Sears R, Nuckolls F, Haura E, Taya Y, Tamai K, Nevins J R
Department of Genetics, Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710, USA.
Genes Dev. 2000 Oct 1;14(19):2501-14. doi: 10.1101/gad.836800.
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.
我们最近的研究表明，Ras/Raf/ERK信号通路的激活可延长Myc蛋白的半衰期，从而增强Myc活性的积累。我们通过研究Myc蛋白N端的两个磷酸化位点（Thr 58和Ser 62）扩展了这些观察结果，已知这两个位点受丝裂原刺激调控。我们现在表明，这两个残基的磷酸化对于确定Myc的稳定性至关重要。Ser 62的磷酸化是Ras诱导的Myc稳定所必需的，可能是通过ERK的作用介导的。相反，Thr 58的磷酸化可能由GSK-3介导，但依赖于Ser 62的预先磷酸化，与Myc的降解相关。进一步分析表明，Ras依赖的PI-3K信号通路对于控制Myc蛋白积累也至关重要，可能是通过控制GSK-3的活性。因此，这些观察结果确定了多种Ras介导的磷酸化信号通路在细胞增殖初始阶段控制Myc蛋白积累中的协同作用。
