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Ubiquitylation of the amino terminus of Myc by SCFβ-TrCP antagonizes SCFFbw7-mediated turnover

Nature Cell Biology volume 12, pages 973–981 (2010)Cite this article

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Abstract

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.

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Figure 1: Depletion of β-TrCP stimulates Fbw7-dependent degradation of Myc.
Figure 2: β-TrCP binds and regulates Myc stability through a consensus recognition motif.
Figure 3: Fbw7 and β-TrCP regulate Myc levels by means of Cdc34-dependent and UbcH5-dependent ubiquitylation, respectively.
Figure 4: Fbw7 and β-TrCP regulate Myc turnover through the assembly of polyubiquitin chains with different linkages on Myc.
Figure 5: β-TrCP-dependent ubiquitylation is required for Myc-dependent cell cycle progression during S and G2 phases.
Figure 6: Polo-like kinase 1 (Plk1) regulates β-TrCP-dependent ubiquitylation and Myc stability in G2 phase.
Figure 7: Model describing our findings.

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Acknowledgements

We thank Markus Welcker and Bruce Clurman for expression vectors encoding Fbw7 and β-TrCP2; Victoria Cowling for IMECs; and Axel Behrens for anti-Fbw7 antibody. This study was supported by grants from the Deutsche Forschungsgemeinschaft through the Transregio 17 ('Ras-dependent pathways in human tumours') project and the Wilhelm Sander Stiftung für Krebsforschung.

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  1. Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, Würzburg, 97074, Germany

    Nikita Popov, Christina Schülein, Laura A. Jaenicke & Martin Eilers

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N.P., C.S. and L.A.J. performed the experimental work. N.P. and M.E. planned the experiments. M.E. wrote the paper.

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Correspondence to Martin Eilers.

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Popov, N., Schülein, C., Jaenicke, L. et al. Ubiquitylation of the amino terminus of Myc by SCFβ-TrCP antagonizes SCFFbw7-mediated turnover. Nat Cell Biol 12, 973–981 (2010). https://doi.org/10.1038/ncb2104

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