f box proteins


Summary: A family of proteins that share the F-BOX MOTIF and are involved in protein-protein interactions. They play an important role in process of protein ubiquition by associating with a variety of substrates and then associating into SCF UBIQUITIN LIGASE complexes. They are held in the ubiquitin-ligase complex via binding to SKP DOMAIN PROTEINS.

Top Publications

  1. Busino L, Bassermann F, Maiolica A, Lee C, Nolan P, Godinho S, et al. SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins. Science. 2007;316:900-4 pubmed
    ..Silencing of Fbxl3 produced no effect in Cry1-/-;Cry2-/- cells, which shows that Fbxl3 controls clock oscillations by mediating the degradation of CRY proteins. ..
  2. Thompson B, Jankovic V, Gao J, Buonamici S, Vest A, Lee J, et al. Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7. J Exp Med. 2008;205:1395-408 pubmed publisher
  3. Dharmasiri N, Dharmasiri S, Weijers D, Lechner E, Yamada M, Hobbie L, et al. Plant development is regulated by a family of auxin receptor F box proteins. Dev Cell. 2005;9:109-19 pubmed
    ..Here we show that three additional F box proteins, called AFB1, 2, and 3, also regulate auxin response...
  4. Wu Q, Guo Y, Yamada A, Perry J, Wang M, Araki M, et al. A role for Cdc2- and PP2A-mediated regulation of Emi2 in the maintenance of CSF arrest. Curr Biol. 2007;17:213-24 pubmed
    ..This balance allows proper maintenance of Cyclin B levels and Cdc2 kinase activity during CSF arrest. ..
  5. Ho M, Tsai P, Chien C. F-box proteins: the key to protein degradation. J Biomed Sci. 2006;13:181-91 pubmed
  6. Frescas D, Guardavaccaro D, Bassermann F, Koyama Nasu R, Pagano M. JHDM1B/FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA genes. Nature. 2007;450:309-13 pubmed
  7. Cope G, Deshaies R. Targeted silencing of Jab1/Csn5 in human cells downregulates SCF activity through reduction of F-box protein levels. BMC Biochem. 2006;7:1 pubmed
    ..We propose that deneddylation of Cul1 is required to sustain optimal activity of SCF ubiquitin ligases by repressing 'autoubiquitination' of F-box proteins within SCF complexes, thereby rescuing them from premature degradation. ..
  8. Tsukada Y, Fang J, Erdjument Bromage H, Warren M, Borchers C, Tempst P, et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature. 2006;439:811-6 pubmed
    ..Thus, we identify the JmjC domain as a novel demethylase signature motif and uncover a protein demethylation mechanism that is conserved from yeast to human. ..
  9. Popov N, Wanzel M, Madiredjo M, Zhang D, Beijersbergen R, Bernards R, et al. The ubiquitin-specific protease USP28 is required for MYC stability. Nat Cell Biol. 2007;9:765-74 pubmed
    ..High expression levels of USP28 are found in colon and breast carcinomas, and stabilization of MYC by USP28 is essential for tumour-cell proliferation. ..

More Information


  1. Madgwick S, Hansen D, Levasseur M, Jackson P, Jones K. Mouse Emi2 is required to enter meiosis II by reestablishing cyclin B1 during interkinesis. J Cell Biol. 2006;174:791-801 pubmed
  2. Hauck N, Ikeda K, Tao R, Iezzoni A. The mutated S1-haplotype in sour cherry has an altered S-haplotype-specific F-box protein gene. J Hered. 2006;97:514-20 pubmed
    ..S(1)' along with 2 other previously characterized Prunus S-haplotype mutants, S(f) and S(6m), illustrate that mobile element insertion is an evolutionary force contributing to the breakdown of GSI. ..
