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Nature Cell Biology 10, 138–148 (1 February 2008) | doi:10.1038/ncb1676

ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation

Jer-Yen Yang , Cong S. Zong , Weiya Xia , Hirohito Yamaguchi , Qingqing Ding , Xiaoming Xie , Jing-Yu Lang , Chien-Chen Lai , Chun-Ju Chang , Wei-Chien Huang , Hsin Huang , Hsu-Ping Kuo , Dung-Fang Lee , Long-Yuan Li , Huang-Chun Lien , Xiaoyun Cheng , King-Jen Chang , Chwan-Deng Hsiao , Fuu-Jen Tsai , Chang-Hai Tsai , Aysegul A. Sahin , William J. Muller , Gordon B. Mills , Dihua Yu , Gabriel N. Hortobagyi & Mien-Chie Hung

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.