Research ArticleDevelopmental Biology

Functional redundancy of the kinases MEK1 and MEK2: Rescue of the Mek1 mutant phenotype by Mek2 knock-in reveals a protein threshold effect

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Sci. Signal.  26 Jan 2016:
Vol. 9, Issue 412, pp. ra9
DOI: 10.1126/scisignal.aad5658

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A MEK redundancy threshold

The kinases MEK1 and MEK2 have the same substrates, ERK1 and ERK2, but mice lacking Mek1 die as embryos due to placental defects and mice lacking Mek2 are viable, implying isoform-specific functions. Aoidi et al. determined that MEK1 and MEK2 are functionally redundant as long as sufficient protein is produced. Mice lacking Mek1 were rescued by placing the coding sequence of Mek2 into both alleles of Mek1, but placental defects and embryonic lethality occurred when the mice carried only one copy of this knock-in allele along with a null allele of Mek1. The data indicated that the proteins functionally substituted for one another, but that the developing placenta is particularly sensitive to the amount of MEK present and producing the minimum amount required at least four copies of Mek2 in the absence of Mek1 or two copies of Mek1 in the absence of Mek2. Thus, the products may be functionally identical, but differences in their expression, translation, and protein half-life enable isoform-specific regulation and phenotypes.

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 (Mek12 allele). Mek12/2 mice were viable with no apparent phenotype, indicating rescue by MEK2 and functional redundancy between the two MEK proteins. However, Mek12/− 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.

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