FBXL6

Summary

FBXL6 (F-box and leucine rich repeat protein 6, HGNC:13603) is a protein-coding gene on chromosome 8q24.3, encoding F-box/LRR-repeat protein 6 (Q8N531). Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.

This gene encodes a member of a family of proteins that are characterized by an F-box motif. The encoded protein also contains leucine-rich repeats. F-box-containing proteins comprise one of the subunits of the SCF (SKP1-cullin-F-box) complex, which functions in phosphorylation-dependent ubiquitination. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 26233 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 143 total
• MANE Select transcript: NM_012162

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13603
Approved symbol	FBXL6
Name	F-box and leucine rich repeat protein 6
Location	8q24.3
Locus type	gene with protein product
Status	Approved
Aliases	FBL6
Ensembl gene	ENSG00000182325
Ensembl biotype	protein_coding
OMIM	609076
Entrez	26233

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 17 protein_coding, 4 protein_coding_CDS_not_defined, 3 retained_intron

ENST00000331890, ENST00000455319, ENST00000524492, ENST00000524909, ENST00000526524, ENST00000527000, ENST00000529279, ENST00000530142, ENST00000530687, ENST00000876696, ENST00000876697, ENST00000876698, ENST00000876699, ENST00000876700, ENST00000876701, ENST00000876702, ENST00000913928, ENST00000913929, ENST00000913930, ENST00000913931, ENST00000948083, ENST00000948084, ENST00000948085, ENST00000948086

RefSeq mRNA: 2 — MANE Select: NM_012162 NM_012162, NM_024555

CCDS: CCDS47942, CCDS6422

Canonical transcript exons

ENST00000331890 — 9 exons

Exon	Start	End
ENSE00001299036	144356990	144357121
ENSE00001303123	144357439	144357502
ENSE00001305802	144357628	144357786
ENSE00001330404	144358032	144358472
ENSE00003468862	144356300	144356531
ENSE00003532737	144355968	144356214
ENSE00003554938	144356600	144356713
ENSE00003606142	144356808	144356915
ENSE00003629111	144355431	144355678

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 96.37.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.8312 / max 145.9400, expressed in 1792 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
95658	12.8312	1792

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	96.37	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.76	gold quality
cerebellar hemisphere	UBERON:0002245	94.41	gold quality
cerebellar cortex	UBERON:0002129	94.33	gold quality
cerebellum	UBERON:0002037	94.29	gold quality
granulocyte	CL:0000094	91.91	gold quality
duodenum	UBERON:0002114	91.16	gold quality
transverse colon	UBERON:0001157	91.13	gold quality
lower esophagus mucosa	UBERON:0035834	91.05	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.11	gold quality
small intestine	UBERON:0002108	89.20	gold quality
apex of heart	UBERON:0002098	88.91	gold quality
right lobe of liver	UBERON:0001114	88.71	gold quality
spleen	UBERON:0002106	88.50	gold quality
colon	UBERON:0001155	87.42	gold quality
pituitary gland	UBERON:0000007	87.19	gold quality
metanephros cortex	UBERON:0010533	87.14	gold quality
intestine	UBERON:0000160	87.08	gold quality
body of stomach	UBERON:0001161	86.98	gold quality
right frontal lobe	UBERON:0002810	86.84	gold quality
body of pancreas	UBERON:0001150	86.73	gold quality
fundus of stomach	UBERON:0001160	86.36	gold quality
esophagus mucosa	UBERON:0002469	86.30	gold quality
adenohypophysis	UBERON:0002196	85.88	gold quality
muscle layer of sigmoid colon	UBERON:0035805	85.79	gold quality
skin of leg	UBERON:0001511	85.58	gold quality
saliva-secreting gland	UBERON:0001044	85.47	gold quality
minor salivary gland	UBERON:0001830	85.45	gold quality
right adrenal gland	UBERON:0001233	85.33	gold quality
esophagus	UBERON:0001043	85.30	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.78

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

7 targeting FBXL6, 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-4307	99.82	70.45	3374
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-372-5P	99.41	69.11	2299
HSA-MIR-5580-5P	99.38	66.96	1139
HSA-MIR-3064-5P	99.26	66.13	1497
HSA-MIR-3085-3P	99.26	66.16	1490
HSA-MIR-6504-5P	99.26	65.95	1487

Literature-anchored findings (GeneRIF, showing 5)

• Fbl6 regulates Tel/Yan protein stability and allows appropriate spatiotemporal control of gene expression by these repressors. (PMID:18426905)
• FBXL6 governs c-MYC to promote hepatocellular carcinoma through ubiquitination and stabilization of HSP90AA1. (PMID:32576198)
• FBXL6 degrades phosphorylated p53 to promote tumor growth. (PMID:33568778)
• FBXL6 is dysregulated in keloids and promotes keloid fibroblast growth by inducing c-Myc expression. (PMID:35606330)
• The E3 ubiquitin ligase FBXL6 controls the quality of newly synthesized mitochondrial ribosomal proteins. (PMID:37267103)

Cross-species orthologs

29 orthologs

Organism	Symbol	Gene ID
mus_musculus	Fbxl6	ENSMUSG00000022559
rattus_norvegicus	Tmem249	ENSRNOG00000025497
drosophila_melanogaster	CG15056	FBGN0030918
drosophila_melanogaster	CG8272	FBGN0033337
drosophila_melanogaster	CG9003	FBGN0033639
drosophila_melanogaster	Skp2	FBGN0037236
drosophila_melanogaster	CG14891	FBGN0038445
drosophila_melanogaster	CG5003	FBGN0039554
drosophila_melanogaster	FipoQ	FBGN0039667
caenorhabditis_elegans		WBGENE00007206
caenorhabditis_elegans		WBGENE00007208
caenorhabditis_elegans		WBGENE00007887
caenorhabditis_elegans		WBGENE00008177
caenorhabditis_elegans		WBGENE00009689
caenorhabditis_elegans	gadr-6	WBGENE00009823
caenorhabditis_elegans		WBGENE00010365
caenorhabditis_elegans	K05C4.9	WBGENE00010585
caenorhabditis_elegans		WBGENE00012655
caenorhabditis_elegans		WBGENE00015350
caenorhabditis_elegans		WBGENE00018561
caenorhabditis_elegans		WBGENE00018613
caenorhabditis_elegans		WBGENE00018766
caenorhabditis_elegans		WBGENE00019239
caenorhabditis_elegans		WBGENE00020884
caenorhabditis_elegans		WBGENE00021053
caenorhabditis_elegans		WBGENE00021180
caenorhabditis_elegans	zeel-1	WBGENE00021463
caenorhabditis_elegans		WBGENE00044459
caenorhabditis_elegans	gadr-5	WBGENE00045058

Paralogs (15): FBXL3 (ENSG00000005812), FBXL19 (ENSG00000099364), FBXL15 (ENSG00000107872), FBXL20 (ENSG00000108306), FBXL4 (ENSG00000112234), FBXL5 (ENSG00000118564), FBXL16 (ENSG00000127585), SKP2 (ENSG00000145604), FBXL17 (ENSG00000145743), FBXL2 (ENSG00000153558), FBXL18 (ENSG00000155034), FBXL13 (ENSG00000161040), FBXL14 (ENSG00000171823), FBXL7 (ENSG00000183580), FBXL22 (ENSG00000197361)

Protein

Protein identifiers

F-box/LRR-repeat protein 6 — Q8N531 (reviewed: Q8N531)

Alternative names: F-box and leucine-rich repeat protein 6, F-box protein FBL6, FBL6A

All UniProt accessions (1): Q8N531

UniProt curated annotations — full annotation on UniProt →

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

Subunit / interactions. Directly interacts with SKP1 and CUL1.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8N531-1	1	yes
Q8N531-2	2

RefSeq proteins (2): NP_036294, NP_078831 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001611	Leu-rich_rpt	Repeat
IPR001810	F-box_dom	Domain
IPR006553	Leu-rich_rpt_Cys-con_subtyp	Repeat
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR036047	F-box-like_dom_sf	Homologous_superfamily
IPR047922	FBXL6_F-box	Domain

Pfam: PF12937, PF13516

UniProt features (20 total): repeat 11, compositionally biased region 3, region of interest 2, chain 1, domain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N531-F1	78.53	0.53

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 78 (showing top): GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MODULE_205, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GOBP_SCF_DEPENDENT_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, GOBP_PROTEIN_CATABOLIC_PROCESS, AIYAR_COBRA1_TARGETS_UP, GOCC_SCF_UBIQUITIN_LIGASE_COMPLEX, GOCC_TRANSFERASE_COMPLEX, GOBP_PROTEOLYSIS, GOCC_CULLIN_RING_UBIQUITIN_LIGASE_COMPLEX, SCGGAAGY_ELK1_02, NIKOLSKY_BREAST_CANCER_8Q23_Q24_AMPLICON, GOMF_ACYLTRANSFERASE_ACTIVITY, GOCC_UBIQUITIN_LIGASE_COMPLEX

GO Biological Process (2): proteolysis (GO:0006508), SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146)

GO Molecular Function (2): ubiquitin-protein transferase activity (GO:0004842), 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
protein metabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
ubiquitin-like protein transferase activity	1
binding	1
cullin-RING ubiquitin ligase complex	1

