FBXO42

Summary

FBXO42 (F-box protein 42, HGNC:29249) is a protein-coding gene on chromosome 1p36.13, encoding F-box only protein 42 (Q6P3S6). Substrate-recognition component of some SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. It is a selective cancer dependency (DepMap: 13.2% of cell lines).

Members of the F-box protein family, such as FBXO42, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1 (SKP1A; MIM 601434), cullin (see CUL1; MIM 603134), and F-box proteins, act as protein-ubiquitin ligases. F-box proteins interact with SKP1 through the F box, and they interact with ubiquitination targets through other protein interaction domains (Jin et al., 2004 [PubMed 15520277]).

Source: NCBI Gene 54455 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 86 total
• Cancer dependency (DepMap): dependent in 13.2% of screened cell lines
• MANE Select transcript: NM_018994

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29249
Approved symbol	FBXO42
Name	F-box protein 42
Location	1p36.13
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1332, Fbx42
Ensembl gene	ENSG00000037637
Ensembl biotype	protein_coding
OMIM	609109
Entrez	54455

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 22 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000375592, ENST00000444116, ENST00000456164, ENST00000478089, ENST00000868586, ENST00000868587, ENST00000868588, ENST00000868589, ENST00000868590, ENST00000868591, ENST00000868592, ENST00000868593, ENST00000868594, ENST00000940178, ENST00000940179, ENST00000940180, ENST00000940181, ENST00000957239, ENST00000957240, ENST00000957241, ENST00000957242, ENST00000957243, ENST00000957244

RefSeq mRNA: 1 — MANE Select: NM_018994 NM_018994

CCDS: CCDS30613

Canonical transcript exons

ENST00000375592 — 10 exons

Exon	Start	End
ENSE00000752040	16252288	16252404
ENSE00000752041	16253096	16253152
ENSE00000752115	16253635	16253731
ENSE00000752116	16255711	16255821
ENSE00000752118	16256606	16256759
ENSE00000752120	16294783	16294917
ENSE00001467559	16246840	16251785
ENSE00001467565	16315169	16315435
ENSE00001467567	16352255	16352480
ENSE00003667664	16305803	16305919

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 92.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.5905 / max 206.2583, expressed in 1822 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
10534	22.4637	1822
10533	0.1267	54

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
diaphragm	UBERON:0001103	92.62	gold quality
hair follicle	UBERON:0002073	91.91	gold quality
olfactory bulb	UBERON:0002264	90.91	gold quality
type B pancreatic cell	CL:0000169	90.51	gold quality
saphenous vein	UBERON:0007318	90.51	gold quality
mucosa of stomach	UBERON:0001199	90.40	gold quality
thoracic aorta	UBERON:0001515	90.34	gold quality
ascending aorta	UBERON:0001496	90.31	gold quality
descending thoracic aorta	UBERON:0002345	90.30	gold quality
superficial temporal artery	UBERON:0001614	90.23	gold quality
lateral globus pallidus	UBERON:0002476	90.16	gold quality
parotid gland	UBERON:0001831	89.97	gold quality
aorta	UBERON:0000947	89.76	gold quality
lower esophagus mucosa	UBERON:0035834	89.72	gold quality
vastus lateralis	UBERON:0001379	89.54	gold quality
vena cava	UBERON:0004087	89.53	gold quality
tongue squamous epithelium	UBERON:0006919	89.53	gold quality
cardia of stomach	UBERON:0001162	89.49	gold quality
popliteal artery	UBERON:0002250	89.33	gold quality
tibial artery	UBERON:0007610	89.30	gold quality
substantia nigra pars reticulata	UBERON:0001966	89.20	gold quality
substantia nigra pars compacta	UBERON:0001965	88.99	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	88.79	gold quality
pericardium	UBERON:0002407	88.77	gold quality
body of tongue	UBERON:0011876	88.75	gold quality
triceps brachii	UBERON:0001509	88.74	gold quality
gluteal muscle	UBERON:0002000	88.70	gold quality
lateral nuclear group of thalamus	UBERON:0002736	88.60	gold quality
quadriceps femoris	UBERON:0001377	88.43	gold quality
skin of leg	UBERON:0001511	88.30	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.11
E-MTAB-6386	no	911.72

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

187 targeting FBXO42, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-12121	99.99	66.64	255
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-5688	99.96	73.23	4504