  3. Kemp Z, Rowan A, Chambers W, Wortham N, Halford S, Sieber O, et al. CDC4 mutations occur in a subset of colorectal cancers but are not predicted to cause loss of function and are not associated with chromosomal instability. Cancer Res. 2005;65:11361-6 pubmed
    ..CDC4 mutations may be selected primarily to drive progression through the cell cycle although CIN might be an important secondary effect in some cancers. ..
  4. Malyukova A, Dohda T, von der Lehr N, Akhoondi S, Akhondi S, Corcoran M, et al. The tumor suppressor gene hCDC4 is frequently mutated in human T-cell acute lymphoblastic leukemia with functional consequences for Notch signaling. Cancer Res. 2007;67:5611-6 pubmed
  5. Pasula S, Jouandot D, Kim J. Biochemical evidence for glucose-independent induction of HXT expression in Saccharomyces cerevisiae. FEBS Lett. 2007;581:3230-4 pubmed
    ..Finally, we show that active Snf1 protein kinase in high glucose prevents degradation of Mth1 and Std1. ..
  6. Matsuoka S, Oike Y, Onoyama I, Iwama A, Arai F, Takubo K, et al. Fbxw7 acts as a critical fail-safe against premature loss of hematopoietic stem cells and development of T-ALL. Genes Dev. 2008;22:986-91 pubmed publisher
    ..Thus, Fbxw7 functions as a fail-safe mechanism against both premature HSC loss and leukemogenesis. ..
  7. Kim H, Oh S, Brownfield L, Hong S, Ryu H, Hwang I, et al. Control of plant germline proliferation by SCF(FBL17) degradation of cell cycle inhibitors. Nature. 2008;455:1134-7 pubmed publisher
    ..Our results identify SCF(FBL17) as an essential male germ cell proliferation complex that promotes twin sperm cell production and double fertilization in flowering plants. ..
  8. Pashkova N, Gakhar L, Winistorfer S, Yu L, Ramaswamy S, Piper R. WD40 repeat propellers define a ubiquitin-binding domain that regulates turnover of F box proteins. Mol Cell. 2010;40:433-43 pubmed publisher
    ..Collectively, our results reveal a molecular mechanism that may account for how ubiquitin controls a broad spectrum of cellular activities. ..
  9. Siepka S, Yoo S, Park J, Song W, Kumar V, Hu Y, et al. Circadian mutant Overtime reveals F-box protein FBXL3 regulation of cryptochrome and period gene expression. Cell. 2007;129:1011-23 pubmed
    ..Thus, Fbxl3(Ovtm) defines a molecular link between CRY turnover and CLOCK/BMAL1-dependent circadian transcription to modulate circadian period. ..
  10. Tung J, Padmanabhan K, Hansen D, Richter J, Jackson P. Translational unmasking of Emi2 directs cytostatic factor arrest in meiosis II. Cell Cycle. 2007;6:725-31 pubmed
    ..Our results demonstrate that cytoplasmic polyadenylation and translational unmasking of Emi2 directs meiosis II-specific CSF arrest. ..
  11. Huang S, Wu H, Li Y, Wu J, Zhang S, Heng W, et al. Competitive interaction between two functional S-haplotypes confer self-compatibility on tetraploid Chinese cherry (Prunus pseudocerasus Lindl. CV. Nanjing Chuisi). Plant Cell Rep. 2008;27:1075-85 pubmed publisher
    ..Furthermore, in terms of recognition specificity, diploid pollen grains carrying PpsS-3'-haplotype are equal to monoploid pollen grains carrying the other functional S-haplotype. ..
  12. Pesin J, Orr Weaver T. Regulation of APC/C activators in mitosis and meiosis. Annu Rev Cell Dev Biol. 2008;24:475-99 pubmed publisher
    ..Here, we review the regulation of APC/C activators during mitosis and the role and regulation of the APC/C during female meiosis. ..
  13. Vernon A, LaBonne C. Slug stability is dynamically regulated during neural crest development by the F-box protein Ppa. Development. 2006;133:3359-70 pubmed
    ..These results provide novel insight into the regulation of Slug, a protein that plays a central role in neural crest precursor formation, as well as in developmental and pathological epithelial to mesenchymal transitions. ..
