FBXL5

Summary

FBXL5 (F-box and leucine rich repeat protein 5, HGNC:13602) is a protein-coding gene on chromosome 4p15.32, encoding F-box/LRR-repeat protein 5 (Q9UKA1). Component of some SCF (SKP1-cullin-F-box) protein ligase complex that plays a central role in iron homeostasis by promoting the ubiquitination and subsequent degradation of IREB2/IRP2.

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

Source: NCBI Gene 26234 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 118 total — 1 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_012161

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13602
Approved symbol	FBXL5
Name	F-box and leucine rich repeat protein 5
Location	4p15.32
Locus type	gene with protein product
Status	Approved
Aliases	FBL4, FBL5, FLR1
Ensembl gene	ENSG00000118564
Ensembl biotype	protein_coding
OMIM	605655
Entrez	26234

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 23 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000341285, ENST00000412094, ENST00000503196, ENST00000504837, ENST00000507700, ENST00000507899, ENST00000509314, ENST00000510802, ENST00000511441, ENST00000512066, ENST00000513163, ENST00000514541, ENST00000515679, ENST00000884013, ENST00000884014, ENST00000884015, ENST00000884016, ENST00000884017, ENST00000884018, ENST00000928640, ENST00000945524, ENST00000945525, ENST00000945526, ENST00000945527, ENST00000945528, ENST00000945529, ENST00000945530

RefSeq mRNA: 3 — MANE Select: NM_012161 NM_001193534, NM_001193535, NM_012161

CCDS: CCDS3415, CCDS54745

Canonical transcript exons

ENST00000341285 — 11 exons

Exon	Start	End
ENSE00001958921	15604381	15605799
ENSE00002025075	15655204	15655357
ENSE00003483963	15636494	15636676
ENSE00003497521	15630666	15630791
ENSE00003521657	15626873	15626955
ENSE00003602427	15640788	15640883
ENSE00003626204	15612266	15612414
ENSE00003628043	15638508	15638694
ENSE00003645779	15627885	15628033
ENSE00003652769	15644493	15644708
ENSE00003682430	15625252	15625977

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 98.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 65.2713 / max 2208.1955, expressed in 1825 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
51446	42.3786	1818
51456	9.2211	1524
51455	3.7377	1369
51447	3.0702	178
51448	2.9064	217
51454	1.6453	791
51450	1.1366	149
51445	0.5449	259
51457	0.4798	285
51449	0.0881	36

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	98.99	gold quality
mononuclear cell	CL:0000842	98.98	gold quality
leukocyte	CL:0000738	98.91	gold quality
choroid plexus epithelium	UBERON:0003911	98.78	gold quality
calcaneal tendon	UBERON:0003701	98.72	gold quality
nephron tubule	UBERON:0001231	98.65	gold quality
adult organism	UBERON:0007023	98.35	gold quality
blood	UBERON:0000178	98.32	gold quality
seminal vesicle	UBERON:0000998	98.26	gold quality
germinal epithelium of ovary	UBERON:0001304	98.25	gold quality
oocyte	CL:0000023	98.09	gold quality
sperm	CL:0000019	98.04	gold quality
secondary oocyte	CL:0000655	98.04	gold quality
bronchial epithelial cell	CL:0002328	97.89	gold quality
mammary duct	UBERON:0001765	97.81	gold quality
epithelium of mammary gland	UBERON:0003244	97.73	gold quality
male germ cell	CL:0000015	97.69	gold quality
urethra	UBERON:0000057	97.62	gold quality
pigmented layer of retina	UBERON:0001782	97.62	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.57	gold quality
jejunum	UBERON:0002115	97.56	gold quality
renal medulla	UBERON:0000362	97.55	gold quality
synovial joint	UBERON:0002217	97.55	gold quality
jejunal mucosa	UBERON:0000399	97.53	gold quality
trabecular bone tissue	UBERON:0002483	97.41	gold quality
caput epididymis	UBERON:0004358	97.40	gold quality
corpus callosum	UBERON:0002336	97.36	gold quality
kidney epithelium	UBERON:0004819	97.35	gold quality
thoracic mammary gland	UBERON:0005200	97.34	gold quality
mammary gland	UBERON:0001911	97.32	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	23.13
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

120 targeting FBXL5, 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-3646	100.00	73.56	5283
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-651-3P	99.94	73.48	5177
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
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-93-5P	99.88	73.98	2606

Literature-anchored findings (GeneRIF, showing 20)

• Our findings provide a potential mechanism by which p150(Glued) protein function is regulated by SCFs. (PMID:17532294)
• iron homeostasis is regulated by a proteolytic pathway that couples IRP2 degradation to intracellular iron levels through the stability and activity of FBXL5 (PMID:19762596)
• observations suggest a mechanistic link between iron sensing via the FBXL5 hemerythrin domain, IRP2 regulation, and cellular responses to maintain mammalian iron homeostasis (PMID:19762597)
• Detailed molecular and structural characterization of the ligand-responsive hemerythrin domain provides insights into the mechanisms by which FBXL5 serves as a unique mammalian metabolic sensor. (PMID:22253436)
• Data indicate that F-box and leucine-rich repeat protein 5 (FBXL5)-Hr (hemerythrin-like domain) undergoes substantive structural changes when iron becomes limiting, accounting for its switch-like behavior. (PMID:22648410)
• F-box and leucine-rich repeat protein 5 (FBXL5) is required for maintenance of cellular and systemic iron homeostasis (PMID:23135277)
• results thus suggest that HERC2 regulates the basal turnover of FBXL5, and that this ubiquitin-dependent degradation pathway contributes to the control of mammalian iron metabolism (PMID:24778179)
• FBXL5 regulates cortactin through induction of its ubiquitylation, and FBXL5 similarly regulates Snail1. (PMID:25832584)
• FBXL5-mediated degradation of CITED2 leads to the activation of HIF-1alpha. (PMID:25956243)
• analysis of the redox sensing mechanism by which FBXL5 can serve as an iron metabolism regulator within mammalian cells (PMID:28131773)
• Transcriptomic analysis shows downregulation of FBXL5 expression in HSCs of patients with myelodysplastic syndrome. (PMID:28714470)
• regulatory circuit involving FBXL5 and CIA acts through both IRPs to control iron metabolism and promote optimal cell growth (PMID:28768766)
• MiR-1306-3p directly targets FBXL5 and modulates FBXL5-meadiated snail protein stability in hepatocellular carcinoma. (PMID:30219228)
• this study demonstrated that FBXL5 functioned as an oncogene in the progression of colon cancer through regulating PTEN/PI3K/AKT signaling (PMID:30257389)
• Dysregulation of FBXL5-mediated cellular iron homeostasis was found to be associated with poor prognosis in human hepatocellular carcinoma, suggesting that FBXL5 plays a key role in defense against hepatocarcinogenesis. (PMID:30877170)
• We demonstrate that the CIA-targeting complex promotes the ability of FBXL5 to degrade iron regulatory proteins. In addition, the FBXL5-CIA-targeting complex interaction is regulated by oxygen (O2) tension displaying a robust association in 21% O2 that is severely diminished in 1% O2 and contributes to O2-dependent regulation of IRP degradation (PMID:31229404)
• This study has identified an iron-sulfur cluster within FBXL5, which promotes IRP2 polyubiquitination and degradation in response to both iron and oxygen concentrations. (PMID:32126207)
• Ferroportin and FBXL5 as Prognostic Markers in Advanced Stage Clear Cell Renal Cell Carcinoma. (PMID:33735560)
• Loss of F-Box and Leucine Rich Repeat Protein 5 (FBXL5) Expression Is Associated With Poor Survival in Patients With Hepatocellular Carcinoma After Curative Resection: A Two-institute Study. (PMID:37093682)
• FBXL5 promotes lipid accumulation in alcoholic fatty liver disease by promoting the ubiquitination and degradation of TFEB. (PMID:37743009)

