Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany.
FEBS Lett. 2011 Jul 21;585(14):2151-7. doi: 10.1016/j.febslet.2011.05.036. Epub 2011 May 24.
The Fbw7 tumor suppressor gene encodes the substrate recognition subunit of the SCF ubiquitin ligase, which targets for degradation a range of oncogenic proteins in a phosphorylation-dependent manner. Substrate phosphorylation is thought to be the main mechanism that ensures timely destruction of Fbw7 substrates. We show here that PI3K dependent phosphorylation of Fbw7 stimulates its ability to ubiquitinate and degrade its substrates. Mutation of the phosphorylation site destabilizes Fbw7 and attenuates degradation of cyclin E and Myc leading to the enhanced expression of a subset of Myc target genes. We suggest that PI3K-dependent phosphorylation of Fbw7 controls the balance between turnover of Fbw7 and its substrates to fine-tune their activity.
Fbw7 肿瘤抑制基因编码 SCF 泛素连接酶的底物识别亚基，该酶以磷酸化依赖的方式靶向降解一系列致癌蛋白。底物磷酸化被认为是确保 Fbw7 底物及时降解的主要机制。我们在这里表明，PI3K 依赖性磷酸化 Fbw7 可刺激其泛素化和降解其底物的能力。磷酸化位点的突变使 Fbw7 不稳定，并减弱了细胞周期蛋白 E 和 Myc 的降解，导致 Myc 靶基因的一部分表达增强。我们认为，PI3K 依赖性 Fbw7 磷酸化控制 Fbw7 和其底物之间周转率的平衡，以微调它们的活性。