  14. Kepinski S, Leyser O. The Arabidopsis F-box protein TIR1 is an auxin receptor. Nature. 2005;435:446-51 pubmed
    ..Here we show that this modification involves the direct binding of auxin to TIR1 and thus that TIR1 is an auxin receptor mediating transcriptional responses to auxin. ..
  15. Liu J, Maller J. Calcium elevation at fertilization coordinates phosphorylation of XErp1/Emi2 by Plx1 and CaMK II to release metaphase arrest by cytostatic factor. Curr Biol. 2005;15:1458-68 pubmed
    ..It acts at the same level as CaMKII in the pathway of calcium-induced CSF release by cooperating with CaMKII to regulate APC/C regulator(s), such as XErp1/Emi2, rather than by directly activating the APC/C itself. ..
  16. van Drogen F, Sangfelt O, Malyukova A, Matskova L, Yeh E, Means A, et al. Ubiquitylation of cyclin E requires the sequential function of SCF complexes containing distinct hCdc4 isoforms. Mol Cell. 2006;23:37-48 pubmed
    ..Furthermore, in the context of Cdc4alpha and cyclin E, mutational data suggest that Pin1 isomerizes a noncanonical proline-proline bond, with the possibility that Cdc4alpha may serve as a cofactor for altering the specificity of Pin1. ..
  17. Miller J, Summers M, Hansen D, Nachury M, Lehman N, Loktev A, et al. Emi1 stably binds and inhibits the anaphase-promoting complex/cyclosome as a pseudosubstrate inhibitor. Genes Dev. 2006;20:2410-20 pubmed
    ..The combination of a degron/E3 recognition site and an anti-ligase function in Emi1 suggests a general model for how E3 substrates evolve to become pseudosubstrate inhibitors. ..
  18. Marrocco K, Zhou Y, Bury E, Dieterle M, Funk M, Genschik P, et al. Functional analysis of EID1, an F-box protein involved in phytochrome A-dependent light signal transduction. Plant J. 2006;45:423-38 pubmed
    ..Finally, our data indicate that the EID1 target interaction domain is composed of two independent modules. ..
  19. O Neil J, Grim J, Strack P, Rao S, Tibbitts D, Winter C, et al. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. J Exp Med. 2007;204:1813-24 pubmed
  20. Kile A, Koepp D. Activation of the S-phase checkpoint inhibits degradation of the F-box protein Dia2. Mol Cell Biol. 2010;30:160-71 pubmed publisher
    ..Together, our results suggest that Dia2 protein turnover does not involve an autocatalytic mechanism and that Dia2 proteolysis is inhibited by activation of the replication stress response. ..
  21. Wu J, Kornbluth S. Across the meiotic divide - CSF activity in the post-Emi2/XErp1 era. J Cell Sci. 2008;121:3509-14 pubmed publisher
  22. Sonnberg S, Seet B, Pawson T, Fleming S, Mercer A. Poxvirus ankyrin repeat proteins are a unique class of F-box proteins that associate with cellular SCF1 ubiquitin ligase complexes. Proc Natl Acad Sci U S A. 2008;105:10955-60 pubmed publisher
    ..We propose that poxviruses use these unique ANK/F-box proteins to dictate target specificity to SCF1 ubiquitin ligases and thereby exploit the cell's ubiquitin-proteasome machinery. ..
  23. Minella A, Welcker M, Clurman B. Ras activity regulates cyclin E degradation by the Fbw7 pathway. Proc Natl Acad Sci U S A. 2005;102:9649-54 pubmed
    ..Thus, we conclude that Ras activity regulates Fbw7-mediated cyclin E proteolysis and suggest that impaired cyclin E proteolysis is a mechanism through which Ras mutations promote tumorigenesis. ..
