FBXO5

Summary

FBXO5 (F-box protein 5, HGNC:13584) is a protein-coding gene on chromosome 6q25.2, encoding F-box only protein 5 (Q9UKT4). Regulator of APC activity during mitotic and meiotic cell cycle. It is a common-essential gene (DepMap: required in 98.0% of cancer cell lines).

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. This protein is similar to xenopus early mitotic inhibitor-1 (Emi1), which is a mitotic regulator that interacts with Cdc20 and inhibits the anaphase promoting complex. Alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 26271 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cerebral palsy (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 11
• Clinical variants (ClinVar): 195 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 20
• Cancer dependency (DepMap): dependent in 98.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_012177

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13584
Approved symbol	FBXO5
Name	F-box protein 5
Location	6q25.2
Locus type	gene with protein product
Status	Approved
Aliases	FBX5, Fbxo31, EMI1
Ensembl gene	ENSG00000112029
Ensembl biotype	protein_coding
OMIM	606013
Entrez	26271

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 retained_intron

ENST00000229758, ENST00000367241, ENST00000477822

RefSeq mRNA: 2 — MANE Select: NM_012177 NM_001142522, NM_012177

CCDS: CCDS47501, CCDS5242

Canonical transcript exons

ENST00000229758 — 5 exons

Exon	Start	End
ENSE00000813807	152972272	152972454
ENSE00001169198	152982857	152983041
ENSE00001242178	152973046	152973136
ENSE00003610080	152974907	152975621
ENSE00003845019	152970535	152971414

Expression profiles

Bgee: expression breadth ubiquitous, 225 present calls, max score 95.78.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.5584 / max 296.9820, expressed in 1649 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
76270	15.3236	1300
76271	3.7778	1347
76269	1.4569	682

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	95.78	gold quality
ganglionic eminence	UBERON:0004023	92.49	gold quality
secondary oocyte	CL:0000655	91.52	gold quality
oocyte	CL:0000023	90.87	gold quality
embryo	UBERON:0000922	89.38	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.57	gold quality
bone marrow	UBERON:0002371	87.49	gold quality
buccal mucosa cell	CL:0002336	85.50	gold quality
cartilage tissue	UBERON:0002418	85.17	gold quality
bone marrow cell	CL:0002092	84.00	gold quality
trabecular bone tissue	UBERON:0002483	83.14	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.42	gold quality
lymph node	UBERON:0000029	79.96	gold quality
stromal cell of endometrium	CL:0002255	79.10	gold quality
endometrium	UBERON:0001295	78.62	gold quality
vermiform appendix	UBERON:0001154	78.24	gold quality
esophagus squamous epithelium	UBERON:0006920	77.98	gold quality
adrenal tissue	UBERON:0018303	77.98	gold quality
mucosa of sigmoid colon	UBERON:0004993	77.34	gold quality
granulocyte	CL:0000094	76.60	gold quality
rectum	UBERON:0001052	76.54	gold quality
colonic mucosa	UBERON:0000317	75.39	gold quality
gingival epithelium	UBERON:0001949	75.04	gold quality
monocyte	CL:0000576	74.95	gold quality
leukocyte	CL:0000738	74.88	gold quality
caecum	UBERON:0001153	74.81	gold quality
oral cavity	UBERON:0000167	74.76	gold quality
mononuclear cell	CL:0000842	74.53	gold quality
gingiva	UBERON:0001828	74.47	gold quality
mucosa of transverse colon	UBERON:0004991	73.93	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7052	yes	332.05
E-ANND-3	yes	4.02

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, E2F2, E2F3, E2F4, STAT1

miRNA regulators (miRDB)

32 targeting FBXO5, 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-8485	100.00	77.57	4731
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-802	99.61	67.70	1254
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-7849-3P	99.47	68.17	1224
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-302A-5P	99.39	68.21	1913
HSA-MIR-6887-5P	98.56	68.49	1295
HSA-MIR-6795-5P	98.52	68.51	1277
HSA-MIR-654-3P	98.38	67.61	905
HSA-MIR-8078	98.32	65.73	361
HSA-MIR-637	97.91	64.05	1517
HSA-MIR-3129-3P	97.85	67.63	1246
HSA-MIR-5583-5P	97.85	67.61	1243
HSA-MIR-3928-3P	97.61	66.53	1096

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 98.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 33)

