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Oncogene PKCε controls INrf2-Nrf2 interaction in normal and cancer cells through phosphorylation of INrf2

Suryakant K Niture1, Averell Gnatt, Anil K Jaiswal

  • 1Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA.

Journal of Cell Science
|October 16, 2013
PubMed

Insights

Protein kinase C epsilon (PKCε) phosphorylates INrf2, controlling the Nrf2-INrf2 interaction. This phosphorylation is crucial for Nrf2 degradation, impacting cellular protection and drug resistance in cancer.

Area of Science:

  • Cellular biology
  • Molecular mechanisms of stress response

Background:

  • The INrf2 (Keap1)-Nrf2 complex is vital for cellular defense against oxidative stress.
  • The precise molecular signals governing Nrf2 regulation by INrf2 remain unclear.

Purpose of the Study:

  • To elucidate the role of protein kinase C epsilon (PKCε) in regulating the INrf2-Nrf2 interaction.
  • To investigate the impact of PKCε-mediated phosphorylation on Nrf2 degradation and cellular responses.

Main Methods:

  • Investigated the phosphorylation sites of INrf2 using molecular modeling.
  • Utilized PKCε inhibition and knockdown, and INrf2 mutants (INrf2S602A) to assess functional consequences.
  • Analyzed human tumor protein arrays to correlate PKCε and Nrf2 levels in cancer.

Main Results:

  • Phosphorylation of INrf2 at Ser599 and Ser602 by PKCε is essential for Nrf2 ubiquitylation and degradation.
  • Inhibition or knockdown of PKCε, or use of the INrf2S602A mutant, prevented INrf2 phosphorylation, disrupted Nrf2 degradation, and enhanced cytoprotection and drug resistance.
  • Molecular modeling revealed S599 phosphorylation facilitates S602 phosphorylation and strengthens INrf2-Nrf2 binding.
  • Human tumor samples showed lower PKCε and higher Nrf2 levels, suggesting a role in cancer survival and drug resistance.

Conclusions:

  • PKCε-mediated phosphorylation of INrf2 is a key regulatory mechanism controlling Nrf2 stability and function.
  • This pathway has significant implications for cancer cell survival and drug resistance, particularly in cancers with reduced PKCε expression.
Keywords:
Cell survivalINrf2 (Keap1)Lung cancerNrf2PKCε

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