Cross-species orthologs

30 orthologs

Organism	Symbol	Gene ID
danio_rerio	fbxl5	ENSDARG00000043046
mus_musculus	Fbxl5	ENSMUSG00000039753
rattus_norvegicus	Fbxl5	ENSRNOG00000005261
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), FBXL16 (ENSG00000127585), SKP2 (ENSG00000145604), FBXL17 (ENSG00000145743), FBXL2 (ENSG00000153558), FBXL18 (ENSG00000155034), FBXL13 (ENSG00000161040), FBXL14 (ENSG00000171823), FBXL6 (ENSG00000182325), FBXL7 (ENSG00000183580), FBXL22 (ENSG00000197361)

Protein

Protein identifiers

F-box/LRR-repeat protein 5 — Q9UKA1 (reviewed: Q9UKA1)

Alternative names: F-box and leucine-rich repeat protein 5, F-box protein FBL4/FBL5, p45SKP2-like protein

All UniProt accessions (9): D6R9Y4, D6RB50, D6RBW7, D6RCR7, D6RED6, D6RHC3, Q9UKA1, H0Y9Y0, H0YAG2

UniProt curated annotations — full annotation on UniProt →

Function. Component of some SCF (SKP1-cullin-F-box) protein ligase complex that plays a central role in iron homeostasis by promoting the ubiquitination and subsequent degradation of IREB2/IRP2. The C-terminal domain of FBXL5 contains a redox-sensitive [2Fe-2S] cluster that, upon oxidation, promotes binding to IRP2 to effect its oxygen-dependent degradation. Under iron deficiency conditions, the N-terminal hemerythrin-like (Hr) region, which contains a diiron metal center, cannot bind iron and undergoes conformational changes that destabilize the FBXL5 protein and cause its ubiquitination and degradation. When intracellular iron levels start rising, the Hr region is stabilized. Additional increases in iron levels facilitate the assembly and incorporation of a redox active [2Fe-2S] cluster in the C-terminal domain. Only when oxygen level is high enough to maintain the cluster in its oxidized state can FBXL5 recruit IRP2 as a substrate for polyubiquitination and degradation. Promotes ubiquitination and subsequent degradation of the dynactin complex component DCTN1. Within the nucleus, promotes the ubiquitination of SNAI1; preventing its interaction with DNA and promoting its degradation. Negatively regulates DNA damage response by mediating the ubiquitin-proteasome degradation of the DNA repair protein NABP2.

Subunit / interactions. Part of a SCF (SKP1-cullin-F-box) protein ligase complex. Interacts with ACO1/IRP1, IREB2/IRP2; the interaction depends on the [2Fe-2S] cluster. Interacts with DCTN1/p150-glued.

Subcellular location. Cytoplasm. Perinuclear region. Nucleus.

Post-translational modifications. Polybiquitinated upon iron and oxygen depletion, leading to its degradation by the proteasome. Ubiquitination is regulated by the hemerythrin-like region that acts as an oxygen and iron sensor. Undergoes constitutive ubiquitin-dependent degradation at the steady state by HERC2.

Activity regulation. An iron-sulfur cluster promotes IRP2 polyubiquitination and degradation in response to both iron and oxygen concentrations.

Domain organisation. The hemerythrin-like region acts as an oxygen and iron sensor by binding oxygen through a diiron metal-center. In absence of oxygen and iron, the protein is ubiquitinated and degraded.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. Binds a diiron center, that can be bridged by a hydroxo group. The hydroxo bridge is not present when FBXL5 is in the reduced form and seems to play a critical role in regulating iron binding.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UKA1-1	1	yes
Q9UKA1-2	2

RefSeq proteins (3): NP_001180463, NP_001180464, NP_036293* (*=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
IPR012312	Hemerythrin-like	Domain
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR036047	F-box-like_dom_sf	Homologous_superfamily
IPR045808	Hr_FBXL5	Domain

Pfam: PF01814, PF12937, PF13516

UniProt features (68 total): helix 19, binding site 13, strand 8, repeat 7, mutagenesis site 7, turn 6, sequence conflict 4, chain 1, domain 1, splice variant 1, region of interest 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
3U9J	X-RAY DIFFRACTION	1.6
3V5X	X-RAY DIFFRACTION	1.85
3U9M	X-RAY DIFFRACTION	1.95
3V5Y	X-RAY DIFFRACTION	2.1
3V5Z	X-RAY DIFFRACTION	2.18
6VCD	ELECTRON MICROSCOPY	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UKA1-F1	69.93	0.46

