Impeded Nedd4-1-mediated Ras degradation underlies Ras-driven tumorigenesis

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

doi:10.1016/j.celrep.2014.03.045

Impeded Nedd4-1-mediated Ras degradation underlies Ras-driven tumorigenesis

Cell Rep. 2014 May 8;7(3):871-82. doi: 10.1016/j.celrep.2014.03.045. Epub 2014 Apr 17.

Authors

Taoling Zeng¹, Qun Wang¹, Jieying Fu¹, Qi Lin¹, Jing Bi¹, Weichao Ding¹, Yikai Qiao¹, Sheng Zhang², Wenxiu Zhao², Huayue Lin¹, Meilin Wang¹, Binfeng Lu³, Xianming Deng¹, Dawang Zhou¹, Zhenyu Yin⁴, Hong-Rui Wang⁵

Affiliations

¹ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
² Department of Surgery, Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361004, China.
³ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
⁴ Department of Surgery, Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361004, China. Electronic address: yinzy@xmu.edu.cn.
⁵ 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.

PMID: 24746824
DOI: 10.1016/j.celrep.2014.03.045

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinogenesis
Cell Line, Tumor
Endosomal Sorting Complexes Required for Transport / antagonists & inhibitors
Endosomal Sorting Complexes Required for Transport / genetics
Endosomal Sorting Complexes Required for Transport / metabolism*
Epidermal Growth Factor / metabolism
HEK293 Cells
HeLa Cells
Hep G2 Cells
Humans
Mice
Mice, Nude
NIH 3T3 Cells
Nedd4 Ubiquitin Protein Ligases
Neoplasms / metabolism
Neoplasms / pathology
PTEN Phosphohydrolase / metabolism
Protein Binding
Signal Transduction
Transplantation, Heterologous
Ubiquitin-Protein Ligases / antagonists & inhibitors
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*
Ubiquitination
Up-Regulation
ras Proteins / metabolism*

Substances

Endosomal Sorting Complexes Required for Transport
Epidermal Growth Factor
Nedd4 Ubiquitin Protein Ligases
Nedd4 protein, human
Nedd4l protein, mouse
Ubiquitin-Protein Ligases
PTEN Phosphohydrolase
ras Proteins