FBXW11 explained

βTrCP2 (beta-transducin repeat containing protein 2; also known as Fbxw11 or HOS) is a protein that in humans is encoded by the FBXW11 (F-box and WD repeat domain containing 11) 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:

• Fbxws containing WD40 repeats,
• Fbxls containing leucine-rich repeats,
• and Fbxos containing either "other" protein-protein interaction modules or no recognizable motifs.

The protein encoded by FBXW11 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 βTrCP2, a paralog protein (called βTrCP1 or FBXW1) also exists, but, so far, their functions appear redundant and indistinguishable.

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 microtubules.^[9]

Functions

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,^[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 growth 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:

• FBXW11^[21]
• DLG1^[22]
• IκBα^{[21] [23]}
• NFKB2^{[24] [25]}
• RELA^[23]
• SKP1A^{[3] [21] [26] [27] [28]}
• CDC34^{[26] [29]}
• CUL1^{[21] [26] [27]}
• β-catenin^[30]
• WEE1
• EMI1
• Cdc25A
• Claspin
• REST^[31]
• PDCD4
• DEPTOR

Clinical Significance

βTrCP behaves as an oncoprotein in some tissues. Elevated levels of βTrCP expression have been found in colorectal,^[32] pancreatic,^[33] hapatoblastoma,^[34] and breast cancers.^[35]

Further reading

• Ishikawa K, Nagase T, Suyama M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O . Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro . DNA Research . 5 . 3 . 169–76 . Jun 1998 . 9734811 . 10.1093/dnares/5.3.169 . free .
• Suzuki H, Chiba T, Suzuki T, Fujita T, Ikenoue T, Omata M, Furuichi K, Shikama H, Tanaka K . Homodimer of two F-box proteins betaTrCP1 or betaTrCP2 binds to IkappaBalpha for signal-dependent ubiquitination . The Journal of Biological Chemistry . 275 . 4 . 2877–84 . Jan 2000 . 10644755 . 10.1074/jbc.275.4.2877 . free .
• Bhatia N, Herter JR, Slaga TJ, Fuchs SY, Spiegelman VS . Mouse homologue of HOS (mHOS) is overexpressed in skin tumors and implicated in constitutive activation of NF-kappaB . Oncogene . 21 . 10 . 1501–9 . Feb 2002 . 11896578 . 10.1038/sj.onc.1205311 . free .
• Dias DC, Dolios G, Wang R, Pan ZQ . CUL7: A DOC domain-containing cullin selectively binds Skp1.Fbx29 to form an SCF-like complex . Proceedings of the National Academy of Sciences of the United States of America . 99 . 26 . 16601–6 . Dec 2002 . 12481031 . 139190 . 10.1073/pnas.252646399 . free .
• Busino L, Donzelli M, Chiesa M, Guardavaccaro D, Ganoth D, Dorrello NV, Hershko A, Pagano M, Draetta GF . Degradation of Cdc25A by beta-TrCP during S phase and in response to DNA damage . Nature . 426 . 6962 . 87–91 . Nov 2003 . 14603323 . 10.1038/nature02082 . 2003Natur.426...87B . 768783 .
• Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G . A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway . Nature Cell Biology . 6 . 2 . 97–105 . Feb 2004 . 14743216 . 10.1038/ncb1086 . 11683986 .
• Watanabe N, Arai H, Nishihara Y, Taniguchi M, Watanabe N, Hunter T, Osada H . M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFbeta-TrCP . Proceedings of the National Academy of Sciences of the United States of America . 101 . 13 . 4419–24 . Mar 2004 . 15070733 . 384762 . 10.1073/pnas.0307700101 . 2004PNAS..101.4419W . free .
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . Oct 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
• Koolen DA, Herbergs J, Veltman JA, Pfundt R, van Bokhoven H, Stroink H, Sistermans EA, Brunner HG, Geurts van Kessel A, de Vries BB . Holoprosencephaly and preaxial polydactyly associated with a 1.24 Mb duplication encompassing FBXW11 at 5q35.1 . Journal of Human Genetics . 51 . 8 . 721–6 . 2006 . 16865294 . 10.1007/s10038-006-0010-8 . free .
• Butticaz C, Michielin O, Wyniger J, Telenti A, Rothenberger S . Silencing of both beta-TrCP1 and HOS (beta-TrCP2) is required to suppress human immunodeficiency virus type 1 Vpu-mediated CD4 down-modulation . Journal of Virology . 81 . 3 . 1502–5 . Feb 2007 . 17121803 . 1797504 . 10.1128/JVI.01711-06 .
• Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D . Large-scale mapping of human protein-protein interactions by mass spectrometry . Molecular Systems Biology . 3 . 1 . 89 . 2007 . 17353931 . 1847948 . 10.1038/msb4100134 .

