Extracellular signal-regulated kinase 2 is necessary for mesoderm differentiation

Abstract

The extracellular signal-regulated kinase (ERK) is a component of the mitogen-activated protein kinase cascade. Exon 2 of erk2 was deleted by homologous recombination and resulted in embryonic lethality at embryonic day 6.5. erk2 mutant embryos did not form mesoderm and showed increased apoptosis but comparable levels of BrdUrd incorporation, indicating a defect in differentiation. erk2 null embryonic stem (ES) cells exhibited reduced total ERK activity upon serum stimulation, augmented ERK1 phosphorylation, and decreased downstream p90Rsk phosphorylation and activity; yet ES cell proliferation was unaffected. Mutant ES cells were capable of forming mesoderm; however, treatment of mutant ES cells with the mitogen-activated protein kinase kinase inhibitor PD184352 decreased total ERK activity and expression of the mesodermal marker brachyury, suggesting that ERK1 can compensate for ERK2 in vitro. Normal embryos at embryonic day 6.5 expressed activated ERK1͞2 in the extraembryonic ectoderm, whereas erk2 mutant embryos had no detectable activated ERK1͞2 in this region, suggesting that activated ERK1 was not expressed, and therefore cannot compensate for loss of ERK2 in vivo. These data indicate that ERK2 plays an essential role in mesoderm differentiation during embryonic development.T he extracellular signal-regulated kinase (ERK) mitogenactivated protein kinase (MAPK) cascade is a key signaling pathway controlling cell proliferation, differentiation, and apoptosis. Two members of this pathway, ERK1 and ERK2, share an overall 75% identity at the amino acid level and up to 90% identity at the C terminus (1), present the same in vitro substrate specificity, and are ubiquitously expressed. The classic MAPK cascade involves sequential activation of the serine͞threonine kinase Raf, the dual-specificity MAPK kinase (MEK) and the MAPK ERK upon stimulation by growth factors, serum, or phorbol esters. Activated ERK phosphorylates numerous substrates on (S͞T) P sites in different cellular compartments (reviewed in ref.2), leading to increased nucleotide synthesis, activated transcription and translation, and enhanced cell cycle progression (reviewed in refs. 3 and 4). It has been shown that the duration and strength of ERK activation can gate cells to antagonistic fates such as proliferation or differentiation (5), cell cycle entry or G 1 arrest (6), and apoptosis or survival (7,8). Thus, the ERK pathway must be tightly controlled to ensure proper outcome of such integrated biological responses.The identification of the exclusive MEK1͞ERK1 scaffold protein MEK Partner 1 (MP1) indicates that ERK1 and ERK2 likely have different roles (9). This view is supported by genetic ablation studies in mice. erk1-deficient mice are viable and fertile, but have defective thymocyte maturation (10). These mice also have enhanced long-term memory and are able to up-regulate ERK2 signaling in response to glutamate (11). These results suggest that ERK2 cannot compensate for all of the functions mediated by ERK1. ERK2 itself may also possess d...

RhoA prevents apoptosis during zebrafish embryogenesis through activation of Mek/Erk pathway

“…Our present study shows that knockdown of RhoA in zebrafish causes increased apoptosis, which is RhoA controls cell survival via Mek/Erk and Bcl-2 S Zhu et al at least resulted from the reduced activation of Mek/ Erk pathway. Consistently, Erk2 knockout mice also show enhanced apoptosis (Yao et al, 2003). However, knockout of Erk leads to the loss of mesoderm, whereas suppression of RhoA signalling does not affect the cell fate determination in both zebrafish and Xenopus (Tahinci and Symes, 2003;Zhu et al, 2006).…”

Critical role for Rsk2 in T-lymphocyte activation

“…Erk1 KO mice have defective thymocyte maturation and TCR-mediated thymocyte proliferation is severely impaired, 57 whereas Erk2 and PDK1 KO mice are embryonic lethal. [58][59][60] Interestingly, deleting PDK1 in T cells blocks thymocyte differentiation whereas hypomorphic expression allows thymocyte differentiation but blocks thymocyte expansion. 61 Given the roles of Erk and PDK1 for activating all the Rsks, it is not surprising that the abnormalities in the Rsk2 KO mice are less severe than those in the Erk and PDK1-deficient mice.…”

MAPK signaling in inflammation-associated cancer development

“…Other studies also show that ERK1-null mice have increased locomotor activity (Mazzucchelli et al, 2002) and impaired adipocyte differentiation (Bost et al, 2005). In contrast, ERK2-null mice show completely different phenotypes; these mice die at embryonic day 6.5-8.5 due to impaired mesoderm differentiation and placental development (Hatano et al, 2003;Saba-El-Leil et al, 2003;Yao et al, 2003).…”