Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability

Our recent work has shown that activation of the Ras/Raf/ERK pathway extend s the half-life of the Myc protein and thus enhances the accumulation of My c activity. We have extended these observations by investigating two N-term inal 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. Phosph orylation of Ser 62 is required for Ras-induced stabilization of Myc, likel y mediated through the action of ERK. Conversely, phosphorylation of Thr 58 , likely mediated by GSK-3 but dependent on the prior phosphorylation of Se r 62, is associated with degradation of Myc. further analysis demonstrates that the Ras-dependent PI-3K pathway is also critical for controlling Myc p rotein accumulation, likely through the control of GSK-3 activity. These ob servations thus define a synergistic role for multiple Ras-mediated phospho rylation pathways in the control of Myc protein accumulation during the ini tial stage of cell proliferation.