  24. Wei W, Jin J, Schlisio S, Harper J, Kaelin W. The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase. Cancer Cell. 2005;8:25-33 pubmed
    ..These findings explain the enhanced stability and oncogenicity of v-Jun relative to its cellular counterpart and reveal that GSK3 and Fbw7 coordinately regulate c-Jun and c-Myc. ..
  25. Wu J, Hansen D, Guo Y, Wang M, Tang W, Freel C, et al. Control of Emi2 activity and stability through Mos-mediated recruitment of PP2A. Proc Natl Acad Sci U S A. 2007;104:16564-9 pubmed
  26. Hansen D, Tung J, Jackson P. CaMKII and polo-like kinase 1 sequentially phosphorylate the cytostatic factor Emi2/XErp1 to trigger its destruction and meiotic exit. Proc Natl Acad Sci U S A. 2006;103:608-13 pubmed
  27. Mamnun Y, Katayama S, Toda T. Fission yeast Mcl1 interacts with SCF(Pof3) and is required for centromere formation. Biochem Biophys Res Commun. 2006;350:125-30 pubmed
    ..Importantly, we identity a novel, specific role for Mcl1 in the transcriptional silencing and the localisation of CENP-A at the centromeres. ..
  28. Lin D, Barbash O, Kumar K, Weber J, Harper J, Klein Szanto A, et al. Phosphorylation-dependent ubiquitination of cyclin D1 by the SCF(FBX4-alphaB crystallin) complex. Mol Cell. 2006;24:355-66 pubmed
    ..We conclude that SCF(FBX4-alphaB crystallin) is an E3 ubiquitin ligase that promotes ubiquitin-dependent degradation of Thr286-phosphorylated cyclin D1. ..
  29. Zhang W, Koepp D. Fbw7 isoform interaction contributes to cyclin E proteolysis. Mol Cancer Res. 2006;4:935-43 pubmed
    ..Overall, this study contributes to the current understanding of the regulation of the Fbw7 tumor-suppressor protein. ..
  30. Di Fiore B, Pines J. Emi1 is needed to couple DNA replication with mitosis but does not regulate activation of the mitotic APC/C. J Cell Biol. 2007;177:425-37 pubmed
    ..Thus, Emi1 plays a crucial role in the cell cycle to couple DNA replication with mitosis, and our results also question the current view that the APC/C has to be inactivated to allow DNA replication. ..
  31. Kwak E, Moberg K, Wahrer D, Quinn J, Gilmore P, Graham C, et al. Infrequent mutations of Archipelago (hAGO, hCDC4, Fbw7) in primary ovarian cancer. Gynecol Oncol. 2005;98:124-8 pubmed
    ..Reconstitution experiments, rather than measuring tumor levels of cyclin E and c-Myc, provide an effective approach to determine the functional significance of AGO mutations identified in human cancers. ..
  32. Mimura S, Komata M, Kishi T, Shirahige K, Kamura T. SCF(Dia2) regulates DNA replication forks during S-phase in budding yeast. EMBO J. 2009;28:3693-705 pubmed publisher
    ..These results demonstrate that Dia2 is involved in the regulation of replisome activity through a direct interaction with replisome components. ..
  33. Liu J, Grimison B, Lewellyn A, Maller J. The anaphase-promoting complex/cyclosome inhibitor Emi2 is essential for meiotic but not mitotic cell cycles. J Biol Chem. 2006;281:34736-41 pubmed
    ..However, depletion of the protein from cycling egg extracts does not prevent mitotic cell cycle progression. Thus, Emi2 plays an essential role in meiotic but not mitotic cell cycles. ..
  34. Dharmasiri N, Dharmasiri S, Estelle M. The F-box protein TIR1 is an auxin receptor. Nature. 2005;435:441-5 pubmed
    ..Finally, TIR1 synthesized in insect cells binds Aux/IAA proteins in an auxin-dependent manner. Together, these results indicate that TIR1 is an auxin receptor that mediates Aux/IAA degradation and auxin-regulated transcription. ..
