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

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

doi:10.1016/j.scr.2014.04.001

Cited by 102 publications

(107 citation statements)

References 45 publications

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“…Consistently, enhanced expression of pluripotency genes, including Nanog, Tbx3, Prdm14, and Klf4, has been observed in Erk2 KO ESCs and Erk2 KO/Erk1 knockdown ESCs (23,30). In addition to transcriptional regulation, Erk may regulate the protein stability of pluripotency factors, such as Nanog and Klf4, by phosphorylation modification (20)(21)(22). The downregulation of pluripotency genes after prolonged culture of Erk KO ESCs might be an indirect effect of loss of Erk signaling.…”

Section: Discussionmentioning

confidence: 66%

“…For example, Erk1 and Erk2 phosphorylate Klf4 at Ser123, leading to recruitment of ubiquitin E3 ligase mediated by βTrCP1 and βTrCP2 and to Klf4 ubiquitination and degradation (20). Nanog is also demonstrated to be a substrate of Erk kinases (21,22). Nanog phosphorylation by Erk reduces Nanog transactivation activity and protein stability (22).…”

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confidence: 99%

“…Nanog is also demonstrated to be a substrate of Erk kinases (21,22). Nanog phosphorylation by Erk reduces Nanog transactivation activity and protein stability (22). Recently, it has been demonstrated that in mouse ESCs, Erk2, in cooperation with PRC2, binds to developmental genes and phosphorylates RNA polymerase II at Ser5 to maintain a poised transcription status (23).…”

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confidence: 99%

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Erk signaling is indispensable for genomic stability and self-renewal of mouse embryonic stem cells

Chen

Guo

Zhang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Inhibition of Mek/Erk signaling by pharmacological Mek inhibitors promotes self-renewal and pluripotency of mouse embryonic stem cells (ESCs). Intriguingly, Erk signaling is essential for human ESC selfrenewal. Here we demonstrate that Erk signaling is critical for mouse ESC self-renewal and genomic stability. Erk-depleted ESCs cannot be maintained. Lack of Erk leads to rapid telomere shortening and genomic instability, in association with misregulated expression of pluripotency genes, reduced cell proliferation, G1 cell-cycle arrest, and increased apoptosis. Erk signaling is also required for the activation of differentiation genes but not for the repression of pluripotency genes during ESC differentiation. Furthermore, we find an Erk-independent function of Mek, which may explain the diverse effects of Mek inhibition and Erk knockout on ESC self-renewal. Together, in contrast to the prevailing view, Erk signaling is required for telomere maintenance, genomic stability, and self-renewal of mouse ESCs.Erk | Mek | embryonic stem cells | self-renewal | genomic stability E mbryonic stem cells (ESCs) are pluripotent and, hence, promising donor cell sources for regenerative medicine. Transcriptional regulation plays an essential role in pluripotency maintenance of ESCs, and a transcriptional regulation network for pluripotency has been characterized (1, 2). The core component of the pluripotency transcriptional regulation network is a feed-forward selfregulating circuitry formed by transcription factors Oct4, Sox2, and Nanog (3, 4). ESCs are cultured in media supplemented with growth factors. Through signaling pathways, growth factors affect the pluripotency transcriptional regulation network and regulate the self-renewal and differentiation of ESCs. For example, LIF and BMP signaling controls the transcriptional activities of the downstream effectors Stat3 and Smad1 to promote the self-renewal of mouse ESCs (5-7).The extracellular signal-regulated kinase (Erk)/mitogen-activated protein kinase (MAPK) signal-transduction cascade mediates the effect of growth factors by sequential activation of Ras-like GTPase, Raf kinase, serine/threonine protein kinase Mek, and Erk to regulate cell-cycle progression, proliferation, differentiation, and carcinogenesis (8, 9). Erk signaling also plays a pivotal role in pluripotency maintenance. Inhibition of Mek/Erk signaling constrains the differentiation of mouse ESCs (10). Mouse ESCs can be derived and maintained in medium supplemented with inhibitors of Mek and Gsk3 signaling (2i) (11). Moreover, inhibition of Mek facilitates the conversion of mouse epiblast stem cells (epiSCs) to ESC-like cells (12). Similarly, the Mek inhibitor PD0325901 is used in establishing and maintaining human ground-state pluripotent stem cells (13-16). Conversely, activation of Mek/Erk signaling promotes the differentiation of ESCs. Ectopic expression of an activated H-RAS mutant leads to mouse ESC differentiation toward the trophectodermal lineage. Mek/Erk signaling is the downstream effector of Ras medi...

