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ERK1/2 can feedback-regulate cellular MEK1/2 levels.

Seung-Keun Hong1, Pui-Kei Wu1, Mansi Karkhanis1

  • 1Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

Cellular Signalling
|July 13, 2015
PubMed
Summary

The Raf/MEK/ERK pathway regulates itself by altering MEK1 and MEK2 protein levels. MEK1 is increased via transcription, while MEK2 is decreased post-translationally, revealing novel feedback mechanisms.

Keywords:
ERK1/2Feedback regulationMEK1MEK2Raf

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Area of Science:

  • Cellular signaling
  • Molecular biology
  • Biochemistry

Background:

  • The Raf/MEK/ERK pathway is crucial for cell signaling and is regulated by feedback mechanisms.
  • The specific regulation of MEK1/2 levels by this pathway has not been previously established.

Purpose of the Study:

  • To investigate whether the Raf/MEK/ERK pathway exhibits feedback regulation on cellular MEK1 and MEK2 levels.
  • To elucidate the mechanisms underlying these feedback regulations.

Main Methods:

  • Stimulation of the Raf/MEK/ERK pathway using ΔRaf-1:ER or B-Raf(V600E).
  • ERK1/2 knockdown via RNA interference.
  • Quantitative PCR (qPCR) and luciferase reporter assays.
  • Treatment with proteasome inhibitors (MG132, bortezomib).

Main Results:

  • Pathway activation led to increased MEK1 and decreased MEK2 levels.
  • These changes were dependent on ERK1/2 activity, indicating feedback regulation.
  • MEK1 upregulation occurred at the transcriptional level.
  • MEK2 downregulation occurred at the post-translational level, involving proteasomal degradation.

Conclusions:

  • The Raf/MEK/ERK pathway possesses feedback mechanisms that modulate MEK1 and MEK2 levels.
  • MEK1 is upregulated transcriptionally, while MEK2 is downregulated post-translationally.
  • These findings reveal novel regulatory strategies within the Raf/MEK/ERK signaling cascade.