FBXL2

Summary

FBXL2 (F-box and leucine rich repeat protein 2, HGNC:13598) is a protein-coding gene on chromosome 3p22.3, encoding F-box/LRR-repeat protein 2 (Q9UKC9). Calcium-activated substrate recognition component of the SCF (SKP1-cullin-F-box protein) E3 ubiquitin-protein ligase complex, SCF(FBXL2), which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.

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 12 tandem leucine-rich repeats. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 25827 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 100 total
• MANE Select transcript: NM_012157

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13598
Approved symbol	FBXL2
Name	F-box and leucine rich repeat protein 2
Location	3p22.3
Locus type	gene with protein product
Status	Approved
Aliases	FBL2, FBL3
Ensembl gene	ENSG00000153558
Ensembl biotype	protein_coding
OMIM	605652
Entrez	25827

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 7 retained_intron, 6 protein_coding_CDS_not_defined, 6 nonsense_mediated_decay, 6 protein_coding

ENST00000283627, ENST00000421391, ENST00000422741, ENST00000425973, ENST00000432809, ENST00000435207, ENST00000451636, ENST00000460186, ENST00000461094, ENST00000463698, ENST00000463736, ENST00000464164, ENST00000464990, ENST00000471208, ENST00000483037, ENST00000484457, ENST00000492662, ENST00000493778, ENST00000497411, ENST00000498807, ENST00000898645, ENST00000898646, ENST00000898647, ENST00000898648, ENST00000958148

RefSeq mRNA: 10 — MANE Select: NM_012157 NM_001349316, NM_001349319, NM_001349320, NM_001349321, NM_001349322, NM_001349323, NM_001349324, NM_001349325, NM_001349326, NM_012157

CCDS: CCDS2658

Canonical transcript exons

ENST00000484457 — 15 exons

Exon	Start	End
ENSE00001846003	33385501	33388092
ENSE00001938718	33277442	33277515
ENSE00003467726	33373578	33373704
ENSE00003484852	33377273	33377333
ENSE00003524735	33378685	33378741
ENSE00003538219	33375288	33375418
ENSE00003545230	33373847	33373921
ENSE00003550848	33383989	33384201
ENSE00003555846	33373260	33373355
ENSE00003598692	33364625	33364719
ENSE00003618713	33297664	33297725
ENSE00003635828	33358967	33359021
ENSE00003640559	33373092	33373160
ENSE00003655046	33378103	33378147
ENSE00003672764	33359283	33359357

Expression profiles

Bgee: expression breadth ubiquitous, 249 present calls, max score 93.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.7288 / max 169.3035, expressed in 1429 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
35946	8.7071	1429
35947	0.0218	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
orbitofrontal cortex	UBERON:0004167	93.91	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.88	gold quality
superior frontal gyrus	UBERON:0002661	93.83	gold quality
middle temporal gyrus	UBERON:0002771	93.83	gold quality
Brodmann (1909) area 46	UBERON:0006483	93.31	gold quality
prefrontal cortex	UBERON:0000451	92.67	gold quality
postcentral gyrus	UBERON:0002581	92.46	gold quality
frontal pole	UBERON:0002795	92.25	gold quality
Brodmann (1909) area 10	UBERON:0013541	92.02	gold quality
cortical plate	UBERON:0005343	91.95	gold quality
entorhinal cortex	UBERON:0002728	91.74	gold quality
frontal cortex	UBERON:0001870	91.48	gold quality
frontal lobe	UBERON:0016525	91.48	gold quality
parietal lobe	UBERON:0001872	91.08	gold quality
Brodmann (1909) area 9	UBERON:0013540	90.95	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	90.70	gold quality
neocortex	UBERON:0001950	90.52	gold quality
secondary oocyte	CL:0000655	90.36	gold quality
sperm	CL:0000019	90.34	gold quality
cerebral cortex	UBERON:0000956	89.76	gold quality
right frontal lobe	UBERON:0002810	89.67	gold quality
right uterine tube	UBERON:0001302	89.35	gold quality
male germ cell	CL:0000015	89.14	gold quality
primary visual cortex	UBERON:0002436	89.12	gold quality
popliteal artery	UBERON:0002250	89.11	gold quality
tibial artery	UBERON:0007610	89.10	gold quality
lateral nuclear group of thalamus	UBERON:0002736	88.93	gold quality
choroid plexus epithelium	UBERON:0003911	88.90	silver quality
CA1 field of hippocampus	UBERON:0003881	88.76	gold quality
endothelial cell	CL:0000115	88.21	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.02

