MEK1/2 dual-specificity protein kinases: structure and regulation

Biochem Biophys Res Commun. 2012 Jan 6;417(1):5-10. doi: 10.1016/j.bbrc.2011.11.145. Epub 2011 Dec 8.

Abstract

MEK1 and MEK2 are related protein kinases that participate in the RAS-RAF-MEK-ERK signal transduction cascade. This cascade participates in the regulation of a large variety of processes including apoptosis, cell cycle progression, cell migration, differentiation, metabolism, and proliferation. Moreover, oncogenic mutations in RAS or B-RAF are responsible for a large proportion of human cancers. MEK1 is activated by phosphorylation of S218 and S222 in its activation segment as catalyzed by RAF kinases in an intricate process that involves a KSR scaffold. Besides functioning as a scaffold, the kinase activity of KSR is also required for MEK activation. MEK1 regulation is unusual in that S212 phosphorylation in its activation segment is inhibitory. Moreover, active ERK catalyzes a feedback inhibitory phosphorylation of MEK1 T292 that serves to downregulate the pathway.

Publication types

  • Review

MeSH terms

  • Animals
  • Catalytic Domain
  • Enzyme Activation
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • MAP Kinase Kinase 1 / chemistry*
  • MAP Kinase Kinase 1 / genetics
  • MAP Kinase Kinase 1 / metabolism*
  • MAP Kinase Kinase 2 / chemistry*
  • MAP Kinase Kinase 2 / genetics
  • MAP Kinase Kinase 2 / metabolism*
  • Mice
  • Phosphorylation
  • Protein Kinases / chemistry
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Protein Multimerization
  • Protein Structure, Tertiary

Substances

  • Protein Kinases
  • KSR-1 protein kinase
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2