BTRC

Summary

BTRC (beta-transducin repeat containing E3 ubiquitin protein ligase, HGNC:1144) is a protein-coding gene on chromosome 10q24.32, encoding F-box/WD repeat-containing protein 1A (Q9Y297). 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.

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; in addition to an F-box, this protein contains multiple WD-40 repeats. The encoded protein mediates degradation of CD4 via its interaction with HIV-1 Vpu. It has also been shown to ubiquitinate phosphorylated NFKBIA (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha), targeting it for degradation and thus activating nuclear factor kappa-B. Alternatively spliced transcript variants have been described. A related pseudogene exists in chromosome 6.

Source: NCBI Gene 8945 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 166 total — 16 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 8
• MANE Select transcript: NM_033637

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1144
Approved symbol	BTRC
Name	beta-transducin repeat containing E3 ubiquitin protein ligase
Location	10q24.32
Locus type	gene with protein product
Status	Approved
Aliases	bTrCP, betaTrCP, FBXW1A, Fwd1, beta-TrCP1, bTrCP1
Ensembl gene	ENSG00000166167
Ensembl biotype	protein_coding
OMIM	603482
Entrez	8945

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 11 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000370183, ENST00000370187, ENST00000393441, ENST00000408038, ENST00000465182, ENST00000475200, ENST00000493877, ENST00000861879, ENST00000861880, ENST00000861881, ENST00000861882, ENST00000861883, ENST00000924128, ENST00000953682

RefSeq mRNA: 3 — MANE Select: NM_033637 NM_001256856, NM_003939, NM_033637

CCDS: CCDS73183, CCDS7511, CCDS7512

Canonical transcript exons

ENST00000370187 — 15 exons

Exon	Start	End
ENSE00001020481	101531237	101531333
ENSE00001020491	101526013	101526199
ENSE00001020495	101532295	101532432
ENSE00001100331	101532952	101533070
ENSE00001100338	101534661	101534910
ENSE00001100367	101550699	101550891
ENSE00001889214	101354165	101354228
ENSE00002493195	101535354	101535472
ENSE00003520784	101521639	101521870
ENSE00003521515	101461981	101462058
ENSE00003562970	101536543	101536653
ENSE00003629846	101430345	101430452
ENSE00003646889	101538293	101538371
ENSE00003674552	101479368	101479457
ENSE00003848637	101553155	101557313

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 93.69.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.7027 / max 200.9506, expressed in 1765 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
106659	11.0937	1759
106658	0.2770	131
106657	0.1735	84
106656	0.1585	78

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	93.69	gold quality
postcentral gyrus	UBERON:0002581	93.58	gold quality
parietal lobe	UBERON:0001872	93.11	gold quality
superior frontal gyrus	UBERON:0002661	91.81	gold quality
entorhinal cortex	UBERON:0002728	91.52	gold quality
oocyte	CL:0000023	89.75	gold quality
cervix squamous epithelium	UBERON:0006922	89.64	silver quality
superior vestibular nucleus	UBERON:0007227	88.91	gold quality
cortical plate	UBERON:0005343	88.87	gold quality
lateral nuclear group of thalamus	UBERON:0002736	88.71	gold quality
adrenal tissue	UBERON:0018303	88.37	gold quality
substantia nigra pars compacta	UBERON:0001965	88.18	gold quality
prefrontal cortex	UBERON:0000451	87.56	gold quality
middle temporal gyrus	UBERON:0002771	87.46	gold quality
medial globus pallidus	UBERON:0002477	87.41	gold quality
substantia nigra pars reticulata	UBERON:0001966	87.10	gold quality
globus pallidus	UBERON:0001875	87.09	gold quality
frontal cortex	UBERON:0001870	87.01	gold quality
lateral globus pallidus	UBERON:0002476	87.01	gold quality
nucleus accumbens	UBERON:0001882	87.00	gold quality
pons	UBERON:0000988	86.94	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	86.94	gold quality
neocortex	UBERON:0001950	86.75	gold quality
cerebral cortex	UBERON:0000956	86.65	gold quality
temporal lobe	UBERON:0001871	86.59	gold quality
ventral tegmental area	UBERON:0002691	86.49	gold quality
right frontal lobe	UBERON:0002810	86.35	gold quality
endothelial cell	CL:0000115	86.24	silver quality
telencephalon	UBERON:0001893	86.23	gold quality
Brodmann (1909) area 23	UBERON:0013554	86.12	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-36552	yes	175.26
E-ANND-3	no	5.14

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CRX, CTNNB1, KMT2A, MYC, NFKB, SMAD4

miRNA regulators (miRDB)

189 targeting BTRC, 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-6833-3P	100.00	70.63	3197
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-329-3P	99.91	66.56	1234

