BTRC (beta-transducin repeat containing)

2008-12-01   Baolin Wang 

Department of Genetic Medicine, Department of Cell, Developmental Biology, Weill Medical College of Cornell University, 1300 York Avenue, W404, New York, NY 10065, USA




Atlas Image
Figure 1. The betaTrCP1 gene structure.


Spans 223.25 kb; 14 exons; 13 coding exons (Figure 1).


Full length transcript of 6011 bp, open reading frame 1707 bp. There is an alternatively spliced transcript (Figure 1).


Atlas Image
Figure 2. Two isoformes of betaTrCP1 protein.


There are two isoforms of betaTrCP1; isoform 1 consists of 569 amino acid residues and isoform 2 comprises 605 amino acid residues. Both isoforms contain an F-box domain and seven WD40 repeats, which bind SKP1 and protein substrates, respectively. Their function is indistinguishable (Figure 2).


BetaTrCP1 is expressed in the majority of human tissues with high levels in the brain, heart, and testis, but undetectable levels in the small intestine and thymus (Cenciarelli et al., 1999).


betaTrCP1 protein is predominantly localized in the nucleus, while betaTrCP2 is primarily found in the cytoplasm (Cenciarelli et al., 1999; Lassot et al., 2001; Davis et al., 2002).
Atlas Image
Figure 3. Diagrammatic drawing showing the SCF complex and how it recognizes its substrate for degradation by the proteasome. (Ub)n, polyubiquitin; P, phosphate group; E1 and E2, ubiquitin E1 and E2 enzymes; Cul1, RBX1, Skp1, and F box protein, SCF components.


BetaTrCP1 is a member of the F-box proteins. Sixty nine F-box proteins have been identified in humans, and they are classified into three groups: those with WD40 domains (FBXWs), those with leucine-rich repeats (FBXLs), and those with other diverse domains (FBXOs) (Cenciarelli et al., 1999; Winston et al., 1999a; Jin et al., 2004). BetaTrCP1 is the substrate recognition subunit, which together with SKP1, Cullin1, and RBX1 (also known as ROC1), makes up the SCF (SKP1-CUL-F-box protein) complex or E3 ubiquitin ligase. BetaTrCP1 recognizes a DSGXXS destruction motif in which the serine residues are phosphorylated by specific kinases (Fig. 3). It also binds the variants of this motif where acidic residues substitute for phosphorylated serine residues (Frescas and Pagano, 2008). The binding of BTrCP results in ubiquitination and subsequent degradation of its substrates by the proteasome (Fig. 3).
Targets of the SCF ubiquitin ligase can be divided into two main groups on the basis of their function: cell cycle regulators and transcription factors. They include: IKappaB (Yaron et al., 1998; Hatakeyama et al., 1999; Kroll et al., 1999; Shirane et al., 1999; Spencer et al., 1999; Tan et al., 1999; Winston et al., 1999b; Wu and Ghosh, 1999), NFkappaB (Orian et al., 2000; Fong and Sun, 2002; Lang et al., 2003; Amir et al., 2004), beta-catenin (Kitagawa et al., 1999; Winston et al., 1999b), GLI2 (Huntzicker et al., 2006; Pan et al., 2006), GLI3 (Wang and Li, 2006; Tempe et al., 2006), REST (Guardavaccaro et al., 2008; Westbrook et al., 2008), ATF4 (Lassot et al., 2001), PER1/PER2 (Eide et al., 2005; Shirogane et al., 2005; Reischl et al., 2007), VPU (Besnard-Guerin et al., 2004), Claspin (Peschiaroli et al., 2006; Mailand et al., 2006), Emi1 (Guardavaccaro et al., 2003), CDC25A (Busino et al., 2003; Kanemori et al., 2005), CDC25B (Kanemori et al., 2005), WEE1 (Watanabe et al., 2004), MLC1 (Ding et al., 2007), etc. Among these targets, NFkappaB, GLI2, and GLI3 are degraded in a limited fashion instead of completely (Fig. 3).


BetaTrCP1 is paralogous to betaTrCP2 (also termed HOS or Fbw1b) (Fuchs et al., 1999; Suzuki et al., 2000; Bhatia et al., 2002); the two are collectively called BTrCP, as their biochemical properties are indistinguishable. BTrCP is homologous to Slimb in Drosophila, which targets Armidillo (the B-catenin homolog) and Ci (the homolog of Gli) for degradation, though limited for the latter (Jiang and Struhl, 1998; Jia et al., 2005; Smelkinson and Kalderon, 2006; Smelkinson et al., 2007).



Mutations in BTrCP in both germinal and somatic cells are rarely found in human tumors, probably because of the redundancy of the two BTrCP paralogues.