Notes and References

1. Fujiwara T, Suzuki M, Tanigami A, Ikenoue T, Omata M, Chiba T, Tanaka K . The BTRC gene, encoding a human F-box/WD40-repeat protein, maps to chromosome 10q24-q25 . Genomics . 58 . 1 . 104–5 . May 1999 . 10331953 . 10.1006/geno.1999.5792 .
2. Web site: Entrez Gene: FBXW11 F-box and WD repeat domain containing 11.
3. Margottin F, Bour SP, Durand H, Selig L, Benichou S, Richard V, Thomas D, Strebel K, Benarous R . 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 . Molecular Cell . 1 . 4 . 565–74 . Mar 1998 . 9660940 . 10.1016/S1097-2765(00)80056-8 . free .
4. Frescas D, Pagano M . Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer . Nature Reviews. Cancer . 8 . 6 . 438–49 . Jun 2008 . 18500245 . 2711846 . 10.1038/nrc2396 .
5. Busino L, Donzelli M, Chiesa M, Guardavaccaro D, Ganoth D, Dorrello NV, Hershko A, Pagano M, Draetta GF . Degradation of Cdc25A by beta-TrCP during S phase and in response to DNA damage . Nature . 426 . 6962 . 87–91 . Nov 2003 . 14603323 . 10.1038/nature02082 . 2003Natur.426...87B . 768783 .
6. Watanabe N, Arai H, Nishihara Y, Taniguchi M, Watanabe N, Hunter T, Osada H . M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFbeta-TrCP . Proceedings of the National Academy of Sciences of the United States of America . 101 . 13 . 4419–24 . Mar 2004 . 15070733 . 384762 . 10.1073/pnas.0307700101 . 2004PNAS..101.4419W . free .
7. Guardavaccaro D, Kudo Y, Boulaire J, Barchi M, Busino L, Donzelli M, Margottin-Goguet F, Jackson PK, Yamasaki L, Pagano M . Control of meiotic and mitotic progression by the F box protein beta-Trcp1 in vivo . Developmental Cell . 4 . 6 . 799–812 . Jun 2003 . 12791266 . 10.1016/S1534-5807(03)00154-0 . free . 2108/51096 . free .
8. Margottin-Goguet F, Hsu JY, Loktev A, Hsieh HM, Reimann JD, Jackson PK . 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 . 813–26 . Jun 2003 . 12791267 . 10.1016/S1534-5807(03)00153-9 . free .
9. Guardavaccaro D, Frescas D, Dorrello NV, Peschiaroli A, Multani AS, Cardozo T, Lasorella A, Iavarone A, Chang S, Hernando E, Pagano M . Control of chromosome stability by the beta-TrCP-REST-Mad2 axis . Nature . 452 . 7185 . 365–9 . Mar 2008 . 18354482 . 2707768 . 10.1038/nature06641 . 2008Natur.452..365G .
10. Jin J, Shirogane T, Xu L, Nalepa G, Qin J, Elledge SJ, Harper JW . SCFbeta-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase . Genes & Development . 17 . 24 . 3062–74 . Dec 2003 . 14681206 . 305258 . 10.1101/gad.1157503 .
11. Peschiaroli A, Dorrello NV, Guardavaccaro D, Venere M, Halazonetis T, Sherman NE, Pagano M . SCFbetaTrCP-mediated degradation of Claspin regulates recovery from the DNA replication checkpoint response . Molecular Cell . 23 . 3 . 319–29 . Aug 2006 . 16885022 . 10.1016/j.molcel.2006.06.013 . free .
12. Mailand N, Bekker-Jensen S, Bartek J, Lukas J . Destruction of Claspin by SCFbetaTrCP restrains Chk1 activation and facilitates recovery from genotoxic stress . Molecular Cell . 23 . 3 . 307–18 . Aug 2006 . 16885021 . 10.1016/j.molcel.2006.06.016 . free .
