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BTRC (beta-transducin repeat containing)

Written2008-12Baolin 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

(Note : for Links provided by Atlas : click)


Other aliasBETA-TRCP
LocusID (NCBI) 8945
Atlas_Id 451
Location 10q24.32  [Link to chromosome band 10q24]
Location_base_pair Starts at and ends at bp from pter
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
BTRC (10q24.32) / ACIN1 (14q11.2)BTRC (10q24.32) / CDH23 (10q22.1)BTRC (10q24.32) / HIF1AN (10q24.31)


  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).


  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).
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).


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 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.


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, Haecker H, Karin M, Ciechanover A.
Oncogene. 2004 Apr 1;23(14):2540-7.
PMID 14676825
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, Belaidouni N, Lassot I, Segeral E, Jobart A, Marchal C, Benarous R.
J Biol Chem. 2004 Jan 2;279(1):788-95. Epub 2003 Oct 14.
PMID 14561767
Mouse homologue of HOS (mHOS) is overexpressed in skin tumors and implicated in constitutive activation of NF-kappaB.
Bhatia N, Herter JR, Slaga TJ, Fuchs SY, Spiegelman VS.
Oncogene. 2002 Feb 28;21(10):1501-9.
PMID 11896578
Degradation of Cdc25A by beta-TrCP during S phase and in response to DNA damage.
Busino L, Donzelli M, Chiesa M, Guardavaccaro D, Ganoth D, Dorrello NV, Hershko A, Pagano M, Draetta GF.
Nature. 2003 Nov 6;426(6962):87-91.
PMID 14603323
Identification of a family of human F-box proteins.
Cenciarelli C, Chiaur DS, Guardavaccaro D, Parks W, Vidal M, Pagano M.
Curr Biol. 1999 Oct 21;9(20):1177-9.
PMID 10531035
Pseudosubstrate regulation of the SCF(beta-TrCP) ubiquitin ligase by hnRNP-U.
Davis M, Hatzubai A, Andersen JS, Ben-Shushan E, Fisher GZ, Yaron A, Bauskin A, Mercurio F, Mann M, Ben-Neriah Y.
Genes Dev. 2002 Feb 15;16(4):439-51.
PMID 11850407
A novel NF-kappa B-inducing kinase-MAPK signaling pathway up-regulates NF-kappa B activity in melanoma cells.
Dhawan P, Richmond A.
J Biol Chem. 2002 Mar 8;277(10):7920-8. Epub 2001 Dec 28.
PMID 11773061
Degradation of Mcl-1 by beta-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization.
Ding Q, He X, Hsu JM, Xia W, Chen CT, Li LY, Lee DF, Liu JC, Zhong Q, Wang X, Hung MC.
Mol Cell Biol. 2007 Jun;27(11):4006-17. Epub 2007 Mar 26..
PMID 17387146
Control of mammalian circadian rhythm by CKIepsilon-regulated proteasome-mediated PER2 degradation.
Eide EJ, Woolf MF, Kang H, Woolf P, Hurst W, Camacho F, Vielhaber EL, Giovanni A, Virshup DM.
Mol Cell Biol. 2005 Apr;25(7):2795-807.
PMID 15767683
Genetic evidence for the essential role of beta-transducin repeat-containing protein in the inducible processing of NF-kappa B2/p100.
Fong A, Sun SC.
J Biol Chem. 2002 Jun 21;277(25):22111-4. Epub 2002 May 6.
PMID 11994270
Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer.
Frescas D, Pagano M.
Nat Rev Cancer. 2008 Jun;8(6):438-49.
PMID 18500245