Literature-anchored findings (GeneRIF, showing 40)

• Genetic evidence for the essential role of beta-transducin repeat-containing protein in the inducible processing of NF-kappa B2/p100 (PMID:11994270)
• Protein kinase CK2 dependent phosphorylation of the E2 ubiquitin conjugating enzyme UBC3B induces its interaction with beta-TRCp and enhances beta-catenin degradation (PMID:12037680)
• Molecular genetic analysis of malignant melanomas for aberrations of the WNT signaling pathway genes CTNNB1, APC, ICAT and BTRC. (PMID:12124804)
• HOS plays a role in inhibiting cell differentiation and cell transformation (PMID:12151397)
• Prophase destruction of emi1 by the betaTrCP ubiquitin ligase activates the anaphase promoting complex to allow progression beyond prometaphase. (PMID:12791267)
• BTRC complexes with Skp1 and beta-catenin. The destruction motif binding and lysine specificity of the SCF (beta-TrCP1) ubiquitin ligase were studied. (PMID:12820959)
• Upon hyperphosphorylation, hDlg interacts with the beta-TrCP ubiquitin ligase receptor through a DSGLPS motif, and consequently, overexpression of beta-TrCP enhances ubiquitination of Dlg protein and decreases its stability. (PMID:12902344)
• alternative splicing and role implicated in interaction with HIV-1 (PMID:14526201)
• Vpu is a strong competitive inhibitor of betaTrCP that impairs the degradation of SCFbetaTrCP substrates as long as Vpu has an intact phosphorylation motif and can bind to betaTrCP. (PMID:14561767)
• beta-TrCP has a crucial role in mediating the response to DNA damage through Cdc25A degradation (PMID:14603323)
• An analysis of the NEDD8 modification on beta-TrCP ubiquitin ligase was made. (PMID:14676825)
• SCF(beta-TrCP1) abrogates TGF-beta function in vivo by decreasing Smad4 stability (PMID:14988407)
• beta-TrCP-dependent degradation of Wee1A is important for the normal onset of M-phase in vivo. (PMID:15070733)
• to investigate the role of betaTrcp1 in mammary gland development, we generated transgenic mice expressing human betaTrcp1 targeted to epithelial cells (PMID:15340078)
• Overexpression of Delta F beta TrCP1 or beta TrCP1 in vivo induce tumors through beta-catenin activation. (PMID:15735746)
• beta-TRCP1 and beta-TRCP2 were identified as F-box proteins that would associate with Per1 in a CK1epsilon-dependent manner (PMID:15917222)
• analysis of conformation of the oncogenic protein beta-catenin containing the phosphorylated motif DpSGXXpS bound to the beta-TrCP protein (PMID:15927956)
• Two Vpu analog phosphopeptides are characterized efficiently by nuclear magnetic resonance to bind to human F-box protein beta-transducin repeat containing (BTRC) protein WD domain. (PMID:16165251)
• These data suggest that p100 processing involves its phosphorylation at specific terminal serines, which form a binding site for beta-TrCP thereby regulating p100 ubiquitination. (PMID:16303288)
• betaTrCP, the vertebrate homolog of Slimb, is required for Gli3 processing, and can bind phosphorylated Gli3 both in vitro and in vivo. (PMID:16371461)
• beta-TrCP2 is a pivotal regulator of Gli2 expression and there may be an important role for posttranslational modulation of GLI2 protein levels in Hh pathway-associated human prostate cancer (PMID:16651270)
• Overexpression of BTRC is associated with Split-hand/split-foot malformation 3 (PMID:16691619)
• Multisite glycogen synthase kinase 3beta (GSK3beta) phosphorylation and ubiquitination by SCFbetaTrCP are required for Gli3 processing. (PMID:16705181)
• constitutive FN degradation, as well as UV-induced degradation, is ubiquitination dependent and controlled by beta-TrCP (PMID:16757476)
• in response to mitogens, PDCD4 was rapidly phosphorylated by protein kinase S6K1 & then degraded by ubiquitin ligase SCF(betaTRCP); it is proposed that regulated degradation of PDCD4 in response to mitogens allows efficient protein synthesis & cell growth (PMID:17053147)
• beta-TRCP1 expression significantly shortens the protein half-life of pro-caspase 3. (PMID:17217622)
• Somatic mutations of the beta-TrCP gene may contribute to the development of gastric cancer through beta-catenin stabilization. (PMID:17295679)
• The bound structure of 24P-IkappaBalpha peptide suggests that these domains are crucial for the interaction of the peptide with its receptor showing the protons identified by STD NMR as exposed in close proximity to the beta-TrCP surface. (PMID:17319651)
• Results indicate that the turnover of Mcl-1 by beta-TrCP is an essential mechanism for GSK-3beta-induced apoptosis and contributes to GSK-3beta-mediated tumor suppression and chemosensitization. (PMID:17387146)
• ESE-1 functions are coordinately regulated by Pak1 phosphorylation and beta-TrCP-dependent ubiquitin-proteasome pathways. (PMID:17491012)
• Study reveals that SCF(betaTrCP1) is an E3 ligase that activates p63 through ubiquitylation. (PMID:17965458)
• NMR allowed the study of competition for binding to beta-TrCP, between the phosphorylation motifs of ATF4 and beta-catenin and identifies the residues of the beta-TrCP receptor involved in ligand recognition. (PMID:18052253)
• GSK3 beta is a bona fide PRLr kinase that phosphorylates PRLr on Ser(349) and is required for the recognition of PRLr by beta Trcp, as well as for PRLr ubiquitination and degradation (PMID:18316598)
• REST is degraded by means of the ubiquitin ligase SCF(beta-TrCP) during the G2 phase of the cell cycle to allow transcriptional derepression of Mad2, an essential component of the spindle assembly checkpoint (PMID:18354482)
• REST is a key target in beta-TRCP-driven transformation and the beta-TRCP-REST axis is a new regulatory pathway controlling neurogenesis (PMID:18354483)
• a high level of p53 downregulates the beta-catenin expression, but this effect is attenuated by non-functional AXIN2 or betaTrCP in lung cancer. (PMID:18372914)
• Proteolysis of Bora requires the Plk1 kinase activity and is mediated by SCF-beta-TrCP; Plk1 phosphorylates a conserved DSGxxT degron in Bora and promotes its interaction with beta-TrCP. (PMID:18378770)
• We conclude that SCF(betaTrCP) is the E3 ubiquitin ligase responsible for securin degradation after UV irradiation, and that it is involved in securin turnover in nonstressed cells. (PMID:18460583)
• beta-TrCP-dependent degradation takes part in controlling cyclin D1 turnover when cancer cells undergo glucose starvation, which endows physiological relevance to this novel mechanism. (PMID:18650423)
• The SCF(beta-TrCP) binding site created by phosphorylation of beta-catenin is highly vulnerable to protein phosphatase 2A (PP2A) and must be protected by the adenomatous polyposis coli (APC) tumor suppressor protein. (PMID:19061640)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Btrc	ENSMUSG00000025217
rattus_norvegicus	Btrc	ENSRNOG00000016280
drosophila_melanogaster	slmb	FBGN0283468
caenorhabditis_elegans		WBGENE00004767

