The SV40 large T antigen contains a decoy phosphodegron that mediates its interactions with Fbw7/hCdc4.
Cell transformation by simian virus 40 (SV40) results mostly from the highly oncogenic activities of the large T antigen (LT), which corrupts the cellular checkpoint mechanisms that guard cell division and the transcription, replication, and repair of DNA. The most prominent LT targets are the retinoblastoma protein (pRb) and p53. Here we report that LT binds directly to Fbw7, the substrate recognition component of the SCF(Fbw7) ubiquitin ligase and a human tumor suppressor. LT binding mislocalizes the nucleolar Fbw7gamma isoform to the nucleoplasm. Interestingly, the binding of LT to Fbw7 occurs via a decoy phospho-epitope within the C terminus of LT that closely mimics the consensus Cdc4 phospho-degron found within Fbw7 substrates. We demonstrate that, using this mode of interaction, LT can interfere with Fbw7-driven cyclin E turnover in vivo and causes increased cyclin E-associated kinase activity. Our data suggest that LT competes with cellular proteins for Fbw7 binding in a substrate-like fashion.
Welcker
Markus
M
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Clurman
Bruce E
BE
D000595:Amino Acid Sequence; D000952:Antigens, Polyomavirus Transforming / Q000737:chemistry / Q000502:physiology*; D000957:Antigens, Viral, Tumor / Q000737:chemistry / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology*; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D019927:Cyclin E / Q000737:chemistry; D003593:Cytoplasm / Q000378:metabolism; D004260:DNA Repair; D000939:Epitopes / Q000737:chemistry; D044783:F-Box Proteins / Q000378:metabolism / Q000502:physiology*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D016160:Retinoblastoma Protein / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism / Q000502:physiology*
D000952:Antigens, Polyomavirus Transforming; D000957:Antigens, Viral, Tumor; D018797:Cell Cycle Proteins; D019927:Cyclin E; D000939:Epitopes; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D020033:Protein Isoforms; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; D005982:Glutathione Transferase