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

93 targeting FBXL2, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-4694-3P	99.79	69.53	2640

Literature-anchored findings (GeneRIF, showing 13)

• FBXL2 is indispensible regulator of mitosis that serves as a tumor suppressor (PMID:22020328)
• FBXL2 targets cyclin D2 for ubiquitination and degradation to inhibit leukemic cell proliferation. (PMID:22323446)
• FBL2 is a novel and dual regulator of amyloid precursor protein (APP) metabolism through FBL2-dependent ubiquitination of APP. (PMID:22399757)
• These results suggested that the involvement of the reduction of FBL2 level is related to AD progression. (PMID:22455980)
• FBXL2 mediates the ubiquitylation and degradation of p85beta on cell membranes. (PMID:23604317)
• FBXL2 recognizes Trp-73 within NALP3 for interaction and targets Lys-689 within NALP3 for ubiquitin ligation and degradation. (PMID:26037928)
• these results uncover a previous unknown network involving FBXL2 and FoxM1 in the regulation of gastric cancer growth. (PMID:26790640)
• PTEN counteracts FBXL2 to promote IP3R3- and Ca(2+)-mediated apoptosis limiting tumour growth (PMID:28614300)
• The interaction with FBXL2 and ubiquitination of FOXM1 were reduced by elevated O-GlcNAcylation. Elevated O-GlcNAcylation contributes to cancer progression by suppressing FBXL2-mediated degradation of FOXM1. (PMID:31679690)
• miR-346-5p promoted colorectal cancer cell growth in vitro and in vivo by targeting FBXL2 and activating the beta-catenin signaling. (PMID:31953162)
• Tumor Necrosis Factor Alpha Regulates Skeletal Myogenesis by Inhibiting SP1 Interaction with cis-Acting Regulatory Elements within the Fbxl2 Gene Promoter. (PMID:32205409)
• FBXL2 counteracts Grp94 to destabilize EGFR and inhibit EGFR-driven NSCLC growth. (PMID:34635651)
• FBXL2 promotes E47 protein instability to inhibit breast cancer stemness and paclitaxel resistance. (PMID:36460773)

Cross-species orthologs

30 orthologs

Organism	Symbol	Gene ID
danio_rerio	fbxl2	ENSDARG00000012135
mus_musculus	Fbxl2	ENSMUSG00000032507
rattus_norvegicus	Fbxl2	ENSRNOG00000027099
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), FBXL18 (ENSG00000155034), FBXL13 (ENSG00000161040), FBXL14 (ENSG00000171823), FBXL6 (ENSG00000182325), FBXL7 (ENSG00000183580), FBXL22 (ENSG00000197361)

Protein

Protein identifiers

F-box/LRR-repeat protein 2 — Q9UKC9 (reviewed: Q9UKC9)

Alternative names: F-box and leucine-rich repeat protein 2, F-box protein FBL2/FBL3

All UniProt accessions (8): Q9UKC9, B4DFQ9, F8WB01, F8WBS9, F8WBW7, F8WC58, F8WCQ8, F8WE99