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, Chen A, Xiong Y, Pan ZQ, Ronai Z.
Oncogene. 1999 Mar 25;18(12):2039-46.
PMID 10321728
APC/CTNNB1 (beta-catenin) pathway alterations in human prostate cancers.
Gerstein AV, Almeida TA, Zhao G, Chess E, Shih IeM, Buhler K, Pienta K, Rubin MA, Vessella R, Papadopoulos N.
Genes Chromosomes Cancer. 2002 May;34(1):9-16.
PMID 11921277
Control of chromosome stability by the beta-TrCP-REST-Mad2 axis.
Guardavaccaro D, Frescas D, Dorrello NV, Peschiaroli A, Multani AS, Cardozo T, Lasorella A, Iavarone A, Chang S, Hernando E, Pagano M.
Nature. 2008 Mar 20;452(7185):365-9.
PMID 18354482
Ubiquitin-dependent degradation of IkappaBalpha is mediated by a ubiquitin ligase Skp1/Cul 1/F-box protein FWD1.
Hatakeyama S, Kitagawa M, Nakayama K, Shirane M, Matsumoto M, Hattori K, Higashi H, Nakano H, Okumura K, Onoe K, Good RA, Nakayama K.
Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3859-63.
PMID 10097128
Dual degradation signals control Gli protein stability and tumor formation.
Huntzicker EG, Estay IS, Zhen H, Lokteva LA, Jackson PK, Oro AE.
Genes Dev. 2006 Feb 1;20(3):276-81. Epub 2006 Jan 18.
PMID 16421275
Phosphorylation by double-time/CKIepsilon and CKIalpha targets cubitus interruptus for Slimb/beta-TRCP-mediated proteolytic processing.
Jia J, Zhang L, Zhang Q, Tong C, Wang B, Hou F, Amanai K, Jiang J.
Dev Cell. 2005 Dec;9(6):819-30.
PMID 16326393
Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb.
Jiang J, Struhl G.
Nature. 1998 Jan 29;391(6666):493-6.
PMID 9461217
Systematic analysis and nomenclature of mammalian F-box proteins.
Jin J, Cardozo T, Lovering RC, Elledge SJ, Pagano M, Harper JW.
Genes Dev. 2004 Nov 1;18(21):2573-80.
PMID 15520277
Beta-TrCP recognizes a previously undescribed nonphosphorylated destruction motif in Cdc25A and Cdc25B phosphatases.
Kanemori Y, Uto K, Sagata N.
Proc Natl Acad Sci U S A. 2005 May 3;102(18):6279-84. Epub 2005 Apr 21.
PMID 15845771
Somatic mutations of the beta-TrCP gene in gastric cancer.
Kim CJ, Song JH, Cho YG, Kim YS, Kim SY, Nam SW, Yoo NJ, Lee JY, Park WS.
APMIS. 2007 Feb;115(2):127-33.
PMID 17295679
An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin.
Kitagawa M, Hatakeyama S, Shirane M, Matsumoto M, Ishida N, Hattori K, Nakamichi I, Kikuchi A, Nakayama K, Nakayama K.
EMBO J. 1999 May 4;18(9):2401-10.
PMID 10228155
Elevated expression of Wnt antagonists is a common event in hepatoblastomas.
Koch A, Waha A, Hartmann W, Hrychyk A, Schuller U, Waha A, Wharton KA Jr, Fuchs SY, von Schweinitz D, Pietsch T.
Clin Cancer Res. 2005 Jun 15;11(12):4295-304.
PMID 15958610
Inducible degradation of IkappaBalpha by the proteasome requires interaction with the F-box protein h-betaTrCP.
Kroll M, Margottin F, Kohl A, Renard P, Durand H, Concordet JP, Bachelerie F, Arenzana-Seisdedos F, Benarous R.
J Biol Chem. 1999 Mar 19;274(12):7941-5.
PMID 10075690
betaTrCP-mediated proteolysis of NF-kappaB1 p105 requires phosphorylation of p105 serines 927 and 932.
Lang V, Janzen J, Fischer GZ, Soneji Y, Beinke S, Salmeron A, Allen H, Hay RT, Ben-Neriah Y, Ley SC.
Mol Cell Biol. 2003 Jan;23(1):402-13.
PMID 12482991
ATF4 degradation relies on a phosphorylation-dependent interaction with the SCF(betaTrCP) ubiquitin ligase.
Lassot I, Segeral E, Berlioz-Torrent C, Durand H, Groussin L, Hai T, Benarous R, Margottin-Goguet F.
Mol Cell Biol. 2001 Mar;21(6):2192-202.
PMID 11238952
Oncogenic BRAF regulates beta-Trcp expression and NF-kappaB activity in human melanoma cells.
Liu J, Suresh Kumar KG, Yu D, Molton SA, McMahon M, Herlyn M, Thomas-Tikhonenko A, Fuchs SY.
Oncogene. 2007 Mar 22;26(13):1954-8. Epub 2006 Sep 25.
PMID 17001349
Destruction of Claspin by SCFbetaTrCP restrains Chk1 activation and facilitates recovery from genotoxic stress.
Mailand N, Bekker-Jensen S, Bartek J, Lukas J.
Mol Cell. 2006 Aug 4;23(3):307-18.
PMID 16885021
Increased expression of the E3-ubiquitin ligase receptor subunit betaTRCP1 relates to constitutive nuclear factor-kappaB activation and chemoresistance in pancreatic carcinoma cells.
Muerkoster S, Arlt A, Sipos B, Witt M, Grossmann M, Kloppel G, Kalthoff H, Folsch UR, Schafer H.
Cancer Res. 2005 Feb 15;65(4):1316-24.
PMID 15735017
SCF(beta)(-TrCP) ubiquitin ligase-mediated processing of NF-kappaB p105 requires phosphorylation of its C-terminus by IkappaB kinase.
Orian A, Gonen H, Bercovich B, Fajerman I, Eytan E, Israel A, Mercurio F, Iwai K, Schwartz AL, Ciechanover A.
EMBO J. 2000 Jun 1;19(11):2580-91.
PMID 10835356
Associations among beta-TrCP, an E3 ubiquitin ligase receptor, beta-catenin, and NF-kappaB in colorectal cancer.
Ougolkov A, Zhang B, Yamashita K, Bilim V, Mai M, Fuchs SY, Minamoto T.
J Natl Cancer Inst. 2004 Aug 4;96(15):1161-70.
PMID 15292388
Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation.
Pan Y, Bai CB, Joyner AL, Wang B.
Mol Cell Biol. 2006 May;26(9):3365-77.
PMID 16611981
SCFbetaTrCP-mediated degradation of Claspin regulates recovery from the DNA replication checkpoint response.
Peschiaroli A, Dorrello NV, Guardavaccaro D, Venere M, Halazonetis T, Sherman NE, Pagano M.
Mol Cell. 2006 Aug 4;23(3):319-29.
PMID 16885022
Beta-TrCP1-mediated degradation of PERIOD2 is essential for circadian dynamics.
Reischl S, Vanselow K, Westermark PO, Thierfelder N, Maier B, Herzel H, Kramer A.
J Biol Rhythms. 2007 Oct;22(5):375-86.
PMID 17876059
Common pathway for the ubiquitination of IkappaBalpha, IkappaBbeta, and IkappaBepsilon mediated by the F-box protein FWD1.
Shirane M, Hatakeyama S, Hattori K, Nakayama K, Nakayama K.
J Biol Chem. 1999 Oct 1;274(40):28169-74.
PMID 10497169
SCFbeta-TRCP controls clock-dependent transcription via casein kinase 1-dependent degradation of the mammalian period-1 (Per1) protein.
Shirogane T, Jin J, Ang XL, Harper JW.
J Biol Chem. 2005 Jul 22;280(29):26863-72. Epub 2005 May 24.
PMID 15917222
Regulation of Ci-SCFSlimb binding, Ci proteolysis, and hedgehog pathway activity by Ci phosphorylation.
Smelkinson MG, Zhou Q, Kalderon D.
Dev Cell. 2007 Oct;13(4):481-95.
PMID 17925225
Signal-induced ubiquitination of IkappaBalpha by the F-box protein Slimb/beta-TrCP.
Spencer E, Jiang J, Chen ZJ.
Genes Dev. 1999 Feb 1;13(3):284-94.
