BTRC (gene)

Beta-transducin repeat containing

PDB rendering based on 1p22.
Identifiers
Symbols BTRC; BETA-TRCP; FBW1A; FBXW1; FBXW1A; FWD1; MGC4643; bTrCP; bTrCP1; betaTrCP
External IDs OMIM: 603482 MGI: 1338871 HomoloGene: 39330 GeneCards: BTRC Gene
Orthologs
Species Human Mouse
Entrez 8945 12234
Ensembl ENSG00000166167 ENSMUSG00000025217
UniProt Q9Y297 n/a
RefSeq (mRNA) NM_003939.3 NM_001037758
RefSeq (protein) NP_003930.1 NP_001032847
Location (UCSC) Chr 10:
103.11 – 103.32 Mb		 Chr 19:
45.44 – 45.61 Mb
PubMed search [1] [2]

F-box/WD repeat-containing protein 1A (FBXW1A) also known as βTrCP1 or Fbxw1 or hsSlimb or pIkappaBalpha-E3 receptor subunit is a protein that in humans is encoded by the BTRC (beta-transducin repeat containing) gene.[1][2]

This gene encodes a member of the F-box protein family which is characterized by an approximately 40 residue structural motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (Skp1-Cul1-F-box protein), which often, but not always, recognize substrates in a phosphorylation-dependent manner. F-box proteins are divided into 3 classes:

The protein encoded by this gene belongs to the Fbxw class as, in addition to an F-box, this protein contains multiple WD40 repeats. This protein is homologous to Xenopus βTrCP, yeast Met30, Neurospora Scon2 and Drosophila Slimb. In mammals, in addition to βTrCP1, a paralog protein (called βTrCP2 or FBXW11) also exists, but, so far, their functions appear redundant and indistinguishable.

Contents

Discovery

Human βTrCP (referred to both βTrCP1 and βTrCP2) was originally identified as a cellular ubiquitin ligase that is bound by the HIV-1 Vpu viral protein to eliminate cellular CD4 by connecting it to the proteolytic machinery.[3] Subsequently, βTrCP was shown to regulate multiple cellular processes by mediating the degradation of various targets.[4] Cell cycle regulators constitute a major group of βTrCP substrates. During S phase, βTrCP keeps CDK1 in check by promoting the degradation of the phosphatase CDC25A,[5] whereas in G2, βTrCP contributes to CDK1 activation by targeting the kinase WEE1 for degradation.[6] In early mitosis, βTrCP mediates the degradation of EMI1,[7][8] an inhibitor of the APC/C ubiquitin ligase complex, which is responsible for the anaphase-metaphase transition (by inducing the proteolysis of Securin) and mitotic exit (by driving the degradation of mitotic CDK1 activating cyclin subunits). Furthermore, βTrCP controls APC/C by targeting REST, thereby removing its transcriptional repression on MAD2, an essential component of the spindle assembly checkpoint that keeps APC/C inactive until all chromatids are attached to the spindle microtubles.[9]

Function

βTrCP plays important roles in regulating cell cycle checkpoints. In response to genotoxic stress, it contributes to turn off CDK1 activity by mediating the degradation of CDC25A in collaboration with Chk1,[5][10] thereby preventing cell cycle progression before the completion of DNA repair. During recovery from DNA replication and DNA damage, βTrCP instead targets Claspin in a Plk1-dependent manner.[11][12][13]

βTrCP has also emerged as an important player in protein translation, cell grow and survival. In response to mitogens, PDCD4, an inhibitor of the translation initiation factor eIF4A, is rapidly degraded in a βTrCP- and S6K1-dependent manner, allowing efficient protein translation and cell growth.[14] βTrCP also cooperates with mTOR and CK1α to induce the degradation of DEPTOR (an mTOR inhibitor), thereby generating an auto-amplification loop to promote the full activation of mTOR.[15][16][17] At the same time, βTrCP mediates the degradation of the pro-apoptotic protein BimEL to promote cell survival.[18]

βTrCP also associates with phosphorylated IkappaBalpha and beta-catenin destruction motifs, probably functioning in multiple transcriptional programs by regulating the NF-kappaB and the WNT pathways.[19][20]

Interactions

BTRC (gene) has been shown to interact with:

Clinical Significance

βTrCP behaves as an oncoprotein in some tissues. Elevated levels of βTrCP expression have been found in colorectal,[31]pancreatic,[32] hapatoblastoma,[33] and breast cancers.[34]

