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

•Nedd4-1 suppresses tumorigenesis by targeting Ras proteins for degradation•Ras signaling upregulates Nedd4-1 transcription•Activated Ras is resistant to Nedd4-1-mediated ubiquitination•Aberrant Ras activation promotes Nedd4-1-dependent PTEN degradation

SummaryRAS 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.

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