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Regulation of MAPK-activated protein kinase 5 activity and subcellular localization by the atypical MAPK ERK4/MAPK4

Espen Aberg1, Maria Perander, Bjarne Johansen

  • 1Department of Pharmacology, Institute of Medical Biology, University of Tromsø, N-9037 Tromsø, Norway, and Cancer Research UK Stress Response Laboratory, Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee, UK.

The Journal of Biological Chemistry
|September 15, 2006
PubMed

Insights

MAPK-activated protein kinase 5 (MK5) is regulated by both ERK3 and ERK4. These atypical MAPKs phosphorylate and activate MK5, influencing its stability and cellular localization.

Area of Science:

  • Cellular signaling pathways
  • Protein kinase regulation
  • Mitogen-activated protein kinases (MAPKs)

Background:

  • MAPK-activated protein kinase 5 (MK5) is a known substrate of the atypical MAPK ERK3.
  • ERK3 binding to MK5 leads to MK5 activation, ERK3 stabilization, and nuclear exclusion of both proteins.
  • ERK3 ablation partially reduces MK5 activity, indicating other regulatory mechanisms.

Purpose of the Study:

  • To identify additional physiological regulators of MK5 activity.
  • To investigate the role of ERK4, an ERK3-related kinase, in MK5 regulation.

Main Methods:

  • Small interfering RNA (siRNA) mediated knockdown of ERK3 and ERK4 in HeLa cells.
  • Analysis of endogenous MK5 activity and protein levels.
  • Co-immunoprecipitation assays to assess protein-protein interactions.
  • Studies using fibroblasts from ERK3 null mice.

Main Results:

  • ERK4 directly interacts with MK5, leading to MK5 phosphorylation and activation.
  • ERK4 binding causes MK5 relocalization from the nucleus to the cytoplasm.
  • Knockdown of ERK4 alone reduces MK5 activity by approximately 50%.
  • Combined knockdown of ERK3 and ERK4 reduces MK5 activity by over 80%.

Conclusions:

  • MK5 activation is dependent on both ERK3 and ERK4.
  • ERK3 and ERK4 act as physiological regulators of MK5 activity.
  • These findings reveal a dual MAPK regulatory mechanism for MK5.

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