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PPP6C negatively regulates oncogenic ERK signaling through dephosphorylation of MEK

Eunice Cho1, Hua Jane Lou1, Leena Kuruvilla1

  • 1Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520, USA.

Cell Reports
|March 31, 2021
PubMed

Insights

Protein phosphatase 6 catalytic subunit (PPP6C) dephosphorylates MEK, a key kinase in the ERK pathway. Loss or mutation of PPP6C in melanoma promotes ERK signaling and reduces MEK inhibitor effectiveness.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Signal Transduction

Background:

  • The RAF-MEK-ERK pathway is crucial in cell signaling and cancer.
  • MEK dephosphorylation by phosphatases is poorly understood.
  • PPP6C is a phosphatase implicated in cancer, but its role in MEK regulation is unknown.

Purpose of the Study:

  • To identify the phosphatase responsible for MEK dephosphorylation.
  • To investigate the role of PPP6C in regulating MEK activity and ERK signaling.
  • To determine the impact of PPP6C alterations on melanoma and MEK inhibitor sensitivity.

Main Methods:

  • Cellular assays to identify MEK phosphatase activity.
  • Co-immunoprecipitation to study protein interactions.
  • Analysis of PPP6C mutations in melanoma patient data.
  • Western blotting to assess MEK phosphorylation states.

Main Results:

  • PPP6C was identified as a major MEK phosphatase in oncogenic ERK pathway-activated cells.
  • MEK interacts with PPP6C via regulatory subunits.
  • Loss of PPP6C leads to MEK hyperphosphorylation, increased ERK signaling, and decreased sensitivity to MEK inhibitors.
  • Melanoma-associated PPP6C mutations result in MEK hyperphosphorylation.

Conclusions:

  • PPP6C is a key negative regulator of ERK signaling by dephosphorylating MEK.
  • PPP6C dysfunction in melanoma promotes oncogenic ERK pathway activation.
  • PPP6C status may predict response to MEK-targeted therapies in melanoma.
Keywords:
MAP kinase signalingcancer cell signalingkinase inhibitor resistancemelanomaprotein phosphatases

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