• These data suggest that E2F can activate both transcription of cyclin A and the hEmi1-dependent stabilization of APC(Cdh1) targets, such as cyclin A, to promote S phase entry. (PMID:11988738)
• Plk1 activates the anaphase promoting complex by directing the SCF-dependent destruction of Emi1 in prophase (PMID:15469984)
• loss of pRb repression of E2F-mediated transcription causing misregulation of Emi1 and APC/C substrates results in the generation of tetraploidy and proliferation of genomically unstable cells in the absence of normal p53 function (PMID:16861914)
• Emi1 associates in a complex with the anaphase-promoting complex/cyclosome (APC/C) and Cdh1; Emi1 binds to the APC/C via a conserved C-terminal destruction (D)-box and can compete for APC/C-substrate interaction. (PMID:16921029)
• bservations reveal a novel mechanism for the control of entry into the first meiotic division: an Emi1-dependent inhibition of APC(Cdh1). (PMID:17190794)
• These data suggest that Emi1 plays a critical role in preserving genome integrity by blocking rereplication, revealing a previously unrecognized function of this inhibitor of anaphase-promoting complex/cyclosome. (PMID:17234884)
• Emi1 plays a crucial role in the cell cycle to couple DNA replication with mitosis (PMID:17485488)
• critical spindle pole-associated mechanism, called the END (Emi1/NuMA/dynein-dynactin) network, spatially restricts APC/C activity in early mitosis (PMID:17609108)
• We investigated Emi1 protein expression in ovarian neoplasms (PMID:18204430)
• Emi1 down-regulation and APC activation leads to stable p21-dependent G2 arrest after DNA damage. (PMID:19211842)
• Results underscore the crucial role of cyclin A2-CDK2 in regulating the PLK1-SCF(beta-TrCP1)-EMI1-APC/C axis and CDC6 to trigger genome reduplication after the activity of CDK1 is suppressed. (PMID:19822658)
• Results suggest that Bcr-Abl increases Emi1 phosphorylation and stability to prevent Skp2 protein degradation via APC/Cdh1-induced ubiquitination and to enhance proliferation of CML cells. (PMID:20717963)
• the ability of Emi1 to inhibit APC/C is negatively regulated by CDKs (PMID:21454540)
• Emi1 participates in human hepatocellular carcinoma (HCC) cell proliferation and that progression is controlled by anaphase-promoting complex/cyclosome (APC/C) inhibition, which stabilized Skp2 and enabled p27(kip1) degradation. (PMID:22995332)
• Emi1 expression (>5%) was seen in 23.3% of ovarian clear cell carcinoma, and associated with high FIGO grades and poor overall survival (PMID:23202783)
• Emi1 depletion enhances the sensitivity of cancer cells to doxorubicin and x-ray irradiation. (PMID:23645673)
• The C-terminal domain inhibits multiple APC/C(CDH1) functions. The intrinsically disordered D-box, linker & tail elements, & a structured Zn-binding domain synergistically block the substrate-binding site & inhibit ubiquitin-chain elongation. (PMID:23708605)
• Human papillomavirus type 16 E7 expression causes increased EMI1 mRNA expression and also inhibits EMI1 degradation. (PMID:24074588)
• Examined eoffect of Emi1 over-expression on Skp2 expression in breast cancer. Found expression of Emi1 was positively related with Skp2 expression; Emi1 expression correlated significantly with histologic grade. Skp2 expression obtained similar results. (PMID:24277465)
• Results from a study on gene variability markers in early-stage human embryos shows that FBXO5 is a putative variability marker for the 3-day, 8-cell embryo stage. (PMID:26288249)
• The fact that Emi1 overexpression promotes chromosome instability (CIN) and the formation of solid cancers in vivo indicates that Emi1 overexpression actively drives solid tumorigenesis. These novel mechanistic insights have important clinical implications. (PMID:27065322)
• Both isoforms of FBXO5 promoted the migration and osteogenic differentiation potential of human periodontal ligament stem cells. (PMID:29850565)
• demonstration using human cell models that cell-cycle commitment is mediated by an EMI1-APC/C(CDH1) dual-negative feedback switch, in which EMI1 is both a substrate and an inhibitor of APC/C(CDH1) (PMID:29875408)
• Higher mRNA expression levels of FBXO1, FBXO31, SKP2, and FBXO5 were significantly associated with worse prognosis for breast cancer patients. (Review) (PMID:30341246)
• A subset of BRCA1-deficient triple-negative breast cancer cells develop resistance to PARP inhibitors by downregulating EMI1 and restoring RAD51-dependent HRR. Reconstitution of EMI1 expression reestablishes PARPi sensitivity both in cellular systems and in an orthotopic mouse model. (PMID:30554948)
• We identified hyperphosphorylation of CDH1, but not pseudosubstrate inhibition by early mitotic inhibitor 1 (EMI1), as a major mechanism driving attenuated APC/C(CDH1) activity in the G1-phase of the cell cycle in cancer stem-like cells (CSC). (PMID:31036696)
• Modulation of Early Mitotic Inhibitor 1 (EMI1) depletion on the sensitivity of PARP inhibitors in BRCA1 mutated triple-negative breast cancer cells. (PMID:33412559)
• PUMA facilitates EMI1-promoted cytoplasmic Rad51 ubiquitination and inhibits DNA repair in stem and progenitor cells. (PMID:33785736)
• Prognostic Significance and Immunological Role of FBXO5 in Human Cancers: A Systematic Pan-Cancer Analysis. (PMID:35720327)
• Exploring the role of FBXO5 in gastric cancer. (PMID:37121410)
• Expression significance of Emi1, UBCH10 and CyclinB1 in esophageal squamous cell carcinoma. (PMID:37168048)
• Effect of Emi1 gene silencing on the proliferation and invasion of human breast cancer cells. (PMID:38041032)
• Loss of EMI1 compromises chromosome stability and is associated with cellular transformation in colonic epithelial cell contexts. (PMID:39358461)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	fbxo5	ENSDARG00000039020
mus_musculus	Fbxo5	ENSMUSG00000019773
rattus_norvegicus	Fbxo5	ENSRNOG00000024077
drosophila_melanogaster	Rca1	FBGN0017551