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 (13): 15; 57; 58; 61; 61; 80; 126; 130; 130; 662; 676; 686 …

Mutagenesis-validated functional residues (7):

Position	Phenotype
15	abolishes iron-binding and promotes its degradation.
57	abolishes iron-binding and promotes its degradation.
61	abolishes iron-binding and promotes its degradation.
662	more than 90% loss of binding to ireb2/irp2.
676	more than 90% loss of binding to ireb2/irp2.
686	more than 90% loss of binding to ireb2/irp2.
687	more than 90% loss of binding to ireb2/irp2.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-390471	Association of TriC/CCT with target proteins during biosynthesis
R-HSA-8951664	Neddylation
R-HSA-917937	Iron uptake and transport
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 265 (showing top): BROWNE_HCMV_INFECTION_6HR_DN, YAGI_AML_WITH_INV_16_TRANSLOCATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, TGACCTY_ERR1_Q2, GNF2_MCL1, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS

GO Biological Process (8): intracellular iron ion homeostasis (GO:0006879), protein ubiquitination (GO:0016567), SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146), positive regulation of protein catabolic process (GO:0045732), multicellular organismal-level iron ion homeostasis (GO:0060586), protein catabolic process (GO:0030163), monoatomic cation homeostasis (GO:0055080), inorganic ion homeostasis (GO:0098771)

GO Molecular Function (6): ubiquitin-protein transferase activity (GO:0004842), iron ion binding (GO:0005506), 2 iron, 2 sulfur cluster binding (GO:0051537), protein binding (GO:0005515), metal ion binding (GO:0046872), iron-sulfur cluster binding (GO:0051536)

GO Cellular Component (6): ubiquitin ligase complex (GO:0000151), nucleus (GO:0005634), cytosol (GO:0005829), SCF ubiquitin ligase complex (GO:0019005), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Chaperonin-mediated protein folding	1
Post-translational protein modification	1
Transport of small molecules	1
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
inorganic ion homeostasis	2
cytoplasm	2
intracellular monoatomic cation homeostasis	1
protein modification by small protein conjugation	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
positive regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
positive regulation of protein metabolic process	1
monoatomic cation homeostasis	1
multicellular organismal-level chemical homeostasis	1
macromolecule catabolic process	1
protein metabolic process	1
monoatomic ion homeostasis	1
chemical homeostasis	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
iron-sulfur cluster binding	1
binding	1
cation binding	1
metal cluster binding	1
intracellular protein-containing complex	1
transferase complex	1
intracellular membrane-bounded organelle	1
cullin-RING ubiquitin ligase complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

827 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBXL5	SKP1	P34991	981
FBXL5	CUL1	Q13616	973
FBXL5	IREB2	P48200	966
FBXL5	ACO1	P21399	860
FBXL5	FBXL14	Q8N1E6	727
FBXL5	BTRC	Q9Y297	640
FBXL5	RBX1	P62877	626
FBXL5	CCNF	P41002	624
FBXL5	FBXO11	Q86XK2	605
FBXL5	FTL	P02792	595
FBXL5	STEAP3	Q658P3	594
FBXL5	FTH1	P02794	592
FBXL5	SKP2	Q13309	578
FBXL5	NCOA4	Q13772	570
FBXL5	FBXO45	P0C2W1	548

IntAct

31 interactions, top by confidence:

