title: Impeded Nedd4-1-mediated Ras degradation underlies Ras-driven tumorigenesis.
abstract: 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.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Taoling
authors.initials: T
authors.lastname: Zeng
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Jieying
authors.initials: J
authors.lastname: Fu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Bi
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Weichao
authors.initials: W
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Yikai
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: Department of Surgery, Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361004, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Surgery, Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361004, China.
authors.forename: Wenxiu
authors.initials: W
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Huayue
authors.initials: H
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Meilin
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Binfeng
authors.initials: B
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Xianming
authors.initials: X
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Dawang
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Department of Surgery, Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361004, China. Electronic address: yinzy@xmu.edu.cn.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. Electronic address: wanghr@xmu.edu.cn.
authors.forename: Hong-Rui
authors.initials: HR
authors.lastname: Wang
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D056827:Endosomal Sorting Complexes Required for Transport / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D000075702:Nedd4 Ubiquitin Protein Ligases; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D015854:Up-Regulation; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D004815:Epidermal Growth Factor; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases; D051059:PTEN Phosphohydrolase; D018631:ras Proteins