FBXO8

Summary

FBXO8 (F-box protein 8, HGNC:13587) is a protein-coding gene on chromosome 4q34.1, encoding F-box only protein 8 (Q9NRD0). May promote guanine-nucleotide exchange on an ARF.

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 the 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. It contains a C-terminal amino acid sequence that bears a significant similarity with a portion of yeast Sec7p, a critical regulator of vesicular protein transport. This human protein may interact with ADP-ribosylation factor(s)(ARFs) and exhibit ARF-GEF (guanine nucleotide exchange factor) activity.

Source: NCBI Gene 26269 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 35 total
• MANE Select transcript: NM_012180

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13587
Approved symbol	FBXO8
Name	F-box protein 8
Location	4q34.1
Locus type	gene with protein product
Status	Approved
Aliases	FBX8, FBS
Ensembl gene	ENSG00000164117
Ensembl biotype	protein_coding
OMIM	605649
Entrez	26269

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 12 protein_coding, 1 nonsense_mediated_decay

ENST00000393674, ENST00000503293, ENST00000513696, ENST00000515664, ENST00000615392, ENST00000851481, ENST00000851482, ENST00000851483, ENST00000851484, ENST00000851485, ENST00000851486, ENST00000927317, ENST00000949149

RefSeq mRNA: 1 — MANE Select: NM_012180 NM_012180

CCDS: CCDS3820

Canonical transcript exons

ENST00000393674 — 6 exons

Exon	Start	End
ENSE00001081593	174236658	174237599
ENSE00001130941	174259699	174259825
ENSE00002082150	174283410	174283667
ENSE00002684461	174262764	174263100
ENSE00003596240	174238994	174239190
ENSE00003602378	174241100	174241218

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 93.97.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.8306 / max 179.1837, expressed in 1765 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
54912	8.8920	1757
54905	0.3463	58
54914	0.1498	44
54913	0.1452	42
54906	0.0956	36
54911	0.0610	14
54904	0.0527	23
54902	0.0220	7
54910	0.0204	4
54907	0.0168	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	93.97	gold quality
epithelial cell of pancreas	CL:0000083	93.04	gold quality
secondary oocyte	CL:0000655	93.01	gold quality
esophagus squamous epithelium	UBERON:0006920	91.87	gold quality
bronchial epithelial cell	CL:0002328	91.63	gold quality
sperm	CL:0000019	91.10	gold quality
placenta	UBERON:0001987	90.89	gold quality
bronchus	UBERON:0002185	90.66	gold quality
amniotic fluid	UBERON:0000173	90.09	gold quality
palpebral conjunctiva	UBERON:0001812	90.07	gold quality
germinal epithelium of ovary	UBERON:0001304	89.79	gold quality
calcaneal tendon	UBERON:0003701	89.61	gold quality
islet of Langerhans	UBERON:0000006	89.50	gold quality
upper leg skin	UBERON:0004262	89.11	gold quality
decidua	UBERON:0002450	88.84	gold quality
epithelium of nasopharynx	UBERON:0001951	88.65	gold quality
parietal pleura	UBERON:0002400	88.51	gold quality
corpus epididymis	UBERON:0004359	88.45	gold quality
gingival epithelium	UBERON:0001949	88.07	gold quality
smooth muscle tissue	UBERON:0001135	88.02	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.93	gold quality
right coronary artery	UBERON:0001625	87.88	gold quality
lower esophagus mucosa	UBERON:0035834	87.87	gold quality
right lobe of liver	UBERON:0001114	87.84	gold quality
liver	UBERON:0002107	87.80	gold quality
popliteal artery	UBERON:0002250	87.79	gold quality
tibial artery	UBERON:0007610	87.78	gold quality
muscle layer of sigmoid colon	UBERON:0035805	87.72	gold quality
tibia	UBERON:0000979	87.71	gold quality
left coronary artery	UBERON:0001626	87.68	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.49

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

94 targeting FBXO8, 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-340-5P	100.00	72.50	4437
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-507	99.97	70.11	1915
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-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394

Literature-anchored findings (GeneRIF, showing 8)

