Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea.
Sci Signal. 2012 Apr 10;5(219):ra30. doi: 10.1126/scisignal.2002242.
Although the guanosine triphosphate/guanosine diphosphate loading switch is a major regulatory mechanism that controls the activity of the guanosine triphosphatase Ras, we report a distinct mechanism for regulating Ras activity through phosphorylation-mediated degradation and describe the role of this second regulatory mechanism in the suppression of cellular transformation and tumors induced by Ras mutations. We found that negative regulators of Wnt/β-catenin signaling contributed to the polyubiquitin-dependent degradation of Ras after its phosphorylation by glycogen synthase kinase 3β (GSK3β) and the subsequent recruitment of β-TrCP-E3 ligase. We found a positive association between tumorigenesis and Ras stabilization resulting from the aberrant activation of Wnt/β-catenin signaling in adenomas from two mouse models of colon cancer, human colonic tumors from various stages, and colon polyps of patients with familial adenomatous polyposis. Our results indicated that GSK3β plays an essential role in Ras degradation and that inhibition of this degradation pathway by aberrant Wnt/β-catenin signaling may contribute to Ras-induced transformation in colorectal tumorigenesis.
尽管三磷酸鸟苷/二磷酸鸟苷加载开关是控制鸟苷三磷酸酶 Ras 活性的主要调节机制，但我们报告了一种通过磷酸化介导的降解来调节 Ras 活性的独特机制，并描述了该第二调节机制在抑制 Ras 突变诱导的细胞转化和肿瘤中的作用。我们发现 Wnt/β-catenin 信号的负调节剂有助于 Ras 在被糖原合酶激酶 3β（GSK3β）磷酸化后通过多聚泛素化依赖性降解，随后募集 β-TrCP-E3 连接酶。我们发现两种结肠癌小鼠模型、来自不同阶段的人类结肠肿瘤和家族性结肠息肉病患者的结肠息肉中的腺瘤中，Wnt/β-catenin 信号的异常激活导致肿瘤发生与 Ras 稳定之间存在正相关。我们的结果表明 GSK3β 在 Ras 降解中起关键作用，异常的 Wnt/β-catenin 信号对这种降解途径的抑制可能导致结直肠肿瘤发生中 Ras 诱导的转化。