Paralogs (1): FBXO43 (ENSG00000156509)

Protein

Protein identifiers

F-box only protein 5 — Q9UKT4 (reviewed: Q9UKT4)

Alternative names: Early mitotic inhibitor 1

All UniProt accessions (1): Q9UKT4

UniProt curated annotations — full annotation on UniProt →

Function. Regulator of APC activity during mitotic and meiotic cell cycle. During mitotic cell cycle plays a role as both substrate and inhibitor of APC-FZR1 complex. During G1 phase, plays a role as substrate of APC-FZR1 complex E3 ligase. Then switches as an inhibitor of APC-FZR1 complex during S and G2 leading to cell-cycle commitment. As APC inhibitor, prevents the degradation of APC substrates at multiple levels: by interacting with APC and blocking access of APC substrates to the D-box coreceptor, formed by FZR1 and ANAPC10; by suppressing ubiquitin ligation and chain elongation by APC by preventing the UBE2C and UBE2S activities. Plays a role in genome integrity preservation by coordinating DNA replication with mitosis through APC inhibition in interphase to stabilize CCNA2 and GMNN in order to promote mitosis and prevent rereplication and DNA damage-induced cellular senescence. During oocyte maturation, plays a role in meiosis through inactivation of APC-FZR1 complex. Inhibits APC through RPS6KA2 interaction that increases FBXO5 affiniy for CDC20 leading to the metaphase arrest of the second meiotic division before fertilization. Controls entry into the first meiotic division through inactivation of APC-FZR1 complex. Promotes migration and osteogenic differentiation of mesenchymal stem cells.

Subunit / interactions. Part of a SCF (SKP1-cullin-F-box) protein ligase complex. Interacts with BTRC; mediates proteolysis by the SCF ubiquitin ligase complex leading to activation of APC in late mitosis and subsequent mitotic progression. Interacts with FZR1/CDH1 and the N-terminal substrate-binding domain of CDC20; prevents APC activation. Also interacts with EVI5 which blocks its phosphorylation by PLK1 and prevents its subsequent binding to BTRC and degradation. Interacts simultaneously with anaphase promoting complex (APC), through at least ANAPC2, CDC23, CDC27, the APC substrate GMNN and the APC activator FZR1. Interacts with UBE2S; interferes with the activity of UBE2S mainly by disrupting the dynamic electrostatic association between the C-terminal tail of UBE2S and ANAPC2. Interacts with RPS6KA2; cooperates to induce the metaphase arrest of early blastomeres; increases and stabilizes interaction of FBXO5 with CDC20.

Subcellular location. Nucleus. Cytoplasm. Cytoskeleton. Spindle.

Post-translational modifications. Phosphorylation by CDK2 and subsequently by PLK1 triggers degradation during early mitosis through ubiquitin-mediated proteolysis by the SCF ubiquitin ligase complex containing the F-box protein BTRC. This degradation is necessary for the activation of APC in late mitosis and subsequent mitotic progression. Phosphorylated by RPS6KA2; increases and stabilizes interaction with CDC20. Ubiquitinated by the SCF(BTRC) complex following phosphorylation by PLK1. Undergoes both ‘Lys-11’ and ‘Lys-48’-linked polyubiquitination by APC-FZR1 complex leading to degradation by proteasome during G1 phase. Degraded through the SCF(BTRC) complex; degradation occurs during oocyte maturation, between germinal vesicle breakdown (GVBD) and meiosis I, and is required for the meiosis I-meiosis II transition.

Induction. Up-regulated at 7 days after osteogenic induction. Down-regulated in late G2 phase or mitosis. Down-regulated in G2 phase after DNA damage in a CDKN1A-dependent manner. Down-regulated in G1 phase when APC-FZR1 complex is active and accumulates at the G1-S transition, coincident with the inactivation of APC-FZR1 complex. At the G1-S transition, transcriptionally induced by the E2F transcription factor.

Pathway. Protein modification; protein ubiquitination.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UKT4-1	1	yes
Q9UKT4-2	2

RefSeq proteins (2): NP_001135994, NP_036309* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001810	F-box_dom	Domain
IPR044064	ZF_ZBR	Domain
IPR047147	FBX5_43	Family

Pfam: PF00646, PF22191

UniProt features (65 total): mutagenesis site 26, region of interest 8, binding site 8, strand 6, turn 5, modified residue 2, sequence variant 2, helix 2, chain 1, domain 1, compositionally biased region 1, zinc finger region 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9GAW	ELECTRON MICROSCOPY	2.9
4UI9	ELECTRON MICROSCOPY	3.6
2M6N	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UKT4-F1	60.07	0.21

Functional residue map

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

Ligand- & substrate-binding residues (8): 378; 381; 396; 401; 406; 409; 414; 419

Post-translational modifications (2): 94, 102

Mutagenesis-validated functional residues (26):