A	B	Type	Score
FBXL5	SKP1	psi-mi:“MI:0915”(physical association)	0.900
SKP1	FBXL5	psi-mi:“MI:0915”(physical association)	0.900
FBXL5	HERC2	psi-mi:“MI:0915”(physical association)	0.620
TARDBP	FBXL5	psi-mi:“MI:0915”(physical association)	0.560
ORC4	FBXL5	psi-mi:“MI:0915”(physical association)	0.440
FBXL5	ORC4	psi-mi:“MI:0403”(colocalization)	0.440
	FBXL5	psi-mi:“MI:0407”(direct interaction)	0.440
FBXL5	IREB2	psi-mi:“MI:0915”(physical association)	0.400
EP300	FBXL5	psi-mi:“MI:0915”(physical association)	0.370
CSNK2B	FBXL5	psi-mi:“MI:0915”(physical association)	0.370
FBXL5	PLK1	psi-mi:“MI:0915”(physical association)	0.370
COPS5	FBLL1	psi-mi:“MI:0914”(association)	0.350
FBXL5	ECI2	psi-mi:“MI:0914”(association)	0.350
FBXL5	RBX1	psi-mi:“MI:0914”(association)	0.350
SKP1	FBXL5	psi-mi:“MI:0915”(physical association)	0.000
FBXL5	MYB	psi-mi:“MI:0915”(physical association)	0.000
rpoB	FBXL5	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (136): CUL1 (Affinity Capture-Western), NABP2 (Affinity Capture-Western), FBXL5 (Affinity Capture-Western), FBXL5 (Reconstituted Complex), FBXL5 (Two-hybrid), SKP1 (Two-hybrid), SNAI1 (Affinity Capture-Western), FBXL5 (Affinity Capture-Western), FBXL5 (Two-hybrid), FBXL5 (Reconstituted Complex), FBXL5 (PCA), ARHGDIB (Affinity Capture-Western), SKP1 (Affinity Capture-Western), CUL1 (Affinity Capture-Western), FBXL5 (Affinity Capture-Western)

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: A2VE78, C0HAC0, Q2YDQ5, Q3T0J1, Q58DG6, Q5R6E1, Q5XGI3, Q6INS1, Q7TPD1, Q7TSL3, Q86XK2, Q8C2S5, Q8IX29, Q96IG2, Q9CZV8, Q9QZH7, Q9QZM9, Q9UKA1, A6H779, B8M7Q5, P34284, Q13309, Q5R3Z8, Q8BH16, Q8N3Y1, Q9FLX3, Q9UKC9, A1L271, C4JPW9, C5GVJ9, C5JD40, D4AM37, D4D8P3, O08653, O14775, P0CS44, P0CS45, P46800, P49177, P62883

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
FBXL5	“down-regulates quantity by destabilization”	DCTN1	binding
FBXL5	“up-regulates activity”	“Cullin 1-RBX1-Skp1”	binding
FBXL5	“down-regulates quantity by destabilization”	NABP2	binding
FBXL5	“down-regulates quantity by destabilization”	IREB2	binding
FBXL5	“down-regulates quantity by destabilization”	SNAI1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	85
Likely benign	3
Benign	9

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
597947	NM_001378615.1(CC2D2A):c.1696G>T (p.Glu566Ter)	Pathogenic
1324020	NM_001378615.1(CC2D2A):c.1692_1699dup (p.Tyr567fs)	Likely pathogenic

SpliceAI

1454 predictions. Top by Δscore:

Variant	Effect	Δscore
4:15612413:CC:C	acceptor_gain	1.0000
4:15612414:CC:C	acceptor_gain	1.0000
4:15625973:ACCAA:A	acceptor_gain	1.0000
4:15625974:CCAA:C	acceptor_gain	1.0000
4:15625974:CCAAC:C	acceptor_gain	1.0000
4:15625975:CAA:C	acceptor_gain	1.0000
4:15625975:CAAC:C	acceptor_gain	1.0000
4:15625976:AA:A	acceptor_gain	1.0000
4:15625978:C:CC	acceptor_gain	1.0000
4:15625978:CT:C	acceptor_loss	1.0000
4:15625979:T:C	acceptor_loss	1.0000
4:15626868:CTAA:C	donor_loss	1.0000
4:15626869:TAA:T	donor_loss	1.0000
4:15626870:AACC:A	donor_loss	1.0000
4:15626871:A:AT	donor_loss	1.0000
4:15626872:CCTG:C	donor_loss	1.0000
4:15626951:CTAAC:C	acceptor_gain	1.0000
4:15628029:CTCTT:C	acceptor_gain	1.0000
4:15628034:C:CC	acceptor_gain	1.0000
4:15630660:GCTTA:G	donor_loss	1.0000
4:15630661:CTTA:C	donor_loss	1.0000
4:15630662:TTA:T	donor_loss	1.0000
4:15630663:TA:T	donor_loss	1.0000
4:15630664:A:AC	donor_gain	1.0000
4:15630664:ACCAG:A	donor_loss	1.0000
4:15630665:C:CA	donor_loss	1.0000
4:15630665:C:CC	donor_gain	1.0000
4:15630665:CCAG:C	donor_gain	1.0000
4:15630665:CCAGA:C	donor_gain	1.0000
4:15630789:CAC:C	acceptor_gain	1.0000