  35. Okabe H, Lee S, Phuchareon J, Albertson D, McCormick F, Tetsu O. A critical role for FBXW8 and MAPK in cyclin D1 degradation and cancer cell proliferation. PLoS ONE. 2006;1:e128 pubmed
    ..Thus, FBXW8 plays an essential role in cancer cell proliferation through proteolysis of cyclin D1. It may present new opportunities to develop therapies targeting destruction of cyclin D1 or its regulator E3 ligase selectively. ..
  36. Hebeisen M, Roy R. CDC-25.1 stability is regulated by distinct domains to restrict cell division during embryogenesis in C. elegans. Development. 2008;135:1259-69 pubmed publisher
    ..1 phosphatase during early embryogenesis to control its stability and turnover, in order to ensure the timely divisions of intestinal cells and coordinate them with the formation of the developing gut. ..
  37. Lee T, Perrem K, Harper J, Lu K, Zhou X. The F-box protein FBX4 targets PIN2/TRF1 for ubiquitin-mediated degradation and regulates telomere maintenance. J Biol Chem. 2006;281:759-68 pubmed
    ..Thus, Fbx4 may play a critical role in telomere maintenance. ..
  38. Popov N, Herold S, Llamazares M, Schülein C, Eilers M. Fbw7 and Usp28 regulate myc protein stability in response to DNA damage. Cell Cycle. 2007;6:2327-31 pubmed
    ..Our data extend previous observations that link Myc function to the cellular response to DNA damage. ..
  39. Shoji S, Yoshida N, Amanai M, Ohgishi M, Fukui T, Fujimoto S, et al. Mammalian Emi2 mediates cytostatic arrest and transduces the signal for meiotic exit via Cdc20. EMBO J. 2006;25:834-45 pubmed
    ..These studies show in intact oocytes that the interaction of Emi2 with Cdc20 links activating stimuli to meiotic resumption at fertilization and during parthenogenesis in mammals. ..
  40. Morishita T, Furukawa F, Sakaguchi C, Toda T, Carr A, Iwasaki H, et al. Role of the Schizosaccharomyces pombe F-Box DNA helicase in processing recombination intermediates. Mol Cell Biol. 2005;25:8074-83 pubmed
    ..Focus formation of Fbh1 protein was induced by treatment that damages DNA. Thus, the F-box DNA helicase appears to process toxic recombination intermediates, the formation of which is dependent on the function of Rhp51. ..
  41. Nishiyama T, Ohsumi K, Kishimoto T. Phosphorylation of Erp1 by p90rsk is required for cytostatic factor arrest in Xenopus laevis eggs. Nature. 2007;446:1096-9 pubmed
    ..Thus, Mos and Erp1 collaboratively establish and maintain metaphase II arrest in Xenopus eggs. The link between Mos and Erp1 provides a molecular explanation for the integral mechanism of CSF arrest in unfertilized vertebrate eggs. ..
  42. Onoyama I, Tsunematsu R, Matsumoto A, Kimura T, de Alboran I, Nakayama K, et al. Conditional inactivation of Fbxw7 impairs cell-cycle exit during T cell differentiation and results in lymphomatogenesis. J Exp Med. 2007;204:2875-88 pubmed
  43. Lu T, Jackson M, Wang B, Yang M, Chance M, Miyagi M, et al. Regulation of NF-kappaB by NSD1/FBXL11-dependent reversible lysine methylation of p65. Proc Natl Acad Sci U S A. 2010;107:46-51 pubmed publisher
    ..We conclude that reversible lysine methylation of NF-kappaB is an important element in the complex regulation of this key transcription factor. ..
