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Gene Review

BTRC  -  beta-transducin repeat containing E3...

Homo sapiens

Synonyms: BETA-TRCP, BTRCP, E3RSIkappaB, Epididymis tissue protein Li 2a, F-box and WD repeats protein beta-TrCP, ...
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Disease relevance of BTRC

  • We found neither mutations nor complete loss of expression of the BTRC gene in our melanoma series [1].
  • METHODS: Levels of beta-TrCP1 mRNA and protein were measured by quantitative reverse transcription-polymerase chain reaction and immunoblotting, respectively, in samples of tumor and normal tissues from 45 patients with colorectal cancer [2].
  • Higher levels of beta-TrCP1 mRNA were detected in primary tumors of patients who had metastases (0.960 arbitrary units, 95% confidence interval = 0.878 to 1.042) than in the tumors of patients who did not (0.722 arbitrary units, 95% confidence interval = 0.600 to 0.844; P =.016) [2].
  • Our findings indicate that overexpression of the Wnt antagonists Nkd-1 and beta-TrCP reveals an activation of the Wnt signaling pathway as a common event in hepatoblastomas [3].
  • In addition, small interference RNA (siRNA)-triggered endogenous beta-TrCP1 suppression increased the protein expression level of both overexpressed SMAD4 mutants and endogenous mutated SMAD4 protein in acute myelogenous leukemia cells [4].
  • Epo-RS462A activation was prolonged and BaF3 cells expressing this receptor are hypersensitive to Epo, suggesting that part of the hypersensitivity to Epo in familial polycythemia could be the result of the lack of beta-Trcp recruitment to the Epo-R [5].

High impact information on BTRC

  • After phosphorylation, the IKK phosphoacceptor sites on IkappaB serve as an essential part of a specific recognition site for E3RS(IkappaB/beta-TrCP), an SCF-type E3 ubiquitin ligase, thereby explaining how IKK controls IkappaB ubiquitination and degradation [6].
  • However, recognition of Cdc25A by beta-TRCP occurs via a noncanonical phosphodegron in Cdc25A containing phosphoserine 79 and phosphoserine 82, sites that are not targeted by Chk1 [7].
  • Depletion of beta-TRCP stabilizes Cdc25A, leading to hyperactive Cdk2 activity [7].
  • Significantly, expression of a stable Claspin mutant unable to bind betaTrCP prolongs the activation of Chk1, thereby attenuating the recovery from the DNA replication stress response and significantly delaying entry into mitosis [8].
  • Phosphorylation of Claspin is mediated by Plk1 and is essential for binding to betaTrCP [8].

Biological context of BTRC


Anatomical context of BTRC


Associations of BTRC with chemical compounds

  • Structure of a beta-TrCP1-Skp1-beta-catenin complex: destruction motif binding and lysine specificity of the SCF(beta-TrCP1) ubiquitin ligase [17].
  • A mutant FGD1 protein, FGD1(SA), in which both of the critical serine residues in the DSGPsiXS motif have been replaced by alanines, does not interact with FWD1/beta-TrCP and exhibits increased stability [18].
  • The F-box-deleted betaTrCP protein behaves as a negative transdominant mutant that inhibits ATF4 ubiquitination and degradation and, subsequently, enhances its activity in cyclic AMP-mediated transcription [19].
  • One domain of Protac-1 contains the I kappa B alpha phosphopeptide that is recognized by the F-box protein beta-TRCP, whereas the other domain is composed of ovalicin [20].
  • In addition, inhibition of beta-TrCP augments the antiproliferative effects of anticancer drugs such as doxorubicin, tamoxifen, and paclitaxel on human mammary tumor cells [21].

Physical interactions of BTRC

  • These results suggest that while both plakoglobin and beta-catenin can comparably interact with beta-TrCP and the ubiquitination system, the sequestration of plakoglobin by the membrane-cytoskeleton system renders it inaccessible to the proteolytic machinery and stabilizes it [22].
  • Here we show that upon hyperphosphorylation, hDlg interacts with the beta-TrCP ubiquitin ligase receptor through a DSGLPS motif within its Src homology 3 domain [14].
  • ATF4 is a substrate of the SCF(betaTrCP) ubiquitin ligase that binds to betaTrCP through phosphorylation on a DSGXXXS motif [23].

Enzymatic interactions of BTRC

  • STD and TRNOESY NMR studies on the conformation of the oncogenic protein beta-catenin containing the phosphorylated motif DpSGXXpS bound to the beta-TrCP protein [11].

