title: Functional redundancy of the kinases MEK1 and MEK2: Rescue of the Mek1 mutant phenotype by Mek2 knock-in reveals a protein threshold effect.
abstract: The mammalian genome contains two mitogen-activated protein kinase (MAPK) kinase (MEK)-encoding genes, Mek1 and Mek2. MEKs phosphorylate and activate the two extracellular signal-regulated kinase (ERK) isoforms ERK1 and ERK2. Mek1(-/-) embryos die due to placental defects, whereas Mek2(-/-) mice survive with a normal life span and fertility, suggesting that MEK1 has functions not shared by MEK2. However, most Mek1(+/-)Mek2(+/-) embryos also die from placental defects, indicating that both Mek genes contribute to placental development. To assess the functional specificity of the Mek1 and Mek2 genes, we produced a Mek1 knock-in allele in which the Mek2 coding sequences were placed under the control of Mek1 regulatory sequences (Mek1(2) allele). Mek1(2/2) mice were viable with no apparent phenotype, indicating rescue by MEK2 and functional redundancy between the two MEK proteins. However, Mek1(2/-) embryos with Mek2 in only one of the Mek1 alleles and the other Mek1 allele null died from abnormal placenta, suggesting a dosage effect. Analysis of mice from a Mek1 Mek2 allelic series revealed that the occurrence of the placenta phenotype correlated with the amount of MEK protein independently of which MEK isoform was produced. Thus, although MEK1 and MEK2 can substitute for each other, a minimum amount of MEK is critical for placenta development and embryo survival.
authors.affiliation: Centre de recherche sur le cancer de l'Université Laval, Centre de recherche du CHU de Québec, L'Hôtel-Dieu de Québec, Québec, Québec G1R 3S3, Canada.
authors.forename: Rifdat
authors.initials: R
authors.lastname: Aoidi
authors.affiliation: Centre de recherche sur le cancer de l'Université Laval, Centre de recherche du CHU de Québec, L'Hôtel-Dieu de Québec, Québec, Québec G1R 3S3, Canada.
authors.forename: Annie
authors.initials: A
authors.lastname: Maltais
authors.affiliation: Centre de recherche sur le cancer de l'Université Laval, Centre de recherche du CHU de Québec, L'Hôtel-Dieu de Québec, Québec, Québec G1R 3S3, Canada. Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec, Québec G1V 0A6, Canada. jean.charron@crhdq.ulaval.ca.
authors.forename: Jean
authors.initials: J
authors.lastname: Charron
mesh_terms: D000483:Alleles; D000818:Animals; D003433:Crosses, Genetic; D000939:Epitopes / Q000737:chemistry; D005260:Female; D055879:Gene Knock-In Techniques; D005838:Genotype; D006579:Heterozygote; D007150:Immunohistochemistry; D048369:MAP Kinase Kinase 1 / Q000737:chemistry / Q000235:genetics*; D048370:MAP Kinase Kinase 2 / Q000737:chemistry / Q000235:genetics*; D051379:Mice; D008856:Microscopy, Fluorescence; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011270:Pregnancy, Animal
chemical_list: D000939:Epitopes; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse