FBXW11

Summary

FBXW11 (F-box and WD repeat domain containing 11, HGNC:13607) is a protein-coding gene on chromosome 5q35.1, encoding F-box/WD repeat-containing protein 11 (Q9UKB1). Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. It is a selective cancer dependency (DepMap: 45.1% of cell lines).

This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of 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 Fbws class and, in addition to an F-box, contains multiple WD40 repeats. This gene contains at least 14 exons, and its alternative splicing generates 3 transcript variants diverging at the presence/absence of two alternate exons.

Source: NCBI Gene 23291 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental, jaw, eye, and digital syndrome (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 32
• Clinical variants (ClinVar): 141 total — 5 likely-pathogenic
• Phenotypes (HPO): 35
• Cancer dependency (DepMap): dependent in 45.1% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity little evidence
• MANE Select transcript: NM_001378974

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13607
Approved symbol	FBXW11
Name	F-box and WD repeat domain containing 11
Location	5q35.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0696, Fbw1b, BTRCP2, BTRC2, Hos, Fbw11
Ensembl gene	ENSG00000072803
Ensembl biotype	protein_coding
OMIM	605651
Entrez	23291

Gene structure

Transcript identifiers

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

ENST00000265094, ENST00000296933, ENST00000393802, ENST00000517395, ENST00000518106, ENST00000518752, ENST00000519693, ENST00000520376, ENST00000522376, ENST00000522507, ENST00000522891, ENST00000523843, ENST00000873745, ENST00000873746, ENST00000873747, ENST00000873748, ENST00000873749, ENST00000940681, ENST00000940682, ENST00000940683, ENST00000962350, ENST00000962351, ENST00000962352, ENST00000962353

RefSeq mRNA: 10 — MANE Select: NM_001378974 NM_001378974, NM_001378975, NM_001378976, NM_001378977, NM_001378978, NM_001378979, NM_001378980, NM_012300, NM_033644, NM_033645

CCDS: CCDS34289, CCDS47340, CCDS47341, CCDS93825

Canonical transcript exons

ENST00000517395 — 14 exons

Exon	Start	End
ENSE00002136331	171861549	171864101
ENSE00002137859	172006458	172006638
ENSE00003480612	171878011	171878129
ENSE00003491278	171876285	171876534
ENSE00003515112	171891467	171891604
ENSE00003525686	171869729	171869807
ENSE00003526557	171910572	171910797
ENSE00003545621	171899004	171899094
ENSE00003550503	171957597	171957698
ENSE00003591657	171870748	171870858
ENSE00003599026	171899914	171900100
ENSE00003669010	171872872	171872990
ENSE00003674434	171868610	171868796
ENSE00003682319	171914343	171914405

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 96.05.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.9028 / max 157.8898, expressed in 1819 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
64835	22.5479	1812
64836	3.3111	1527
64837	1.5697	1047
64834	0.3667	171
64833	0.1075	59

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus callosum	UBERON:0002336	96.05	gold quality
medial globus pallidus	UBERON:0002477	95.95	gold quality
globus pallidus	UBERON:0001875	95.68	gold quality
islet of Langerhans	UBERON:0000006	95.17	gold quality
subthalamic nucleus	UBERON:0001906	94.82	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.75	gold quality
substantia nigra pars compacta	UBERON:0001965	94.72	gold quality
cartilage tissue	UBERON:0002418	94.72	gold quality
superior vestibular nucleus	UBERON:0007227	94.67	gold quality
cerebellar vermis	UBERON:0004720	94.46	gold quality
endothelial cell	CL:0000115	94.45	silver quality
cortical plate	UBERON:0005343	94.45	gold quality
lateral globus pallidus	UBERON:0002476	94.44	gold quality
prefrontal cortex	UBERON:0000451	94.42	gold quality
secondary oocyte	CL:0000655	94.37	gold quality
medulla oblongata	UBERON:0001896	94.34	gold quality
middle temporal gyrus	UBERON:0002771	94.20	gold quality
heart right ventricle	UBERON:0002080	94.04	gold quality
inferior vagus X ganglion	UBERON:0005363	93.95	gold quality
superior frontal gyrus	UBERON:0002661	93.94	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	93.91	gold quality
primary visual cortex	UBERON:0002436	93.88	gold quality
spinal cord	UBERON:0002240	93.82	gold quality
pons	UBERON:0000988	93.81	gold quality
entorhinal cortex	UBERON:0002728	93.78	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	93.77	gold quality
calcaneal tendon	UBERON:0003701	93.71	gold quality
Ammon’s horn	UBERON:0001954	93.64	gold quality
postcentral gyrus	UBERON:0002581	93.58	gold quality
lateral nuclear group of thalamus	UBERON:0002736	93.56	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.93
E-CURD-10	no	139.54

