BTRC (beta-transducin repeat containing)
2008-12-01 Baolin Wang AffiliationDepartment of Genetic Medicine, Department of Cell, Developmental Biology, Weill Medical College of Cornell University, 1300 York Avenue, W404, New York, NY 10065, USA
Identity
HGNC
LOCATION
10q24.32
LOCUSID
ALIAS
BETA-TRCP,FBW1A,FBXW1,FBXW1A,FWD1,bTrCP,bTrCP1,betaTrCP
FUSION GENES
DNA/RNA
Figure 1. The betaTrCP1 gene structure.
Description
Spans 223.25 kb; 14 exons; 13 coding exons (Figure 1).
Transcription
Full length transcript of 6011 bp, open reading frame 1707 bp. There is an alternatively spliced transcript (Figure 1).
Proteins
Figure 2. Two isoformes of betaTrCP1 protein.
Description
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).
Expression
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).
Localisation
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).
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.
Function
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).
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).
Homology
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
Note
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
Oncogenesis
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.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 14676825 | 2004 | Mechanism 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 |
| 14561767 | 2004 | HIV-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 |
| 11896578 | 2002 | Mouse homologue of HOS (mHOS) is overexpressed in skin tumors and implicated in constitutive activation of NF-kappaB. | Bhatia N et al |
| 14603323 | 2003 | Degradation of Cdc25A by beta-TrCP during S phase and in response to DNA damage. | Busino L et al |
| 10531035 | 1999 | Identification of a family of human F-box proteins. | Cenciarelli C et al |
| 11850407 | 2002 | Pseudosubstrate regulation of the SCF(beta-TrCP) ubiquitin ligase by hnRNP-U. | Davis M et al |
| 11773061 | 2002 | A novel NF-kappa B-inducing kinase-MAPK signaling pathway up-regulates NF-kappa B activity in melanoma cells. | Dhawan P et al |
| 17387146 | 2007 | Degradation of Mcl-1 by beta-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization. | Ding Q et al |
| 15767683 | 2005 | Control of mammalian circadian rhythm by CKIepsilon-regulated proteasome-mediated PER2 degradation. | Eide EJ et al |
| 11994270 | 2002 | Genetic evidence for the essential role of beta-transducin repeat-containing protein in the inducible processing of NF-kappa B2/p100. | Fong A et al |
| 18500245 | 2008 | Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer. | Frescas D et al |
| 10321728 | 1999 | HOS, 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 |
| 11921277 | 2002 | APC/CTNNB1 (beta-catenin) pathway alterations in human prostate cancers. | Gerstein AV et al |
| 18354482 | 2008 | Control of chromosome stability by the beta-TrCP-REST-Mad2 axis. | Guardavaccaro D et al |
| 10097128 | 1999 | Ubiquitin-dependent degradation of IkappaBalpha is mediated by a ubiquitin ligase Skp1/Cul 1/F-box protein FWD1. | Hatakeyama S et al |
| 16421275 | 2006 | Dual degradation signals control Gli protein stability and tumor formation. | Huntzicker EG et al |
| 16326393 | 2005 | Phosphorylation by double-time/CKIepsilon and CKIalpha targets cubitus interruptus for Slimb/beta-TRCP-mediated proteolytic processing. | Jia J et al |
| 9461217 | 1998 | Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb. | Jiang J et al |
| 15520277 | 2004 | Systematic analysis and nomenclature of mammalian F-box proteins. | Jin J et al |
| 15845771 | 2005 | Beta-TrCP recognizes a previously undescribed nonphosphorylated destruction motif in Cdc25A and Cdc25B phosphatases. | Kanemori Y et al |
| 17295679 | 2007 | Somatic mutations of the beta-TrCP gene in gastric cancer. | Kim CJ et al |
| 10228155 | 1999 | An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin. | Kitagawa M et al |
| 15958610 | 2005 | Elevated expression of Wnt antagonists is a common event in hepatoblastomas. | Koch A et al |
| 10075690 | 1999 | Inducible degradation of IkappaBalpha by the proteasome requires interaction with the F-box protein h-betaTrCP. | Kroll M et al |
| 12482991 | 2003 | betaTrCP-mediated proteolysis of NF-kappaB1 p105 requires phosphorylation of p105 serines 927 and 932. | Lang V et al |
| 11238952 | 2001 | ATF4 degradation relies on a phosphorylation-dependent interaction with the SCF(betaTrCP) ubiquitin ligase. | Lassot I et al |
| 17001349 | 2007 | Oncogenic BRAF regulates beta-Trcp expression and NF-kappaB activity in human melanoma cells. | Liu J et al |
| 16885021 | 2006 | Destruction of Claspin by SCFbetaTrCP restrains Chk1 activation and facilitates recovery from genotoxic stress. | Mailand N et al |
| 15735017 | 2005 | Increased 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 |
| 10835356 | 2000 | SCF(beta)(-TrCP) ubiquitin ligase-mediated processing of NF-kappaB p105 requires phosphorylation of its C-terminus by IkappaB kinase. | Orian A et al |
| 15292388 | 2004 | Associations among beta-TrCP, an E3 ubiquitin ligase receptor, beta-catenin, and NF-kappaB in colorectal cancer. | Ougolkov A et al |
