ERK1 phosphorylates Nanog to regulate protein stability and stem cell self-renewal

Sung Hyun Kim; Myoung Ok Kim; Yong Yeon Cho; Ke Yao; Dong Joon Kim; Chul Ho Jeong; Dong Hoon Yu; Ki Beom Bae; Eun Jin Cho; Sung Keun Jung; Mee Hyun Lee; Hanyong Chen; Jae Young Kim; Ann M. Bode; Zigang Dong

doi:10.1016/j.scr.2014.04.001

ERK1 phosphorylates Nanog to regulate protein stability and stem cell self-renewal

Sung Hyun Kim, Myoung Ok Kim, Yong Yeon Cho, Ke Yao, Dong Joon Kim, Chul Ho Jeong, Dong Hoon Yu, Ki Beom Bae, Eun Jin Cho, Sung Keun Jung, Mee Hyun Lee, Hanyong Chen, Jae Young Kim, Ann M. Bode, Zigang Dong

The Hormel Institute

Research output: Contribution to journal › Article › peer-review

83 Scopus citations

Abstract

Nanog regulates human and mouse embryonic stem (ES) cell self-renewal activity. Activation of ERKs signaling negatively regulates ES cell self-renewal and induces differentiation, but the mechanisms are not understood. We found that ERK1 binds and phosphorylates Nanog. Activation of MEK/ERKs signaling and phosphorylation of Nanog inhibit Nanog transactivation, inducing ES cell differentiation. Conversely, suppression of MEK/ERKs signaling enhances Nanog transactivation to inhibit ES cell differentiation. We observed that phosphorylation of Nanog by ERK1 decreases Nanog stability through ubiquitination-mediated protein degradation. Further, we found that this phosphorylation induces binding of FBXW8 with Nanog to reduce Nanog protein stability. Overall, our results demonstrated that ERKs-mediated Nanog phosphorylation plays an important role in self-renewal of ES cells through FBXW8-mediated Nanog protein stability.

Original language	English (US)
Pages (from-to)	1-11
Number of pages	11
Journal	Stem Cell Research
Volume	13
Issue number	1
DOIs	https://doi.org/10.1016/j.scr.2014.04.001
State	Published - Jul 2014

Bibliographical note

Funding Information:
This work was supported by the Hormel Foundation and Cooperative Research Program for the Next-Generation BioGreen 21 Program (Project No. PJ009560 ).

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title = "ERK1 phosphorylates Nanog to regulate protein stability and stem cell self-renewal",

abstract = "Nanog regulates human and mouse embryonic stem (ES) cell self-renewal activity. Activation of ERKs signaling negatively regulates ES cell self-renewal and induces differentiation, but the mechanisms are not understood. We found that ERK1 binds and phosphorylates Nanog. Activation of MEK/ERKs signaling and phosphorylation of Nanog inhibit Nanog transactivation, inducing ES cell differentiation. Conversely, suppression of MEK/ERKs signaling enhances Nanog transactivation to inhibit ES cell differentiation. We observed that phosphorylation of Nanog by ERK1 decreases Nanog stability through ubiquitination-mediated protein degradation. Further, we found that this phosphorylation induces binding of FBXW8 with Nanog to reduce Nanog protein stability. Overall, our results demonstrated that ERKs-mediated Nanog phosphorylation plays an important role in self-renewal of ES cells through FBXW8-mediated Nanog protein stability.",

author = "Kim, {Sung Hyun} and Kim, {Myoung Ok} and Cho, {Yong Yeon} and Ke Yao and Kim, {Dong Joon} and Jeong, {Chul Ho} and Yu, {Dong Hoon} and Bae, {Ki Beom} and Cho, {Eun Jin} and Jung, {Sung Keun} and Lee, {Mee Hyun} and Hanyong Chen and Kim, {Jae Young} and Bode, {Ann M.} and Zigang Dong",

note = "Funding Information: This work was supported by the Hormel Foundation and Cooperative Research Program for the Next-Generation BioGreen 21 Program (Project No. PJ009560 ). ",

year = "2014",

month = jul,

doi = "10.1016/j.scr.2014.04.001",

language = "English (US)",

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journal = "Stem Cell Research",

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T1 - ERK1 phosphorylates Nanog to regulate protein stability and stem cell self-renewal

AU - Kim, Sung Hyun

AU - Kim, Myoung Ok

AU - Cho, Yong Yeon

AU - Yao, Ke

AU - Kim, Dong Joon

AU - Jeong, Chul Ho

AU - Yu, Dong Hoon

AU - Bae, Ki Beom

AU - Cho, Eun Jin

AU - Jung, Sung Keun

AU - Lee, Mee Hyun

AU - Chen, Hanyong

AU - Kim, Jae Young

AU - Bode, Ann M.

AU - Dong, Zigang

N1 - Funding Information: This work was supported by the Hormel Foundation and Cooperative Research Program for the Next-Generation BioGreen 21 Program (Project No. PJ009560 ).

PY - 2014/7

Y1 - 2014/7

N2 - Nanog regulates human and mouse embryonic stem (ES) cell self-renewal activity. Activation of ERKs signaling negatively regulates ES cell self-renewal and induces differentiation, but the mechanisms are not understood. We found that ERK1 binds and phosphorylates Nanog. Activation of MEK/ERKs signaling and phosphorylation of Nanog inhibit Nanog transactivation, inducing ES cell differentiation. Conversely, suppression of MEK/ERKs signaling enhances Nanog transactivation to inhibit ES cell differentiation. We observed that phosphorylation of Nanog by ERK1 decreases Nanog stability through ubiquitination-mediated protein degradation. Further, we found that this phosphorylation induces binding of FBXW8 with Nanog to reduce Nanog protein stability. Overall, our results demonstrated that ERKs-mediated Nanog phosphorylation plays an important role in self-renewal of ES cells through FBXW8-mediated Nanog protein stability.

AB - Nanog regulates human and mouse embryonic stem (ES) cell self-renewal activity. Activation of ERKs signaling negatively regulates ES cell self-renewal and induces differentiation, but the mechanisms are not understood. We found that ERK1 binds and phosphorylates Nanog. Activation of MEK/ERKs signaling and phosphorylation of Nanog inhibit Nanog transactivation, inducing ES cell differentiation. Conversely, suppression of MEK/ERKs signaling enhances Nanog transactivation to inhibit ES cell differentiation. We observed that phosphorylation of Nanog by ERK1 decreases Nanog stability through ubiquitination-mediated protein degradation. Further, we found that this phosphorylation induces binding of FBXW8 with Nanog to reduce Nanog protein stability. Overall, our results demonstrated that ERKs-mediated Nanog phosphorylation plays an important role in self-renewal of ES cells through FBXW8-mediated Nanog protein stability.

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ERK1 phosphorylates Nanog to regulate protein stability and stem cell self-renewal

Abstract

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