Paralogs (14): WDR54 (ENSG00000005448), FBXW11 (ENSG00000072803), FBXW7 (ENSG00000109670), TRAF7 (ENSG00000131653), FBXW9 (ENSG00000132004), FBXO36 (ENSG00000153832), WDR64 (ENSG00000162843), FBXW12 (ENSG00000164049), WDR49 (ENSG00000174776), FBXW8 (ENSG00000174989), PAAF1 (ENSG00000175575), WDR86 (ENSG00000187260), FBXO16 (ENSG00000214050), EFCAB8 (ENSG00000215529)

Protein

Protein identifiers

F-box/WD repeat-containing protein 1A — Q9Y297 (reviewed: Q9Y297)

Alternative names: E3RSIkappaB, Epididymis tissue protein Li 2a, F-box and WD repeats protein beta-TrCP, pIkappaBalpha-E3 receptor subunit

All UniProt accessions (5): A0A0S2Z4P6, A0A0S2Z507, B7Z3H4, Q9Y297, Q5T1W7

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. Recognizes and binds to phosphorylated target proteins. SCF(BTRC) mediates the ubiquitination of CTNNB1 and participates in Wnt signaling. SCF(BTRC) mediates the ubiquitination of phosphorylated NFKB1, ATF4, CDC25A, DLG1, FBXO5, PER1, SMAD3, SMAD4, SNAI1 and probably NFKB2. SCF(BTRC) mediates the ubiquitination of NFKBIA, NFKBIB and NFKBIE; the degradation frees the associated NFKB1 to translocate into the nucleus and to activate transcription. Ubiquitination of NFKBIA occurs at ‘Lys-21’ and ‘Lys-22’. 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(BTRC) mediates the ubiquitination of CEP68; this is required for centriole separation during mitosis. SCF(BTRC) mediates the ubiquitination and subsequent degradation of nuclear NFE2L1. Has an essential role in the control of the clock-dependent transcription via degradation of phosphorylated PER1 and PER2. May be involved in ubiquitination and subsequent proteasomal degradation through a DBB1-CUL4 E3 ubiquitin-protein ligase. Required for activation of NFKB-mediated transcription by IL1B, MAP3K14, MAP3K1, IKBKB and TNF. Required for proteolytic processing of GLI3. Mediates ubiquitination of REST, thereby leading to its proteasomal degradation. SCF(BTRC) mediates the ubiquitination and subsequent proteasomal degradation of KLF4; thereby negatively regulating cell pluripotency maintenance and embryogenesis. SCF(BTRC) acts as a regulator of mTORC1 signaling pathway by catalyzing ubiquitination and subsequent proteasomal degradation of phosphorylated DEPTOR, TFE3 and MITF. SCF(BTRC) directs ‘Lys-48’-linked ubiquitination of UBR2 in the T-cell receptor signaling pathway.