• FBX8 is a novel c-Myc binding protein and that c-Myc induces cell invasive activity (PMID:20848231)
• Study demonstrates that down-regulation of FBX8 in hepatocellular carcinoma (HCC) correlates with poor survival of patients. All of the functional experiments confirm FBX8 as a tumor suppressor in the progression of HCC. The preferential down-regulation of FBX8 in HCC patients with invasion and metastasis suggested that FBX8 may be a significant biomarker for HCC progression. (PMID:23826080)
• FBX8 down-expression was an independent prognostic indicator for glioma patient’s survival. (PMID:25550853)
• FBX8 was markedly down-regulated in gastric cancer tissues. Knocking down FBX8 promoted proliferation and invasion in tumor cell line. Patients with low FBX8 had poor prognosis. (PMID:25801334)
• FBX8 as a metastasis suppressor that functions through mTOR signaling pathway and has significant prognostic power. (PMID:27916606)
• FBX8 directly targets GSTP1 for ubiquitin-mediated proteasome degradation in colorectal carcinoma. The inactivation of FBX8 negatively correlated with increased levels and stability of GSTP1 in clinical CRC tissues and FBX8 knockout transgenic mice. (PMID:31024008)
• FBX8 promotes metastatic dormancy of colorectal cancer in liver. (PMID:32796813)
• FBXO8 is a novel prognostic biomarker in different molecular subtypes of breast cancer and suppresses breast cancer progression by targeting c-MYC. (PMID:38301858)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	fbxo8	ENSDARG00000007477
mus_musculus	Fbxo8	ENSMUSG00000038206
rattus_norvegicus	Fbxo8	ENSRNOG00000010502
caenorhabditis_elegans		WBGENE00008685

Paralogs (15): CYTH3 (ENSG00000008256), PSD (ENSG00000059915), MON2 (ENSG00000061987), ARFGEF1 (ENSG00000066777), CYTH4 (ENSG00000100055), CYTH2 (ENSG00000105443), GBF1 (ENSG00000107862), CYTH1 (ENSG00000108669), IQSEC3 (ENSG00000120645), ARFGEF2 (ENSG00000124198), IQSEC2 (ENSG00000124313), PSD4 (ENSG00000125637), IQSEC1 (ENSG00000144711), PSD2 (ENSG00000146005), PSD3 (ENSG00000156011)

Protein

Protein identifiers

F-box only protein 8 — Q9NRD0 (reviewed: Q9NRD0)

Alternative names: F-box/SEC7 protein FBS

All UniProt accessions (4): Q9NRD0, A0A0S2Z5D1, D6RIC0, D6RJ92

UniProt curated annotations — full annotation on UniProt →

Function. May promote guanine-nucleotide exchange on an ARF. Promotes the activation of ARF through replacement of GDP with GTP (Potential).

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NRD0-1	1	yes
Q9NRD0-2	2

RefSeq proteins (1): NP_036312* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000904	Sec7_dom	Domain
IPR001810	F-box_dom	Domain
IPR023394	Sec7_C_sf	Homologous_superfamily
IPR035999	Sec7_dom_sf	Homologous_superfamily
IPR036047	F-box-like_dom_sf	Homologous_superfamily
IPR048003	FBXO8_F-box	Domain

Pfam: PF01369, PF12937

UniProt features (10 total): sequence variant 3, sequence conflict 3, domain 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NRD0-F1	81.49	0.61

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 157 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, chr4q34, GOBP_VESICLE_MEDIATED_TRANSPORT, UEDA_PERIFERAL_CLOCK, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, WCTCNATGGY_UNKNOWN, GOBP_SCF_DEPENDENT_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, HAND1E47_01, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, GOBP_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, TTTGCAC_MIR19A_MIR19B, GOBP_PROTEIN_CATABOLIC_PROCESS, GOCC_SCF_UBIQUITIN_LIGASE_COMPLEX

GO Biological Process (2): ubiquitin-dependent protein catabolic process (GO:0006511), regulation of ARF protein signal transduction (GO:0032012)

GO Molecular Function (2): guanyl-nucleotide exchange factor activity (GO:0005085), protein binding (GO:0005515)

GO Cellular Component (1): ubiquitin ligase complex (GO:0000151)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein ubiquitination	1
modification-dependent protein catabolic process	1
ARF protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
binding	1
intracellular protein-containing complex	1
transferase complex	1

