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 TsaiAysegul A. Sahin, William J. Muller, Gordon B. Mills, Dihua Yu, Gabriel N. Hortobagyi, Mien Chie Hung

Research output: Contribution to journalArticlepeer-review

473 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)138-148
Number of pages11
JournalNature Cell Biology
Volume10
Issue number2
DOIs
StatePublished - Feb 2008
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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