Ubiquitylation of the amino terminus of Myc by SCF(β-TrCP) antagonizes SCF(Fbw7)-mediated turnover.
The SCFFbw7 ubiquitin ligase mediates growth-factor-regulated turnover of the Myc oncoprotein. Here we show that SCFβ-TrCP binds to Myc by means of a characteristic phosphodegron and ubiquitylates Myc; this results in enhanced Myc stability. SCFFbw7 and SCFβ-TrCP can exert these differential effects through polyubiquitylation of the amino terminus of Myc. Whereas SCFFbw7 with the Cdc34 ubiquitin-conjugating enzyme specifically requires lysine 48 (K48) of ubiquitin, SCFβ-TrCP uses the UbcH5 ubiquitin-conjugating enzyme to form heterotypic polyubiquitin chains on Myc. Ubiquitylation of Myc by SCFβ-TrCP is required for Myc-dependent acceleration of cell cycle progression after release from an arrest in S phase. Therefore, alternative ubiquitylation events at the N terminus can lead to the ubiquitylation-dependent stabilization of Myc.
Popov
Nikita
N
Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Schülein
Christina
C
Jaenicke
Laura A
LA
Eilers
Martin
M
D020816:Amino Acid Motifs; D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D016384:Consensus Sequence; D044783:F-Box Proteins / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D016195:G2 Phase; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D025821:Polyubiquitin / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry* / Q000378:metabolism*; D016196:S Phase; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
D064173:Anaphase-Promoting Complex-Cyclosome; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D025821:Polyubiquitin; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D044763:Ubiquitin-Conjugating Enzymes; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases; D044844:beta-Transducin Repeat-Containing Proteins; D000097869:Polo-Like Kinase 1; C471644:BTRC protein, human; C513273:FBXW7 protein, human; C577447:CDC34 protein, human; C097308:UBE2D1 protein, human