Implicated in

Entity name
Various Cancer
Overwhelming evidence indicates that BTrCP mostly displays an oncogenic activity. Two point mutations in betaTrCP1 have been found from 22 prostate cancer samples (Gerstein et al., 2002). Five missense mutations have also been identified in 95 gastric cancers (Kim et al., 2007). In addition, an in-frame deletion of three amino acid residues in betaTrCP2 has been detected in breast cancers in a large scale genomic DNA sequencing project (Wood et al., 2007). However, it is not clear whether these mutations causally associate with tumorigenesis, as the function of these mutated BTrCP gene products has not been determined. On the other hand, it has been well established that overexpression of bTrCP proteins is associated with several types of human tumors, including colorectal cancers (Ougolkov et al., 2004), pancreatic cancers (Muerkoster et al., 2005), and breast cancers (Spiegelman et al., 2002), melanoma (Dhawan and Richmond, 2002; Liu et al., 2007), and hepatoblastomas (Koch et al., 2005). In most of these tumors, overexpression of BTrCP results in the degradation of IKappaB, an inhibitor for the NFkappaB transcription factor, and thus the activation of NFkappaB. In others, the increased BTrCP expression also correlates with the activation of beta-catenin, the transcription regulator for WNT signaling. Therefore, it is believed that the activation of either NFkappaB, beta-catenin, or both is the main mechanism by which the upregulated BTrCP expression results in uncontrolled cell proliferation in these tumors.


Pubmed IDLast YearTitleAuthors
146768252004Mechanism of processing of the NF-kappa B2 p100 precursor: identification of the specific polyubiquitin chain-anchoring lysine residue and analysis of the role of NEDD8-modification on the SCF(beta-TrCP) ubiquitin ligase.Amir RE et al
145617672004HIV-1 Vpu sequesters beta-transducin repeat-containing protein (betaTrCP) in the cytoplasm and provokes the accumulation of beta-catenin and other SCFbetaTrCP substrates.Besnard-Guerin C et al
118965782002Mouse homologue of HOS (mHOS) is overexpressed in skin tumors and implicated in constitutive activation of NF-kappaB.Bhatia N et al
146033232003Degradation of Cdc25A by beta-TrCP during S phase and in response to DNA damage.Busino L et al
105310351999Identification of a family of human F-box proteins.Cenciarelli C et al
118504072002Pseudosubstrate regulation of the SCF(beta-TrCP) ubiquitin ligase by hnRNP-U.Davis M et al
117730612002A novel NF-kappa B-inducing kinase-MAPK signaling pathway up-regulates NF-kappa B activity in melanoma cells.Dhawan P et al
173871462007Degradation of Mcl-1 by beta-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization.Ding Q et al
157676832005Control of mammalian circadian rhythm by CKIepsilon-regulated proteasome-mediated PER2 degradation.Eide EJ et al
119942702002Genetic evidence for the essential role of beta-transducin repeat-containing protein in the inducible processing of NF-kappa B2/p100.Fong A et al
185002452008Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer.Frescas D et al
103217281999HOS, a human homolog of Slimb, forms an SCF complex with Skp1 and Cullin1 and targets the phosphorylation-dependent degradation of IkappaB and beta-catenin.Fuchs SY et al
119212772002APC/CTNNB1 (beta-catenin) pathway alterations in human prostate cancers.Gerstein AV et al
183544822008Control of chromosome stability by the beta-TrCP-REST-Mad2 axis.Guardavaccaro D et al
100971281999Ubiquitin-dependent degradation of IkappaBalpha is mediated by a ubiquitin ligase Skp1/Cul 1/F-box protein FWD1.Hatakeyama S et al
164212752006Dual degradation signals control Gli protein stability and tumor formation.Huntzicker EG et al
163263932005Phosphorylation by double-time/CKIepsilon and CKIalpha targets cubitus interruptus for Slimb/beta-TRCP-mediated proteolytic processing.Jia J et al
