Impeded Nedd4-1-mediated Ras degradation underlies Ras-driven tumorigenesis.
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.
Mesh Terms:
Animals, Carcinogenesis, Cell Line, Tumor, Endosomal Sorting Complexes Required for Transport, Epidermal Growth Factor, HEK293 Cells, HeLa Cells, Hep G2 Cells, Humans, Mice, Mice, Nude, NIH 3T3 Cells, Nedd4 Ubiquitin Protein Ligases, Neoplasms, PTEN Phosphohydrolase, Protein Binding, Signal Transduction, Transplantation, Heterologous, Ubiquitin-Protein Ligases, Ubiquitination, Up-Regulation, ras Proteins
Animals, Carcinogenesis, Cell Line, Tumor, Endosomal Sorting Complexes Required for Transport, Epidermal Growth Factor, HEK293 Cells, HeLa Cells, Hep G2 Cells, Humans, Mice, Mice, Nude, NIH 3T3 Cells, Nedd4 Ubiquitin Protein Ligases, Neoplasms, PTEN Phosphohydrolase, Protein Binding, Signal Transduction, Transplantation, Heterologous, Ubiquitin-Protein Ligases, Ubiquitination, Up-Regulation, ras Proteins
Cell Rep
Date: May. 08, 2014
PubMed ID: 24746824
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