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 13.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 6)

• JFK promotes p53 turnover through assembly of an SCF (Skp1-Cul1-F-box) complex, revealing a pathway for the control of p53 degradation and providing a link between the SCF complex and p53 regulation. (PMID:19509332)
• Substrate phosphorylation and feedback regulation in JFK-promoted p53 destabilization. (PMID:21127074)
• The findings of this study suggest that a haplotype of the FBXO42 gene might be associated with a higher susceptibility to PD. (PMID:24063688)
• SCF(JFK) as a bona fide E3 ligase for ING4 and unraveled the JFK-ING4-NF-kappaB axis as an important player in the development and progression of breast cancer (PMID:25792601)
• A genome-wide CRISPR screen identifies FBXO42 involvement in resistance toward MEK inhibition in NRAS-mutant melanoma. (PMID:31549767)
• Comprehensive analysis identifies ubiquitin ligase FBXO42 as a tumor-promoting factor in neuroblastoma. (PMID:39134694)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	fbxo42	ENSDARG00000087545
mus_musculus	Fbxo42	ENSMUSG00000028920
rattus_norvegicus	Fbxo42	ENSRNOG00000014305
drosophila_melanogaster	Fbxo42	FBGN0034704

Paralogs (10): LZTR1 (ENSG00000099949), KLHDC4 (ENSG00000104731), HCFC2 (ENSG00000111727), KLHDC3 (ENSG00000124702), KLHDC10 (ENSG00000128607), RABEPK (ENSG00000136933), KLHDC9 (ENSG00000162755), KLHDC2 (ENSG00000165516), HCFC1 (ENSG00000172534), KLHDC1 (ENSG00000197776)

Protein

Protein identifiers

F-box only protein 42 — Q6P3S6 (reviewed: Q6P3S6)

Alternative names: Just one F-box and Kelch domain-containing protein

All UniProt accessions (2): Q6P3S6, X6RKU3

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-recognition component of some SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. Specifically recognizes p53/TP53, promoting its ubiquitination and degradation.

Subunit / interactions. Component of some SCF complex, composed of CUL1, SKP1, RBX1 and FBXO42. Interacts (via the kelch domain) with p53/TP53; interaction is direct.

RefSeq proteins (1): NP_061867* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001810	F-box_dom	Domain
IPR015915	Kelch-typ_b-propeller	Homologous_superfamily
IPR036047	F-box-like_dom_sf	Homologous_superfamily
IPR052821	F-box_only_SRC	Family

Pfam: PF12937, PF13415

UniProt features (21 total): compositionally biased region 5, modified residue 4, repeat 4, region of interest 3, sequence conflict 2, chain 1, domain 1, sequence variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9O04	ELECTRON MICROSCOPY	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6P3S6-F1	64.53	0.34

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 (4): 365, 373, 378, 552

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 143 (showing top): MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, TATTATA_MIR374, GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BLUE_DN, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, GROSS_HYPOXIA_VIA_ELK3_DN, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, GOBP_SCF_DEPENDENT_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, GOBP_PROTEIN_CATABOLIC_PROCESS, GOCC_SCF_UBIQUITIN_LIGASE_COMPLEX, GOCC_TRANSFERASE_COMPLEX, GOBP_PROTEOLYSIS, GOCC_CULLIN_RING_UBIQUITIN_LIGASE_COMPLEX, GOCC_UBIQUITIN_LIGASE_COMPLEX

GO Biological Process (0):

GO Molecular Function (2): ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (1): SCF ubiquitin ligase complex (GO:0019005)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
enzyme-substrate adaptor activity	1
binding	1
cullin-RING ubiquitin ligase complex	1

Protein interactions and networks

STRING

1750 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBXO42	CUL1	Q13616	694
FBXO42	SKP1	P34991	675
FBXO42	CUL3	Q13618	634
FBXO42	RNF25	Q96BH1	512
FBXO42	RBX1	P62877	496
FBXO42	FBXO34	Q9NWN3	494
FBXO42	TP53	P04637	492
FBXO42	INTS15	Q96N11	487
FBXO42	FBXO41	Q8TF61	447
FBXO42	FBXO6	Q9NRD1	443
FBXO42	FBXO17	Q96EF6	435
FBXO42	FBXO2	Q9UK22	434
FBXO42	UBE3D	Q7Z6J8	428
FBXO42	FBXO47	Q5MNV8	415
FBXO42	PTPN21	Q16825	402
FBXO42	FBXO46	Q6PJ61	402