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

198 targeting FBXW11, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 1 (little evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 45.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 17)

• FBXW11 may be the most likely candidate gene for the Holoprosencephaly and prexial polydactyly phenotype. (PMID:16865294)
• two splice variants of beta-transducin repeat containing protein 2 (BTRCP2) localise exclusively to either the nucleus or the cytosol. (PMID:21138764)
• Data indicate that knockdown of beta-TrCP1 and beta-TrCP2 markedly reduced IL-17-induced, phosphorylation-dependent ubiquitination and degradation of Act1. (PMID:22045853)
• Knockdown of beta-TrCP1 and beta-TrCP2 attenuated the K48-linked ubiquitination and degradation of IRAK1. (PMID:22851693)
• Data indicate that miR-106b-25 cluster (miR-106b, miR-93 and miR-25) targets the 3’UTR of the beta-TRCP2 transcript and increases the expression of Snail. (PMID:23611780)
• SCF(FBXW11) bound, polyubiquitylated, and destabilized RAPGEF2, a guanine nucleotide exchange factor that activates the small GTPase RAP1 (PMID:25332235)
• Fbxw11 expression is upregulated in patients with ALL. High levels of Fbxw11 expression stimulate the proliferation of L1210 lymphocytic leukemia cells in vitro and promote tumor formation in vivo by regulating the cell cycle. Most importantly, activation of both the NF-kappaB and beta-catenin/TCF signaling pathways is involved in this process. (PMID:29555946)
• beta-TrCP was identified as a novel interacting partner of ASK1 that is capable of ubiquitinating and degrading ASK1 through the ubiquitin-proteasome system. These findings suggest that beta-TrCP is capable of suppressing oxidative stress-induced caspase 3-dependent apoptosis through suppression of ASK1. (PMID:30031111)
• findings support the role of FBXW11 in multiple developmental processes, including those involving the brain, eye, digits, and jaw (PMID:31402090)
• USP9X promotes tumorigenesis and FBXW11 suppresses tumorigenesis through PTENalpha/beta. (PMID:31685992)
• The characteristics and roles of beta-TrCP1/2 in carcinogenesis. (PMID:33021036)
• MicroRNA-221 Promotes Cell Proliferation and Inhibits Apoptosis in Osteosarcoma Cells by Directly Targeting FBXW11 and Regulating Wnt Signaling. (PMID:33131925)
• FBXW11 contributes to stem-cell-like features and liver metastasis through regulating HIC1-mediated SIRT1 transcription in colorectal cancer. (PMID:34642302)
• F-Box Protein 11 Suppresses Cell Proliferation and Aerobic Glycolysis in Glioblastomas by Mediating the Ubiquitin Degradation of Cdc25A. (PMID:35582896)
• Association of FBXW11 levels with tumor development and prognosis in chondrosarcoma. (PMID:36404534)
• Expression of FBXW11 in normal and disease-associated osteogenic cells. (PMID:37199076)
• E3 ubiquitin ligase FBXW11 as a novel inflammatory biomarker is associated with immune infiltration and NF-kappaB pathway activation in pancreatitis and pancreatic cancer. (PMID:38182068)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	fbxw11b	ENSDARG00000017230
danio_rerio	fbxw11a	ENSDARG00000104806
mus_musculus	Fbxw11	ENSMUSG00000020271
rattus_norvegicus	Fbxw11	ENSRNOG00000004395
caenorhabditis_elegans		WBGENE00003009

Paralogs (14): WDR54 (ENSG00000005448), FBXW7 (ENSG00000109670), TRAF7 (ENSG00000131653), FBXW9 (ENSG00000132004), FBXO36 (ENSG00000153832), WDR64 (ENSG00000162843), FBXW12 (ENSG00000164049), BTRC (ENSG00000166167), WDR49 (ENSG00000174776), FBXW8 (ENSG00000174989), PAAF1 (ENSG00000175575), WDR86 (ENSG00000187260), FBXO16 (ENSG00000214050), EFCAB8 (ENSG00000215529)

Protein

Protein identifiers

F-box/WD repeat-containing protein 11 — Q9UKB1 (reviewed: Q9UKB1)

Alternative names: F-box and WD repeats protein beta-TrCP2, F-box/WD repeat-containing protein 1B, Homologous to Slimb protein

All UniProt accessions (4): Q9UKB1, E5RG78, E5RGC1, E5RH92

UniProt curated annotations — full annotation on UniProt →

Function. Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Probably recognizes and binds to phosphorylated target proteins: the interaction with substrates requires the phosphorylation of the two serine residues in the substrates’ destruction motif D-S-G-X(2,3,4)-S. SCF(FBXW11) mediates the ubiquitination of phosphorylated CTNNB1 and participates in Wnt signaling regulation. SCF(FBXW11) plays a key role in NF-kappa-B activation by mediating ubiquitination of phosphorylated NFKBIA, leading to its degradation by the proteasome, thereby allowing the associated NF-kappa-B complex to translocate into the nucleus and to activate transcription. The SCF(FBXW11) complex also regulates NF-kappa-B by mediating ubiquitination of phosphorylated NFKB1: specifically ubiquitinates the p105 form of NFKB1, leading to its degradation. SCF(FBXW11) mediates the ubiquitination of IFNAR1. SCF(FBXW11) mediates the ubiquitination of CEP68; this is required for centriole separation during mitosis. Involved in the oxidative stress-induced a ubiquitin-mediated decrease in RCAN1. Mediates the degradation of CDC25A induced by ionizing radiation in cells progressing through S phase and thus may function in the intra-S-phase checkpoint. Has an essential role in the control of the clock-dependent transcription via degradation of phosphorylated PER1 and phosphorylated PER2. SCF(FBXW11) mediates the ubiquitination of CYTH1, and probably CYTH2. SCF(FBXW11) acts as a regulator of mTORC1 signaling pathway by catalyzing ubiquitination and subsequent proteasomal degradation of phosphorylated DEPTOR, TFE3 and MITF. (Microbial infection) Target of human immunodeficiency virus type 1 (HIV-1) protein VPU to polyubiquitinate and deplete BST2 from cells and antagonize its antiviral action.

Subunit / interactions. Self-associates. Component of the SCF(FBXW11) complex formed of CUL1, SKP1, RBX1 and a FBXW11 dimer. Interacts with BST2 and USP47. Interacts with TRIM21. Interacts with PER3. Interacts with INAVA. Interacts with REST. (Microbial infection) Interact with Rift valley fever virus NSs (via omegaXaV motif); this interaction is important for EIF2AK2/PKR degradation.

Subcellular location. Cytoplasm. Nucleus.

Disease relevance. Neurodevelopmental, jaw, eye, and digital syndrome (NEDJED) [MIM:618914] An autosomal dominant syndrome characterized by variable features including mild-to-severe developmental delay, speech delay, autistic and/or stereotypical behaviors, ocular anomalies, under- or overdeveloped jaw, and digital anomalies such as brachydactyly, clinodactyly, syndactyly, and contractures. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The N-terminal D domain mediates homodimerization.

Induction. Expression is negatively regulated by Wnt/beta-catenin pathway.

Pathway. Protein modification; protein ubiquitination.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UKB1-1	C	yes
Q9UKB1-2	A
Q9UKB1-3	B

RefSeq proteins (10): NP_001365903, NP_001365904, NP_001365905, NP_001365906, NP_001365907, NP_001365908, NP_001365909, NP_036432, NP_387448, NP_387449 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR001810	F-box_dom	Domain
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR019775	WD40_repeat_CS	Conserved_site
IPR020472	WD40_PAC1	Repeat
IPR021977	Beta-TrCP_D	Domain
IPR036047	F-box-like_dom_sf	Homologous_superfamily
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR050995	WD-F-box_domain-protein	Family

Pfam: PF00400, PF12125, PF12937

UniProt features (62 total): strand 29, helix 10, sequence variant 7, repeat 7, turn 4, splice variant 2, chain 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

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

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UKB1-F1	85.62	0.71

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-1169091	Activation of NF-kappaB in B cells
R-HSA-202424	Downstream TCR signaling
R-HSA-2565942	Regulation of PLK1 Activity at G2/M Transition
R-HSA-2871837	FCERI mediated NF-kB activation
R-HSA-5607761	Dectin-1 mediated noncanonical NF-kB signaling
R-HSA-5607764	CLEC7A (Dectin-1) signaling
R-HSA-5676590	NIK–>noncanonical NF-kB signaling
R-HSA-5684264	MAP3K8 (TPL2)-dependent MAPK1/3 activation
R-HSA-69601	Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A
R-HSA-8951664	Neddylation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-9932298	Degradation of CRY and PER proteins

MSigDB gene sets: 574 (showing top): PID_FANCONI_PATHWAY, GOBP_CIRCADIAN_RHYTHM, MORF_MTA1, GOBP_ESTABLISHMENT_OF_SPINDLE_ORIENTATION, GCM_MAP4K4, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_AXO_DENDRITIC_TRANSPORT, GCM_PTPRD, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, KEGG_HEDGEHOG_SIGNALING_PATHWAY, GOBP_VESICLE_LOCALIZATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION

GO Biological Process (22): establishment of mitotic spindle orientation (GO:0000132), protein polyubiquitination (GO:0000209), protein dephosphorylation (GO:0006470), ubiquitin-dependent protein catabolic process (GO:0006511), nuclear migration (GO:0007097), germ cell development (GO:0007281), retrograde axonal transport (GO:0008090), Wnt signaling pathway (GO:0016055), protein ubiquitination (GO:0016567), microtubule organizing center organization (GO:0031023), SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146), protein destabilization (GO:0031648), positive regulation of circadian rhythm (GO:0042753), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), positive regulation of proteolysis (GO:0045862), positive regulation of DNA-templated transcription (GO:0045893), vesicle transport along microtubule (GO:0047496), rhythmic process (GO:0048511), brain morphogenesis (GO:0048854), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), negative regulation of non-canonical NF-kappaB signal transduction (GO:1901223)

GO Molecular Function (7): protein dimerization activity (GO:0046983), microtubule plus-end binding (GO:0051010), dynein complex binding (GO:0070840), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515), ubiquitin protein ligase activity (GO:0061630)

GO Cellular Component (14): ubiquitin ligase complex (GO:0000151), kinetochore (GO:0000776), nucleus (GO:0005634), nuclear envelope (GO:0005635), nucleoplasm (GO:0005654), centrosome (GO:0005813), cytosol (GO:0005829), microtubule associated complex (GO:0005875), cytoplasmic microtubule (GO:0005881), SCF ubiquitin ligase complex (GO:0019005), neuron projection (GO:0043005), neuronal cell body (GO:0043025), axon cytoplasm (GO:1904115), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Downstream signaling events of B Cell Receptor (BCR)	1
TCR signaling	1
G2/M Transition	1
Fc epsilon receptor (FCERI) signaling	1
CLEC7A (Dectin-1) signaling	1
C-type lectin receptors (CLRs)	1
TNFR2 non-canonical NF-kB pathway	1
MAP kinase activation	1
Interleukin-1 signaling	1
p53-Independent G1/S DNA Damage Checkpoint	1
Post-translational protein modification	1
Class I MHC mediated antigen processing & presentation	1
Circadian clock	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein ubiquitination	2
cytoplasm	2
mitotic cell cycle	1
establishment of mitotic spindle localization	1
establishment of spindle orientation	1
dephosphorylation	1
protein modification process	1
modification-dependent protein catabolic process	1
intracellular transport	1
nucleus localization	1
establishment of organelle localization	1
developmental process involved in reproduction	1
gamete generation	1
cellular process involved in reproduction in multicellular organism	1
cell development	1
axonal transport	1
axon cytoplasm	1
cell surface receptor signaling pathway	1
protein modification by small protein conjugation	1
microtubule cytoskeleton organization	1
microtubule-based process	1
cellular component organization	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
regulation of protein stability	1
circadian rhythm	1
regulation of circadian rhythm	1
positive regulation of biological process	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
proteolysis	1
regulation of proteolysis	1
positive regulation of protein metabolic process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
organelle transport along microtubule	1

Protein interactions and networks

STRING

1869 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBXW11	CUL1	Q13616	960
FBXW11	CUL7	Q14999	915
FBXW11	SKP1	P34991	907
FBXW11	RBX1	P62877	850
FBXW11	CCNF	P41002	830
FBXW11	SKP2	Q13309	813
FBXW11	GSK3B	P49841	807
FBXW11	AXIN1	O15169	763
FBXW11	UBA3	Q8TBC4	717
FBXW11	CUL3	Q13618	703
FBXW11	GLMN	Q92990	675
FBXW11	CTNNB1	P35222	613
FBXW11	A0A087WY85	A0A087WY85	566
FBXW11	CREBBP	Q92793	532
FBXW11	BTRC	Q9Y297	529

IntAct

225 interactions, top by confidence:

A	B	Type	Score
FBXW11	SKP1	psi-mi:“MI:0914”(association)	0.940
FBXW11	SKP1	psi-mi:“MI:0915”(physical association)	0.940
SKP1	FBXW11	psi-mi:“MI:0915”(physical association)	0.940
CDC25B	YWHAZ	psi-mi:“MI:0914”(association)	0.940
AXIN1	CTNNB1	psi-mi:“MI:0914”(association)	0.940
FBXW11	CUL1	psi-mi:“MI:0915”(physical association)	0.930
CUL1	FBXW11	psi-mi:“MI:2364”(proximity)	0.930
DLD	PDHX	psi-mi:“MI:0914”(association)	0.880
CASP7	XIAP	psi-mi:“MI:0914”(association)	0.840
CDC25A	FBXW11	psi-mi:“MI:0914”(association)	0.820
KHDRBS2	KHDRBS3	psi-mi:“MI:0914”(association)	0.800
CTNNBIP1	APC	psi-mi:“MI:0914”(association)	0.740
COPS6	RHOBTB1	psi-mi:“MI:0914”(association)	0.730
RAPGEF1	CRKL	psi-mi:“MI:0914”(association)	0.720
CTNNB1	FBXW11	psi-mi:“MI:0915”(physical association)	0.720
FOXN2	RFX1	psi-mi:“MI:0914”(association)	0.710
AMER1	CTNNB1	psi-mi:“MI:0914”(association)	0.710
AMER1	FBXW11	psi-mi:“MI:0915”(physical association)	0.710
NFKB1	FBXW11	psi-mi:“MI:0914”(association)	0.690
NFKBIA	POLRMT	psi-mi:“MI:0914”(association)	0.670
NFKBIB	CHUK	psi-mi:“MI:0914”(association)	0.670

BioGRID (981): FBXW11 (Affinity Capture-MS), FBXW11 (Affinity Capture-Western), TRIM9 (Affinity Capture-Western), BHLHE40 (Affinity Capture-Western), BHLHE40 (Biochemical Activity), NUDC (Affinity Capture-MS), RAP1GAP (Affinity Capture-Western), FBXW11 (Affinity Capture-Western), DOCK1 (Affinity Capture-Western), NUDC (Affinity Capture-Western), DAP3 (Affinity Capture-Western), USP47 (Affinity Capture-Western), STK3 (Affinity Capture-Western), STK4 (Affinity Capture-Western), TBC1D4 (Affinity Capture-Western)

ESM2 similar proteins: A0A2R8QFQ6, A0A2R8RWN9, D3Z7P3, E9PV86, G3MWR8, O54865, O60907, O89050, O94925, P13264, P16068, P20595, P58058, Q02153, Q08211, Q12800, Q13042, Q14722, Q28141, Q28D01, Q3MHJ2, Q3ULA2, Q4R8H1, Q4ZHR9, Q5R874, Q5RB35, Q5SP67, Q5SRY7, Q5ZHN3, Q6DN14, Q7RTP6, Q7T2U9, Q7Z6J6, Q8BTG7, Q8C6G8, Q8CJ19, Q8K4Q0, Q8N122, Q8N2K0, Q8R349

Diamond homologs: A0A2R8QFQ6, A0A2R8RWN9, Q09990, Q3ULA2, Q5SRY7, Q91854, Q9UKB1, Q9Y297, P39014, Q9VZF4, A4R3M4, C4JPW9, C5FP68, C5FWH1, D1ZEM6, D3Z902, D4AM37, D4AZ50, D4D8P3, D4DG66, F1MNN4, P27612, P54319, P97452, Q008S8, Q54R82, Q61FW2, Q7S7L4, Q86I31, Q8IX29, Q8VBV4, Q93794, Q969H0, Q9QZM9

SIGNOR signaling

20 interactions.

A	Effect	B	Mechanism
FBXW11	up-regulates	SMAD3	ubiquitination
FBXW11	up-regulates	SMAD4	ubiquitination
FBXW11	down-regulates	PER1	ubiquitination
FBXW11	down-regulates	CLSPN	ubiquitination
FBXW11	down-regulates	EEF2K	ubiquitination
FBXW11	“down-regulates quantity by destabilization”	ZNF281	ubiquitination
FBXW11	down-regulates	NFKBIA	ubiquitination
FBXW11	“down-regulates quantity by destabilization”	AICDA	binding
FBXW11	“up-regulates activity”	“Cullin 7-RBX1-Skp1”	binding
FBXW11	“down-regulates quantity by destabilization”	IKBKB	binding
FBXW11	“down-regulates quantity by destabilization”	CHUK	binding
FBXW11	“up-regulates activity”	“Cullin 1-RBX1-Skp1”	binding
FBXW11	“down-regulates quantity by destabilization”	BTRC	binding
FBXW11	down-regulates	CTNNB1	binding
FBXW11	up-regulates	SKP1	binding
FBXW11	up-regulates	SUFU	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 220 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
MAP3K8 (TPL2)-dependent MAPK1/3 activation	6	28.7×	1e-05
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	27.1×	1e-05
RIP-mediated NFkB activation via ZBP1	5	22.5×	2e-04
Activation of BH3-only proteins	5	16.7×	5e-04
TRAF6 mediated NF-kB activation	5	15.3×	6e-04
Regulation of necroptotic cell death	5	14.7×	7e-04
Activation of NF-kappaB in B cells	10	13.2×	3e-06
NIK–>noncanonical NF-kB signaling	8	12.3×	3e-05

GO biological processes:

GO term	Partners	Fold	FDR
non-canonical NF-kappaB signal transduction	5	20.4×	3e-03
negative regulation of cytokine production involved in inflammatory response	6	12.3×	4e-03
mitotic spindle organization	7	9.2×	4e-03
protein polyubiquitination	10	5.6×	4e-03
proteasome-mediated ubiquitin-dependent protein catabolic process	20	5.1×	4e-06

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	5
Uncertain significance	109
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
1064510	NM_001378974.1(FBXW11):c.1393G>A (p.Glu465Lys)	Likely pathogenic
1064512	NM_001378974.1(FBXW11):c.1403G>T (p.Arg468Leu)	Likely pathogenic
3256589	NM_001378974.1(FBXW11):c.1277G>T (p.Gly426Val)	Likely pathogenic
4686669	NM_001378974.1(FBXW11):c.794A>G (p.Tyr265Cys)	Likely pathogenic
917897	NM_001378974.1(FBXW11):c.1154C>A (p.Ala385Asp)	Likely pathogenic

SpliceAI

2588 predictions. Top by Δscore:

Variant	Effect	Δscore
5:171876279:A:AC	donor_gain	1.0000
5:171876280:C:CC	donor_gain	1.0000
5:171876280:CTTA:C	donor_gain	1.0000
5:171876281:TTACT:T	donor_loss	1.0000
5:171876283:A:AC	donor_gain	1.0000
5:171876283:ACTTT:A	donor_loss	1.0000
5:171876284:C:CT	donor_gain	1.0000
5:171876284:CT:C	donor_gain	1.0000
5:171876284:CTT:C	donor_gain	1.0000
5:171876284:CTTT:C	donor_gain	1.0000
5:171876284:CTTTG:C	donor_gain	1.0000
5:171876531:CACT:C	acceptor_gain	1.0000
5:171876533:CT:C	acceptor_gain	1.0000
5:171876535:C:CC	acceptor_gain	1.0000
5:171891462:TTCAC:T	donor_loss	1.0000
5:171891463:TCACC:T	donor_loss	1.0000
5:171891464:CACC:C	donor_loss	1.0000
5:171891466:CCT:C	donor_loss	1.0000
5:171891601:TAGT:T	acceptor_gain	1.0000
5:171891605:C:CC	acceptor_gain	1.0000
5:171891605:C:T	acceptor_loss	1.0000
5:171899908:ACTT:A	donor_loss	1.0000
5:171899909:CTT:C	donor_loss	1.0000
5:171899910:TTA:T	donor_loss	1.0000
5:171899912:ACCAC:A	donor_gain	1.0000
5:171899913:CCA:C	donor_gain	1.0000
5:171899913:CCACC:C	donor_gain	1.0000
5:171900099:CT:C	acceptor_gain	1.0000
5:171900101:C:CC	acceptor_gain	1.0000
5:171910793:CTTAT:C	acceptor_gain	1.0000

AlphaMissense

3700 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:171868707:G:C	F519L	1.000
5:171868707:G:T	F519L	1.000
5:171868708:A:C	F519C	1.000
5:171868708:A:G	F519S	1.000
5:171868709:A:G	F519L	1.000
5:171868713:C:A	W517C	1.000
5:171868713:C:G	W517C	1.000
5:171868714:C:G	W517S	1.000
5:171868715:A:G	W517R	1.000
5:171868715:A:T	W517R	1.000
5:171868720:A:G	L515S	1.000
5:171868723:A:C	I514S	1.000
5:171868723:A:G	I514T	1.000
5:171868723:A:T	I514N	1.000
5:171868729:T:A	D512V	1.000
5:171868729:T:G	D512A	1.000
5:171868730:C:A	D512Y	1.000
5:171868730:C:G	D512H	1.000
5:171868731:A:C	D511E	1.000
5:171868731:A:T	D511E	1.000
5:171868732:T:A	D511V	1.000
5:171868732:T:C	D511G	1.000
5:171868732:T:G	D511A	1.000
5:171868733:C:A	D511Y	1.000
5:171868733:C:G	D511H	1.000
5:171868734:A:C	H510Q	1.000
5:171868734:A:T	H510Q	1.000
5:171868735:T:C	H510R	1.000
5:171868736:G:C	H510D	1.000
5:171868738:G:A	S509F	1.000

dbSNP variants (sampled 300 via entrez): RS1000055208 (5:171886576 A>C), RS1000056226 (5:171982355 C>T), RS1000073028 (5:171921444 T>C), RS1000108282 (5:171982567 G>C), RS1000149477 (5:171895604 A>C), RS1000170531 (5:171882664 T>C), RS1000185716 (5:171926539 A>G), RS1000198687 (5:171933271 C>G,T), RS1000268992 (5:171933506 A>T), RS1000285500 (5:171927534 C>T), RS1000296497 (5:171985111 C>T), RS1000322146 (5:171915511 G>C), RS1000324747 (5:171889620 T>A), RS1000331300 (5:171940851 C>T), RS1000347989 (5:171965051 A>G,T)

Disease associations

OMIM: gene MIM:605651 | disease phenotypes: MIM:618914

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental, jaw, eye, and digital syndrome	Strong	Autosomal dominant
syndromic intellectual disability	Supportive	Autosomal dominant

Mondo (2): neurodevelopmental, jaw, eye, and digital syndrome (MONDO:0030057), syndromic intellectual disability (MONDO:0000508)

Orphanet (0):

