MEK is a dual-specificity kinase that activates the extracellular signal-regulated kinase (ERK) mitogenactivated protein (MAP) kinase upon agonist binding to receptors. The ERK/MAP kinase cascade is involved in cell fate determination in many organisms. In mammals, this pathway is proposed to regulate cell growth and differentiation. Genetic studies have shown that although a single Mek gene is present in Caenorhabditis elegans, Drosophila melanogaster, and Xenopus laevis, two Mek homologs, Mek1 and Mek2, are present in the mammalian cascade. The inactivation of the Mek1 gene leads to embryonic lethality and has revealed the unique role played by Mek1 during embryogenesis. To investigate the biological function of the second homolog, we have generated mice deficient in Mek2 function. Mek2 mutant mice are viable and fertile, and they do not present flagrant morphological alteration. Although several components of the ERK/MAP kinase cascade have been implicated in thymocyte development, no such involvement was observed for MEK2, which appears to be nonessential for thymocyte differentiation and T-cell-receptor-induced proliferation and apoptosis. Altogether, our findings demonstrate that MEK2 is not necessary for the normal development of the embryo and T-cell lineages, suggesting that the loss of MEK2 can be compensated for by MEK1.The mitogen-activated protein (MAP) kinase signaling pathways consist of protein kinase cascades linking extracellular stimuli to various targets scattered in the cytoplasm, the cytoskeleton, the membrane, and the nucleus (38). There are at least three distinct MAP kinase signaling pathways in mammals, including the extracellular signal-regulated kinases (ERKs), the c-Jun N-terminal kinases, and the p38 MAP kinase (12). These kinases are activated in cascades by phosphorylation on both threonine and tyrosine residues in the regulatory TXY loop present in all MAP kinases. This phosphorylation is carried out via distinct upstream dual-specificity MAP kinase kinases (MAPKKs). The classical pathway, which appears to be the major one in growth factor signaling, uses MAP kinaseor ERK-activating kinases (MEK and MAPKK) and ERK isoforms (MAP kinase) and is named the ERK/MAP kinasesignaling pathway. In mammals, MAPKK constitutes a small family of related proteins, but only MEK1 and MEK2 are known participants in the ERK/MAP kinase cascade (38). Directly downstream of MEK1 and MEK2, ERK1 and ERK2 phosphorylate a large number of substrates located in the cytoplasm and the nucleus (13,25,27,38,45).The ERK/MAP kinase pathway is also involved in cell fate determination in Caenorhabditis elegans, Drosophila melanogaster, and Xenopus laevis (21,28,41,44). While two different MEK proteins are present in the ERK/MAP kinase cascade in mammals, a single Mek gene fulfills this role in these species. Sequence analysis revealed that the murine MEK1 protein is more related to the Xenopus MEK than to the mouse MEK2.Indeed, MEK2 protein is only 80% identical and 90% similar to MEK1, whereas Xenopus MEK is 91% i...

The mammalian genome contains two ERK/MAP kinase kinase genes, Map2k1 and Map2k2, which encode dual-specificity kinases responsible for ERK/MAP kinase activation. In the mouse, loss of Map2k1 function causes embryonic lethality, whereas Map2k2 mutants survive with a normal lifespan, suggesting that Map2k1 masks the phenotype due to the Map2k2 mutation. To uncover the specific function of MAP2K2 and the threshold requirement of MAP2K proteins during embryo formation, we have successively ablated the Map2k gene functions. We report here that Map2k2 haploinsufficiency affects the normal development of placenta in the absence of one Map2k1 allele. Most Map2k1 Map2k2+/-embryos die during gestation because of placenta defects restricted to extra-embryonic tissues. The impaired viability of Map2k1 Map2k2+/-embryos can be rescued when the Map2k1 deletion is restricted to the embryonic tissues. The severity of the placenta phenotype is dependent on the number of Map2k mutant alleles, the deletion of the Map2k1 allele being more deleterious. Moreover, the deletion of one or both Map2k2 alleles in the context of one null Map2k1 allele leads to the formation of multinucleated trophoblast giant (MTG) cells. Genetic experiments indicate that these structures are derived from Gcm1-expressing syncytiotrophoblasts (SynT), which are affected in their ability to form the uniform SynT layer II lining the maternal sinuses. Thus, even though Map2k1 plays a predominant role, these results enlighten the function of Map2k2 in placenta development.