  44. Tang X, Orlicky S, Lin Z, Willems A, Neculai D, Ceccarelli D, et al. Suprafacial orientation of the SCFCdc4 dimer accommodates multiple geometries for substrate ubiquitination. Cell. 2007;129:1165-76 pubmed
    SCF ubiquitin ligases recruit substrates for degradation via F box protein adaptor subunits. WD40 repeat F box proteins, such as Cdc4 and beta-TrCP, contain a conserved dimerization motif called the D domain...
  45. Kitagawa K, Hiramatsu Y, Uchida C, Isobe T, Hattori T, Oda T, et al. Fbw7 promotes ubiquitin-dependent degradation of c-Myb: involvement of GSK3-mediated phosphorylation of Thr-572 in mouse c-Myb. Oncogene. 2009;28:2393-405 pubmed publisher
    ..In consequence, the c-Myb protein was markedly stabilized by the substitution of Thr-572 to Ala. These observations suggest that SCF(Fbw7) ubiquitin ligase regulates phosphorylation-dependent degradation of c-Myb protein. ..
  46. Osman F, Dixon J, Barr A, Whitby M. The F-Box DNA helicase Fbh1 prevents Rhp51-dependent recombination without mediator proteins. Mol Cell Biol. 2005;25:8084-96 pubmed
    ..Furthermore, analysis of different fbh1 mutant alleles suggests that both the F-box and helicase activities of Fbh1 contribute to controlling Rhp51. ..
  47. Ohe M, Inoue D, Kanemori Y, Sagata N. Erp1/Emi2 is essential for the meiosis I to meiosis II transition in Xenopus oocytes. Dev Biol. 2007;303:157-64 pubmed
    ..Thus, our results show the essential role for Erp1 in the meiosis I/meiosis II transition in Xenopus oocytes and can explain why normally maturing oocytes cannot arrest at Meta-I. ..
  48. Akhoondi S, Sun D, von der Lehr N, Apostolidou S, Klotz K, Maljukova A, et al. FBXW7/hCDC4 is a general tumor suppressor in human cancer. Cancer Res. 2007;67:9006-12 pubmed
    ..Our study is the first comprehensive screen of FBXW7 mutations in various human malignancies and shows that FBXW7 is a general tumor suppressor in human cancer. ..
  49. Olson B, Hock M, Ekholm Reed S, Wohlschlegel J, Dev K, Kralli A, et al. SCFCdc4 acts antagonistically to the PGC-1alpha transcriptional coactivator by targeting it for ubiquitin-mediated proteolysis. Genes Dev. 2008;22:252-64 pubmed publisher
    ..These results suggest that attenuation of SCF(Cdc4)-dependent proteasomal degradation of PGC-1alpha has a role in mediating the PGC-1alpha-dependent transcriptional response to oxidative stress. ..
  50. Welcker M, Clurman B. FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nat Rev Cancer. 2008;8:83-93 pubmed
    ..This Review focuses on structural and functional aspects of FBW7 and its role in the development of cancer. ..
  51. Rauh N, Schmidt A, Bormann J, Nigg E, Mayer T. Calcium triggers exit from meiosis II by targeting the APC/C inhibitor XErp1 for degradation. Nature. 2005;437:1048-52 pubmed
    ..These results provide a molecular explanation for how the fertilization-induced calcium increase triggers exit from meiosis II. ..
  52. Lehman N, Verschuren E, Hsu J, Cherry A, Jackson P. Overexpression of the anaphase promoting complex/cyclosome inhibitor Emi1 leads to tetraploidy and genomic instability of p53-deficient cells. Cell Cycle. 2006;5:1569-73 pubmed
    ..This represents a potentially important mechanism by which pRb and p53 dysfunction may contribute to tumorigenesis through the generation of genomic instability. ..
  53. Machida Y, Dutta A. The APC/C inhibitor, Emi1, is essential for prevention of rereplication. Genes Dev. 2007;21:184-94 pubmed
    ..These data suggest that Emi1 plays a critical role in preserving genome integrity by blocking rereplication, revealing a previously unrecognized function of this inhibitor of APC/C. ..