Protein interactions and networks

STRING

980 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBXO8	CCNF	P41002	684
FBXO8	NXT2	Q9NPJ8	601
FBXO8	CEP44	Q9C0F1	593
FBXO8	NSL1	Q96IY1	582
FBXO8	SKP1	P34991	575
FBXO8	TMEM107	Q6UX40	544
FBXO8	BTRC	Q9Y297	535
FBXO8	SKP2	Q13309	530
FBXO8	ENY2	Q9NPA8	529
FBXO8	KRT18	P05783	528
FBXO8	AWAT2	Q6E213	523
FBXO8	SDHAF3	Q9NRP4	447
FBXO8	FAM162A	Q96A26	445
FBXO8	NMUR1	Q9HB89	435
FBXO8	TMEM64	Q6YI46	433

IntAct

7 interactions, top by confidence:

A	B	Type	Score
FBXO8	GSTP1	psi-mi:“MI:0915”(physical association)	0.460
FBXO8	GSTP1	psi-mi:“MI:0403”(colocalization)	0.460
CDK16	FBXO8	psi-mi:“MI:0915”(physical association)	0.370
FBXO8	SH3GLB2	psi-mi:“MI:0915”(physical association)	0.370
BIN3	NME2P1	psi-mi:“MI:0914”(association)	0.350

BioGRID (34): FBXO8 (Reconstituted Complex), FBXO8 (Synthetic Lethality), MTOR (Affinity Capture-Western), FBXO8 (Affinity Capture-Western), MTOR (Reconstituted Complex), FBXO8 (Affinity Capture-MS), TRIP13 (Two-hybrid), FBXO8 (Synthetic Lethality), FBXO8 (Affinity Capture-Western), FBXO8 (Affinity Capture-Western), FBXO8 (Affinity Capture-Western), FBXO8 (Reconstituted Complex), FBXO8 (Reconstituted Complex), FBXO8 (Reconstituted Complex), NFX1 (Affinity Capture-MS)

ESM2 similar proteins: A0A3L7I2I8, A6JFQ6, A6JUQ6, A7MBL8, E1C3P4, O08874, O60733, O70291, O94806, P41034, P49638, P97570, P97819, Q02384, Q07889, Q07890, Q16513, Q2KIX2, Q3LAC4, Q4R678, Q5E9G6, Q5F361, Q5M7E1, Q5RCA6, Q5SPP0, Q5SYC1, Q641K1, Q66H63, Q6NRC7, Q70Z35, Q8BG92, Q8BM85, Q8BWP5, Q8BWW9, Q8CA95, Q8IUQ0, Q8K1Y2, Q8NHP6, Q8TEA7, Q8W4D4

Diamond homologs: A0A0G2JUG7, A2A5R2, A5PKW4, D4A631, E1JIT7, F1MUS9, F4IXW2, F4JN05, F4JSZ5, F4K2K3, G3X9K3, G5EET6, O08967, O13690, O13817, O43739, O46382, P11075, P34512, P39993, P47102, P63034, P63035, P97694, P97696, Q10491, Q15438, Q2KI41, Q2PFD7, Q3TES0, Q42510, Q54KA7, Q5DTT2, Q5DU25, Q5E9G6, Q5JU85, Q6DFZ1, Q6DN90, Q6P1I6, Q76M68

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
FBXO8	“down-regulates quantity by destabilization”	GSTP1	binding
FBXO8	“up-regulates activity”	“Cullin 1-RBX1-Skp1”	binding
FBXO8	“down-regulates quantity by destabilization”	ARF6	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	18
Likely benign	0
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1255 predictions. Top by Δscore:

Variant	Effect	Δscore
4:174237597:CAT:C	acceptor_gain	1.0000
4:174237598:ATCTG:A	acceptor_loss	1.0000
4:174237599:TCT:T	acceptor_loss	1.0000
4:174237600:C:CC	acceptor_gain	1.0000
4:174237601:T:A	acceptor_loss	1.0000
4:174239080:TCTC:T	donor_gain	1.0000
4:174239081:CTCC:C	donor_gain	1.0000
4:174239082:T:A	donor_gain	1.0000
4:174239186:CTCTC:C	acceptor_gain	1.0000
4:174239188:CTC:C	acceptor_gain	1.0000
4:174239189:TC:T	acceptor_gain	1.0000
4:174239190:CC:C	acceptor_gain	1.0000
4:174241095:TTTAC:T	donor_loss	1.0000
4:174241097:TAC:T	donor_loss	1.0000
4:174241215:CTCC:C	acceptor_gain	1.0000
4:174241216:TCC:T	acceptor_gain	1.0000
4:174241217:CC:C	acceptor_gain	1.0000
4:174241217:CCC:C	acceptor_gain	1.0000
4:174241217:CCCT:C	acceptor_loss	1.0000
4:174241218:CC:C	acceptor_gain	1.0000
4:174241219:C:CC	acceptor_gain	1.0000
4:174241219:CTAA:C	acceptor_loss	1.0000
4:174249914:A:AC	donor_gain	1.0000
4:174249915:C:CC	donor_gain	1.0000
4:174249917:T:TA	donor_gain	1.0000
4:174262762:AC:A	donor_gain	1.0000
4:174262763:CC:C	donor_gain	1.0000
4:174262896:T:A	donor_gain	1.0000
4:174237595:AGCAT:A	acceptor_gain	0.9900
4:174237596:GCAT:G	acceptor_gain	0.9900

AlphaMissense

2127 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:174237428:C:A	G315V	1.000
4:174237428:C:T	G315D	1.000
4:174237429:C:G	G315R	1.000
4:174237434:A:G	L313P	1.000
4:174237446:T:A	D309V	1.000
4:174237446:T:C	D309G	1.000
4:174237446:T:G	D309A	1.000
4:174237447:C:A	D309Y	1.000
4:174237447:C:G	D309H	1.000
4:174237450:A:C	Y308D	1.000
4:174237452:A:G	L307P	1.000
4:174237499:A:C	N291K	1.000
4:174237499:A:T	N291K	1.000
4:174237501:T:C	N291D	1.000
4:174237503:C:G	R290P	1.000
4:174237508:A:C	F288L	1.000
4:174237508:A:T	F288L	1.000
4:174237509:A:C	F288C	1.000
4:174237509:A:G	F288S	1.000
4:174237510:A:G	F288L	1.000
4:174237512:T:A	E287V	1.000
4:174237513:C:T	E287K	1.000
4:174237514:C:A	R286S	1.000
4:174237514:C:G	R286S	1.000
4:174237517:T:A	K285N	1.000
4:174237517:T:G	K285N	1.000
4:174237518:T:A	K285I	1.000
4:174237518:T:G	K285T	1.000
4:174237519:T:C	K285E	1.000
4:174237523:C:A	M283I	1.000

dbSNP variants (sampled 300 via entrez): RS1000010769 (4:174247624 A>T), RS1000102645 (4:174268239 ACT>A), RS1000133072 (4:174247261 T>C), RS1000200614 (4:174254192 A>T), RS1000206766 (4:174261304 G>A), RS1000210084 (4:174271594 C>G,T), RS1000275300 (4:174236922 C>G,T), RS1000287233 (4:174264663 T>C), RS1000320640 (4:174260952 A>G), RS1000341812 (4:174251657 A>G), RS1000432989 (4:174267511 C>A), RS1000461987 (4:174257954 T>C), RS1000658466 (4:174259471 T>C), RS1000889555 (4:174265848 T>G), RS1000938346 (4:174252618 G>T)

Disease associations

OMIM: gene MIM:605649 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001859_19	Thiazide-induced adverse metabolic effects in hypertensive patients	4.000000e-06
GCST002938_20	Copper levels	2.000000e-06
GCST003989_16	Chin dimples	3.000000e-17
GCST006218_89	Erosive tooth wear (severe vs non-severe)	9.000000e-06
GCST006226_14	Erosive tooth wear (severe vs none or mild)	5.000000e-06
GCST010796_260	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004327	electrocardiography

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

36 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	increases reaction, decreases expression, affects expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
dicrotophos	decreases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	affects cotreatment, increases expression	1
sodium arsenite	increases expression	1
pinosylvin	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
K 7174	increases expression	1
14-deoxy-11,12-didehydroandrographolide	increases expression	1
abrine	increases expression	1
jinfukang	decreases expression	1
NSC 689534	affects binding, increases expression	1
Temozolomide	decreases expression	1
Leflunomide	increases expression	1
Panobinostat	affects expression, increases reaction	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Copper	increases expression, affects binding	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Drugs, Chinese Herbal	increases expression	1
Estradiol	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Hydrogen Peroxide	affects cotreatment, decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Methyl Methanesulfonate	increases expression	1
Naphthoquinones	increases expression	1
Theophylline	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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