Position	Phenotype
143	delays degradation.
144	does not affect protein stability.
145	does not affect protein stability; when associated with a-149.
145	degraded in similar manner to wild-type.
145	not mitotically degraded. shows impaired interaction with btrc and reduced phosphate incorporation; when associated with
146	does not affect protein stability.
148	degraded in similar manner to wild-type.
149	does not affect protein stability; when associated with a-145.
149	degraded in similar manner to wild-type.
149	not mitotically degraded. shows impaired interaction with btrc and reduced phosphate incorporation; when associated with
182	shows impaired interaction with btrc.
210–216	loss of interaction with evi5.
322–325	does not affect inhibition of ube2s-catalyzed chain elongation. efficiently inhibits the degradation of pttg1 at relativ
339–345	impairs ccnb1 ubiquitination by ube2c; when associated with 356-y–r-358 del.
345	substantially impairs inhibition of ccnb1 ubiquitination by ube2c; when associated with 346-s–t-355 del.
346–355	inhibits ccnb1 ubiquitination by ube2c. substantially impairs inhibition of ccnb1 ubiquitination by ube2c; when associat
356–358	impairs ccnb1 ubiquitination by ube2c; when associated with 339-k–l-345 del.
356	substantially impairs inhibition of ccnb1 ubiquitination by ube2c; when associated with 346-s–t-355 del.
358	substantially impairs inhibition of ccnb1 ubiquitination by ube2c; when associated with 346-s–t-355 del.
375	decreases ube2c-mediated ubiquitination.
376	decreases ube2c-mediated ubiquitination.
393	decreases ube2c-mediated ubiquitination.
401	reduced inhibition of apc. does not affect the fbxo5-mediated inhibitory activity against ubiquitin chain assembly. does
406	does not affect the inhibitory activity against chain assembly; when associated with s-401.
409	decreases ube2c-mediated ubiquitination.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-174113	SCF-beta-TrCP mediated degradation of Emi1
R-HSA-176408	Regulation of APC/C activators between G1/S and early anaphase
R-HSA-176417	Phosphorylation of Emi1
R-HSA-68881	Mitotic Metaphase/Anaphase Transition
R-HSA-69205	G1/S-Specific Transcription

MSigDB gene sets: 579 (showing top): GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, E2F_Q4, GOBP_CHROMOSOME_ORGANIZATION, E2F_Q4_01, GOBP_NEGATIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, REACTOME_G1_S_SPECIFIC_TRANSCRIPTION, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, E2F4DP1_01, GOBP_REGULATION_OF_DNA_TEMPLATED_DNA_REPLICATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_NUCLEAR_DIVISION, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, GOBP_CELL_CYCLE_DNA_REPLICATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION

GO Biological Process (24): oocyte maturation (GO:0001556), regulation of DNA replication (GO:0006275), DNA damage response (GO:0006974), spindle assembly involved in female meiosis I (GO:0007057), regulation of mitotic nuclear division (GO:0007088), regulation of mitotic cell cycle (GO:0007346), positive regulation of cell population proliferation (GO:0008284), positive regulation of G2/M transition of mitotic cell cycle (GO:0010971), vesicle organization (GO:0016050), protein ubiquitination (GO:0016567), negative regulation of DNA endoreduplication (GO:0032876), positive regulation of osteoblast differentiation (GO:0045669), negative regulation of meiotic nuclear division (GO:0045835), negative regulation of mitotic metaphase/anaphase transition (GO:0045841), microtubule polymerization (GO:0046785), cell division (GO:0051301), negative regulation of ubiquitin-protein transferase activity (GO:0051444), positive regulation of biomineral tissue development (GO:0070169), negative regulation of ubiquitin protein ligase activity (GO:1904667), positive regulation of mesenchymal stem cell migration (GO:1905322), negative regulation of cellular senescence (GO:2000773), negative regulation of cell cycle process (GO:0010948), regulation of meiotic nuclear division (GO:0040020), spindle assembly (GO:0051225)

GO Molecular Function (7): zinc ion binding (GO:0008270), anaphase-promoting complex binding (GO:0010997), protein kinase binding (GO:0019901), molecular function inhibitor activity (GO:0140678), ubiquitin ligase inhibitor activity (GO:1990948), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), spindle (GO:0005819), cytosol (GO:0005829), meiotic spindle (GO:0072687), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Regulation of APC/C activators between G1/S and early anaphase	2
APC/C-mediated degradation of cell cycle proteins	1
Mitotic Metaphase and Anaphase	1
G1/S Transition	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
negative regulation of cell cycle process	2
intracellular membraneless organelle	2
developmental process involved in reproduction	1
cell maturation	1
oocyte development	1
DNA replication	1
regulation of DNA metabolic process	1
cellular response to stress	1
spindle assembly involved in female meiosis	1
female meiosis I	1
regulation of mitotic cell cycle	1
regulation of cell cycle process	1
regulation of nuclear division	1
mitotic nuclear division	1
mitotic cell cycle	1
regulation of cell cycle	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
G2/M transition of mitotic cell cycle	1
regulation of G2/M transition of mitotic cell cycle	1
positive regulation of mitotic cell cycle phase transition	1
positive regulation of cell cycle G2/M phase transition	1
organelle organization	1
protein modification by small protein conjugation	1
regulation of DNA endoreduplication	1
DNA endoreduplication	1
negative regulation of DNA-templated DNA replication	1
osteoblast differentiation	1
positive regulation of cell differentiation	1
regulation of osteoblast differentiation	1
regulation of meiotic nuclear division	1
negative regulation of meiotic cell cycle	1
negative regulation of nuclear division	1
meiotic nuclear division	1
metaphase/anaphase transition of mitotic cell cycle	1
regulation of mitotic metaphase/anaphase transition	1
negative regulation of mitotic nuclear division	1
negative regulation of mitotic cell cycle phase transition	1