| 16611981 | 2006 | Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation. | Pan Y et al |
| 16885022 | 2006 | SCFbetaTrCP-mediated degradation of Claspin regulates recovery from the DNA replication checkpoint response. | Peschiaroli A et al |
| 17876059 | 2007 | Beta-TrCP1-mediated degradation of PERIOD2 is essential for circadian dynamics. | Reischl S et al |
| 10497169 | 1999 | Common pathway for the ubiquitination of IkappaBalpha, IkappaBbeta, and IkappaBepsilon mediated by the F-box protein FWD1. | Shirane M et al |
| 15917222 | 2005 | SCFbeta-TRCP controls clock-dependent transcription via casein kinase 1-dependent degradation of the mammalian period-1 (Per1) protein. | Shirogane T et al |
| 17925225 | 2007 | Regulation of Ci-SCFSlimb binding, Ci proteolysis, and hedgehog pathway activity by Ci phosphorylation. | Smelkinson MG et al |
| 9990853 | 1999 | Signal-induced ubiquitination of IkappaBalpha by the F-box protein Slimb/beta-TrCP. | Spencer E et al |
| 12151397 | 2002 | Induction of homologue of Slimb ubiquitin ligase receptor by mitogen signaling. | Spiegelman VS et al |
| 10644755 | 2000 | Homodimer of two F-box proteins betaTrCP1 or betaTrCP2 binds to IkappaBalpha for signal-dependent ubiquitination. | Suzuki H et al |
| 10230406 | 1999 | Recruitment of a ROC1-CUL1 ubiquitin ligase by Skp1 and HOS to catalyze the ubiquitination of I kappa B alpha. | Tan P et al |
| 16705181 | 2006 | Multisite protein kinase A and glycogen synthase kinase 3beta phosphorylation leads to Gli3 ubiquitination by SCFbetaTrCP. | Tempé D et al |
| 16371461 | 2006 | Evidence for the direct involvement of {beta}TrCP in Gli3 protein processing. | Wang B et al |
| 15070733 | 2004 | M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFbeta-TrCP. | Watanabe N et al |
| 18354483 | 2008 | SCFbeta-TRCP controls oncogenic transformation and neural differentiation through REST degradation. | Westbrook TF et al |
| 9990852 | 1999 | The 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 |
| 17932254 | 2007 | The genomic landscapes of human breast and colorectal cancers. | Wood LD et al |
| 10514424 | 1999 | beta-TrCP mediates the signal-induced ubiquitination of IkappaBbeta. | Wu C et al |
| 9859996 | 1998 | Identification 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
Variants:
dbSNP: 8945
ClinVar: 8945
TCGA: ENSG00000166167
COSMIC: BTRC
RNA/Proteins
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 37776184 | 2024 | Sequence variants in DLX5, HOXD13 and 445 kb-microduplication surrounding BTRC cause split-hand/foot malformation in three different families. | 0 |
| 38195659 | 2024 | Decidual stromal cells-derived exosomes incurred insufficient migration and invasion of trophoblast by disturbing of β-TrCP-mediated snail ubiquitination and degradation in unexplained recurrent spontaneous abortion. | 1 |
| 37776184 | 2024 | Sequence variants in DLX5, HOXD13 and 445 kb-microduplication surrounding BTRC cause split-hand/foot malformation in three different families. | 0 |
| 38195659 | 2024 | Decidual stromal cells-derived exosomes incurred insufficient migration and invasion of trophoblast by disturbing of β-TrCP-mediated snail ubiquitination and degradation in unexplained recurrent spontaneous abortion. | 1 |
| 36846904 | 2023 | Ubiquitin E3 ligase β-TrCP negatively regulates surface protein of hepatitis B virus. | 1 |
| 37287397 | 2023 | Exosomal GPT2 derived from triple-negative breast cancer cells promotes metastasis by activating BTRC. | 1 |
| 36846904 | 2023 | Ubiquitin E3 ligase β-TrCP negatively regulates surface protein of hepatitis B virus. | 1 |
| 37287397 | 2023 | Exosomal GPT2 derived from triple-negative breast cancer cells promotes metastasis by activating BTRC. | 1 |
| 34197030 | 2022 | WBP2 promotes BTRC mRNA stability to drive migration and invasion in triple-negative breast cancer via NF-κB activation. | 11 |
| 34990616 | 2022 | The transcript ENST00000444125 of lncRNA LINC01503 promotes cancer stem cell properties of glioblastoma cells via reducing FBXW1 mediated GLI2 degradation. | 9 |
| 36181972 | 2022 | The current status and future prospects for therapeutic targeting of KEAP1-NRF2 and β-TrCP-NRF2 interactions in cancer chemoresistance. | 9 |
| 36438474 | 2022 | circHIPK3 prevents cardiac senescence by acting as a scaffold to recruit ubiquitin ligase to degrade HuR. | 10 |
| 36591289 | 2022 | Pan-cancer analysis of FBXW family with potential implications in prognosis and immune infiltration. | 1 |
| 34197030 | 2022 | WBP2 promotes BTRC mRNA stability to drive migration and invasion in triple-negative breast cancer via NF-κB activation. | 11 |
| 34990616 | 2022 | The transcript ENST00000444125 of lncRNA LINC01503 promotes cancer stem cell properties of glioblastoma cells via reducing FBXW1 mediated GLI2 degradation. | 9 |
Citation
Baolin Wang
BTRC (beta-transducin repeat containing)
Atlas Genet Cytogenet Oncol Haematol. 2008-12-01
Online version: http://atlasgeneticsoncology.org/gene/451/btrc-(beta-transducin-repeat-containing)