AlphaMissense

4591 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:15640849:A:G	L112P	1.000
4:15612373:A:G	L631P	0.999
4:15636557:A:G	W235R	0.999
4:15636557:A:T	W235R	0.999
4:15638651:A:G	L147P	0.999
4:15638651:A:T	L147H	0.999
4:15638678:A:G	L138S	0.999
4:15640815:A:C	F123L	0.999
4:15640815:A:T	F123L	0.999
4:15640816:A:G	F123S	0.999
4:15640817:A:G	F123L	0.999
4:15640827:A:C	F119L	0.999
4:15640827:A:T	F119L	0.999
4:15640828:A:G	F119S	0.999
4:15640829:A:G	F119L	0.999
4:15644619:C:A	E58D	0.999
4:15644619:C:G	E58D	0.999
4:15644620:T:A	E58V	0.999
4:15644632:A:G	F54S	0.999
4:15644662:A:G	L44P	0.999
4:15655235:A:G	M18T	0.999
4:15655255:G:C	F11L	0.999
4:15655255:G:T	F11L	0.999
4:15655256:A:C	F11C	0.999
4:15655256:A:G	F11S	0.999
4:15655257:A:G	F11L	0.999
4:15612280:C:T	C662Y	0.998
4:15612281:A:G	C662R	0.998
4:15612367:A:G	L633P	0.998
4:15625294:A:G	L603P	0.998

dbSNP variants (sampled 300 via entrez): RS1000022359 (4:15616003 C>T), RS1000151274 (4:15656957 G>A), RS1000174257 (4:15634351 ACTAATTT>A), RS1000185416 (4:15627530 A>G), RS1000222190 (4:15658403 A>G), RS1000231753 (4:15670201 T>C), RS1000257884 (4:15621283 A>C), RS1000296650 (4:15640194 C>T), RS1000304078 (4:15655730 G>A), RS10003739 (4:15617063 A>C), RS1000391807 (4:15633566 G>A), RS10003929 (4:15617226 A>C,G,T), RS1000412343 (4:15639919 A>C), RS1000418538 (4:15656613 T>C), RS10005158 (4:15649651 G>A)

Disease associations

OMIM: gene MIM:605655 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): prostate cancer (MONDO:0008315)

Orphanet (1): Familial prostate cancer (Orphanet:1331)

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST008745_43	Estimated glomerular filtration rate in non-diabetics	3.000000e-11
GCST90002403_566	Red blood cell count	1.000000e-21

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004305	erythrocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression, increases stability (+1 more)	4
Benzo(a)pyrene	increases expression	4
Valproic Acid	decreases methylation, affects expression, decreases expression	3
potassium chromate(VI)	affects cotreatment, decreases expression	2
Arsenic	affects expression, affects cotreatment, increases abundance, increases expression	2
Cadmium	decreases expression, increases abundance, increases expression	2
Tretinoin	increases expression	2
Particulate Matter	increases expression, decreases expression, increases abundance, affects cotreatment	2
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression	1
CGP 52608	increases reaction, affects binding	1
abrine	increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	decreases expression	1
jinfukang	decreases expression	1
Sunitinib	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Cisplatin	decreases expression	1
Coumestrol	decreases expression	1
Formaldehyde	decreases expression	1
Gasoline	affects cotreatment, increases abundance, increases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, increases abundance, increases expression	1
Selenium	decreases expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer