Functional Redundancy of ERK1 and ERK2 MAP Kinases during Development

Frémin, Christophe; Saba-El-Leil, Marc K.; Lévesque, Kim; Ang, Siew‐Lan; Meloche, Sylvain

doi:10.1016/j.celrep.2015.07.011

Cited by 90 publications

(103 citation statements)

References 30 publications

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“…Activated Erk1/2 is observable in the limb bud mesenchyme, and AER and has been shown to depend on Fgfr signaling (Corson et al 2003). Hindlimb agenesis accompanied by distal forelimb defects is also observed in conditional mutants that lack Mapk1 in the embryo proper (Fremin et al 2015). It is not known why loss of Mapk1 produces more severe defects in hindlimb development, although this may suggest that forelimbs and hindlimbs require different levels of Erk1/2 signaling.…”

Section: Fgf-erk1/2 Signaling Regulates Epithelial-mesenchymal Interamentioning

confidence: 95%

“…However, results from this approach may be difficult to interpret, as many biological contexts require signaling through multiple RTKs. For example, the labyrinth compartment of the placenta requires Fgfr2, Met, Egfr, Igf1r, and many signaling pathways, including p38α, Erk1/2, and Akt (Liu et al 1993;Bladt et al 1995;Sibilia and Wagner 1995;Threadgill et al 1995;Xu et al 1998b;Adams et al 2000;Mudgett et al 2000;Hatano et al 2003;Yang et al 2003Yang et al , 2005Fremin et al 2015). Since Fgfr2 is capable of engaging all of these pathways, it is difficult to know whether Fgfr2-associated placental defects are simply due to decreases in Erk1/2 signaling or whether these phenotypes are the result of lowering the activity of multiple signaling pathways.…”

Section: Considerations and Future Directionsmentioning

confidence: 99%

“…Erk1 and Erk2 proteins are functionally equivalent kinases (Fremin et al 2015), making it difficult but still genetically tractable to disrupt both the Mapk3 and Mapk1 genes. This is considerably more challenging for the PI3K/Akt pathway, since there are five isoforms of the p85 regulatory subunit, three isoforms of the p110 catalytic subunit, and three isoforms of Akt (Thorpe et al 2015).…”

Section: Considerations and Future Directionsmentioning

confidence: 99%

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Genetic insights into the mechanisms of Fgf signaling

2016

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The fibroblast growth factor (Fgf) family of ligands and receptor tyrosine kinases is required throughout embryonic and postnatal development and also regulates multiple homeostatic functions in the adult. Aberrant Fgf signaling causes many congenital disorders and underlies multiple forms of cancer. Understanding the mechanisms that govern Fgf signaling is therefore important to appreciate many aspects of Fgf biology and disease. Here we review the mechanisms of Fgf signaling by focusing on genetic strategies that enable in vivo analysis. These studies support an important role for Erk1/2 as a mediator of Fgf signaling in many biological processes but have also provided strong evidence for additional signaling pathways in transmitting Fgf signaling in vivo.

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Section: Fgf-erk1/2 Signaling Regulates Epithelial-mesenchymal Interamentioning

confidence: 95%

Section: Considerations and Future Directionsmentioning

confidence: 99%

Section: Considerations and Future Directionsmentioning

confidence: 99%

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Genetic insights into the mechanisms of Fgf signaling

2016

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“…The CRISPR/Cas system seems to be more efficient than the TALENs (Table S1). Due to the redundant role of Erk1 and Erk2 (34), it is necessary to generate Erk1 and Erk2 double KO ESCs to study the function of Erk signaling. Thus, we attempted to knock out Erk1 and Erk2 in Erk2 −/− and Erk1 −/− ESCs, respectively.…”

Section: Significancementioning

confidence: 99%

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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“…These strong phenotypic differences suggested that ERK2 may play a more significant role in mouse development or that temporal or quantitative expression of the genes differed during development. ERK2 protein is generally expressed at higher levels than ERK1 levels in most mammalian tissues (Fremin, Saba-El-Leil, Levesque, Ang, & Meloche, 2015). Numerous studies in cells and mice using knockdown and knockout strategies have suggested specific individual biological functions for ERK1 or ERK2 based on observations when one protein or the other is lost.…”

Section: Erk1 and Erk2mentioning

confidence: 99%

Extracellular-Regulated Kinases: Signaling From Ras to ERK Substrates to Control Biological Outcomes

Eblen

2018

Advances in Cancer Research

151

104

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The extracellular regulated kinases ERK1 and ERK2 are evolutionarily conserved, ubiquitous serine-threonine kinases that are involved in regulating cellular signaling in both normal and pathological conditions. Their expression is critical for development and their hyperactivation is a major factor in cancer development and progression. Since their discovery as one of the major signaling mediators activated by mitogens and Ras mutation, we have learned much about their regulation, including their activation, binding partners and substrates. In this review, I will discuss some of what has been discovered about the members of the Ras to ERK pathway, including regulation of their activation by growth factors and cell adhesion pathways. Looking downstream of ERK activation, I will also highlight some of the many ERK substrates that have been discovered, including those involved in feedback regulation, cell migration, and cell cycle progression through the control of transcription, pre-mRNA splicing and protein synthesis.

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Functional Redundancy of ERK1 and ERK2 MAP Kinases during Development

Cited by 90 publications

References 30 publications

Genetic insights into the mechanisms of Fgf signaling

Genetic insights into the mechanisms of Fgf signaling

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

Extracellular-Regulated Kinases: Signaling From Ras to ERK Substrates to Control Biological Outcomes

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