Molecular mechanisms underlying cellular effects of human MEK1 mutations.

TitleMolecular mechanisms underlying cellular effects of human MEK1 mutations.
Publication TypeJournal Article
Year of Publication2021
AuthorsMarmion, RA, Yang, L, Goyal, Y, Jindal, GA, Wetzel, JL, Singh, M, Schüpbach, T, Shvartsman, SY
JournalMol Biol Cell
Volume32
Issue9
Pagination974-983
Date Published2021 04 19
ISSN1939-4586
KeywordsAnimals, 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>

DOI10.1091/mbc.E20-10-0625
Alternate JournalMol Biol Cell
PubMed ID33476180
PubMed Central IDPMC8108529
Grant ListR01 GM076275 / GM / NIGMS NIH HHS / United States
R01 GM086537 / GM / NIGMS NIH HHS / United States
R01 HD085870 / HD / NICHD NIH HHS / United States