Protein interactions and networks

STRING

2640 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBXO5	CDC20	Q12834	978
FBXO5	EVI5	O60447	863
FBXO5	SKP1	P34991	845
FBXO5	BTRC	Q9Y297	798
FBXO5	PLK1	P53350	785
FBXO5	GMNN	O75496	731
FBXO5	CCNA2	P20248	727
FBXO5	CCNA1	P78396	725
FBXO5	CCNL2	Q96S94	719
FBXO5	CCNB1	P14635	678
FBXO5	PTTG2	Q9NZH5	660
FBXO5	CUL1	Q13616	639
FBXO5	PTTG1	O95997	612
FBXO5	CHEK1	O14757	593
FBXO5	FZR1	Q9UM11	591

IntAct

59 interactions, top by confidence:

A	B	Type	Score
SKP1	FBXO5	psi-mi:“MI:0915”(physical association)	0.850
ANAPC5	CDC27	psi-mi:“MI:0914”(association)	0.810
CDC16	BUB1B	psi-mi:“MI:0914”(association)	0.790
CDC23	BUB1B	psi-mi:“MI:0914”(association)	0.790
ANAPC16	BUB1B	psi-mi:“MI:0914”(association)	0.730
ANAPC2	BUB1B	psi-mi:“MI:0914”(association)	0.730
FBXO5	CDC27	psi-mi:“MI:0915”(physical association)	0.670
CDC27	FBXO5	psi-mi:“MI:0914”(association)	0.670
EVI5	PLK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.660
EVI5	FBXO5	psi-mi:“MI:0915”(physical association)	0.650
FBXO5	EVI5	psi-mi:“MI:0407”(direct interaction)	0.650
FBXO5	EVI5	psi-mi:“MI:0915”(physical association)	0.650
CDC26	BUB1B	psi-mi:“MI:0914”(association)	0.640
ANAPC13	CDC27	psi-mi:“MI:0914”(association)	0.640
SKP1	MYCBP2	psi-mi:“MI:0914”(association)	0.640
Cdc23	BUB1B	psi-mi:“MI:0915”(physical association)	0.560
Cdc16	BUB1B	psi-mi:“MI:0915”(physical association)	0.560
Cdc26	BUB1B	psi-mi:“MI:0915”(physical association)	0.560
ANAPC5	BUB1B	psi-mi:“MI:0914”(association)	0.530
FZR1	TK1	psi-mi:“MI:0914”(association)	0.530
SPSB4	ARHGEF10	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
PLK1	FBXO5	psi-mi:“MI:0217”(phosphorylation reaction)	0.440

BioGRID (145): FBXO5 (Affinity Capture-MS), FBXO5 (Affinity Capture-RNA), FBXO5 (Affinity Capture-RNA), FBXO5 (Affinity Capture-RNA), FBXO5 (Affinity Capture-RNA), FBXO5 (Biochemical Activity), FBXO5 (Affinity Capture-MS), FBXO5 (Co-purification), SKP1 (Affinity Capture-Western), FBXO5 (Proximity Label-MS), FBXO5 (Affinity Capture-MS), FBXO5 (Affinity Capture-MS), FBXO5 (Affinity Capture-MS), FBXO5 (Affinity Capture-MS), FBXO5 (Affinity Capture-MS)

ESM2 similar proteins: A2RRS8, A2VE78, A5WW08, A6NFN9, C0HAC0, D3YYM4, O14607, O17482, P79457, Q08AW4, Q0V9Y8, Q2HJ90, Q2KI79, Q2YDQ5, Q3MJ13, Q3V0L5, Q4KLV2, Q4KM95, Q562E2, Q5F479, Q5R6E1, Q5RFQ4, Q5SUS0, Q5XGI3, Q5XX13, Q6B4Z3, Q6GPJ8, Q6GQ34, Q6GQV7, Q6INS1, Q6IRU7, Q6P1H6, Q6ZPF3, Q7TP65, Q7ZVU1, Q8C0W1, Q8C2S5, Q8IVF5, Q8IW35, Q8IZM8

Diamond homologs: Q0V967, Q28GK6, Q4G163, Q4V7W2, Q66H04, Q7TSG3, Q8AXF4, Q8CDI2, Q90Z80, Q9UKT4