UniProt curated annotations — full annotation on UniProt →

Function. Calcium-activated substrate recognition component of the SCF (SKP1-cullin-F-box protein) E3 ubiquitin-protein ligase complex, SCF(FBXL2), which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Unlike many F-box proteins, FBXL2 does not seem to target phosphodegron within its substrates but rather calmodulin-binding motifs and is thereby antagonized by calmodulin. This is the case for the cyclins CCND2 and CCND3 which polyubiquitination and subsequent degradation are inhibited by calmodulin. Through CCND2 and CCND3 degradation induces cell-cycle arrest in G(0). SCF(FBXL2) also mediates PIK3R2 ubiquitination and proteasomal degradation thereby regulating phosphatidylinositol 3-kinase signaling and autophagy. PCYT1A monoubiquitination by SCF(FBXL2) and subsequent degradation regulates synthesis of phosphatidylcholine, which is utilized for formation of membranes and of pulmonary surfactant. The SCF(FBXL2) complex acts as a regulator of inflammation by mediating ubiquitination and degradation of TRAF proteins (TRAF1, TRAF2, TRAF3, TRAF4, TRAF5 and TRAF6). The SCF(FBXL2) complex acts as a negative regulator of the NLRP3 inflammasome by mediating ubiquitination and degradation of NLRP3. The GGTase-3 complex, composed of PTAR1 and RABGGTB, geranylgeranylates and targets FBXL2 to the cellular membranes, where FBXL2 forms part of the SCF(FBXL2) complex that mediates the degradation of membrane-anchored proteins.

Subunit / interactions. Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXL2) composed of CUL1, SKP1, RBX1 and FBXL2. Interacts with calmodulin; may antagonize substrate ubiquitination by SCF(FBXL2). May interact with PIK3R1. Interacts with PTPN13. (Microbial infection) Interacts with hepatitis C virus non-structural protein 5A (NS5A) and less efficiently, with hepatitis C virus non-structural protein 5B (NS5B); a reaction crucial for hepatitis C virus RNA replication.

Subcellular location. Membrane.

Tissue specificity. Expressed in brain, heart, kidney, liver, lung, pancreas and placenta.

Post-translational modifications. Phosphorylated by GSK-beta (GSK3B), promoting recognition by FBXO3, leading to its ubiquitination by the SCF(FBXO3) complex. Ubiquitinated at Lys-201 by the SCF(FBXO3) complex in response to lipopolysaccharide (LPS), leading to its degradation by the proteasome. Geranylgeranylation at Cys-420 is mediated by the GGTase-3 complex and is required for its association with cell membranes and the recruitment of substrates to the active SCF(FBXL2) complex.

Domain organisation. The CAAX motif is a signal for the geranylgeranylation of FBXL2 and is required for its association with cell membranes and the recruitment of substrates to the active SCF(FBXL2) complex.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. Deletion of the F-box domain creates a dominant-negative protein that inhibits replication of hepatitis C virus RNA when overexpressed in a hepatoma cell line; this inhibition could be overcome by NS5A coexpression.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UKC9-1	1	yes
Q9UKC9-2	2

RefSeq proteins (10): NP_001336245, NP_001336248, NP_001336249, NP_001336250, NP_001336251, NP_001336252, NP_001336253, NP_001336254, NP_001336255, NP_036289* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001810	F-box_dom	Domain
IPR006553	Leu-rich_rpt_Cys-con_subtyp	Repeat
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR050648	F-box_LRR-repeat	Family
IPR057207	FBXL15_LRR	Domain

Pfam: PF12937, PF25372

UniProt features (67 total): helix 19, strand 14, repeat 13, sequence conflict 7, mutagenesis site 4, chain 1, domain 1, region of interest 1, short sequence motif 1, modified residue 1, lipid moiety-binding region 1, cross-link 1, splice variant 1, sequence variant 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6O60	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UKC9-F1	92.45	0.82

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 (3): 404, 420, 201

Mutagenesis-validated functional residues (4):

Position	Phenotype
43–44	abolishes interaction with ptar1.
43	impairs interaction with ptar1.
398–400	abolishes interaction with ptar1.
420	loss of geranylgeranylation and association to membranes. loss of interaction with ns5a, pik3r1 and pik3r2. no effect on