HPO phenotypes

35 total (30 of 35 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000089	Renal hypoplasia
HP:0000278	Retrognathia
HP:0000303	Mandibular prognathia
HP:0000347	Micrognathia
HP:0000378	Cupped ear
HP:0000465	Webbed neck
HP:0000486	Strabismus
HP:0000545	Myopia
HP:0000568	Microphthalmia
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000750	Delayed speech and language development
HP:0001156	Brachydactyly
HP:0001245	Small thenar eminence
HP:0001249	Intellectual disability
HP:0001270	Motor delay
HP:0001276	Hypertonia
HP:0001290	Generalized hypotonia
HP:0001537	Umbilical hernia
HP:0001642	Pulmonic stenosis
HP:0001655	Patent foramen ovale
HP:0001852	Sandal gap
HP:0002079	Hypoplasia of the corpus callosum
HP:0004691	2-3 toe syndactyly
HP:0006956	Lateral ventricle dilatation
HP:0009183	Joint contracture of the 5th finger
HP:0009274	Joint contracture of the 4th finger

GWAS associations

32 associations (top):

Study	Trait	p-value
GCST000817_19	Height	4.000000e-08
GCST000817_92	Height	4.000000e-12
GCST001956_33	Height	3.000000e-10
GCST002647_128	Height	3.000000e-29
GCST002702_96	Height	2.000000e-06
GCST004063_159	Waist circumference adjusted for body mass index	4.000000e-06
GCST004063_162	Waist circumference adjusted for body mass index	3.000000e-09
GCST004500_49	Waist circumference adjusted for BMI (adjusted for smoking behaviour)	1.000000e-06
GCST004500_97	Waist circumference adjusted for BMI (adjusted for smoking behaviour)	6.000000e-06
GCST004501_40	Waist circumference adjusted for BMI (joint analysis main effects and smoking interaction)	6.000000e-07
GCST004504_44	Waist circumference adjusted for BMI in non-smokers	1.000000e-06
GCST004562_124	Waist circumference adjusted for body mass index	5.000000e-09
GCST004562_165	Waist circumference adjusted for body mass index	8.000000e-09
GCST004562_204	Waist circumference adjusted for body mass index	4.000000e-07
GCST004563_101	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	7.000000e-10
GCST004563_167	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	3.000000e-07
GCST004563_238	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	6.000000e-09
GCST004564_165	Waist circumference adjusted for BMI in active individuals	8.000000e-08
GCST004564_166	Waist circumference adjusted for BMI in active individuals	6.000000e-09
GCST004564_167	Waist circumference adjusted for BMI in active individuals	2.000000e-10
GCST008163_139	Height	8.000000e-06
GCST008163_373	Height	6.000000e-09
GCST008839_177	Height	3.000000e-25
GCST012226_63	Waist circumference adjusted for body mass index	2.000000e-16
GCST012226_64	Waist circumference adjusted for body mass index	9.000000e-09
GCST012227_201	Hip circumference adjusted for BMI	2.000000e-12
GCST012227_202	Hip circumference adjusted for BMI	5.000000e-11
GCST90000025_503	Appendicular lean mass	1.000000e-24
GCST90020028_1006	Hip circumference adjusted for BMI	1.000000e-11
GCST90020028_1007	Hip circumference adjusted for BMI	3.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007789	BMI-adjusted waist circumference
EFO:0004318	smoking behavior
EFO:0008002	physical activity measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
GSK-J4	increases expression	1
FR900359	increases phosphorylation	1
bisphenol A	decreases methylation	1
arsenite	affects binding, decreases reaction	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
bisphenol S	increases methylation	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Caffeine	increases phosphorylation	1
Dieldrin	increases response to substance	1
Drugs, Chinese Herbal	decreases expression	1
Gallic Acid	decreases expression	1
Phthalic Acids	decreases methylation	1
Smoke	decreases expression, increases abundance	1
Tobacco Smoke Pollution	increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Cadmium Chloride	increases expression	1
Copper Sulfate	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SN29	HAP1 FBXW11 (-) 1	Cancer cell line	Male
CVCL_XN73	HAP1 FBXW11 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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