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
FBXO5	down-regulates	ANAPC7	binding
FBXO5	down-regulates	FZR1	ubiquitination
PLK1	down-regulates	FBXO5	phosphorylation
SRC	up-regulates	FBXO5	phosphorylation
CDK1	“down-regulates quantity by destabilization”	FBXO5	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 43 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
Inhibition of the proteolytic activity of APC/C required for the onset of anaphase by mitotic spindle checkpoint components	11	205.3×	6e-23
Phosphorylation of the APC/C	11	175.9×	5e-22
Inactivation of APC/C via direct inhibition of the APC/C complex	11	167.9×	7e-22
Conversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphase	10	152.7×	2e-19
Aberrant regulation of mitotic exit in cancer due to RB1 defects	10	152.7×	2e-19
APC:Cdc20 mediated degradation of cell cycle proteins prior to satisfation of the cell cycle checkpoint	12	149.3×	6e-23
Activation of APC/C and APC/C:Cdc20 mediated degradation of mitotic proteins	12	143.9×	9e-23
APC-Cdc20 mediated degradation of Nek2A	11	136.8×	1e-20

GO biological processes:

GO term	Partners	Fold	FDR
regulation of meiotic cell cycle	11	216.1×	4e-22
protein branched polyubiquitination	10	216.1×	2e-20
anaphase-promoting complex-dependent catabolic process	11	198.1×	7e-22
protein K11-linked ubiquitination	11	110.5×	8e-19
regulation of mitotic cell cycle	12	74.1×	2e-18
mitotic spindle assembly checkpoint signaling	5	72.0×	2e-07
protein K48-linked ubiquitination	12	51.9×	1e-16
cell division	17	20.1×	5e-17

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	132
Likely benign	26
Benign	5

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
155905	NM_024735.5(FBXO31):c.847_852delinsA (p.Cys283fs)	Pathogenic
3246023	NC_000006.11:g.(?152949380)(154441965_?)del	Pathogenic
813309	GRCh37/hg19 16q24.1-24.2(chr16:84872102-87678641)	Pathogenic
3376842	NM_024735.5(FBXO31):c.842+1G>A	Likely pathogenic

SpliceAI

3751 predictions. Top by Δscore:

Variant	Effect	Δscore
16:87331506:AAAAA:A	acceptor_gain	1.0000
16:87331511:C:CC	acceptor_gain	1.0000
16:87334135:T:TA	donor_gain	1.0000
16:87334283:CGCC:C	acceptor_gain	1.0000
16:87334285:CC:C	acceptor_gain	1.0000
16:87334286:CC:C	acceptor_gain	1.0000
16:87334287:C:CC	acceptor_gain	1.0000
16:87334288:T:A	acceptor_loss	1.0000
16:87335299:CTCA:C	donor_loss	1.0000
16:87335302:A:AC	donor_gain	1.0000
16:87335303:C:CC	donor_gain	1.0000
16:87335453:AGTTG:A	acceptor_gain	1.0000
16:87335454:GTTG:G	acceptor_gain	1.0000
16:87335455:TTG:T	acceptor_gain	1.0000
16:87335456:TG:T	acceptor_gain	1.0000
16:87335457:GC:G	acceptor_loss	1.0000
16:87335458:C:CC	acceptor_gain	1.0000
16:87335458:CT:C	acceptor_loss	1.0000
16:87336153:A:AC	donor_gain	1.0000
16:87336154:C:CA	donor_gain	1.0000
16:87336154:CT:C	donor_gain	1.0000
16:87336159:A:AC	donor_gain	1.0000
16:87336160:C:CC	donor_gain	1.0000
16:87336160:CTGA:C	donor_gain	1.0000
16:87336163:A:AC	donor_gain	1.0000
16:87336164:C:CC	donor_gain	1.0000
16:87336269:C:CT	acceptor_gain	1.0000
16:87342878:T:TA	donor_gain	1.0000
16:87342949:AAT:A	acceptor_gain	1.0000
16:87342950:ATCT:A	acceptor_loss	1.0000

AlphaMissense

2942 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:152973114:A:G	W281R	0.997
6:152973114:A:T	W281R	0.997
6:152971329:C:G	R393P	0.996
6:152971321:A:G	C396R	0.995
6:152971375:A:G	C378R	0.995
6:152971365:C:G	C381S	0.994
6:152971366:A:G	C381R	0.994
6:152971366:A:T	C381S	0.994
6:152972278:G:C	F362L	0.994
6:152972278:G:T	F362L	0.994
6:152972280:A:G	F362L	0.994
6:152971320:C:G	C396S	0.993
6:152971321:A:T	C396S	0.993
6:152971327:C:G	A394P	0.993
6:152971354:C:G	A385P	0.993
6:152971289:A:C	C406W	0.992
6:152971291:A:G	C406R	0.992
6:152971319:G:C	C396W	0.992
6:152975123:A:T	V201D	0.992
6:152971353:G:T	A385E	0.991
6:152971282:A:G	C409R	0.989
6:152971306:A:G	C401R	0.989
6:152971320:C:T	C396Y	0.989
6:152971373:A:C	C378W	0.989
6:152971305:C:G	C401S	0.988
6:152971306:A:T	C401S	0.988
6:152973112:C:A	W281C	0.988
6:152973112:C:G	W281C	0.988
6:152971167:A:G	L447S	0.987
6:152973121:G:C	S278R	0.987

dbSNP variants (sampled 300 via entrez): RS1000530212 (6:152985100 G>C), RS1000583458 (6:152979244 G>A), RS1000770116 (6:152972556 G>T), RS1000859209 (6:152984815 T>G), RS1000936503 (6:152971707 A>T), RS1001115077 (6:152978264 T>C), RS1001138953 (6:152972132 A>G), RS1001627010 (6:152985240 T>C), RS1001727724 (6:152981149 G>A), RS1001827408 (6:152972947 C>A,T), RS1001942153 (6:152973337 T>C), RS1002151037 (6:152980035 A>T), RS1002214182 (6:152979774 T>C), RS1002275351 (6:152984727 G>T), RS1002302996 (6:152984921 C>T)

