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

• DOI: 10.1016/j.celrep.2014.03.045
• Publication Date: 2014-04-17T11:49:34Z
• 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
• Keywords: NEDD4

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 E3 ligase Nedd4-1, Ras, and PTEN. We found that signaling stimulates expression of which turn acts as an ubiquitin regulates levels. Importantly, activation, either by oncogenic mutations or epidermal growth factor (EGF) signaling, prevents Nedd4-1-mediated ubiquitination. This leads to Ras-induced Nedd4-1 overexpression, subsequent degradation tumor suppressor PTEN both human cancer samples cells. Our study thus unravels molecular mechanisms underlying interplay suggests basis for high prevalence Ras-activating EGF hypersignaling