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Negative and positive regulation of MAPK phosphatase 3 controls platelet-derived growth factor-induced Erk activation

Aleksandra Jurek1, Kenichi Amagasaki, Agnieszka Gembarska

  • 1Ludwig Institute for Cancer Research, Uppsala University, Box 595, SE-751 24 Uppsala, Sweden.

The Journal of Biological Chemistry
|December 25, 2008
PubMed

Insights

Platelet-derived growth factor BB (PDGF-BB) regulates MAPK phosphatase 3 (MKP3) through a novel mechanism. MKP3 controls Erk phosphorylation via feed-forward and feed-back loops, impacting cell growth.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Signal transduction

Background:

  • MAPK phosphatases (MKPs) are crucial negative regulators of Mitogen-Activated Protein Kinases (MAPKs).
  • MKP3 (DUSP6) is recognized for its high selectivity towards Erk (Extracellular signal-regulated kinase).
  • Understanding MKP3's role in growth factor signaling is vital for deciphering cellular proliferation mechanisms.

Purpose of the Study:

  • To investigate the regulation of MKP3 by platelet-derived growth factor BB (PDGF-BB).
  • To elucidate the role of MKP3 in PDGF-induced Erk phosphorylation and mitogenic responses.
  • To characterize the feedback mechanisms involving MKP3 in the PDGF signaling pathway.

Main Methods:

  • Western blotting to detect protein phosphorylation and degradation.
  • Site-directed mutagenesis to study specific phosphorylation sites (Ser-174, Ser-300).
  • Small interfering RNA (siRNA) to reduce MKP3 levels.
  • Analysis of Erk and Mek activation in response to PDGF-BB stimulation.

Main Results:

  • PDGF-BB stimulation triggers rapid proteasomal degradation of MKP3, dependent on Mek activation and MKP3 phosphorylation at Ser-174.
  • MKP3 positively regulates Mek and negatively regulates Erk, forming a feed-forward loop for Erk phosphorylation.
  • Activated Erk induces mkp3 expression, establishing a negative feedback loop that restores MKP3 levels and dephosphorylates Erk.
  • Reduced MKP3 levels enhance Erk activation and mitogenic responses to PDGF-BB.

Conclusions:

  • MKP3 is a key regulator of PDGF-induced Erk phosphorylation, operating through both rapid feed-forward and delayed feed-back mechanisms.
  • The dynamic regulation of MKP3 by PDGF-BB is essential for controlling Erk signaling and cellular proliferation.
  • This study reveals a complex interplay between MKP3, Mek, and Erk in response to growth factor stimulation.

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