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Post-translational regulation of mitogen-activated protein kinase phosphatase-2 (MKP-2) by ERK

Dong-Jun Peng1, Jun-Ying Zhou, Gen Sheng Wu

  • 1Program in Molecular Biology and Genetics, Karmanos Cancer Institute, Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.

Cell Cycle (Georgetown, Tex.)
|November 19, 2010
PubMed

Insights

Mitogen-activated protein kinase phosphatase-2 (MKP-2) protein stability is regulated by ERK phosphorylation, creating a feedback loop to control ERK signaling pathways.

Area of Science:

  • Cellular signaling pathways
  • Protein regulation
  • Molecular biology

Background:

  • Mitogen-activated protein kinase phosphatase-2 (MKP-2) dephosphorylates and inactivates mitogen-activated protein kinases (MAPKs).
  • ERK signaling can induce MKP-2, but its post-translational regulation remains largely uncharacterized.

Purpose of the Study:

  • To investigate the post-translational regulation of MKP-2 by ERK signaling.
  • To elucidate the impact of phosphorylation on MKP-2 protein stability and activity.

Main Methods:

  • Investigated MKP-2 phosphorylation by ERK in vitro and in cell models.
  • Utilized site-directed mutagenesis to identify phosphorylation sites (Ser386 and Ser391).
  • Assessed protein degradation pathways (proteasomal degradation) and phosphatase activity.

Main Results:

  • ERK directly phosphorylates MKP-2 on C-terminal serine residues (Ser386 and Ser391).
  • Phosphorylation by ERK stabilizes MKP-2 protein, preventing proteasomal degradation.
  • Inhibition of ERK activation leads to increased MKP-2 degradation.
  • Phosphorylation does not alter MKP-2's phosphatase activity.

Conclusions:

  • MKP-2 undergoes ERK-mediated phosphorylation, enhancing its protein stability.
  • This phosphorylation acts as a crucial feedback mechanism to regulate ERK activity.
  • Identified specific phosphorylation sites (Ser386, Ser391) involved in MKP-2 stabilization.

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