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

3 Citations (Scopus)

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 - Jan 1 2017

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Phosphorylation
Nucleic Acid Regulatory Sequences
Mutation
Zebrafish
Enzymes
Embryonic Development
Conformations
Carcinogenesis
Substitution reactions
Phosphotransferases
Genes
Joints
Chemical activation
Proteins
Experiments

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Jindal, G. A., Goyal, Y., Humphreys, J. M., Yeung, E., Tian, K., Patterson, V. L., ... 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

How activating mutations affect MEK1 regulation and function. / Jindal, 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.

In: Journal of Biological Chemistry, Vol. 292, No. 46, 01.01.2017, p. 18814-18820.

Research output: Contribution to journalArticle

Jindal, GA, Goyal, Y, Humphreys, JM, Yeung, E, Tian, K, Patterson, VL, He, H, Burdine, RD, Goldsmith, EJ & Shvartsman, SY 2017, 'How activating mutations affect MEK1 regulation and function', Journal of Biological Chemistry, vol. 292, no. 46, pp. 18814-18820. https://doi.org/10.1074/jbc.C117.806067
Jindal GA, Goyal Y, Humphreys JM, Yeung E, Tian K, Patterson VL et al. How activating mutations affect MEK1 regulation and function. Journal of Biological Chemistry. 2017 Jan 1;292(46):18814-18820. https://doi.org/10.1074/jbc.C117.806067
Jindal, 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. / How activating mutations affect MEK1 regulation and function. In: Journal of Biological Chemistry. 2017 ; Vol. 292, No. 46. pp. 18814-18820.
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