Characterization of the atypical MAPK ERK4 and its activation of the MAPK-activated protein kinase MK5

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Shashi Kant1, Stefanie Schumacher, Manvendra Kumar Singh

  • 1Institute of Biochemistry, Medical School Hannover, Hannover 30625, Germany.

The Journal of Biological Chemistry
|September 16, 2006
PubMed

Insights

Extracellular-regulated kinase (ERK) 4 is a stable protein that activates MAPK-activated protein kinase 5. ERK4 and ERK3 cooperate to activate MK5, revealing a novel signaling pathway.

Area of Science:

  • Cellular Biology
  • Molecular Signaling
  • Protein Kinase Research

Background:

  • Extracellular-regulated kinases (ERK) 3 (MAPK6) and ERK4 (MAPK4) are atypical MAPKs with related structures but distinct properties.
  • ERK3 is typically an unstable, cytoplasmic protein known to interact with and activate MAPK-activated protein kinase (MK) 5.

Purpose of the Study:

  • To investigate the stability and expression of ERK4.
  • To analyze ERK4's ability to bind, translocate, and activate MK5.
  • To elucidate the cooperative roles of ERK3 and ERK4 in MK5 activation.

Main Methods:

  • Protein expression and stability assays.
  • Co-immunoprecipitation to assess protein binding.
  • Cellular localization studies (translocation).
  • In vitro kinase assays to determine activation and phosphorylation.

Main Results:

  • ERK4 is a stable protein, unlike ERK3.
  • ERK4 binds to endogenous MK5, inducing MK5 translocation to the cytoplasm and activation via phosphorylation.
  • Catalytic activity of ERK4 is essential for MK5 activation, suggesting direct phosphorylation.
  • ERK4 can dimerize/oligomerize with ERK3, implying a mechanism for inactive ERK3 to recruit active ERK4.

Conclusions:

  • ERK4 is a stable activator of MK5.
  • ERK4 directly phosphorylates and activates MK5.
  • ERK3 and ERK4 functionally cooperate in the activation of MK5, uncovering a new signaling complex.

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