13. Mamely I, van Vugt MA, Smits VA, Semple JI, Lemmens B, Perrakis A, Medema RH, Freire R . Polo-like kinase-1 controls proteasome-dependent degradation of Claspin during checkpoint recovery . Current Biology . 16 . 19 . 1950–5 . Oct 2006 . 16934469 . 10.1016/j.cub.2006.08.026 . 2928268 . free . 2006CBio...16.1950M .
14. Dorrello NV, Peschiaroli A, Guardavaccaro D, Colburn NH, Sherman NE, Pagano M . S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth . Science . 314 . 5798 . 467–71 . Oct 2006 . 17053147 . 10.1126/science.1130276 . 2006Sci...314..467D . 84039829 .
15. Duan S, Skaar JR, Kuchay S, Toschi A, Kanarek N, Ben-Neriah Y, Pagano M . mTOR generates an auto-amplification loop by triggering the βTrCP- and CK1α-dependent degradation of DEPTOR . Molecular Cell . 44 . 2 . 317–24 . Oct 2011 . 22017877 . 3212871 . 10.1016/j.molcel.2011.09.005 .
16. Zhao Y, Xiong X, Sun Y . DEPTOR, an mTOR inhibitor, is a physiological substrate of SCF(βTrCP) E3 ubiquitin ligase and regulates survival and autophagy . Molecular Cell . 44 . 2 . 304–16 . Oct 2011 . 22017876 . 3216641 . 10.1016/j.molcel.2011.08.029 .
17. Gao D, Inuzuka H, Tan MK, Fukushima H, Locasale JW, Liu P, Wan L, Zhai B, Chin YR, Shaik S, Lyssiotis CA, Gygi SP, Toker A, Cantley LC, Asara JM, Harper JW, Wei W . mTOR drives its own activation via SCF(βTrCP)-dependent degradation of the mTOR inhibitor DEPTOR . Molecular Cell . 44 . 2 . 290–303 . Oct 2011 . 22017875 . 3229299 . 10.1016/j.molcel.2011.08.030 .
18. Dehan E, Bassermann F, Guardavaccaro D, Vasiliver-Shamis G, Cohen M, Lowes KN, Dustin M, Huang DC, Taunton J, Pagano M . betaTrCP- and Rsk1/2-mediated degradation of BimEL inhibits apoptosis . Molecular Cell . 33 . 1 . 109–16 . Jan 2009 . 19150432 . 2655121 . 10.1016/j.molcel.2008.12.020 .
19. Winston JT, Strack P, Beer-Romero P, Chu CY, Elledge SJ, Harper JW . The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro . Genes & Development . 13 . 3 . 270–83 . Feb 1999 . 9990852 . 316433 . 10.1101/gad.13.3.270 .
20. Latres E, Chiaur DS, Pagano M . The human F box protein beta-Trcp associates with the Cul1/Skp1 complex and regulates the stability of beta-catenin . Oncogene . 18 . 4 . 849–54 . Jan 1999 . 10023660 . 10.1038/sj.onc.1202653 . free .
21. Suzuki H, Chiba T, Suzuki T, Fujita T, Ikenoue T, Omata M, Furuichi K, Shikama H, Tanaka K . Homodimer of two F-box proteins betaTrCP1 or betaTrCP2 binds to IkappaBalpha for signal-dependent ubiquitination . The Journal of Biological Chemistry . 275 . 4 . 2877–84 . Jan 2000 . 10644755 . 10.1074/jbc.275.4.2877 . free .
22. Mantovani F, Banks L . Regulation of the discs large tumor suppressor by a phosphorylation-dependent interaction with the beta-TrCP ubiquitin ligase receptor . The Journal of Biological Chemistry . 278 . 43 . 42477–86 . Oct 2003 . 12902344 . 10.1074/jbc.M302799200 . free .
23. Spencer E, Jiang J, Chen ZJ . Signal-induced ubiquitination of IkappaBalpha by the F-box protein Slimb/beta-TrCP . Genes & Development . 13 . 3 . 284–94 . Feb 1999 . 9990853 . 316434 . 10.1101/gad.13.3.284 .
24. Fong A, Sun SC . Genetic evidence for the essential role of beta-transducin repeat-containing protein in the inducible processing of NF-kappa B2/p100 . The Journal of Biological Chemistry . 277 . 25 . 22111–4 . Jun 2002 . 11994270 . 10.1074/jbc.C200151200 . free .