Disease associations

OMIM: gene MIM:606013 | disease phenotypes: MIM:615979, MIM:610743, MIM:612998, MIM:265380

GenCC curated gene-disease

Disease	Classification	Inheritance
cerebral palsy	Strong	Autosomal dominant
intellectual disability, autosomal recessive	Strong	Autosomal recessive
autosomal recessive non-syndromic intellectual disability	Supportive	Autosomal recessive
intellectual disability, autosomal recessive 45	Limited	Autosomal recessive

Mondo (9): intellectual disability, autosomal recessive 45 (MONDO:0014430), spastic cerebral palsy (MONDO:0000396), thyroid ectopia (MONDO:0019854), autosomal recessive ataxia, Beauce type (MONDO:0012549), Emery-Dreifuss muscular dystrophy 4, autosomal dominant (MONDO:0013071), alveolar capillary dysplasia with misalignment of pulmonary veins (MONDO:0009934), cerebral palsy (MONDO:0006497), intellectual disability, autosomal recessive (MONDO:0100597), autosomal recessive non-syndromic intellectual disability (MONDO:0019502)

Orphanet (5): Autosomal recessive non-syndromic intellectual disability (Orphanet:88616), Thyroid ectopia (Orphanet:95712), Emery-Dreifuss muscular dystrophy (Orphanet:261), Autosomal recessive ataxia, Beauce type (Orphanet:88644), Congenital alveolar capillary dysplasia (Orphanet:210122)

HPO phenotypes

20 total (20 of 20 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000278	Retrognathia
HP:0000280	Coarse facial features
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000331	Short chin
HP:0000336	Prominent supraorbital ridges
HP:0000414	Bulbous nose
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000490	Deeply set eye
HP:0000494	Downslanted palpebral fissures
HP:0000574	Thick eyebrow
HP:0000582	Upslanted palpebral fissure
HP:0000664	Synophrys
HP:0001249	Intellectual disability
HP:0002553	Highly arched eyebrow
HP:0011220	Prominent forehead
HP:0012368	Flat face
HP:0012471	Thick vermilion border

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST001469_5	Major depressive disorder	5.000000e-06
GCST001942_11	Prostate cancer	4.000000e-18
GCST005232_16	Neuroticism	1.000000e-06
GCST005951_154	Body mass index	1.000000e-09
GCST006940_162	Neurociticism	6.000000e-09
GCST006944_59	Experiencing mood swings	4.000000e-11
GCST006948_1	Feeling nervous	3.000000e-08
GCST007565_142	Morning person	4.000000e-33
GCST007576_1	Chronotype	4.000000e-33
GCST007576_423	Chronotype	9.000000e-30
GCST010703_87	Brain morphology (MOSTest)	2.000000e-90