References

  1. ^ Fujiwara T, Suzuki M, Tanigami A, Ikenoue T, Omata M, Chiba T, Tanaka K (Jul 1999). "The BTRC gene, encoding a human F-box/WD40-repeat protein, maps to chromosome 10q24-q25". Genomics 58 (1): 104–105. doi:10.1006/geno.1999.5792. PMID 10331953. 
  2. ^ "Entrez Gene: BTRC beta-transducin repeat containing". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8945. 
  3. ^ a b Margottin F, Bour SP, Durand H, Selig L, Benichou S, Richard V, Thomas D, Strebel K, Benarous R (Jul 1998). "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". Mol Cell 1 (4): 565–574. doi:10.1016/S1097-2765(00)80056-8. PMID 9660940. 
  4. ^ Frescas, D.; Pagano, M. (2008). "Deregulated proteolysis by the F-box proteins SKP2 and β-TrCP: Tipping the scales of cancer". Nature Reviews Cancer 8 (6): 438–449. doi:10.1038/nrc2396. PMC 2711846. PMID 18500245. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2711846.  edit
  5. ^ a b c Busino, L.; Donzelli, M.; Chiesa, M.; Guardavaccaro, D.; Ganoth, D.; Valerio Dorrello, N.; Hershko, A.; Pagano, M. et al. (2003). "Degradation of Cdc25A by β-TrCP during S phase and in response to DNA damage". Nature 426 (6962): 87–91. doi:10.1038/nature02082. PMID 14603323.  edit
  6. ^ Watanabe, N.; Arai, H.; Nishihara, Y.; Taniguchi, M.; Watanabe, N.; Hunter, T.; Osada, H. (2004). "M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFβ-TrCP". Proceedings of the National Academy of Sciences 101 (13): 4419–4424. doi:10.1073/pnas.0307700101. PMC 384762. PMID 15070733. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=384762.  edit
  7. ^ a b c Guardavaccaro, D.; Kudo, Y.; Boulaire, J.; Barchi, M.; Busino, L.; Donzelli, M.; Margottin-Goguet, F.; Jackson, P. K. et al. (2003). "Control of meiotic and mitotic progression by the F box protein beta-Trcp1 in vivo". Developmental Cell 4 (6): 799–812. doi:10.1016/S1534-5807(03)00154-0. PMID 12791266.  edit
  8. ^ a b Margottin-Goguet, F.; Hsu, J. Y.; Loktev, A.; Hsieh, H. M.; Reimann, J. D.; Jackson, P. K. (2003). "Prophase destruction of Emi1 by the SCF(betaTrCP/Slimb) ubiquitin ligase activates the anaphase promoting complex to allow progression beyond prometaphase". Developmental cell 4 (6): 813–826. doi:10.1016/S1534-5807(03)00153-9. PMID 12791267.  edit
  9. ^ Guardavaccaro, D.; Frescas, D.; Dorrello, N. V.; Peschiaroli, A.; Multani, A. S.; Cardozo, T.; Lasorella, A.; Iavarone, A. et al. (2008). "Control of chromosome stability by the β-TrCP–REST–Mad2 axis". Nature 452 (7185): 365–369. doi:10.1038/nature06641. PMC 2707768. PMID 18354482. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2707768.  edit
  10. ^ a b Jin, J.; Shirogane, T.; Xu, L.; Nalepa, G.; Qin, J.; Elledge, S. J.; Harper, J. W. (2003). "SCFβ-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase". Genes & Development 17 (24): 3062–3074. doi:10.1101/gad.1157503. PMC 305258. PMID 14681206. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=305258.  edit
  11. ^ a b Peschiaroli, A.; Dorrello, N. V.; Guardavaccaro, D.; Venere, M.; Halazonetis, T.; Sherman, N. E.; Pagano, M. (2006). "SCFβTrCP-Mediated Degradation of Claspin Regulates Recovery from the DNA Replication Checkpoint Response". Molecular Cell 23 (3): 319–329. doi:10.1016/j.molcel.2006.06.013. PMID 16885022.  edit
  12. ^ a b Mailand, N.; Bekker-Jensen, S.; Bartek, J.; Lukas, J. (2006). "Destruction of Claspin by SCFβTrCP Restrains Chk1 Activation and Facilitates Recovery from Genotoxic Stress". Molecular Cell 23 (3): 307–318. doi:10.1016/j.molcel.2006.06.016. PMID 16885021.  edit