94612171998Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb.Jiang J et al
155202772004Systematic analysis and nomenclature of mammalian F-box proteins.Jin J et al
158457712005Beta-TrCP recognizes a previously undescribed nonphosphorylated destruction motif in Cdc25A and Cdc25B phosphatases.Kanemori Y et al
172956792007Somatic mutations of the beta-TrCP gene in gastric cancer.Kim CJ et al
102281551999An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin.Kitagawa M et al
159586102005Elevated expression of Wnt antagonists is a common event in hepatoblastomas.Koch A et al
100756901999Inducible degradation of IkappaBalpha by the proteasome requires interaction with the F-box protein h-betaTrCP.Kroll M et al
124829912003betaTrCP-mediated proteolysis of NF-kappaB1 p105 requires phosphorylation of p105 serines 927 and 932.Lang V et al
112389522001ATF4 degradation relies on a phosphorylation-dependent interaction with the SCF(betaTrCP) ubiquitin ligase.Lassot I et al
170013492007Oncogenic BRAF regulates beta-Trcp expression and NF-kappaB activity in human melanoma cells.Liu J et al
168850212006Destruction of Claspin by SCFbetaTrCP restrains Chk1 activation and facilitates recovery from genotoxic stress.Mailand N et al
157350172005Increased expression of the E3-ubiquitin ligase receptor subunit betaTRCP1 relates to constitutive nuclear factor-kappaB activation and chemoresistance in pancreatic carcinoma cells.Müerköster S et al
108353562000SCF(beta)(-TrCP) ubiquitin ligase-mediated processing of NF-kappaB p105 requires phosphorylation of its C-terminus by IkappaB kinase.Orian A et al
152923882004Associations among beta-TrCP, an E3 ubiquitin ligase receptor, beta-catenin, and NF-kappaB in colorectal cancer.Ougolkov A et al
166119812006Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation.Pan Y et al
168850222006SCFbetaTrCP-mediated degradation of Claspin regulates recovery from the DNA replication checkpoint response.Peschiaroli A et al
178760592007Beta-TrCP1-mediated degradation of PERIOD2 is essential for circadian dynamics.Reischl S et al
104971691999Common pathway for the ubiquitination of IkappaBalpha, IkappaBbeta, and IkappaBepsilon mediated by the F-box protein FWD1.Shirane M et al
159172222005SCFbeta-TRCP controls clock-dependent transcription via casein kinase 1-dependent degradation of the mammalian period-1 (Per1) protein.Shirogane T et al
179252252007Regulation of Ci-SCFSlimb binding, Ci proteolysis, and hedgehog pathway activity by Ci phosphorylation.Smelkinson MG et al
99908531999Signal-induced ubiquitination of IkappaBalpha by the F-box protein Slimb/beta-TrCP.Spencer E et al
121513972002Induction of homologue of Slimb ubiquitin ligase receptor by mitogen signaling.Spiegelman VS et al
106447552000Homodimer of two F-box proteins betaTrCP1 or betaTrCP2 binds to IkappaBalpha for signal-dependent ubiquitination.Suzuki H et al
102304061999Recruitment of a ROC1-CUL1 ubiquitin ligase by Skp1 and HOS to catalyze the ubiquitination of I kappa B alpha.Tan P et al
167051812006Multisite protein kinase A and glycogen synthase kinase 3beta phosphorylation leads to Gli3 ubiquitination by SCFbetaTrCP.Tempé D et al
163714612006Evidence for the direct involvement of {beta}TrCP in Gli3 protein processing.Wang B et al
150707332004M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFbeta-TrCP.Watanabe N et al
183544832008SCFbeta-TRCP controls oncogenic transformation and neural differentiation through REST degradation.Westbrook TF et al
99908521999The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro.Winston JT et al
179322542007The genomic landscapes of human breast and colorectal cancers.Wood LD et al
105144241999beta-TrCP mediates the signal-induced ubiquitination of IkappaBbeta.Wu C et al
98599961998Identification of the receptor component of the IkappaBalpha-ubiquitin ligase.Yaron A et al