PMID 9990853
Induction of homologue of Slimb ubiquitin ligase receptor by mitogen signaling.
Spiegelman VS, Tang W, Chan AM, Igarashi M, Aaronson SA, Sassoon DA, Katoh M, Slaga TJ, Fuchs SY.
J Biol Chem. 2002 Sep 27;277(39):36624-30. Epub 2002 Jul 31.
PMID 12151397
Homodimer of two F-box proteins betaTrCP1 or betaTrCP2 binds to IkappaBalpha for signal-dependent ubiquitination.
Suzuki H, Chiba T, Suzuki T, Fujita T, Ikenoue T, Omata M, Furuichi K, Shikama H, Tanaka K.
J Biol Chem. 2000 Jan 28;275(4):2877-84.
PMID 10644755
Recruitment of a ROC1-CUL1 ubiquitin ligase by Skp1 and HOS to catalyze the ubiquitination of I kappa B alpha.
Tan P, Fuchs SY, Chen A, Wu K, Gomez C, Ronai Z, Pan ZQ.
Mol Cell. 1999 Apr;3(4):527-33.
PMID 10230406
Multisite protein kinase A and glycogen synthase kinase 3beta phosphorylation leads to Gli3 ubiquitination by SCFbetaTrCP.
Tempe D, Casas M, Karaz S, Blanchet-Tournier MF, Concordet JP.
Mol Cell Biol. 2006 Jun;26(11):4316-26.
PMID 16705181
Evidence for the direct involvement of {beta}TrCP in Gli3 protein processing.
Wang B, Li Y.
Proc Natl Acad Sci U S A. 2006 Jan 3;103(1):33-8. Epub 2005 Dec 21.
PMID 16371461
M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFbeta-TrCP.
Watanabe N, Arai H, Nishihara Y, Taniguchi M, Watanabe N, Hunter T, Osada H.
Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4419-24. Epub 2004 Mar 22.
PMID 15070733
SCFbeta-TRCP controls oncogenic transformation and neural differentiation through REST degradation.
Westbrook TF, Hu G, Ang XL, Mulligan P, Pavlova NN, Liang A, Leng Y, Maehr R, Shi Y, Harper JW, Elledge SJ.
Nature. 2008 Mar 20;452(7185):370-4.
PMID 18354483
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, Strack P, Beer-Romero P, Chu CY, Elledge SJ, Harper JW.
Genes Dev. 1999b Feb 1;13(3):270-83.
PMID 9990852
The genomic landscapes of human breast and colorectal cancers.
Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, Silliman N, Szabo S, Dezso Z, Ustyanksky V, Nikolskaya T, Nikolsky Y, Karchin R, Wilson PA, Kaminker JS, Zhang Z, Croshaw R, Willis J, Dawson D, Shipitsin M, Willson JK, Sukumar S, Polyak K, Park BH, Pethiyagoda CL, Pant PV, Ballinger DG, Sparks AB, Hartigan J, Smith DR, Suh E, Papadopoulos N, Buckhaults P, Markowitz SD, Parmigiani G, Kinzler KW, Velculescu VE, Vogelstein B.
Science. 2007 Nov 16;318(5853):1108-13. Epub 2007 Oct 11.
PMID 17932254
beta-TrCP mediates the signal-induced ubiquitination of IkappaBbeta.
Wu C, Ghosh S.
J Biol Chem. 1999 Oct 15;274(42):29591-4.
PMID 10514424
Identification of the receptor component of the IkappaBalpha-ubiquitin ligase.
Yaron A, Hatzubai A, Davis M, Lavon I, Amit S, Manning AM, Andersen JS, Mann M, Mercurio F, Ben-Neriah Y.
Nature. 1998 Dec 10;396(6711):590-4.
PMID 9859996


This paper should be referenced as such :
Wang, B
BTRC (beta-transducin repeat containing)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(11):784-787.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ]
  t(10;10)(q22;q24) BTRC/CDH23
BTRC/HIF1AN (10q24)

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