  13. ^ a b Mamely, I.; Van Vugt, M. A. M.; Smits, V. A.; Semple, J. I.; Lemmens, B.; Perrakis, A.; Medema, R. H.; Freire, R. (2006). "Polo-like Kinase-1 Controls Proteasome-Dependent Degradation of Claspin during Checkpoint Recovery". Current Biology 16 (19): 1950–1955. doi:10.1016/j.cub.2006.08.026. PMID 16934469.  edit
  14. ^ a b Dorrello, N. V.; Peschiaroli, A.; Guardavaccaro, D.; Colburn, N. H.; Sherman, N. E.; Pagano, M. (2006). "S6K1- and  TRCP-Mediated Degradation of PDCD4 Promotes Protein Translation and Cell Growth". Science 314 (5798): 467–471. doi:10.1126/science.1130276. PMID 17053147.  edit
  15. ^ a b Duan, S.; Skaar, J. R.; Kuchay, S.; Toschi, A.; Kanarek, N.; Ben-Neriah, Y.; Pagano, M. (2011). "MTOR Generates an Auto-Amplification Loop by Triggering the βTrCP- and CK1α-Dependent Degradation of DEPTOR". Molecular Cell 44 (2): 317–324. doi:10.1016/j.molcel.2011.09.005. PMID 22017877.  edit
  16. ^ a b Zhao, Y.; Xiong, X.; Sun, Y. (2011). "DEPTOR, an mTOR Inhibitor, is a Physiological Substrate of SCFβTrCP E3 Ubiquitin Ligase and Regulates Survival and Autophagy". Molecular Cell 44 (2): 304–316. doi:10.1016/j.molcel.2011.08.029. PMID 22017876.  edit
  17. ^ a b Gao, D.; Inuzuka, H.; Tan, M. K. M.; Fukushima, H.; Locasale, J. W.; Liu, P.; Wan, L.; Zhai, B. et al. (2011). "MTOR Drives Its Own Activation via SCFβTrCP-Dependent Degradation of the mTOR Inhibitor DEPTOR". Molecular Cell 44 (2): 290–303. doi:10.1016/j.molcel.2011.08.030. PMID 22017875.  edit
  18. ^ a b Dehan, E.; Bassermann, F.; Guardavaccaro, D.; Vasiliver-Shamis, G.; Cohen, M.; Lowes, K. N.; Dustin, M.; Huang, D. C. S. et al. (2009). "ΒTrCP- and Rsk1/2-mediated degradation of BimEL inhibits apoptosis". Molecular Cell 33 (1): 109–116. doi:10.1016/j.molcel.2008.12.020. PMC 2655121. PMID 19150432. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2655121.  edit
  19. ^ Winston, J. T.; Strack, P.; Beer-Romero, P.; Chu, C. Y.; Elledge, S. J.; Harper, J. W. (1999). "The SCFβ-TRCP–ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IκBα and β-catenin and stimulates IκBα ubiquitination in vitro". Genes & development 13 (3): 270–283. doi:10.1101/gad.13.3.270. PMC 316433. PMID 9990852. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=316433.  edit
  20. ^ Latres, E.; Chiaur, D. S.; Pagano, M. (1999). "The human F box protein β-Trcp associates with the Cul1/Skp1 complex and regulates the stability of β-catenin". Oncogene 18 (4): 849–854. doi:10.1038/sj.onc.1202653. PMID 10023660.  edit
  21. ^ Liu, C.; Kato, Y.; Zhang, Z.; Do, V. M.; Yankner, B. A.; He, X. (1999). "Β-Trcp couples β-catenin phosphorylation-degradation and regulates Xenopus axis formation". Proceedings of the National Academy of Sciences of the United States of America 96 (11): 6273–6278. PMC 26871. PMID 10339577. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=26871.  edit
  22. ^ Latres, E.; Chiaur, D. S.; Pagano, M. (1999). "The human F box protein β-Trcp associates with the Cul1/Skp1 complex and regulates the stability of β-catenin". Oncogene 18 (4): 849–854. doi:10.1038/sj.onc.1202653. PMID 10023660.  edit
  23. ^ Semplici F, Meggio F, Pinna LA, Oliviero S (June 2002). "CK2-dependent phosphorylation of the E2 ubiquitin conjugating enzyme UBC3B induces its interaction with beta-TrCP and enhances beta-catenin degradation". Oncogene 21 (25): 3978–87. doi:10.1038/sj.onc.1205574. PMID 12037680. 
