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

Zeng, T and Wang, Q and Fu, J and Lin, Q and Bi, J and Ding, W and Qiao, Y and Zhang, S and Zhao, W and Lin, H and Wang, M and Lu, B and Deng, X and Zhou, D and Yin, Z and Wang, HR (2014) Impeded Nedd4-1-Mediated Ras Degradation Underlies Ras-Driven Tumorigenesis. Cell Reports, 7 (3). 871 - 882.

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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. © 2014 The Authors.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Zeng, T
Wang, Q
Fu, J
Lin, Q
Bi, J
Ding, W
Qiao, Y
Zhang, S
Zhao, W
Lin, H
Wang, M
Lu, Bbinfeng@pitt.eduBINFENG
Deng, X
Zhou, D
Yin, Z
Wang, HR
Date: 1 January 2014
Date Type: Publication
Journal or Publication Title: Cell Reports
Volume: 7
Number: 3
Page Range: 871 - 882
DOI or Unique Handle: 10.1016/j.celrep.2014.03.045
Schools and Programs: School of Medicine > Immunology
Refereed: Yes
Date Deposited: 22 May 2015 21:51
Last Modified: 02 Feb 2019 16:58


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