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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

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p21-activated kinase 1 phosphorylates the death agonist bad and protects cells from apoptosis

A Schürmann1, A F Mooney, L C Sanders

  • 1Institut für Pharmakologie und Toxikologie, Medizinische Fakulät, Rheinisch-Westfälische Technische Hochschule Aachen, D52057 Aachen, Germany.

Molecular and Cellular Biology
|December 28, 1999
PubMed

Insights

p21-activated kinase 1 (PAK1) promotes cell survival by phosphorylating Bad, a protein that triggers cell death. This phosphorylation reduces Bad's interaction with anti-apoptotic proteins, thus inhibiting cell death pathways.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Apoptosis Research

Background:

  • Bad is a key regulator of intrinsic cell death, promoting apoptosis via heterodimerization with Bcl-2 and Bcl-x(L).
  • Growth factors induce cell survival by phosphorylating Bad, leading to its dissociation from Bcl-2/Bcl-x(L) and binding to 14-3-3tau.
  • Interleukin-3 (IL-3)-dependent cell survival is compromised by Clostridium difficile toxin B, highlighting the role of signaling pathways in cell fate.

Purpose of the Study:

  • To investigate the role of p21-activated kinase 1 (PAK1) in regulating Bad-mediated apoptosis.
  • To determine if PAK1 activation by IL-3 influences the survival of FL5.12 lymphoid progenitor cells.
  • To elucidate the molecular mechanism by which PAK1 affects Bad's interaction with Bcl-2 family proteins.

Main Methods:

  • Utilized IL-3-dependent FL5.12 cells and NIH 3T3 cells.
  • Investigated PAK1 activation by IL-3 and its inhibition by LY294002 (phosphatidylinositol 3-kinase inhibitor).
  • Employed overexpression of constitutively active PAK1 mutants and PAK autoinhibitory domains to assess effects on cell survival and apoptosis.
  • Performed in vitro and in vivo phosphorylation assays to determine PAK1's targets on Bad.

Main Results:

  • IL-3 activates PAK1 in FL5.12 cells, an activation dependent on phosphatidylinositol 3-kinase.
  • Overexpression of active PAK1 enhanced cell survival, while inhibiting PAK1 activity promoted apoptosis.
  • PAK1 directly phosphorylates Bad at Ser112 and Ser136.
  • PAK1-mediated phosphorylation of Bad reduced its binding to Bcl-2 and Bcl-x(L) and increased its association with 14-3-3tau.

Conclusions:

  • PAK1 inhibits the pro-apoptotic function of Bad through direct phosphorylation.
  • PAK1 plays a significant role in promoting cell survival pathways by modulating Bad activity.
  • These findings identify PAK1 as a critical mediator in the regulation of apoptosis and cell survival.

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