@article{1381,
  author = {Robert Marmion and Liu Yang and Yogesh Goyal and Granton Jindal and Joshua Wetzel and Mona Singh and Trudi Sch{\"u}pbach and Stanislav Shvartsman},
  title = {Molecular mechanisms underlying cellular effects of human MEK1 mutations.},
  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>
},
  year = {2021},
  journal = {Molecular biology of the cell},
  volume = {32},
  pages = {974-983},
  month = {04/2021},
  issn = {1939-4586},
  doi = {10.1091/mbc.E20-10-0625},
  language = {eng},
}