T	donor_gain	1.0000
8:435704:CAAAG:C	donor_loss	1.0000

AlphaMissense

2408 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:435652:G:C	R109P	0.999
8:435655:T:C	L110S	0.998
8:458513:T:A	W269R	0.998
8:458513:T:C	W269R	0.998
8:463145:T:A	W328R	0.998
8:463145:T:C	W328R	0.998
8:450033:G:A	G142D	0.997
8:463049:T:A	W296R	0.997
8:463049:T:C	W296R	0.997
8:463121:T:C	C320R	0.997
8:413122:T:A	W15R	0.996
8:413122:T:C	W15R	0.996
8:413143:T:A	W22R	0.996
8:413143:T:C	W22R	0.996
8:432913:T:A	V89D	0.996
8:435642:G:C	A106P	0.996
8:435643:C:A	A106D	0.996
8:449991:T:C	L128P	0.996
8:450029:A:C	S141R	0.996
8:450031:T:A	S141R	0.996
8:450031:T:G	S141R	0.996
8:463123:T:G	C320W	0.996
8:463132:C:G	C323W	0.996
8:463140:T:C	L326P	0.996
8:413086:T:C	F3L	0.995
8:413088:T:A	F3L	0.995
8:413088:T:G	F3L	0.995
8:435636:G:A	G104R	0.995
8:435636:G:C	G104R	0.995
8:451388:T:A	W199R	0.995

dbSNP variants (sampled 300 via entrez): RS1000004420 (8:469836 T>G), RS1000019438 (8:454599 C>G), RS1000025450 (8:463405 A>C), RS1000119633 (8:405605 C>G,T), RS1000123442 (8:441443 G>A), RS1000191576 (8:477544 C>A,T), RS1000256364 (8:473933 C>G), RS1000279440 (8:467162 G>A), RS1000306160 (8:477754 G>A), RS1000324586 (8:426358 A>C), RS1000331855 (8:422184 C>G), RS1000335710 (8:475663 T>G), RS1000338929 (8:470694 G>A), RS1000379071 (8:422092 T>C), RS1000423322 (8:415161 G>A)

Disease associations

OMIM: gene MIM:609098 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006622_21	Neonatal cytokine/chemokine levels (fetal genetic effect)	2.000000e-09
GCST011155_11	Nontraumatic osteonecrosis of the femoral head	2.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004747	protein measurement
EFO:0007959	fetal genotype effect measurement
EFO:0008184	interleukin 4 measurement
EFO:1001930	idiopathic osteonecrosis of the femoral head

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases methylation	6
Tetrachlorodibenzodioxin	increases expression, affects expression	4
Benzo(a)pyrene	increases expression, decreases methylation	3
Cyclosporine	increases expression	3
sodium arsenite	decreases expression	2
GSK-J4	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
terbufos	decreases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
9,10-dihydro-9,10-dihydroxybenzo(a)pyrene	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Arsenic Trioxide	affects cotreatment, decreases expression	1
Leflunomide	increases expression	1
Acetaminophen	decreases expression	1
Gemcitabine	increases expression	1
Doxorubicin	decreases expression	1
Fonofos	decreases methylation	1
Lead	affects expression	1
Parathion	decreases methylation	1
Quercetin	decreases expression	1
Tretinoin	affects cotreatment, decreases expression	1
Triclosan	increases expression	1
Aflatoxin B1	decreases methylation	1
beta-Naphthoflavone	increases expression	1

Clinical trials (associated diseases)

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