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 156 (showing top): GGGACCA_MIR133A_MIR133B, RNGTGGGC_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_REGULATION_OF_AUTOPHAGY, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_INFLAMMATORY_RESPONSE, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_MODULATION_OF_PROCESS_OF_ANOTHER_ORGANISM, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_HOST_MEDIATED_PERTURBATION_OF_VIRAL_PROCESS, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, CREB_Q4, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, YOKOE_CANCER_TESTIS_ANTIGENS

GO Biological Process (12): proteolysis (GO:0006508), protein monoubiquitination (GO:0006513), regulation of autophagy (GO:0010506), protein ubiquitination (GO:0016567), SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146), protein modification process (GO:0036211), host-mediated perturbation of viral RNA genome replication (GO:0044830), regulation of inflammatory response (GO:0050727), regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051896), negative regulation of NLRP3 inflammasome complex assembly (GO:1900226), ubiquitin-dependent protein catabolic process (GO:0006511), regulation of defense response (GO:0031347)

GO Molecular Function (5): calmodulin binding (GO:0005516), protein phosphatase binding (GO:0019903), phosphatidylinositol 3-kinase regulatory subunit binding (GO:0036312), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (3): cytoplasm (GO:0005737), membrane (GO:0016020), SCF ubiquitin ligase complex (GO:0019005)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	2
protein ubiquitination	2
cellular anatomical structure	2
autophagy	1
regulation of catabolic process	1
protein modification by small protein conjugation	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
macromolecule modification	1
viral RNA genome replication	1
host-mediated perturbation of viral process	1
inflammatory response	1
regulation of defense response	1
regulation of response to external stimulus	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of intracellular signal transduction	1
negative regulation of protein-containing complex assembly	1
NLRP3 inflammasome complex assembly	1
negative regulation of inflammasome-mediated signaling pathway	1
regulation of NLRP3 inflammasome complex assembly	1
modification-dependent protein catabolic process	1
defense response	1
regulation of response to stress	1
protein binding	1
phosphatase binding	1
phosphatidylinositol 3-kinase binding	1
enzyme-substrate adaptor activity	1
binding	1
intracellular anatomical structure	1
cullin-RING ubiquitin ligase complex	1

Protein interactions and networks

STRING

686 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBXL2	PIK3R2	O00459	829
FBXL2	SKP1	P34991	774
FBXL2	FBXO3	Q9UK99	723
FBXL2	CUL1	Q13616	686
FBXL2	ITPR3	Q14573	660
FBXL2	MARCHF7	Q9H992	648
FBXL2	RABGGTB	P53611	615
FBXL2	RBX1	P62877	585
FBXL2	TRIM31	Q9BZY9	578
FBXL2	CCNF	P41002	548
FBXL2	CCND3	P30281	546
FBXL2	CREB3L4	Q8TEY5	541
FBXL2	CCND2	P30279	538
FBXL2	ARIH2	O95376	522
FBXL2	CALML6	Q8TD86	521

IntAct

43 interactions, top by confidence:

A	B	Type	Score
PTAR1	RABGGTB	psi-mi:“MI:0914”(association)	0.920
FBXL2	SKP1	psi-mi:“MI:0914”(association)	0.900
FBXL2	SKP1	psi-mi:“MI:0915”(physical association)	0.900
SKP1	FBXL2	psi-mi:“MI:0915”(physical association)	0.900
SKP1	MYCBP2	psi-mi:“MI:0914”(association)	0.640
FBXL2	CCT5	psi-mi:“MI:0915”(physical association)	0.560
FBXL2	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.560
FBXL2	HSP90AB1	psi-mi:“MI:0914”(association)	0.560
YPEL1	STRN3	psi-mi:“MI:0914”(association)	0.530
FBXL2	RABGGTB	psi-mi:“MI:0915”(physical association)	0.500
FBXL2	RABGGTB	psi-mi:“MI:0914”(association)	0.500
PTAR1	FBXL2	psi-mi:“MI:0915”(physical association)	0.500
FBXL2	HSPD1	psi-mi:“MI:0915”(physical association)	0.400
FBXL2	HACD3	psi-mi:“MI:0915”(physical association)	0.400
	FBXL2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (97): FBXL2 (Reconstituted Complex), APP (Biochemical Activity), NLRP3 (Affinity Capture-Western), FBXL2 (Affinity Capture-Western), NLRP3 (Biochemical Activity), UBE2D1 (Reconstituted Complex), UBE2G1 (Reconstituted Complex), FOXM1 (Affinity Capture-MS), FOXM1 (Affinity Capture-Western), SKP1 (Affinity Capture-Western), CUL1 (Affinity Capture-Western), FBXL2 (Affinity Capture-MS), FBXL2 (Affinity Capture-MS), ITPR3 (Affinity Capture-MS), SKP1 (Affinity Capture-Western)

