Impeded Nedd4-1-Mediated Ras Degradation Underlies Ras-Driven Tumorigenesis

• Main Authors: Taoling Zeng, Qun Wang, Jieying Fu, Qi Lin, Jing Bi, Weichao Ding, Yikai Qiao, Sheng Zhang, Wenxiu Zhao, Huayue Lin, Meilin Wang, Binfeng Lu, Xianming Deng, Dawang Zhou, Zhenyu Yin, Hong-Rui Wang
• Format: Article
• Language: English
• Published: Elsevier 2014-05-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124714002423

RAS genes are among the most frequently mutated proto-oncogenes in cancer. However, how Ras stability is regulated remains largely unknown. Here, we report a regulatory loop involving the E3 ligase Nedd4-1, Ras, and PTEN. We found that Ras signaling stimulates the expression of Nedd4-1, which in turn acts as an E3 ubiquitin ligase that regulates Ras levels. Importantly, Ras activation, either by oncogenic mutations or by epidermal growth factor (EGF) signaling, prevents Nedd4-1-mediated Ras ubiquitination. This leads to Ras-induced Nedd4-1 overexpression, and subsequent degradation of the tumor suppressor PTEN in both human cancer samples and cancer cells. Our study thus unravels the molecular mechanisms underlying the interplay of Ras, Nedd4-1, and PTEN and suggests a basis for the high prevalence of Ras-activating mutations and EGF hypersignaling in cancer.