Regulatory relationships of BTRC

  • Ectopic expression of SCF complex containing beta-TrCP1 is sufficient to induce the ubiquitination and degradation of Smad4 [24].
  • In the present study, we show that phosphorylation of S123 (pS123) by CDK promoted the binding of Wee1A to beta-TrCP through three independent mechanisms [25].
  • Oncogenic BRAF regulates beta-Trcp expression and NF-kappaB activity in human melanoma cells [15].
  • Destruction of beta-catenin is regulated through phosphorylation-dependent interactions with the F box protein beta-TrCP [26].
  • Expression of a F-box-deleted betaTrCP inhibits IkappaBalpha degradation, promotes accumulation of phosphorylated Ser32-Ser36 IkappaBalpha, and prevents NF-kappaB-dependent transcription [27].

Other interactions of BTRC

  • Biochemical studies have suggested that beta-TrCP targets the oncogenic protein beta-catenin for ubiquitination and followed by proteasome degradation [11].
  • Furthermore, small interfering RNA-triggered endogenous beta-TrCP1 suppression increases the expression of Smad4 protein [24].
  • An F-box deletion mutant of beta TrCP had a dominant-negative effect on Vpu-mediated CD4 degradation [28].
  • Although only a minute fraction of total cellular Cul-1 is modified by Nedd8, the Cul-1 associated with ectopically expressed betaTrCP was highly enriched for the Nedd8-conjugated form [29].
  • beta-TrCP mediates the signal-induced ubiquitination of IkappaBbeta [10].

Analytical, diagnostic and therapeutic context of BTRC

  • Here we show, using two different techniques, FISH and quantitative PCR that SHFM3 is caused by a minimal 325 kb duplication containing only two genes (BTRC and POLL) [30].