Subunit / interactions. Homodimer. Self-associates. Component of the SCF(BTRC) complex formed of CUL1, SKP1, RBX1 and a BTRC dimer. Direct interaction with SKP1 occurs via the F-box domain. Interacts with phosphorylated ubiquitination substrates SMAD3 and SMAD4. Interacts with phosphorylated ubiquitination substrates CTNNB1, NFKBIA, NFKBIB, NFKBIE, NFKB1/nuclear factor NF-kappa-B p105 subunit, ATF4, CDC25A, DLG1, FBXO5 and SNAI1; the interaction requires the phosphorylation of the 2 serine residues in the substrate destruction motif D-S-G-X(2,3,4)-S. Binds UBQLN1. Interacts with CDC34 and UBE2R2. Interacts with FBXW11. Interacts with CUL4A and DDB1. Part of a SCF(BTRC)-like complex lacking CUL1, which is associated with phosphorylated NKBIA and RELA; RELA interacts directly with NFKBIA. Interacts with the phosphorylated form of GLI3. Interacts with CLU. Interacts with PER1 (phosphorylated), PER2 (phosphorylated) and PER3. Interacts with phosphorylated ubiquitination substrate CEP68. Interacts with ZC3H12A; this interaction occurs when ZC3H12A is phosphorylated in a IKBKB/IKKB-dependent manner. Interacts with HSF1; this interaction occurs during mitosis and induces HSF1 ubiquitin-dependent degradation, a process inhibited by CDC20. Interacts with NFE2L1. Interacts with INAVA. Interacts with IL10RA; this interaction leads to IL10RA ubiquitination and subsequent degradation. Interacts with REST. Interacts with KLF4; this interaction leads to KLF4 ubiquitination and subsequent degradation. Interacts with UBR2, as part of a SCF(BTRC) complex; the interaction mediates ‘Lys-48’-linked ubiquitination of UBR2 and is regulated by DUSP22 in the T-cell receptor signaling pathway. (Microbial infection) Interacts with vaccinia virus A49; this interaction inhibits NF-kappa-B activation. (Microbial infection) Interacts with HIV-1 Vpu.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Expressed in epididymis (at protein level).

Post-translational modifications. Ubiquitinated. Deubiquitinated by OTUD5, promoting its stability.

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

Pathway. Protein modification; protein ubiquitination.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y297-1	1	yes
Q9Y297-2	2

RefSeq proteins (3): NP_001243785, NP_003930, NP_378663* (*=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 (64 total): strand 29, helix 14, repeat 7, turn 4, mutagenesis site 3, region of interest 2, sequence variant 2, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
9T9W	X-RAY DIFFRACTION	1.16
9TES	X-RAY DIFFRACTION	1.22
9TDZ	X-RAY DIFFRACTION	1.35
9TG7	X-RAY DIFFRACTION	1.68
9T8Y	X-RAY DIFFRACTION	1.79
9TFU	X-RAY DIFFRACTION	2
6M90	X-RAY DIFFRACTION	2.05
9T95	X-RAY DIFFRACTION	2.15
6M92	X-RAY DIFFRACTION	2.35
6M91	X-RAY DIFFRACTION	2.4
2P64	X-RAY DIFFRACTION	2.5
6M93	X-RAY DIFFRACTION	2.5
6M94	X-RAY DIFFRACTION	2.7
1P22	X-RAY DIFFRACTION	2.95
6TTU	ELECTRON MICROSCOPY	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y297-F1	80.33	0.63

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (3):

Position	Phenotype
307	abolished binding to tfe3 and mitf substrates.
321	abolished binding to tfe3 and mitf substrates.
510	abolished binding to deptor, tfe3 and mitf substrates.

