ERK1 and ERK2 regulate embryonic stem cell self-renewal through phosphorylation of Klf4.
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.
The Hormel Institute, University of Minnesota, Austin, Minnesota, USA.
Myoung Ok
MO
Kim
Sung-Hyun
SH
Kim
Yong-Yeon
YY
Cho
Janos
J
Nadas
Chul-Ho
CH
Jeong
Ke
K
Yao
Dong Joon
DJ
Kim
Dong-Hoon
DH
Yu
Young-Sam
YS
Keum
Kun-Yeong
KY
Lee
Zunnan
Z
Huang
Ann M
AM
Bode
Zigang
Z
Dong
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D008958:Models, Molecular; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs; D020836:Protein Structure, Quaternary; D013379:Substrate Specificity
C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3