MAPK/ERK kinase (MEK) 1/2 are central signaling proteins that serve as specificity determinants of the MAPK/ERK cascade. More than twenty activating mutations have been reported for MEK1/2, and many of them are known to cause diseases such as cancers, arteriovenous malformation and RASopathies. Changes in their intrinsic activity do not seem to correlate with the severity of the diseases. Here we studied four MEK1/2 mutations using biochemical and molecular dynamic methods. Although the studied mutants elevated the activating phosphorylation of MEK they had no effect on the stimulated ERK1/2 phosphorylation. Studying the regulatory mechanism that may explain this lack of effect, we found that one type of mutation affects MEK stability and two types of mutations demonstrate a reduced sensitivity to PP2A. Together, our results indicate that some MEK mutations exert their function not only by their elevated intrinsic activity, but also by modulation of regulatory elements such as protein stability or dephosphorylation.

We would like to thanks Mrs. Shira Wexler for her help in producing Fig. 7F. This study was supported by grants from ISF to RS. RS is an incumbent of the Yale S. Lewine and Ella Miller Lewine professorial chair for cancer research. CP acknowledges Severo Ochoa grant (SEV-2015-0493) for financial support. FLG acknowledges EPSRC [grant no EP/P022138/1; EP/P011306/1; EP/M013898/1] for financial support. HecBioSim [EPSRC grant no EP/P022138/1], Archer, JADE, the Hartree Centre, the Barcelona Supercomputing Center and PRACE are acknowledged for computer time. JF-R acknowledges Spanish MICINN grant [number BIO2016-79930-R] for financial support.

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