  1. Molecular genetic analysis of malignant melanomas for aberrations of the WNT signaling pathway genes CTNNB1, APC, ICAT and BTRC. Reifenberger, J., Knobbe, C.B., Wolter, M., Blaschke, B., Schulte, K.W., Pietsch, T., Ruzicka, T., Reifenberger, G. Int. J. Cancer (2002) [Pubmed]
  2. 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, S.Y., Minamoto, T. J. Natl. Cancer Inst. (2004) [Pubmed]
  3. Elevated expression of Wnt antagonists is a common event in hepatoblastomas. Koch, A., Waha, A., Hartmann, W., Hrychyk, A., Schüller, U., Waha, A., Wharton, K.A., Fuchs, S.Y., von Schweinitz, D., Pietsch, T. Clin. Cancer Res. (2005) [Pubmed]
  4. Acute myelogenous leukemia-derived SMAD4 mutations target the protein to ubiquitin-proteasome degradation. Yang, L., Wang, N., Tang, Y., Cao, X., Wan, M. Hum. Mutat. (2006) [Pubmed]
  5. beta-Trcp mediates ubiquitination and degradation of the erythropoietin receptor and controls cell proliferation. Meyer, L., Deau, B., Forejtníková, H., Duménil, D., Margottin-Goguet, F., Lacombe, C., Mayeux, P., Verdier, F. Blood (2007) [Pubmed]
  6. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Karin, M., Ben-Neriah, Y. Annu. Rev. Immunol. (2000) [Pubmed]
  7. SCFbeta-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase. Jin, J., Shirogane, T., Xu, L., Nalepa, G., Qin, J., Elledge, S.J., Harper, J.W. Genes Dev. (2003) [Pubmed]
  8. SCFbetaTrCP-mediated degradation of Claspin regulates recovery from the DNA replication checkpoint response. Peschiaroli, A., Dorrello, N.V., Guardavaccaro, D., Venere, M., Halazonetis, T., Sherman, N.E., Pagano, M. Mol. Cell (2006) [Pubmed]
  9. The BTRC gene, encoding a human F-box/WD40-repeat protein, maps to chromosome 10q24-q25. Fujiwara, T., Suzuki, M., Tanigami, A., Ikenoue, T., Omata, M., Chiba, T., Tanaka, K. Genomics (1999) [Pubmed]
  10. beta-TrCP mediates the signal-induced ubiquitination of IkappaBbeta. Wu, C., Ghosh, S. J. Biol. Chem. (1999) [Pubmed]
  11. STD and TRNOESY NMR studies on the conformation of the oncogenic protein beta-catenin containing the phosphorylated motif DpSGXXpS bound to the beta-TrCP protein. Megy, S., Bertho, G., Gharbi-Benarous, J., Evrard-Todeschi, N., Coadou, G., Ségéral, E., Iehle, C., Quéméneur, E., Benarous, R., Girault, J.P. J. Biol. Chem. (2005) [Pubmed]
  12. 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, N.V., Hershko, A., Pagano, M., Draetta, G.F. Nature (2003) [Pubmed]
  13. 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) [Pubmed]
  14. Regulation of the discs large tumor suppressor by a phosphorylation-dependent interaction with the beta-TrCP ubiquitin ligase receptor. Mantovani, F., Banks, L. J. Biol. Chem. (2003) [Pubmed]
  15. Oncogenic BRAF regulates beta-Trcp expression and NF-kappaB activity in human melanoma cells. Liu, J., Suresh Kumar, K.G., Yu, D., Molton, S.A., McMahon, M., Herlyn, M., Thomas-Tikhonenko, A., Fuchs, S.Y. Oncogene (2007) [Pubmed]
  16. Absence of detectable alterations in the putative tumor suppressor gene BTRC in cerebellar medulloblastomas and cutaneous basal cell carcinomas. Wolter, M., Scharwächter, C., Reifenberger, J., Koch, A., Pietsch, T., Reifenberger, G. Acta Neuropathol. (2003) [Pubmed]
  17. Structure of a beta-TrCP1-Skp1-beta-catenin complex: destruction motif binding and lysine specificity of the SCF(beta-TrCP1) ubiquitin ligase. Wu, G., Xu, G., Schulman, B.A., Jeffrey, P.D., Harper, J.W., Pavletich, N.P. Mol. Cell (2003) [Pubmed]
  18. The FWD1/beta-TrCP-mediated degradation pathway establishes a 'turning off switch' of a Cdc42 guanine nucleotide exchange factor, FGD1. Hayakawa, M., Kitagawa, H., Miyazawa, K., Kitagawa, M., Kikugawa, K. Genes Cells (2005) [Pubmed]
  19. ATF4 degradation relies on a phosphorylation-dependent interaction with the SCF(betaTrCP) ubiquitin ligase. Lassot, I., Ségéral, E., Berlioz-Torrent, C., Durand, H., Groussin, L., Hai, T., Benarous, R., Margottin-Goguet, F. Mol. Cell. Biol. (2001) [Pubmed]
  20. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Sakamoto, K.M., Kim, K.B., Kumagai, A., Mercurio, F., Crews, C.M., Deshaies, R.J. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  21. Targeting beta-transducin repeat-containing protein E3 ubiquitin ligase augments the effects of antitumor drugs on breast cancer cells. Tang, W., Li, Y., Yu, D., Thomas-Tikhonenko, A., Spiegelman, V.S., Fuchs, S.Y. Cancer Res. (2005) [Pubmed]
  22. Differential interaction of plakoglobin and beta-catenin with the ubiquitin-proteasome system. Sadot, E., Simcha, I., Iwai, K., Ciechanover, A., Geiger, B., Ben-Ze'ev, A. Oncogene (2000) [Pubmed]
  23. p300 modulates ATF4 stability and transcriptional activity independently of its acetyltransferase domain. Lassot, I., Estrabaud, E., Emiliani, S., Benkirane, M., Benarous, R., Margottin-Goguet, F. J. Biol. Chem. (2005) [Pubmed]
  24. Smad4 protein stability is regulated by ubiquitin ligase SCF beta-TrCP1. Wan, M., Tang, Y., Tytler, E.M., Lu, C., Jin, B., Vickers, S.M., Yang, L., Shi, X., Cao, X. J. Biol. Chem. (2004) [Pubmed]
  25. Cyclin-dependent kinase (CDK) phosphorylation destabilizes somatic Wee1 via multiple pathways. Watanabe, N., Arai, H., Iwasaki, J., Shiina, M., Ogata, K., Hunter, T., Osada, H. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  26. Siah-1, SIP, and Ebi collaborate in a novel pathway for beta-catenin degradation linked to p53 responses. Matsuzawa, S.I., Reed, J.C. Mol. Cell (2001) [Pubmed]
  27. 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, J.P., Bachelerie, F., Arenzana-Seisdedos, F., Benarous, R. J. Biol. Chem. (1999) [Pubmed]
  28. A novel human WD protein, h-beta TrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif. Margottin, F., Bour, S.P., Durand, H., Selig, L., Benichou, S., Richard, V., Thomas, D., Strebel, K., Benarous, R. Mol. Cell (1998) [Pubmed]
  29. Nedd8 modification of cul-1 activates SCF(beta(TrCP))-dependent ubiquitination of IkappaBalpha. Read, M.A., Brownell, J.E., Gladysheva, T.B., Hottelet, M., Parent, L.A., Coggins, M.B., Pierce, J.W., Podust, V.N., Luo, R.S., Chau, V., Palombella, V.J. Mol. Cell. Biol. (2000) [Pubmed]
  30. Split-hand/split-foot malformation 3 (SHFM3) at 10q24, development of rapid diagnostic methods and gene expression from the region. Lyle, R., Radhakrishna, U., Blouin, J.L., Gagos, S., Everman, D.B., Gehrig, C., Delozier-Blanchet, C., Solanki, J.V., Patel, U.C., Nath, S.K., Gurrieri, F., Neri, G., Schwartz, C.E., Antonarakis, S.E. Am. J. Med. Genet. A (2006) [Pubmed]
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