Protein interactions and networks

STRING

950 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBXL6	CUL1	Q13616	718
FBXL6	SKP1	P34991	701
FBXL6	ADCK5	Q3MIX3	605
FBXL6	FBXL8	Q96CD0	582
FBXL6	FBXL16	Q8N461	532
FBXL6	FBXO16	Q8IX29	493
FBXL6	FBXL12	Q9NXK8	479
FBXL6	SLC52A2	Q9HAB3	456
FBXL6	FBXO4	Q9UKT5	449
FBXL6	SLC33A2	Q96ES6	426
FBXL6	MROH1	Q8NDA8	420
FBXL6	SLC39A4	Q6P5W5	409
FBXL6	WDR97	A6NE52	409
FBXL6	FBXO2	Q9UK22	409
FBXL6	SCRT1	Q9BWW7	397

IntAct

41 interactions, top by confidence:

A	B	Type	Score
SKP1	FBXL6	psi-mi:“MI:0915”(physical association)	0.740
ZNRD2	MYO9A	psi-mi:“MI:0914”(association)	0.530
COPS6	KLHL18	psi-mi:“MI:0914”(association)	0.530
Rpl35	RPS6	psi-mi:“MI:0914”(association)	0.350
Naa50	WDR46	psi-mi:“MI:0914”(association)	0.350
Mad2l1bp	ARHGAP32	psi-mi:“MI:0914”(association)	0.350
TFG	NCOA4	psi-mi:“MI:0914”(association)	0.350
UBE2A	CD59	psi-mi:“MI:0914”(association)	0.350
Srp72		psi-mi:“MI:0914”(association)	0.350
MPHOSPH8	HCFC1	psi-mi:“MI:0914”(association)	0.350
Rrbp1	PIPSL	psi-mi:“MI:0914”(association)	0.350
Cenph	CENPX	psi-mi:“MI:0914”(association)	0.350
HNRNPU		psi-mi:“MI:0914”(association)	0.350
CAMKK1		psi-mi:“MI:0914”(association)	0.350
NLRP3	PHRF1	psi-mi:“MI:0914”(association)	0.350
KBTBD7	THOC2	psi-mi:“MI:0914”(association)	0.350
HASPIN	KPNA6	psi-mi:“MI:0914”(association)	0.350
Spire2	KLF4	psi-mi:“MI:0914”(association)	0.350
Eif3e	RPSA	psi-mi:“MI:0914”(association)	0.350
Sart1	PRPF4	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
ATG7	IFT56	psi-mi:“MI:0914”(association)	0.350
FTL	SH3PXD2B	psi-mi:“MI:0914”(association)	0.350
NPAS1	CIBAR1	psi-mi:“MI:0914”(association)	0.350
RBM4B	ZNF320	psi-mi:“MI:0914”(association)	0.350
HES6	RGPD3	psi-mi:“MI:0914”(association)	0.350
D2HGDH	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
NEUROG3	MYO9A	psi-mi:“MI:0914”(association)	0.350
CIAO2A		psi-mi:“MI:0914”(association)	0.350

BioGRID (661): FBXL6 (Co-fractionation), FBXL6 (Synthetic Growth Defect), FBXL6 (Affinity Capture-MS), FBXL6 (Affinity Capture-MS), FBXL6 (Affinity Capture-MS), FBXL6 (Affinity Capture-MS), FBXL6 (Affinity Capture-MS), FBXL6 (Affinity Capture-MS), FBXL6 (Affinity Capture-MS), FBXL6 (Affinity Capture-MS), FBXL6 (Affinity Capture-MS), FBXL6 (Affinity Capture-MS), FBXL6 (Affinity Capture-MS), FBXL6 (Affinity Capture-MS), FBXL6 (Affinity Capture-MS)

ESM2 similar proteins: A1L3C1, A2RRU4, A6QM06, A6QNS9, F1LQY6, O94827, P29372, P29590, P97260, Q01113, Q02833, Q04841, Q12770, Q13505, Q29RM4, Q32KT5, Q32L49, Q3UGX3, Q4R5F9, Q5BK01, Q5I0I4, Q5MNU5, Q5SQH8, Q66T02, Q69Z89, Q6GQT6, Q6RFZ7, Q6UXT9, Q6ZN54, Q70EL4, Q7Z6G3, Q86WI3, Q86YD3, Q8IW40, Q8N1F8, Q8N531, Q8N9H8, Q8TCX5, Q91ZP9, Q920N2

Diamond homologs: A1A5X2, P34284, Q13309, Q32PG9, Q5BJ29, Q5XGI3, Q6INS1, Q7TPD1, Q7TSL3, Q86XK2, Q8N531, Q9EPX5, Q9NXK8, Q9UJT9, Q9Z0Z3, Q96CD0, Q9QXW0, Q9QZN1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
FBXL6	“up-regulates activity”	TKT	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	104
Likely benign	10
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1321 predictions. Top by Δscore:

Variant	Effect	Δscore
8:144356046:A:AC	donor_gain	1.0000
8:144356081:A:AC	donor_gain	1.0000
8:144356082:C:CC	donor_gain	1.0000
8:144356085:AACC:A	donor_gain	1.0000
8:144356100:AAGT:A	donor_gain	1.0000
8:144356314:T:TA	donor_gain	1.0000
8:144356709:CTGCC:C	acceptor_gain	1.0000
8:144356710:TGCC:T	acceptor_gain	1.0000
8:144356712:CC:C	acceptor_gain	1.0000
8:144356713:CC:C	acceptor_gain	1.0000
8:144356714:C:CC	acceptor_gain	1.0000
8:144356715:T:C	acceptor_loss	1.0000
8:144356722:A:AC	acceptor_gain	1.0000
8:144356804:TTA:T	donor_loss	1.0000
8:144356805:TA:T	donor_loss	1.0000
8:144356806:A:AC	donor_gain	1.0000
8:144356806:AC:A	donor_gain	1.0000
8:144356807:C:CT	donor_gain	1.0000
8:144356807:CC:C	donor_gain	1.0000
8:144356807:CCA:C	donor_gain	1.0000
8:144356807:CCAG:C	donor_gain	1.0000
8:144356914:ACCT:A	acceptor_loss	1.0000
8:144356916:CTGGG:C	acceptor_loss	1.0000
8:144357117:ACCAG:A	acceptor_gain	1.0000
8:144357118:CCAG:C	acceptor_gain	1.0000
8:144357118:CCAGC:C	acceptor_gain	1.0000
8:144357119:CAGC:C	acceptor_gain	1.0000
8:144357120:AG:A	acceptor_gain	1.0000
8:144357122:C:CC	acceptor_gain	1.0000
8:144355534:G:C	donor_gain	0.9900

AlphaMissense

3396 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:144357764:A:G	W147R	0.993
8:144357764:A:T	W147R	0.993
8:144355603:C:A	K516N	0.990
8:144355603:C:G	K516N	0.990
8:144357762:C:A	W147C	0.988
8:144357762:C:G	W147C	0.988
8:144355643:A:G	L503P	0.987
8:144355643:A:T	L503H	0.986
8:144355971:A:T	V490D	0.985
8:144356001:A:G	L480P	0.984
8:144356128:A:G	W438R	0.984
8:144356128:A:T	W438R	0.984
8:144355627:G:C	C508W	0.983
8:144355628:C:T	C508Y	0.983
8:144356106:A:G	L445P	0.982
8:144357773:A:G	C144R	0.982
8:144356443:A:G	L361P	0.981
8:144356001:A:T	L480H	0.980
8:144355629:A:G	C508R	0.979
8:144356604:A:T	L330H	0.979
8:144357734:A:G	W157R	0.979
8:144357734:A:T	W157R	0.979
8:144357763:C:G	W147S	0.979
8:144355637:A:G	L505P	0.978
8:144356353:A:T	L391H	0.977
8:144355986:A:T	V485D	0.975
8:144356353:A:G	L391P	0.975
8:144356460:G:C	F355L	0.975
8:144356460:G:T	F355L	0.975
8:144356461:A:G	F355S	0.975

dbSNP variants (sampled 300 via entrez): RS1001418068 (8:144360211 C>A), RS1001469926 (8:144360404 C>T), RS1001646326 (8:144355357 C>T), RS1002424042 (8:144359138 T>C), RS1004998551 (8:144357637 A>G), RS1005716528 (8:144355139 G>A,T), RS1009060977 (8:144357039 A>G), RS1009525003 (8:144357292 G>A,C,T), RS1011236482 (8:144355639 G>A,C), RS1011905400 (8:144357851 G>A,C), RS1012907528 (8:144356741 C>T), RS1015353494 (8:144358778 C>T), RS1016614259 (8:144359916 C>T), RS1017061568 (8:144355151 C>T), RS1019069468 (8:144358465 G>A,C)

Disease associations

OMIM: gene MIM:609076 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression, decreases expression	3
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance, increases expression	2
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
beta-lapachone	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
monomethylarsonous acid	decreases expression	1
abrine	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Plant Extracts	affects cotreatment, decreases expression	1
Quercetin	increases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	decreases expression	1
Valproic Acid	decreases expression, increases methylation	1
Cyclosporine	increases expression	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	decreases expression	1
Palmitic Acid	decreases expression	1
Volatile Organic Compounds	affects cotreatment, increases oxidation	1

Clinical trials (associated diseases)

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