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p21-activated protein kinase gamma-PAK suppresses programmed cell death of BALB3T3 fibroblasts

R Jakobi1, E Moertl, M A Koeppel

  • 1Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. rjacobi@mcw.edu

The Journal of Biological Chemistry
|March 30, 2001
PubMed

Insights

Full-length p21-activated protein kinase gamma-PAK (γ-PAK) promotes cell survival and suppresses stress-induced cell death. Activated γ-PAK protects cells by regulating the pro-apoptotic protein Bad and stress-activated pathways.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Signal Transduction

Background:

  • Cells activate opposing survival and death pathways under stress.
  • p21-activated protein kinase gamma-PAK (γ-PAK) participates in both cell survival and death.
  • Stress stimulants activate γ-PAK as full-length enzyme and proteolytic fragment.

Purpose of the Study:

  • To investigate the role of full-length γ-PAK in stress-induced cell death.
  • To determine if activated γ-PAK promotes cell survival.
  • To elucidate the mechanisms by which γ-PAK influences cell fate.

Main Methods:

  • Expression of constitutively active γ-PAK-T402E in BALB3T3 fibroblasts.
  • Assessment of cell survival under various stress conditions (TNF-α, growth factor withdrawal, UVC light).
  • Analysis of Bad protein phosphorylation and cell death induced by Bad.
  • Monitoring of ERK, JNK, and p38 pathway activation.

Main Results:

  • Constitutively active γ-PAK-T402E expression enhanced fibroblast survival against multiple stressors.
  • Survival promotion was primarily via cell death protection, not proliferation.
  • γ-PAK-T402E increased Bad phosphorylation and protected against Bad-induced cell death.
  • γ-PAK-T402E modulated early and late activation of ERK, JNK, and p38 pathways.

Conclusions:

  • Full-length γ-PAK activation is a pro-survival mechanism.
  • γ-PAK regulates cell survival by inhibiting the pro-apoptotic activity of Bad.
  • γ-PAK influences stress-induced activation of key survival/death signaling pathways (ERK, JNK, p38).

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