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How activating mutations affect MEK1 regulation and function.

Author(s): Jindal, Granton A; Goyal, Yogesh; Humphreys, John M; Yeung, Eyan; Tian, Kaijia; et al

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dc.contributor.authorJindal, Granton Aen_US
dc.contributor.authorGoyal, Yogeshen_US
dc.contributor.authorHumphreys, John Men_US
dc.contributor.authorYeung, Eyanen_US
dc.contributor.authorTian, Kaijiaen_US
dc.contributor.authorPatterson, Victoria Len_US
dc.contributor.authorHe, Haixiaen_US
dc.contributor.authorBurdine, Rebecca Den_US
dc.contributor.authorGoldsmith, Elizabeth Jen_US
dc.contributor.authorShvartsman, Stanislav Yen_US
dc.identifier.citationJindal, Granton A, Goyal, Yogesh, Humphreys, John M, Yeung, Eyan, Tian, Kaijia, Patterson, Victoria L, He, Haixia, Burdine, Rebecca D, Goldsmith, Elizabeth J, Shvartsman, Stanislav Y. (2017). How activating mutations affect MEK1 regulation and function.. The Journal of biological chemistry, 292 (46), 18814 - 18820. doi:10.1074/jbc.C117.806067en_US
dc.description.abstractThe MEK1 kinase directly phosphorylates ERK2, after the activation loop of MEK1 is itself phosphorylated by Raf. Studies over the past decade have revealed a large number of disease-related mutations in the MEK1 gene that lead to tumorigenesis and abnormal development. Several of these mutations result in MEK1 constitutive activity, but how they affect MEK1 regulation and function remains largely unknown. Here, we address these questions focusing on two pathogenic variants of the Phe-53 residue, which maps to the well-characterized negative regulatory region of MEK1. We found that these variants are phosphorylated by Raf faster than the wild-type enzyme, and this phosphorylation further increases their enzymatic activity. However, the maximal activities of fully phosphorylated wild-type and mutant enzymes are indistinguishable. On the basis of available structural information, we propose that the activating substitutions destabilize the inactive conformation of MEK1, resulting in its constitutive activity and making it more prone to Raf-mediated phosphorylation. Experiments in zebrafish revealed that the effects of activating variants on embryonic development reflect the joint control of the negative regulatory region and activating phosphorylation. Our results underscore the complexity of the effects of activating mutations on signaling systems, even at the level of a single protein.en_US
dc.format.extent18814 - 18820en_US
dc.relation.ispartofThe Journal of biological chemistryen_US
dc.titleHow activating mutations affect MEK1 regulation and function.en_US
dc.typeJournal Article-

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