25. Vatsyayan J, Qing G, Xiao G, Hu J . SUMO1 modification of NF-kappaB2/p100 is essential for stimuli-induced p100 phosphorylation and processing . EMBO Reports . 9 . 9 . 885–90 . Sep 2008 . 18617892 . 2529344 . 10.1038/embor.2008.122 .
26. Cenciarelli C, Chiaur DS, Guardavaccaro D, Parks W, Vidal M, Pagano M . Identification of a family of human F-box proteins . Current Biology . 9 . 20 . 1177–9 . Oct 1999 . 10531035 . 10.1016/S0960-9822(00)80020-2 . 7467493 . free . 1999CBio....9.1177C .
27. Min KW, Hwang JW, Lee JS, Park Y, Tamura TA, Yoon JB . TIP120A associates with cullins and modulates ubiquitin ligase activity . The Journal of Biological Chemistry . 278 . 18 . 15905–10 . May 2003 . 12609982 . 10.1074/jbc.M213070200 . free .
28. Strack P, Caligiuri M, Pelletier M, Boisclair M, Theodoras A, Beer-Romero P, Glass S, Parsons T, Copeland RA, Auger KR, Benfield P, Brizuela L, Rolfe M . SCF(beta-TRCP) and phosphorylation dependent ubiquitinationof I kappa B alpha catalyzed by Ubc3 and Ubc4 . Oncogene . 19 . 31 . 3529–36 . Jul 2000 . 10918611 . 10.1038/sj.onc.1203647 . free .
29. Semplici F, Meggio F, Pinna LA, Oliviero S . 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 . Jun 2002 . 12037680 . 10.1038/sj.onc.1205574 . free .
30. Liu C, Kato Y, Zhang Z, Do VM, Yankner BA, He X . beta-Trcp couples beta-catenin phosphorylation-degradation and regulates Xenopus axis formation . Proceedings of the National Academy of Sciences of the United States of America . 96 . 11 . 6273–8 . May 1999 . 10339577 . 26871 . 10.1073/pnas.96.11.6273 . 1999PNAS...96.6273L . free .
31. Westbrook TF, Hu G, Ang XL, Mulligan P, Pavlova NN, Liang A, Leng Y, Maehr R, Shi Y, Harper JW, Elledge SJ . SCFbeta-TRCP controls oncogenic transformation and neural differentiation through REST degradation . Nature . 452 . 7185 . 370–4 . Mar 2008 . 18354483 . 2688689 . 10.1038/nature06780 . 2008Natur.452..370W .
32. Ougolkov A, Zhang B, Yamashita K, Bilim V, Mai M, Fuchs SY, Minamoto T . Associations among beta-TrCP, an E3 ubiquitin ligase receptor, beta-catenin, and NF-kappaB in colorectal cancer . Journal of the National Cancer Institute . 96 . 15 . 1161–70 . Aug 2004 . 15292388. 10.1093/jnci/djh219 . free .
33. Müerköster S, Arlt A, Sipos B, Witt M, Grossmann M, Klöppel G, Kalthoff H, Fölsch UR, Schäfer H . Increased expression of the E3-ubiquitin ligase receptor subunit betaTRCP1 relates to constitutive nuclear factor-kappaB activation and chemoresistance in pancreatic carcinoma cells . Cancer Research . 65 . 4 . 1316–24 . Feb 2005 . 15735017 . 10.1158/0008-5472.CAN-04-1626 . free .
34. Koch A, Waha A, Hartmann W, Hrychyk A, Schüller U, Waha A, Wharton KA, Fuchs SY, von Schweinitz D, Pietsch T . Elevated expression of Wnt antagonists is a common event in hepatoblastomas . Clinical Cancer Research . 11 . 12 . 4295–304 . Jun 2005 . 15958610 . 10.1158/1078-0432.CCR-04-1162 . free .
35. Spiegelman VS, Tang W, Chan AM, Igarashi M, Aaronson SA, Sassoon DA, Katoh M, Slaga TJ, Fuchs SY . Induction of homologue of Slimb ubiquitin ligase receptor by mitogen signaling . The Journal of Biological Chemistry . 277 . 39 . 36624–30 . Sep 2002 . 12151397 . 10.1074/jbc.M204524200 . free .