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

• Published in: Nature structural & molecular biology Vol. 19; no. 3; pp. 283 - 290
• Main Authors: Kim, Myoung Ok, Kim, Sung-Hyun, Cho, Yong-Yeon, Nadas, Janos, Jeong, Chul-Ho, Yao, Ke, Kim, Dong Joon, Yu, Dong-Hoon, Keum, Young-Sam, Lee, Kun-Yeong, Huang, Zunnan, Bode, Ann M, Dong, Zigang
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.03.2012
• Subjects: Animals; Cell Differentiation; Cell Line; Cellular biology; Embryonic stem cells; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Embryos; Genetic aspects; Genetic vectors; Humans; Kruppel-Like Transcription Factors - metabolism; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Models, Molecular; Molecular biology; Phosphorylation; Physiological aspects; Protein Interaction Domains and Motifs; Protein kinases; Protein Structure, Quaternary; Stem cells; Substrate Specificity; Transcription factors; South Korea
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/nsmb.2217

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.