Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability

Rosalie Sears, Faison Nuckolls, Eric Haura, Yoichi Taya, Katsuyuki Tamai, Joseph R. Nevins

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779 Scopus citations

Abstract

Our recent work has shown that activation of the Ras/Raf/ERK pathway extends the half-life of the Myc protein and thus enhances the accumulation of Myc activity. We have extended these observations by investigating two N-terminal phosphorylation sites in Myc, Thr 58 and Ser 62, which are known to be regulated by mitogen stimulation. We now show that the phosphorylation of these two residues is critical for determining the stability of Myc. Phosphorylation of Ser 62 is required for Ras-induced stabilization of Myc, likely mediated through the action of ERK. Conversely, phosphorylation of Thr 58, likely mediated by GSK-3 but dependent on the prior phosphorylation of Ser 62, is associated with degradation of Myc. Further analysis demonstrates that the Ras-dependent PI-3K pathway is also critical for controlling Myc protein accumulation, likely through the control of GSK-3 activity. These observations thus define a synergistic role for multiple Ras-mediated phosphorylation pathways in the control of Myc protein accumulation during the initial stage of cell proliferation.

Original languageEnglish (US)
Pages (from-to)2501-2514
Number of pages14
JournalGenes and Development
Volume14
Issue number19
DOIs
Publication statusPublished - Oct 1 2000
Externally publishedYes

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Keywords

  • ERK
  • GSK-3
  • Myc
  • Ras
  • Ser 62
  • Stability
  • Thr 58

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Sears, R., Nuckolls, F., Haura, E., Taya, Y., Tamai, K., & Nevins, J. R. (2000). Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes and Development, 14(19), 2501-2514. https://doi.org/10.1101/gad.836800