ESM2 similar proteins: A0A2R8QFQ6, A0A2R8RWN9, A6H779, B5DFK7, O35345, O60684, Q01730, Q15303, Q15404, Q17QS6, Q28D01, Q2HJ19, Q3ULA2, Q502M6, Q503E9, Q58DG6, Q5E9C0, Q5R3Z8, Q5R4Q7, Q5RBV0, Q5SP67, Q5SRY7, Q5XIJ5, Q5ZIN0, Q5ZJX1, Q61527, Q62956, Q67FW5, Q6DD70, Q6GL10, Q862Z2, Q8BH16, Q8C6G8, Q8N653, Q8N6D5, Q8VBX0, Q8VCV1, Q8VEG6, Q8WXK3, Q91854

Diamond homologs: A2VE78, A6H779, B8M7Q5, P34284, Q13309, Q2YDQ5, Q58DG6, Q5R3Z8, Q5R6E1, Q8BH16, Q8C2S5, Q8N3Y1, Q96IG2, Q9CZV8, Q9FLX3, Q9QZH7, Q9UKA1, Q9UKC9, A0JMQ0, A1C7E4, A1DDL6, A1DHW6, A2QCU8, B0XTS1, B3MHX6, B3NLK7, B4GIU9, B4HN85, B4J9K1, B4KQU8, B4MYI5, B4P528, B6GZA1, B6Q4Z5, B6QC06, B6QC56, B8M0Q1, B8NGT5, B9WD30, C4JPW9

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
FBXL2	“down-regulates quantity by destabilization”	CCND3	binding
FBXL2	“up-regulates activity”	“Cullin 1-RBX1-Skp1”	binding
FBXL2	“down-regulates quantity by destabilization”	PIK3R2	binding
FBXL2	up-regulates	“Cullin 3-RBX1-Skp1”	binding
FBXL2	“down-regulates quantity by destabilization”	NLRP3	binding
FBXO3	“down-regulates quantity by destabilization”	FBXL2	binding
“Cullin 1-RBX1-Skp1”	“down-regulates quantity by destabilization”	FBXL2	polyubiquitination
FBXL2	“down-regulates quantity by destabilization”	CCND2	binding
FBXL2	“down-regulates quantity by destabilization”	AURKB	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	70
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3608 predictions. Top by Δscore:

Variant	Effect	Δscore
3:33277513:ATGG:A	donor_loss	1.0000
3:33277514:TG:T	donor_gain	1.0000
3:33277515:GG:G	donor_gain	1.0000
3:33277515:GGTG:G	donor_loss	1.0000
3:33277516:G:GG	donor_gain	1.0000
3:33277517:T:A	donor_loss	1.0000
3:33297658:TTCCA:T	acceptor_loss	1.0000
3:33297659:TCCA:T	acceptor_loss	1.0000
3:33297660:CCAGG:C	acceptor_loss	1.0000
3:33297661:CA:C	acceptor_loss	1.0000
3:33297663:G:GT	acceptor_loss	1.0000
3:33359354:AGAG:A	donor_loss	1.0000
3:33359355:GAGGT:G	donor_loss	1.0000
3:33359356:AGG:A	donor_loss	1.0000
3:33359357:GGTA:G	donor_loss	1.0000
3:33359358:G:C	donor_loss	1.0000
3:33359359:T:A	donor_loss	1.0000
3:33373088:TTA:T	acceptor_loss	1.0000
3:33373089:TAG:T	acceptor_loss	1.0000
3:33373090:A:AG	acceptor_gain	1.0000
3:33373090:A:C	acceptor_loss	1.0000
3:33373090:AG:A	acceptor_gain	1.0000
3:33373091:G:A	acceptor_loss	1.0000
3:33373091:G:GA	acceptor_gain	1.0000
3:33373091:GG:G	acceptor_gain	1.0000
3:33373091:GGA:G	acceptor_gain	1.0000
3:33373091:GGAC:G	acceptor_gain	1.0000
3:33373091:GGACC:G	acceptor_gain	1.0000
3:33373156:GACAG:G	donor_gain	1.0000
3:33373157:ACAG:A	donor_gain	1.0000

