ERK1 and ERK2 regulate embryonic stem cell self-renewal through phosphorylation of Klf4

Myoung Ok Kim, Sung Hyun Kim, Yong Yeon Cho, Janos Nadas, Chul Ho Jeong, Ke Yao, Dong Joon Kim, Dong Hoon Yu, Young Sam Keum, Kun Yeong Lee, Zunnan Huang, Ann M. Bode, Zigang Dong

Research output: Contribution to journalArticlepeer-review

102 Scopus citations

Abstract

Understanding and controlling the mechanism by which stem cells balance self-renewal versus differentiation is of great importance for stem cell therapeutics. Klf4 promotes the self-renewal of embryonic stem cells, but the precise mechanism regulating this role of Klf4 is unclear. We found that ERK1 or ERK2 binds the activation domain of Klf4 and directly phosphorylates Klf4 at Ser123. This phosphorylation suppresses Klf4 activity, inducing embryonic stem cell differentiation. Conversely, inhibition of Klf4 phosphorylation enhances Klf4 activity and suppresses embryonic stem cell differentiation. Notably, phosphorylation of Klf4 by ERKs causes recruitment and binding of the F-box proteins βTrCP1 or βTrCP2 (components of an ubiquitin E3 ligase) to the Klf4 N-terminal domain, which results in Klf4 ubiquitination and degradation. Overall, our data provide a molecular basis for the role of ERK1 and ERK2 in regulating Klf4-mediated mouse embryonic stem cell self-renewal.

Original languageEnglish (US)
Pages (from-to)283-290
Number of pages8
JournalNature Structural and Molecular Biology
Volume19
Issue number3
DOIs
StatePublished - Mar 2012

Bibliographical note

Funding Information:
We thank M. Pagano (New York University School of Medicine) for the kind gift of plasmids, including βTrCP1/2 and several F boxes. We thank H. Niwa (RIKEN Center for Developmental Biology (CDB)) for the kind gift of plasmids, including the Lefty1 core promoter. We wish to thank T.M. Poorman for secretarial assistance. This work was supported by The Hormel Foundation.

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