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007660	neuroticism measurement
EFO:0004340	body mass index
EFO:0008475	mood instability measurement
EFO:0009597	feeling nervous measurement
EFO:0008328	chronotype measurement
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D002547	Cerebral Palsy	C10.228.140.140.254
C536590	Alveolar capillary dysplasia (supp.)
C567831	Emery-Dreifuss Muscular Dystrophy 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, decreases methylation, increases expression	4
Benzo(a)pyrene	decreases expression, increases expression	4
Valproic Acid	affects expression, decreases expression	4
Cyclosporine	affects expression, decreases expression, increases expression	4
trichostatin A	affects cotreatment, decreases expression	2
Air Pollutants	decreases expression, increases abundance	2
Cisplatin	affects cotreatment, decreases expression, increases expression	2
Estradiol	increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Rotenone	decreases expression	2
Tetrachlorodibenzodioxin	affects expression, decreases expression	2
Aflatoxin B1	affects expression, decreases methylation, increases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
afuresertib	decreases expression	1
echimidine	decreases expression, increases metabolic processing	1
lasiocarpine	decreases expression, increases metabolic processing	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
geraniol	decreases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
2-butenal	decreases expression	1
riddelliine	decreases expression, increases metabolic processing	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	decreases expression	1
rutecarpine	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
cupric chloride	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00154830	PHASE4	COMPLETED	Alterations of Functional Activities and Leg Stiffness After Hamstring Lengthening in Cerebral Palsy Children
NCT00432055	PHASE4	COMPLETED	Effects of Botulinum Toxin Type A in Adults With Cerebral Palsy
NCT00549471	PHASE4	TERMINATED	Improvement After Botulinum Toxin Injections to the Arms in Children With Cerebral Palsy
NCT00752934	PHASE4	TERMINATED	Does Oral Baclofen Improve Care and Comfort in Spastic Children in Nursing Homes?
NCT00964639	PHASE4	COMPLETED	Postoperative Pain in Children With Cerebral Palsy After Pelvic and Femoral Osteotomies
NCT01386255	PHASE4	WITHDRAWN	Placebo Controlled Study of Baclofen for GERD in Children With Cerebral Palsy
NCT02546999	PHASE4	COMPLETED	Does Botulinum Toxin A Make Walking Easier in Children With Cerebral Palsy?
NCT02633241	PHASE4	COMPLETED	A Pilot Study of Dexmedetomidine-Propofol in Children Undergoing Magnetic Resonance Imaging
NCT03117322	PHASE4	COMPLETED	Synbiotic, Prebiotics and Probiotics in Children With Cerebral Palsy and Constipation
NCT03648658	PHASE4	UNKNOWN	Paracetamol Study in Patients With Low Muscle Mass
NCT04074265	PHASE4	COMPLETED	Peri-operative Use of a Pain Injection in Pediatric Patients With Cerebral Palsy
NCT04273737	PHASE4	TERMINATED	Amantadine in Treating Cognitive & Motor Impairments in Adolescents and Adults With Cerebral Palsy
NCT04523935	PHASE4	COMPLETED	Excessive Crying in Children With Cerebral Palsy and Communication Deficits
NCT05887765	PHASE4	COMPLETED	Effect of Systematic Dexamethasone on the Duration of Popliteal Nerve Block for Anesthesia After Pediatric Ankle Surgery
NCT06176430	PHASE4	UNKNOWN	Comparison of Twice Weekly Versus Daily Iron Therapy in Treating Anemia in Children With Cerebral Palsy
NCT06189781	PHASE4	RECRUITING	Pain Injection Versus Epidural Anesthesia for Hip Surgery in Pediatric Patients With Cerebral Palsy
NCT00732537	PHASE4	COMPLETED	Inhaled Nitric Oxide by Oxygen Hood in Neonates
NCT00014989	PHASE3	COMPLETED	Beneficial Effects of Antenatal Magnesium Sulfate (BEAM Trial)
NCT00065949	PHASE3	UNKNOWN	Magnesium Sulfate to Prevent Brain Injury in Premature Infants
NCT00367068	PHASE3	COMPLETED	Dutch National ITB Study in Children With Cerebral Palsy
NCT00491894	PHASE3	COMPLETED	Safety and Efficacy Study of Oral Glycopyrrolate Liquid for the Treatment of Pathologic (Chronic Moderate to Severe) Drooling in Pediatric Patients 3 to 18 Years of Age With Cerebral Palsy or Other Neurologic Conditions
NCT00632528	PHASE3	COMPLETED	MEOPA to Improve Physical Therapy Results After Multilevel Surgery
NCT00822029	PHASE3	TERMINATED	Use of Oral Bisphosphonates in the Treatment of Osteoporosis of Non-walking Children With Cerebral Palsy
NCT00922077	PHASE3	COMPLETED	Individualized Neurodevelopmental Treatment
NCT01249417	PHASE3	COMPLETED	Dysport® Pediatric Lower Limb Spasticity Study
NCT01251380	PHASE3	COMPLETED	Dysport® Pediatric Lower Limb Spasticity Follow-on Study
NCT01437644	PHASE3	COMPLETED	The Post-Operative Pain in Cerebral Palsy (POPPIES) Trial
NCT01492608	PHASE3	COMPLETED	Magnesium Sulphate for Preterm Birth (MASP Study)
NCT01603602	PHASE3	COMPLETED	BOTOX® Treatment in Pediatric Upper Limb Spasticity
NCT01603615	PHASE3	COMPLETED	BOTOX® Open-Label Treatment in Pediatric Upper Limb Spasticity
NCT01603628	PHASE3	COMPLETED	BOTOX® Treatment in Pediatric Lower Limb Spasticity
NCT01603641	PHASE3	COMPLETED	BOTOX® Open-Label Treatment in Pediatric Lower Limb Spasticity
NCT01633736	PHASE3	UNKNOWN	Targeted Hip Strength Training in Children With Cerebral Palsy (CP)
NCT01898520	PHASE3	COMPLETED	A Safety, Efficacy and Tolerability Study of Sativex for the Treatment of Spasticity in Children Aged 8 to 18 Years
NCT01929434	PHASE3	COMPLETED	Efficacy of Stem Cell Transplantation Compared to Rehabilitation Treatment of Patients With Cerebral Paralysis
NCT02002884	PHASE3	COMPLETED	Dose-response Study of Efficacy and Safety of Botulinum Toxin Type A to Treat Spasticity of the Arm(s) or of Arm(s) and Leg(s) in Cerebral Palsy
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02839785	PHASE3	TERMINATED	Analgesia and Physiotherapy in Children With Cerebral Palsy (ANTALKINECP)
NCT03110341	PHASE3	UNKNOWN	Effect of Erythropoietin in Premature Infants on White Matter Lesions and Neurodevelopmental Outcome
NCT03302871	PHASE3	COMPLETED	Integrated Management Enhances Functional Gains in Children With Cerebral Palsy Treated by BoNT-A