biostudies-literature001270Yang JYNCI NIH HHS138-48https://www.ebi.ac.uk/biostudies/studies/S-EPMC2376808biostudies-literatureUnknown10(2)The RAS-ERK pathway is known to play a pivotal role in differentiation, proliferation and tumour progression. Here, we show that Erk downregulates Forkhead box O 3a (FOXO3a) by directly interacting with and phosphorylating FOXO3a at Ser 294, Ser 344 and Ser 425, which consequently promotes cell proliferation and tumorigenesis. The ERK-phosphorylated FOXO3a degrades via an MDM2-mediated ubiquitin-proteasome pathway. However, the non-phosphorylated FOXO3a mutant is resistant to the interaction and degradation by murine double minute 2 (MDM2), thereby resulting in a strong inhibition of cell proliferation and tumorigenicity. Taken together, our study elucidates a novel pathway in cell growth and tumorigenesis through negative regulation of FOXO3a by RAS-ERK and MDM2.Nature cell biologyERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation.PMC2376808P50 CA116199-01R01 CA109311P50 CA116199P30 CA016672CA116199CA16672P01 CA099031P01 CA 099031P01 CA099031-01P01 CA099031-010001Hsiao CDHuang HChang CJYu DDing QCheng XChang KJTsai CHZong CSYamaguchi HLee DFLien HCYang JYHortobagyi GNXie XXia WHuang WCLi LYMuller WJSahin AATsai FJHung MCLai CCLang JYKuo HPMills GB127falseERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation.The RAS-ERK pathway is known to play a pivotal role in differentiation, proliferation and tumour progression. Here, we show that Erk downregulates Forkhead box O 3a (FOXO3a) by directly interacting with and phosphorylating FOXO3a at Ser 294, Ser 344 and Ser 425, which consequently promotes cell proliferation and tumorigenesis. The ERK-phosphorylated FOXO3a degrades via an MDM2-mediated ubiquitin-proteasome pathway. However, the non-phosphorylated FOXO3a mutant is resistant to the interaction and degradation by murine double minute 2 (MDM2), thereby resulting in a strong inhibition of cell proliferation and tumorigenicity. Taken together, our study elucidates a novel pathway in cell growth and tumorigenesis through negative regulation of FOXO3a by RAS-ERK and MDM2.2008-01-01T00:00:00Z2008 Feb2024-12-04T05:04:12.951Z2019-03-27T02:45:04ZS-EPMC23768081820443910.1038/ncb1676