Other Information

Locus ID:

NCBI: 8945
MIM: 603482
HGNC: 1144
Ensembl: ENSG00000166167


dbSNP: 8945
ClinVar: 8945
TCGA: ENSG00000166167


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Ubiquitin mediated proteolysisKEGGko04120
Wnt signaling pathwayKEGGko04310
Hedgehog signaling pathwayKEGGko04340
Circadian rhythmKEGGko04710
Ubiquitin mediated proteolysisKEGGhsa04120
Wnt signaling pathwayKEGGhsa04310
Hedgehog signaling pathwayKEGGhsa04340
Circadian rhythmKEGGhsa04710
Oocyte meiosisKEGGko04114
Oocyte meiosisKEGGhsa04114
SCF-BTRC complexKEGGhsa_M00380
Hippo signaling pathwayKEGGhsa04390
Hippo signaling pathwayKEGGko04390
SCF-BTRC complexKEGGM00380
Infectious diseaseREACTOMER-HSA-5663205
HIV InfectionREACTOMER-HSA-162906
Host Interactions of HIV factorsREACTOMER-HSA-162909
Vpu mediated degradation of CD4REACTOMER-HSA-180534
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
TCR signalingREACTOMER-HSA-202403
Downstream TCR signalingREACTOMER-HSA-202424
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Downstream signaling events of B Cell Receptor (BCR)REACTOMER-HSA-1168372
Activation of NF-kappaB in B cellsREACTOMER-HSA-1169091
Class I MHC mediated antigen processing & presentationREACTOMER-HSA-983169
Antigen processing: Ubiquitination & Proteasome degradationREACTOMER-HSA-983168
Innate Immune SystemREACTOMER-HSA-168249
Toll-Like Receptors CascadesREACTOMER-HSA-168898
Toll Like Receptor 10 (TLR10) CascadeREACTOMER-HSA-168142
MyD88 cascade initiated on plasma membraneREACTOMER-HSA-975871
MAP kinase activation in TLR cascadeREACTOMER-HSA-450294
Toll Like Receptor 3 (TLR3) CascadeREACTOMER-HSA-168164
MyD88-independent TLR3/TLR4 cascadeREACTOMER-HSA-166166
TRIF-mediated TLR3/TLR4 signalingREACTOMER-HSA-937061
Toll Like Receptor 5 (TLR5) CascadeREACTOMER-HSA-168176
Toll Like Receptor 7/8 (TLR7/8) CascadeREACTOMER-HSA-168181
MyD88 dependent cascade initiated on endosomeREACTOMER-HSA-975155
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activationREACTOMER-HSA-975138
Toll Like Receptor 9 (TLR9) CascadeREACTOMER-HSA-168138
Toll Like Receptor 4 (TLR4) CascadeREACTOMER-HSA-166016
Activated TLR4 signallingREACTOMER-HSA-166054
MyD88:Mal cascade initiated on plasma membraneREACTOMER-HSA-166058
Toll Like Receptor 2 (TLR2) CascadeREACTOMER-HSA-181438
Toll Like Receptor TLR1:TLR2 CascadeREACTOMER-HSA-168179
Toll Like Receptor TLR6:TLR2 CascadeREACTOMER-HSA-168188
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated NF-kB activationREACTOMER-HSA-2871837
C-type lectin receptors (CLRs)REACTOMER-HSA-5621481
CLEC7A (Dectin-1) signalingREACTOMER-HSA-5607764
Dectin-1 mediated noncanonical NF-kB signalingREACTOMER-HSA-5607761
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-1 signalingREACTOMER-HSA-446652
Prolactin receptor signalingREACTOMER-HSA-1170546
TNFR2 non-canonical NF-kB pathwayREACTOMER-HSA-5668541
NIK-->noncanonical NF-kB signalingREACTOMER-HSA-5676590
Signal TransductionREACTOMER-HSA-162582
Signaling by WntREACTOMER-HSA-195721
Degradation of beta-catenin by the destruction complexREACTOMER-HSA-195253
TCF dependent signaling in response to WNTREACTOMER-HSA-201681
Deactivation of the beta-catenin transactivating complexREACTOMER-HSA-3769402
Signaling by HedgehogREACTOMER-HSA-5358351
Hedgehog 'off' stateREACTOMER-HSA-5610787
GLI3 is processed to GLI3R by the proteasomeREACTOMER-HSA-5610785
Degradation of GLI2 by the proteasomeREACTOMER-HSA-5610783
Degradation of GLI1 by the proteasomeREACTOMER-HSA-5610780
Cell CycleREACTOMER-HSA-1640170
Cell Cycle, MitoticREACTOMER-HSA-69278
Mitotic G2-G2/M phasesREACTOMER-HSA-453274
G2/M TransitionREACTOMER-HSA-69275
Regulation of PLK1 Activity at G2/M TransitionREACTOMER-HSA-2565942
Regulation of mitotic cell cycleREACTOMER-HSA-453276
APC/C-mediated degradation of cell cycle proteinsREACTOMER-HSA-174143
Regulation of APC/C activators between G1/S and early anaphaseREACTOMER-HSA-176408
SCF-beta-TrCP mediated degradation of Emi1REACTOMER-HSA-174113
Circadian ClockREACTOMER-HSA-400253
MAP3K8 (TPL2)-dependent MAPK1/3 activationREACTOMER-HSA-5684264

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
200480012010A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP).443
170531472006S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth.259
128209592003Structure of a beta-TrCP1-Skp1-beta-catenin complex: destruction motif binding and lysine specificity of the SCF(beta-TrCP1) ubiquitin ligase.248
195157792009Vpu directs the degradation of the human immunodeficiency virus restriction factor BST-2/Tetherin via a {beta}TrCP-dependent mechanism.216
194788682009Vpu antagonizes BST-2-mediated restriction of HIV-1 release via beta-TrCP and endo-lysosomal trafficking.206
150707332004M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFbeta-TrCP.192
146033232003Degradation of Cdc25A by beta-TrCP during S phase and in response to DNA damage.182
173871462007Degradation of Mcl-1 by beta-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization.180
229646422013Nrf2 is controlled by two distinct β-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity.158
183544832008SCFbeta-TRCP controls oncogenic transformation and neural differentiation through REST degradation.152


Baolin Wang

BTRC (beta-transducin repeat containing)

Atlas Genet Cytogenet Oncol Haematol. 2008-12-01

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