Title | Molecular mechanisms underlying cellular effects of human MEK1 mutations. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Marmion, RA, Yang, L, Goyal, Y, Jindal, GA, Wetzel, JL, Singh, M, Schüpbach, T, Shvartsman, SY |
Journal | Mol Biol Cell |
Volume | 32 |
Issue | 9 |
Pagination | 974-983 |
Date Published | 2021 Apr 19 |
ISSN | 1939-4586 |
Keywords | Animals, Drosophila melanogaster, Drosophila Proteins, Dual-Specificity Phosphatases, Extracellular Signal-Regulated MAP Kinases, Humans, MAP Kinase Kinase 1, MAP Kinase Signaling System, Mutation, Phosphorylation, Signal Transduction |
Abstract | <p>Terminal regions of embryos are patterned by signaling through ERK, which is genetically deregulated in multiple human diseases. Quantitative studies of terminal patterning have been recently used to investigate gain-of-function variants of human MEK1, encoding the MEK kinase that directly activates ERK by dual phosphorylation. Unexpectedly, several mutations reduced ERK activation by extracellular signals, possibly through a negative feedback triggered by signal-independent activity of the mutant variants. Here we present experimental evidence supporting this model. Using a MEK variant that combines a mutation within the negative regulatory region with alanine substitutions in the activation loop, we prove that pathogenic variants indeed acquire signal-independent kinase activity. We also demonstrate that signal-dependent activation of these variants is independent of kinase suppressor of Ras, a conserved adaptor that is indispensable for activation of normal MEK. Finally, we show that attenuation of ERK activation by extracellular signals stems from transcriptional induction of Mkp3, a dual specificity phosphatase that deactivates ERK by dephosphorylation. These findings in the embryo highlight its power for investigating diverse effects of human disease mutations.</p> |
DOI | 10.1091/mbc.E20-10-0625 |
Alternate Journal | Mol Biol Cell |
PubMed ID | 33476180 |
PubMed Central ID | PMC8108529 |
Grant List | R01 GM076275 / GM / NIGMS NIH HHS / United States R01 GM086537 / GM / NIGMS NIH HHS / United States R01 HD085870 / HD / NICHD NIH HHS / United States |