Abstract
MEK1 and MEK2, the only known activators of ERK, are attractive therapeutic candidates for both cancer and autoimmune diseases. However, how MEK signaling finely regulates immune cell activation is only partially understood. To address this question, we specifically delete Mek1 in hematopoietic cells in the Mek2 null background. Characterization of an allelic series of Mek mutants reveals the presence of distinct degrees of spontaneous B cell activation, which are inversely proportional to the levels of MEK proteins and ERK activation. While Mek1 and Mek2 null mutants have a normal lifespan, 1Mek1 and 1Mek2 mutants retaining only one functional Mek1 or Mek2 allele in hematopoietic cell lineages die from glomerulonephritis and lymphoproliferative disorders, respectively. This establishes that the fine-tuning of the ERK/MAPK pathway is critical to regulate B and Tcell activation and function and that each MEK isoform plays distinct roles during lymphocyte activation and disease development.
Highlights
The extracellular signal-regulated kinase (ERK) pathway is activated by various surface receptors such as B and T cell antigen receptors to control B and T cell differentiation, selection, and activation (Alberola-Ila and Hernandez-Hoyos, 2003; Gold, 2008; Teixeiro and Daniels, 2010)
ERK activation in response to immune stimuli depends on the number of Mek alleles Using a Mek1 Mek2 allelic series, we have previously shown that the severity of the placenta phenotype correlates with the levels of MEK protein activity independent of the MEK isoform produced (Aoidi et al, 2016)
To determine if the Mek1 gene produces more MEK protein than the Mek2 gene in B and T cells, MEK protein levels were measured in B220+ and CD4+ splenocytes from WT, Mek1À/À, and Mek2À/À mice using an antibody that cross-reacts with MEK1 and MEK2 in flow cytometry analyses (Figure 1A; Aoidi et al, 2016)
Summary
The extracellular signal-regulated kinase (ERK) pathway is activated by various surface receptors such as B and T cell antigen receptors to control B and T cell differentiation, selection, and activation (Alberola-Ila and Hernandez-Hoyos, 2003; Gold, 2008; Teixeiro and Daniels, 2010). MEKs are considered promising therapeutic targets, since overactivation of the ERK pathway is observed in many cancers and autoimmune diseases (Caunt et al, 2015; Lindstrom and Robinson, 2010; Zhao and Adjei, 2014). Promising results were obtained in solid cancers, their application in rheumatoid arthritis was disappointing, suggesting that MEK1 and MEK2 play more complex roles in the regulation of the immune response (Lindstrom and Robinson, 2010)
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