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.
Highlights
Ras proteins (K-Ras, H-Ras, and N-Ras) are small guanosine triphosphatases (GTPases) that act as key molecular switches in regulating a wide range of cellular processes, especially in controlling cell proliferation, transformation, differentiation, and survival (Ahearn et al, 2012; Malumbres and Barbacid, 2003)
We found that Ras signaling stimulates the expression of Nedd4-1, which in turn acts as an E3 ubiquitin ligase that regulates Ras levels
Our study unravels the molecular mechanisms underlying the interplay of Ras, Nedd4-1, and phosphatase and tensin homolog (PTEN) and suggests a basis for the high prevalence of Ras-activating mutations and epidermal growth factor (EGF) hypersignaling in cancer
Summary
Ras proteins (K-Ras, H-Ras, and N-Ras) are small guanosine triphosphatases (GTPases) that act as key molecular switches in regulating a wide range of cellular processes, especially in controlling cell proliferation, transformation, differentiation, and survival (Ahearn et al, 2012; Malumbres and Barbacid, 2003). Their activities are tightly controlled by cycling between active guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate (GDP)-bound states (Ahearn et al, 2012). For the past 4 decades, intensive efforts have been made to determine the underlying mechanism for regulation of Ras activity and Ras-induced tumorigenesis
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