  24. ^ a b c d Suzuki H, Chiba T, Suzuki T, Fujita T, Ikenoue T, Omata M, Furuichi K, Shikama H, Tanaka K (January 2000). "Homodimer of two F-box proteins betaTrCP1 or betaTrCP2 binds to IkappaBalpha for signal-dependent ubiquitination". J. Biol. Chem. 275 (4): 2877–84. doi:10.1074/jbc.275.4.2877. PMID 10644755. 
  25. ^ Mantovani F, Banks L (October 2003). "Regulation of the discs large tumor suppressor by a phosphorylation-dependent interaction with the beta-TrCP ubiquitin ligase receptor". J. Biol. Chem. 278 (43): 42477–86. doi:10.1074/jbc.M302799200. PMID 12902344. 
  26. ^ a b Spencer E, Jiang J, Chen ZJ (February 1999). "Signal-induced ubiquitination of IkappaBalpha by the F-box protein Slimb/beta-TrCP". Genes Dev. 13 (3): 284–94. doi:10.1101/gad.13.3.284. PMC 316434. PMID 9990853. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=316434. 
  27. ^ Fong A, Sun SC (June 2002). "Genetic evidence for the essential role of beta-transducin repeat-containing protein in the inducible processing of NF-kappa B2/p100". J. Biol. Chem. 277 (25): 22111–4. doi:10.1074/jbc.C200151200. PMID 11994270. 
  28. ^ Vatsyayan J, Qing G, Xiao G, Hu J (September 2008). "SUMO1 modification of NF-kappaB2/p100 is essential for stimuli-induced p100 phosphorylation and processing". EMBO Rep. 9 (9): 885–90. doi:10.1038/embor.2008.122. PMC 2529344. PMID 18617892. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2529344. 
  29. ^ Westbrook, T. F.; Hu, G.; Ang, X. L.; Mulligan, P.; Pavlova, N. N.; Liang, A.; Leng, Y.; Maehr, R. et al. (2008). "SCFβTRCPControls Oncogenic Transformation and Neural Differentiation Through REST Degradation". Nature 452 (7185): 370–374. doi:10.1038/nature06780. PMC 2688689. PMID 18354483. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2688689.  edit
  30. ^ Watanabe, N.; Arai, H.; Nishihara, Y.; Taniguchi, M.; Watanabe, N.; Hunter, T.; Osada, H. (2004). "M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFβ-TrCP". Proceedings of the National Academy of Sciences 101 (13): 4419–4424. doi:10.1073/pnas.0307700101. PMC 384762. PMID 15070733. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=384762.  edit
  31. ^ Ougolkov, A.; Zhang, B.; Yamashita, K.; Bilim, V.; Mai, M.; Fuchs, S. Y.; Minamoto, T. (2004). "Associations Among  -TrCP, an E3 Ubiquitin Ligase Receptor,  -Catenin, and NF- B in Colorectal Cancer". JNCI Journal of the National Cancer Institute 96 (15): 1161. doi:10.1093/jnci/djh219.  edit
  32. ^ Muerkoster, S.; Arlt, A.; Sipos, B.; Witt, M.; Grossmann, M.; Klöppel, G.; Kalthoff, H.; Fölsch, U. R. et al. (2005). "Increased Expression of the E3-Ubiquitin Ligase Receptor Subunit  TRCP1 Relates to Constitutive Nuclear Factor- B Activation and Chemoresistance in Pancreatic Carcinoma Cells". Cancer Research 65 (4): 1316–1324. doi:10.1158/0008-5472.CAN-04-1626. PMID 15735017.  edit
  33. ^ Koch, A.; Waha, A.; Hartmann, W.; Hrychyk, A.; Schüller, U.; Waha, A.; Wharton Jr, K. A.; Fuchs, S. Y. et al. (2005). "Elevated Expression of Wnt Antagonists is a Common Event in Hepatoblastomas". Clinical Cancer Research 11 (12): 4295–4304. doi:10.1158/1078-0432.CCR-04-1162. PMID 15958610.  edit
  34. ^ Spiegelman, V. S.; Tang, W.; Chan, A. M.; Igarashi, M.; Aaronson, S. A.; Sassoon, D. A.; Katoh, M.; Slaga, T. J. et al. (2002). "Induction of Homologue of Slimb Ubiquitin Ligase Receptor by Mitogen Signaling". Journal of Biological Chemistry 277 (39): 36624–36630. doi:10.1074/jbc.M204524200. PMID 12151397.  edit

Further reading