AlphaMissense

2752 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:33359286:T:A	W42R	1.000
3:33359286:T:C	W42R	1.000
3:33359299:C:A	A46D	1.000
3:33359305:A:T	D48V	1.000
3:33359307:G:A	G49R	1.000
3:33359307:G:C	G49R	1.000
3:33359308:G:A	G49E	1.000
3:33359316:T:A	W52R	1.000
3:33359316:T:C	W52R	1.000
3:33359317:G:C	W52S	1.000
3:33359318:G:C	W52C	1.000
3:33359318:G:T	W52C	1.000
3:33359340:T:C	F60L	1.000
3:33359342:T:A	F60L	1.000
3:33359342:T:G	F60L	1.000
3:33364664:T:C	F79L	1.000
3:33364665:T:C	F79S	1.000
3:33364666:C:A	F79L	1.000
3:33364666:C:G	F79L	1.000
3:33364677:T:C	L83P	1.000
3:33373108:T:C	C103R	1.000
3:33373127:T:C	L109S	1.000
3:33373133:T:C	L111P	1.000
3:33373304:T:C	L135P	1.000
3:33378131:T:C	L293P	1.000
3:33384022:G:T	G329W	1.000
3:33384023:G:A	G329E	1.000
3:33384083:A:T	D349V	1.000
3:33384087:C:A	N350K	1.000
3:33384087:C:G	N350K	1.000

dbSNP variants (sampled 300 via entrez): RS1000010952 (3:33294394 G>A), RS1000021124 (3:33287815 C>A,T), RS1000042094 (3:33404450 A>G), RS1000069396 (3:33317054 A>G), RS1000076868 (3:33300982 T>C), RS1000084413 (3:33363959 C>A,T), RS1000100453 (3:33347513 T>A), RS1000140679 (3:33413680 C>A), RS1000154138 (3:33294201 A>G), RS1000183010 (3:33353879 C>G), RS1000233187 (3:33313640 G>A,C,T), RS1000257366 (3:33413991 G>C), RS1000263160 (3:33286219 G>A), RS1000278454 (3:33357285 A>G), RS1000283473 (3:33361204 C>T)

Disease associations

OMIM: gene MIM:605652 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST006979_59	Heel bone mineral density	6.000000e-20
GCST009221_6	Rostral anterior cingulate cortex volume	3.000000e-06
GCST90013406_202	Liver enzyme levels (alkaline phosphatase)	2.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0004533	alkaline phosphatase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression, affects expression	4
cobaltous chloride	decreases expression	2
potassium chromate(VI)	decreases expression, affects cotreatment	2
bufotalin	increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	affects expression	1
beta-lapachone	increases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
manganese chloride	increases abundance, increases expression, affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Arsenic	increases abundance, affects cotreatment, decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Capsaicin	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Lead	affects expression	1
Manganese	decreases expression, increases abundance, increases expression, affects cotreatment	1
Quercetin	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Vanadates	increases expression	1
Cyclosporine	decreases expression	1
Antirheumatic Agents	increases expression	1
Acrylamide	decreases expression	1
Permethrin	decreases expression	1

Clinical trials (associated diseases)

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