Function

Pathways and Gene Ontology

Reactome pathways

23 pathways

ID	Pathway
R-HSA-1169091	Activation of NF-kappaB in B cells
R-HSA-1170546	Prolactin receptor signaling
R-HSA-174113	SCF-beta-TrCP mediated degradation of Emi1
R-HSA-180534	Vpu mediated degradation of CD4
R-HSA-195253	Degradation of beta-catenin by the destruction complex
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-3769402	Deactivation of the beta-catenin transactivating complex
R-HSA-5607761	Dectin-1 mediated noncanonical NF-kB signaling
R-HSA-5607764	CLEC7A (Dectin-1) signaling
R-HSA-5610780	Degradation of GLI1 by the proteasome
R-HSA-5610783	Degradation of GLI2 by the proteasome
R-HSA-5610785	GLI3 is processed to GLI3R by the proteasome
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-9020702	Interleukin-1 signaling
R-HSA-9762114	GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-9929356	GSK3B-mediated proteasomal degradation of PD-L1(CD274)
R-HSA-9932298	Degradation of CRY and PER proteins

MSigDB gene sets: 403 (showing top): GOBP_CIRCADIAN_RHYTHM, GOBP_REGULATION_OF_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GCM_MAP4K4, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MAMMARY_GLAND_MORPHOGENESIS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_GLAND_MORPHOGENESIS, GCM_PTPRD, KEGG_HEDGEHOG_SIGNALING_PATHWAY, GCM_GSPT1, DACOSTA_UV_RESPONSE_VIA_ERCC3_XPCS_DN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM

GO Biological Process (36): negative regulation of transcription by RNA polymerase II (GO:0000122), protein polyubiquitination (GO:0000209), protein dephosphorylation (GO:0006470), ubiquitin-dependent protein catabolic process (GO:0006511), signal transduction (GO:0007165), Wnt signaling pathway (GO:0016055), protein ubiquitination (GO:0016567), SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146), protein destabilization (GO:0031648), mammary gland epithelial cell proliferation (GO:0033598), non-canonical NF-kappaB signal transduction (GO:0038061), regulation of circadian rhythm (GO:0042752), positive regulation of circadian rhythm (GO:0042753), regulation of canonical NF-kappaB signal transduction (GO:0043122), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), positive regulation of proteolysis (GO:0045862), negative regulation of smoothened signaling pathway (GO:0045879), positive regulation of DNA-templated transcription (GO:0045893), rhythmic process (GO:0048511), negative regulation of T cell receptor signaling pathway (GO:0050860), regulation of cell cycle (GO:0051726), branching involved in mammary gland duct morphogenesis (GO:0060444), regulation of canonical Wnt signaling pathway (GO:0060828), regulation of proteasomal protein catabolic process (GO:0061136), protein K48-linked ubiquitination (GO:0070936), autophagosome assembly (GO:0000045), lysosome organization (GO:0007040), negative regulation of autophagy (GO:0010507), positive regulation of autophagy (GO:0010508), protein catabolic process (GO:0030163), cellular response to nutrient levels (GO:0031669), TORC1 signaling (GO:0038202), T cell receptor signaling pathway (GO:0050852), positive regulation of T cell receptor signaling pathway (GO:0050862), protein K63-linked ubiquitination (GO:0070534), negative regulation of TORC1 signaling (GO:1904262)

GO Molecular Function (8): beta-catenin binding (GO:0008013), ligase activity (GO:0016874), protein phosphorylated amino acid binding (GO:0045309), protein dimerization activity (GO:0046983), ubiquitin protein ligase activity (GO:0061630), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), ubiquitin ligase activator activity (GO:1990757), protein binding (GO:0005515)

GO Cellular Component (5): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), SCF ubiquitin ligase complex (GO:0019005), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-19 pathways:

Category	Pathways
Hedgehog ‘off’ state	3
Downstream signaling events of B Cell Receptor (BCR)	1
Cytokine Signaling in Immune system	1
Regulation of APC/C activators between G1/S and early anaphase	1
Host Interactions of HIV factors	1
Signaling by WNT	1
TCR signaling	1
G2/M Transition	1
Fc epsilon receptor (FCERI) signaling	1
TCF dependent signaling in response to WNT	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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein ubiquitination	2
circadian rhythm	2
protein binding	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
dephosphorylation	1
protein modification process	1
modification-dependent protein catabolic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell surface receptor signaling pathway	1
protein modification by small protein conjugation	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
regulation of protein stability	1
epithelial cell proliferation	1
mammary gland epithelium development	1
intracellular signaling cassette	1
regulation of biological process	1
regulation of circadian rhythm	1
positive regulation of biological process	1
canonical NF-kappaB signal transduction	1
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
smoothened signaling pathway	1
regulation of smoothened signaling pathway	1
negative regulation of signal transduction	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
biological_process	1
T cell receptor signaling pathway	1

Protein interactions and networks

STRING

3340 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BTRC	SKP1	P34991	999
BTRC	CUL1	Q13616	999
BTRC	RBX1	P62877	997
BTRC	CTNNB1	P35222	997
BTRC	AXIN1	O15169	996
BTRC	GSK3B	P49841	996
BTRC	NFKBIA	P25963	984
BTRC	SKP2	Q13309	975
BTRC	DDB1	Q16531	973
BTRC	APC	P25054	963
BTRC	CUL4A	Q13619	951
BTRC	AXIN2	Q9Y2T1	926
BTRC	CCNF	P41002	921
BTRC	IGF2BP1	Q9NZI8	892
BTRC	CUL3	Q13618	880