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Section: Discussionmentioning

confidence: 66%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Erk signaling is indispensable for genomic stability and self-renewal of mouse embryonic stem cells

Chen

Guo

Zhang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Several studies have investigated the mechanism by which the UPS controls the protein levels of key pluripotency factors. As a key pluripotency factor, Nanog is a short-lived protein that is rapidly degraded by E3 ligase FBXW8-mediated ubiquitination17. However, the DUBs that regulate Nanog stability are unknown.…”

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confidence: 99%

The deubiquitinase USP21 maintains the stemness of mouse embryonic stem cells via stabilization of Nanog

et al. 2016

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Nanog is a master pluripotency factor of embryonic stem cells (ESCs). Stable expression of Nanog is essential to maintain the stemness of ESCs. However, Nanog is a short-lived protein and quickly degraded by the ubiquitin-dependent proteasome system. Here we report that the deubiquitinase USP21 interacts with, deubiquitinates and stabilizes Nanog, and therefore maintains the protein level of Nanog in mouse ESCs (mESCs). Loss of USP21 results in Nanog degradation, mESCs differentiation and reduces somatic cell reprogramming efficiency. USP21 is a transcriptional target of the LIF/STAT3 pathway and is downregulated upon differentiation. Moreover, differentiation cues promote ERK-mediated phosphorylation and dissociation of USP21 from Nanog, thus leading to Nanog degradation. In addition, USP21 is recruited to gene promoters by Nanog to deubiquitinate histone H2A at K119 and thus facilitates Nanog-mediated gene expression. Together, our findings provide a regulatory mechanism by which extrinsic signals regulate mESC fate via deubiquitinating Nanog.

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“…Klf4 protein has a high turn-over rate and it is a target for proteasome-mediated proteolysis by pVHL however DUB for Klf4 is not well defined [31]. USP21 deubiquitylates and stabilizes Nanog and reverses the F-box/WD repeat-containing protein 8 (FBXW8)-mediated Lys48-linked polyubiquitylation of Nanog [41,42]. Thus, USP21 might have a significant role in maintaining the pluripotency of iPSCs and ESCs, iPSCs generation and offers novel insights for therapeutic interventions [42].…”

Section: Application Of Dubs For Rapid and Efficient Ipsc Generationmentioning

confidence: 99%

Future Application of Deubiquitylating Enzymes for Rapid and Efficient Cellular Reprogramming

Haq¹,

Ramakrishna²

2017

JSRT

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In stem cell pluripotency and differentiation, ubiquitylation and deubiquitylation modifications of stem cell core transcription proteinsis of high significance, as it influences stem cell fate determination. Two key enzymes i.e. an E3 ubiquitin ligase enzyme; known for tagging ubiquitin molecules to the target proteins for degradation, and the deubiquitylating enzyme (DUB), that counteracts the proteolysis, have to be well balanced for cellular homeostasis. Interestingly, the notion of DUBs enhancing the stability and half-life of stem cell core transcription factors has presented a new vision about significance of applying DUBs to control stem cell fate determination and cellular reprogramming. In this review, we propose the applications of DUBs along with stem cells core transcription factors i.e. Oct4, Sox2, Klf4, c-Myc, Nanog and Lin28 for an efficient generation of protein induced pluripotent stem cells.

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

Cited by 102 publications

References 45 publications

Erk signaling is indispensable for genomic stability and self-renewal of mouse embryonic stem cells

Erk signaling is indispensable for genomic stability and self-renewal of mouse embryonic stem cells

The deubiquitinase USP21 maintains the stemness of mouse embryonic stem cells via stabilization of Nanog

Future Application of Deubiquitylating Enzymes for Rapid and Efficient Cellular Reprogramming

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