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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

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

Published on: December 27, 2016

PIM1 phosphorylates and negatively regulates ASK1-mediated apoptosis

J J Gu1, Z Wang, R Reeves

  • 1School of Molecular Biosciences, Washington State University, Pullman, WA 99164-7520, USA.

Oncogene
|September 15, 2009
PubMed

Insights

The serine/threonine kinase PIM1 phosphorylates ASK1, a stress-activated kinase, inhibiting its activity and promoting cell survival. This discovery reveals a new mechanism by which PIM1 protects cells from death during oxidative stress.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Apoptosis Research

Background:

  • PIM1 kinase promotes cell survival by inhibiting proapoptotic proteins.
  • Apoptosis signaling kinase 1 (ASK1) mediates stress-induced apoptotic cell death pathways.

Purpose of the Study:

  • To investigate the interaction between PIM1 and ASK1.
  • To elucidate the role of PIM1 in regulating ASK1 activity and cell survival under stress.

Main Methods:

  • In vitro and in vivo phosphorylation assays.
  • Co-immunoprecipitation to detect protein binding.
  • Kinase activity assays in H1299 cells.
  • Western blotting for phosphorylated proteins and caspases.
  • PIM1 knockdown experiments.

Main Results:

  • PIM1 directly phosphorylates ASK1 at serine 83 (Ser83) both in vitro and in vivo.
  • PIM1 binds to ASK1 in cells.
  • PIM1 phosphorylation of ASK1 reduces its kinase activity, inhibiting downstream phosphorylation of c-Jun N-terminal kinase and p38 kinase.
  • This PIM1-mediated inhibition of ASK1 signaling reduces caspase-3 activation and cell death under oxidative stress.
  • Knockdown of PIM1 increases ASK1 phosphorylation at Ser83 and decreases cell viability following H2O2 treatment.

Conclusions:

  • PIM1 negatively regulates the stress-activated kinase ASK1 through phosphorylation at Ser83.
  • This interaction represents a novel mechanism by which PIM1 enhances cell survival by dampening the apoptotic response to oxidative stress.

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