IntAct

375 interactions, top by confidence:

A	B	Type	Score
CUL1	RBX1	psi-mi:“MI:0914”(association)	0.980
SKP1	BTRC	psi-mi:“MI:0915”(physical association)	0.960
SKP1	BTRC	psi-mi:“MI:2364”(proximity)	0.960
BTRC	SKP1	psi-mi:“MI:0915”(physical association)	0.960
BTRC	SKP1	psi-mi:“MI:0914”(association)	0.960
BTRC	SKP1	psi-mi:“MI:2364”(proximity)	0.960
ATF4	BTRC	psi-mi:“MI:0915”(physical association)	0.950
BTRC	ATF4	psi-mi:“MI:0915”(physical association)	0.950

BioGRID (1769): BTRC (Affinity Capture-Western), BTRC (Affinity Capture-MS), BTRC (Affinity Capture-Western), TRIM9 (Affinity Capture-Western), NFKBIA (Affinity Capture-Western), CDK1 (Affinity Capture-MS), CDK1 (Affinity Capture-Western), CTNNB1 (Affinity Capture-Western), CCNB1 (Affinity Capture-Western), CCNB1 (Affinity Capture-MS), BTRC (Affinity Capture-Western), CDK1 (Biochemical Activity), BTRC (Affinity Capture-Western), RASSF5 (Affinity Capture-Western), BHLHE40 (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

27 interactions.

A	Effect	B	Mechanism
BTRC	down-regulates	SMAD3	ubiquitination
BTRC	down-regulates	SMAD4	ubiquitination
BTRC	up-regulates	CDC25A	ubiquitination
BTRC	down-regulates	WEE1	binding
BTRC	down-regulates	PER1	ubiquitination
BTRC	“down-regulates quantity by destabilization”	GLI3	ubiquitination
BTRC	down-regulates	PDCD4	ubiquitination
BTRC	down-regulates	YAP1	ubiquitination
BTRC	down-regulates	RAP1GAP	ubiquitination
BTRC	down-regulates	EZH2	ubiquitination
PRKAA1	“down-regulates quantity by destabilization”	BTRC	phosphorylation
FBXW11	“down-regulates quantity by destabilization”	BTRC	binding
“Cullin 1-RBX1-Skp1”	“down-regulates quantity by destabilization”	BTRC	polyubiquitination
ATM	“up-regulates quantity by stabilization”	BTRC	phosphorylation
BTRC	“form complex”	SCF-betaTRCP	binding
BTRC	down-regulates	CTNNB1	ubiquitination
BTRC	“down-regulates quantity by destabilization”	GLI2	ubiquitination
BTRC	“down-regulates quantity by destabilization”	GLI1	ubiquitination
mTORC1	“up-regulates activity”	BTRC	phosphorylation
BTRC	“down-regulates quantity by destabilization”	ATF2	ubiquitination
BTRC	“down-regulates quantity by destabilization”	NFKBIB	binding
BTRC	“up-regulates activity”	“Cullin 1-RBX1-Skp1”	binding
BTRC	“down-regulates quantity by destabilization”	NFKB1	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 82 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	5	58.5×	2e-06
Activation of NF-kappaB in B cells	7	22.6×	2e-06
FCERI mediated NF-kB activation	8	20.5×	2e-06
FBXL7 down-regulates AURKA during mitotic entry and in early mitosis	5	20.4×	2e-04
GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2	5	20.4×	2e-04
Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A	6	20.1×	3e-05
Degradation of beta-catenin by the destruction complex	7	19.9×	5e-06
Negative regulation of NOTCH4 signaling	5	19.5×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process	5	25.3×	3e-04
canonical NF-kappaB signal transduction	5	24.8×	3e-04
cellular response to glucose starvation	5	22.8×	3e-04
positive regulation of epithelial to mesenchymal transition	5	21.5×	3e-04
mitotic spindle organization	5	18.4×	6e-04
positive regulation of protein ubiquitination	6	17.3×	3e-04
positive regulation of proteasomal ubiquitin-dependent protein catabolic process	6	17.1×	3e-04
osteoblast differentiation	7	11.5×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	2
Uncertain significance	98
Likely benign	29
Benign	6

Top pathogenic / likely-pathogenic (18)

Variant ID	HGVS	Classification
148343	GRCh38/hg38 10q24.32(chr10:101209582-101748381)x3	Pathogenic
155194	GRCh38/hg38 10q24.31-24.32(chr10:101177305-101719109)x3	Pathogenic
1807766	GRCh37/hg19 10q24.31-24.32(chr10:102958930-103445585)x3	Pathogenic
2684618	GRCh37/hg19 10q24.31-24.32(chr10:102958930-103525401)x3	Pathogenic
3250369	NC_000010.10:g.103012761_103546704dup	Pathogenic
3250370	NC_000010.10:g.103001852_103543913dup	Pathogenic
395169	GRCh37/hg19 10q24.32(chr10:103208804-103449273)x3	Pathogenic
4075980	GRCh37/hg19 10q24.31-24.32(chr10:102927452-103392888)x3	Pathogenic
442850	GRCh37/hg19 10q24.31-24.32(chr10:102947729-103488168)x3	Pathogenic
443140	GRCh37/hg19 10q24.31-24.32(chr10:102949227-103482524)x3	Pathogenic
443365	GRCh37/hg19 10q24.31-24.32(chr10:102949737-103432420)x3	Pathogenic
58778	GRCh38/hg38 10q24.32(chr10:101416272-101689575)x1	Pathogenic
590885	Single allele	Pathogenic
59708	GRCh38/hg38 10q24.31-24.32(chr10:101120347-101831908)x3	Pathogenic
59709	GRCh38/hg38 10q24.32(chr10:101253669-101395093)x3	Pathogenic
59725	GRCh38/hg38 10q24.32(chr10:101297763-101618190)x3	Pathogenic
3063127	GRCh37/hg19 10q24.31-24.32(chr10:102981549-103472860)x3	Likely pathogenic
3063128	GRCh37/hg19 10q24.31-24.32(chr10:102965124-103403057)x3	Likely pathogenic

SpliceAI

3483 predictions. Top by Δscore:

Variant	Effect	Δscore
10:101461977:ACAG:A	acceptor_loss	1.0000
10:101461978:CA:C	acceptor_loss	1.0000
10:101461979:A:AG	acceptor_gain	1.0000
10:101461979:AG:A	acceptor_loss	1.0000
10:101461980:G:GG	acceptor_gain	1.0000
10:101461980:GA:G	acceptor_gain	1.0000
10:101462056:CAGGT:C	donor_loss	1.0000
10:101462057:AGGTA:A	donor_loss	1.0000
10:101462058:GG:G	donor_loss	1.0000
10:101462059:G:GC	donor_loss	1.0000
10:101462060:T:A	donor_loss	1.0000
10:101479455:AAAGT:A	donor_loss	1.0000
10:101479456:AA:A	donor_gain	1.0000
10:101479457:AGTA:A	donor_loss	1.0000
10:101479458:G:GG	donor_gain	1.0000
10:101479459:TAAG:T	donor_loss	1.0000
10:101504241:T:G	donor_gain	1.0000
10:101525991:T:TA	acceptor_gain	1.0000
10:101526007:T:A	acceptor_gain	1.0000
10:101526011:A:AG	acceptor_gain	1.0000
10:101526012:G:GG	acceptor_gain	1.0000
10:101526195:GGATG:G	donor_gain	1.0000
10:101526196:GATGG:G	donor_gain	1.0000
10:101532290:CTCA:C	acceptor_loss	1.0000
10:101532291:TCAG:T	acceptor_loss	1.0000
10:101532292:CA:C	acceptor_loss	1.0000
10:101532293:A:AG	acceptor_gain	1.0000
10:101532294:G:GA	acceptor_gain	1.0000
10:101532294:GA:G	acceptor_gain	1.0000
10:101532294:GAC:G	acceptor_gain	1.0000

AlphaMissense

3959 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:101521781:T:C	L156P	1.000
10:101521829:T:C	L172P	1.000
10:101521841:T:C	L176S	1.000
10:101521849:G:C	D179H	1.000
10:101521850:A:C	D179A	1.000
10:101521850:A:G	D179G	1.000
10:101521850:A:T	D179V	1.000
10:101526046:T:C	L197P	1.000
10:101526099:T:A	W215R	1.000
10:101526099:T:C	W215R	1.000
10:101526101:G:C	W215C	1.000
10:101526101:G:T	W215C	1.000
10:101526129:T:A	W225R	1.000
10:101526129:T:C	W225R	1.000
10:101526130:G:C	W225S	1.000
10:101526131:G:C	W225C	1.000
10:101526131:G:T	W225C	1.000
10:101526171:T:A	W239R	1.000
10:101526171:T:C	W239R	1.000
10:101526198:T:A	W248R	1.000
10:101526198:T:C	W248R	1.000
10:101532310:T:A	W286R	1.000
10:101532310:T:C	W286R	1.000
10:101532311:G:C	W286S	1.000
10:101532312:G:C	W286C	1.000
10:101532312:G:T	W286C	1.000
10:101532346:T:C	C298R	1.000
10:101532347:G:A	C298Y	1.000
10:101532348:C:G	C298W	1.000
10:101532367:G:A	G305R	1.000

dbSNP variants (sampled 300 via entrez): RS1000015349 (10:101502477 A>G), RS1000032919 (10:101510230 C>T), RS1000040645 (10:101450633 A>G), RS1000059982 (10:101353764 A>T), RS1000068187 (10:101536316 C>T), RS1000073680 (10:101490372 G>T), RS1000075707 (10:101390812 G>A,T), RS1000076567 (10:101503817 C>T), RS1000081703 (10:101520489 G>A), RS1000085493 (10:101483447 G>T), RS1000087041 (10:101502832 G>A), RS1000098924 (10:101437441 A>G), RS1000139338 (10:101371714 G>A,C), RS1000140796 (10:101415935 C>T), RS1000209705 (10:101462697 A>C)

Disease associations

OMIM: gene MIM:603482 | disease phenotypes: MIM:183600

GenCC curated gene-disease

Mondo (1): split hand-foot malformation (MONDO:0016576)

Orphanet (1): Isolated split hand-split foot malformation (Orphanet:2440)

HPO phenotypes

8 total (8 of 8 shown, HPO-id order):

HPO	Term
HP:0000407	Sensorineural hearing impairment
HP:0000526	Aniridia
HP:0001171	Split hand
HP:0001839	Split foot
HP:0004050	Absent hand
HP:0004058	Hand monodactyly
HP:0006101	Finger syndactyly
HP:0012165	Oligodactyly

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST005996_49	Red blood cell count	3.000000e-08
GCST006627_19	Diastolic blood pressure	3.000000e-10
GCST007327_72	Smoking status (ever vs never smokers)	4.000000e-08
GCST011122_69	Walking pace	4.000000e-10
GCST011703_46	Smoking initiation	2.000000e-10
GCST90000015_3	Parkinson’s disease motor subtype (tremor to postural instability/gait difficulty score ratio)	8.000000e-07
GCST90002404_498	Red cell distribution width	1.000000e-15

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004305	erythrocyte count
EFO:0006336	diastolic blood pressure
EFO:0004318	smoking behavior
EFO:0005670	smoking initiation
EFO:0600011	Parkinson’s disease symptom measurement
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10883617	BTRC		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole	decreases expression, decreases reaction, affects cotreatment	2
Benzo(a)pyrene	affects methylation, decreases expression	2
WEHI-539	increases expression, increases reaction, affects cotreatment, decreases expression, decreases reaction (+1 more)	1
2-anisidine	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
bisphenol A	increases methylation, affects cotreatment	1
trichostatin A	affects expression	1
sodium arsenite	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
hydroquinone	affects reaction, increases expression, increases reaction, affects cotreatment, decreases expression (+1 more)	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
PKF115-584	increases expression	1
bisphenol S	affects cotreatment, decreases expression	1
venetoclax	increases expression, increases reaction, affects cotreatment, decreases expression, decreases reaction (+1 more)	1
Fulvestrant	affects cotreatment, increases methylation	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Air Pollutants	decreases expression, increases abundance, affects cotreatment	1
Carbamazepine	affects expression	1
Chloroquine	decreases reaction, affects cotreatment, decreases expression	1
Dactinomycin	affects cotreatment, decreases expression, increases reaction	1
Daunorubicin	decreases expression, decreases reaction, increases expression, increases stability	1
Dexamethasone	decreases expression, affects cotreatment	1
Drugs, Chinese Herbal	increases expression, affects reaction	1
Estradiol	affects binding, affects cotreatment, increases reaction, decreases reaction	1
Indomethacin	affects cotreatment, decreases expression	1
Lead	decreases expression	1
Methotrexate	increases expression	1

Cellosaurus cell lines

10 cell lines: 8 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2T5	Abcam HEK293T BTRC KO	Transformed cell line	Female
CVCL_B7WC	Abcam Raji BTRC KO	Cancer cell line	Male
CVCL_B9WV	Abcam THP-1 BTRC KO	Cancer cell line	Male
CVCL_C6YW	Abcam PC-3 BTRC KO	Cancer cell line	Male
CVCL_D7L4	Ubigene A-549 BTRC KO	Cancer cell line	Male
CVCL_D8HZ	Ubigene HCT 116 BTRC KO	Cancer cell line	Male
CVCL_D9AD	Ubigene HEK293 BTRC KO	Transformed cell line	Female
CVCL_D9YV	Ubigene HeLa BTRC KO	Cancer cell line	Female
CVCL_SF91	HAP1 BTRC (-) 1	Cancer cell line	Male
CVCL_SF92	HAP1 BTRC (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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