ERK1 and ERK2 Regulate Embryonic Stem Cell Self-renewal Through Phosphorylation of Klf4

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2012 Feb 7

PMID 22307056

Citations 91

Authors

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

Affiliations

Soon will be listed here.

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.

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