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Endogenous cGMP-dependent protein kinase reverses EGF-induced MAPK/ERK signal transduction through phosphorylation of

Yan Tao1, Yin-Jie Gu, Zhi-Hong Cao

  • 1School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013;

Oncology Letters
|November 20, 2012
PubMed

Insights

Endogenous protein kinase G (PKG) activity inhibits epidermal growth factor (EGF)-induced MAPK/ERK signaling in lung cancer cells by phosphorylating VASP. This finding reveals a novel mechanism for controlling cancer cell signaling pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Type II cGMP-dependent protein kinase (PKG II) is downregulated in human cancer cells.
  • Exogenous PKG II inhibits epidermal growth factor (EGF)-induced MAPK/ERK signaling.

Purpose of the Study:

  • To investigate the inhibitory effect of endogenous PKG activity on EGF-induced MAPK/ERK signal transduction in human lung cancer cells.
  • To elucidate the underlying mechanism of this inhibition.

Main Methods:

  • Human small cell lung carcinoma cells (SCLCs) were treated with a PKG activator (8-pCPT-cGMP) and/or EGF.
  • Key signaling proteins including EGFR, Sos1, Grb2, Ras, MEK, ERK, and VASP were analyzed for phosphorylation and binding interactions.
  • VASP phosphorylation site (Ser239) was mutated to block PKG's effect.

Main Results:

  • Increased endogenous PKG activity inhibited EGF-induced phosphorylation of EGFR, Sos1-Grb2 binding, and Ras activation.
  • EGF-induced MEK and ERK phosphorylation were suppressed by endogenous PKG.
  • PKG activation led to increased VASP phosphorylation at Ser239.
  • Blocking VASP phosphorylation at Ser239 abolished PKG's inhibitory effects on the MAPK/ERK pathway.

Conclusions:

  • Endogenous PKG activity reverses EGF-induced MAPK/ERK signaling in lung cancer cells.
  • This reversal is mediated through the phosphorylation of VASP at Ser239.
  • PKG acts as a negative regulator of the EGF-driven MAPK/ERK pathway in this context.

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