IntAct

40 interactions, top by confidence:

A	B	Type	Score
COPS6	RHOBTB1	psi-mi:“MI:0914”(association)	0.730
GSK3A	FBXO42	psi-mi:“MI:0915”(physical association)	0.660
FBXO42	GSK3A	psi-mi:“MI:0914”(association)	0.660
SKP1	MYCBP2	psi-mi:“MI:0914”(association)	0.640
FBXO42	RBPJ	psi-mi:“MI:0915”(physical association)	0.620
CUL1	FBXO21	psi-mi:“MI:0914”(association)	0.600
FBXO42	TPP1	psi-mi:“MI:0915”(physical association)	0.560
FBXO42	DNM2	psi-mi:“MI:0915”(physical association)	0.560
FBXO42	NDUFV1	psi-mi:“MI:0915”(physical association)	0.560
FBXO42	WFS1	psi-mi:“MI:0915”(physical association)	0.560
CCDC6	LZTS3	psi-mi:“MI:0914”(association)	0.530
RHOB	FBXO42	psi-mi:“MI:0915”(physical association)	0.370
RBPJ	SAMD1	psi-mi:“MI:0914”(association)	0.350
RBPJ	RPA2	psi-mi:“MI:0914”(association)	0.350
CUL1	LGALS8	psi-mi:“MI:0914”(association)	0.350
COPS6	DDX3X	psi-mi:“MI:0914”(association)	0.350
ROCK2	POLR1C	psi-mi:“MI:0914”(association)	0.350
FBXO42	CST1	psi-mi:“MI:0914”(association)	0.350

BioGRID (318): FBXO42 (Affinity Capture-MS), FBXO42 (Affinity Capture-MS), RBPJ (Affinity Capture-MS), GSK3A (Affinity Capture-MS), FBXO42 (Affinity Capture-MS), CUL1 (Affinity Capture-MS), RAB28 (Affinity Capture-MS), SKP1 (Affinity Capture-MS), CCDC6 (Affinity Capture-MS), CST1 (Affinity Capture-MS), KLK6 (Affinity Capture-MS), FBXO42 (Affinity Capture-Western), TP53 (Reconstituted Complex), FBXO42 (Affinity Capture-RNA), FBXO42 (Affinity Capture-MS)

ESM2 similar proteins: A0JN71, A2AFR3, A5PMU4, F1LXF1, O15034, O35274, O75995, O88382, O94967, P0C6S7, P11274, P22681, P22682, P59672, Q14161, Q14CM0, Q32LP7, Q3U0J8, Q50H33, Q5RDA9, Q66H91, Q68FF6, Q6DRP4, Q6P3S6, Q6PAJ1, Q6R891, Q6ZWB6, Q7Z5H3, Q7Z6G8, Q80U40, Q86UL8, Q8BIZ1, Q8CGF6, Q8K2Y9, Q8K352, Q8QFX1, Q8TEK3, Q8VDD9, Q8WXH2, Q92625

Diamond homologs: A8JAM0, D3ZN95, G5EC23, P38853, P51610, P51611, Q10AZ7, Q4V8F4, Q53EP0, Q5RDA9, Q5RKG2, Q61191, Q6AYI2, Q6NWW9, Q6P3S6, Q7M3S9, Q8H4D4, Q8VEM9, Q93XW5, Q9BQ90, Q9D968, Q9V4C8, Q9Y5Z7, G5EF96, P16621, Q6PDJ6, Q9V410, Q5EA50, P32634, P53094, A6QQY2, P32228, Q09563, Q10579, Q2T9Z7, Q6ZPT1, Q80TF4, Q9LYY5, Q9P2J3, Q9P2N7

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 33 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	6	10.9×	6e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	77
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2876 predictions. Top by Δscore:

Variant	Effect	Δscore
1:16255709:A:AC	donor_gain	1.0000
1:16255710:C:CC	donor_gain	1.0000
1:16255710:CA:C	donor_gain	1.0000
1:16255710:CAT:C	donor_gain	1.0000
1:16255819:CACCT:C	acceptor_loss	1.0000
1:16255821:CC:C	acceptor_loss	1.0000
1:16255821:CCTAA:C	acceptor_gain	1.0000
1:16255822:C:A	acceptor_loss	1.0000
1:16255823:T:A	acceptor_loss	1.0000
1:16294780:TACC:T	donor_loss	1.0000
1:16294781:A:AC	donor_gain	1.0000
1:16294781:ACC:A	donor_loss	1.0000
1:16294782:C:CC	donor_gain	1.0000
1:16294782:CCTG:C	donor_loss	1.0000
1:16294913:TGCAC:T	acceptor_gain	1.0000
1:16294914:GCAC:G	acceptor_gain	1.0000
1:16294915:CAC:C	acceptor_gain	1.0000
1:16294915:CACC:C	acceptor_gain	1.0000
1:16294916:AC:A	acceptor_gain	1.0000
1:16294917:CC:C	acceptor_gain	1.0000
1:16294918:C:CC	acceptor_gain	1.0000
1:16305797:ACTT:A	donor_loss	1.0000
1:16305798:CTT:C	donor_loss	1.0000
1:16305799:TTA:T	donor_loss	1.0000
1:16305800:TA:T	donor_loss	1.0000
1:16305801:A:AC	donor_gain	1.0000
1:16305801:AC:A	donor_loss	1.0000
1:16305802:C:CA	donor_gain	1.0000
1:16305802:CT:C	donor_gain	1.0000
1:16305802:CTGT:C	donor_gain	1.0000

AlphaMissense

4676 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:16250688:A:C	F712L	1.000
1:16250688:A:T	F712L	1.000
1:16250689:A:G	F712S	1.000
1:16250690:A:G	F712L	1.000
1:16250693:A:C	Y711D	1.000
1:16250746:C:T	G693E	1.000
1:16250747:C:G	G693R	1.000
1:16250747:C:T	G693R	1.000
1:16250749:C:A	G692V	1.000
1:16250749:C:T	G692E	1.000
1:16250750:C:G	G692R	1.000
1:16250750:C:T	G692R	1.000
1:16250751:A:C	F691L	1.000
1:16250751:A:T	F691L	1.000
1:16250752:A:G	F691S	1.000
1:16250753:A:G	F691L	1.000
1:16250755:A:C	I690R	1.000
1:16250755:A:T	I690K	1.000
1:16250761:A:G	L688P	1.000
1:16250774:C:G	G684R	1.000
1:16250791:A:G	L678P	1.000
1:16250810:C:G	G672R	1.000
1:16250810:C:T	G672R	1.000
1:16250838:C:A	W662C	1.000
1:16250838:C:G	W662C	1.000
1:16250839:C:G	W662S	1.000
1:16250840:A:G	W662R	1.000
1:16250840:A:T	W662R	1.000
1:16250845:A:T	V660D	1.000
1:16250878:A:G	L649P	1.000

dbSNP variants (sampled 300 via entrez): RS1000008027 (1:16292254 A>T), RS1000042450 (1:16295870 G>A), RS1000048001 (1:16317002 C>T), RS1000099011 (1:16308115 A>C,G), RS1000142923 (1:16260240 A>G), RS1000190856 (1:16310222 G>A), RS1000212435 (1:16330490 G>C), RS1000286572 (1:16260059 A>C,G), RS1000338603 (1:16277977 G>A), RS1000417194 (1:16338905 A>G), RS1000421500 (1:16319588 T>G), RS1000457517 (1:16297720 A>C), RS1000469220 (1:16339243 T>C), RS1000563695 (1:16290890 G>A), RS1000571182 (1:16342746 G>A)

Disease associations

OMIM: gene MIM:609109 | 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
GCST010204_174	Low density lipoprotein cholesterol levels	7.000000e-13
GCST012490_524	Femur bone mineral density x serum urate levels interaction	8.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004531	urate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, affects cotreatment, decreases expression, increases abundance, increases expression	3
Cyclosporine	increases expression	3
Valproic Acid	affects expression, increases expression	2
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
coumarin	increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
K 7174	increases expression	1
Sunitinib	increases expression	1
Vorinostat	decreases expression	1
Acetaminophen	increases expression	1
Arsenic	decreases expression, increases abundance, affects cotreatment	1
Benzo(a)pyrene	affects methylation	1
Dexamethasone	decreases expression	1
Doxorubicin	decreases expression	1
Formaldehyde	increases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Sulindac	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	decreases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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