How activating mutations affect MEK1 regulation and function

Granton A. Jindal, Yogesh Goyal, John M. Humphreys, Eyan Yeung, Kaijia Tian, Victoria L. Patterson, Haixia He, Rebecca D. Burdine, Elizabeth J. Goldsmith, Stanislav Y. Shvartsman

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

The 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 diseaserelated 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 wildtype 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.

Original languageEnglish (US)
Pages (from-to)18814-18820
Number of pages7
JournalJournal of Biological Chemistry
Volume292
Issue number46
DOIs
StatePublished - Nov 17 2017

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Jindal, G. A., Goyal, Y., Humphreys, J. M., Yeung, E., Tian, K., Patterson, V. L., He, H., Burdine, R. D., Goldsmith, E. J., & Shvartsman, S. Y. (2017). How activating mutations affect MEK1 regulation and function. Journal of Biological Chemistry, 292(46), 18814-18820. https://doi.org/10.1074/jbc.C117.806067