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Activation of extracellular signal-regulated protein kinase 5 downregulates FasL upon osmotic stress

X Wang1, K G Finegan, A C Robinson

  • 1Faculty of Life Sciences, University of Manchester, Manchester, UK.

Cell Death and Differentiation
|May 20, 2006
PubMed

Insights

Extracellular signal-regulated protein kinase 5 (ERK5) is crucial for fibroblast survival, particularly under osmotic stress. Its pathway downregulates Fas ligand (FasL) to prevent apoptosis, highlighting its role in cell protection.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Apoptosis regulation

Background:

  • Extracellular signal-regulated protein kinase 5 (ERK5) is a mitogen-activated protein kinase (MAPK) activated by MEK5.
  • Targeted deletion of ERK5 or MEK5 genes in mice leads to early embryonic death, indicating physiological importance.
  • ERK5 signaling is implicated in cellular responses to stress and survival.

Purpose of the Study:

  • To investigate the role of ERK5 in fibroblast survival under basal and stress conditions.
  • To elucidate the molecular mechanisms by which ERK5 influences apoptosis and cell survival.
  • To examine the relationship between ERK5, Fas ligand (FasL), protein kinase B (PKB), and Forkhead box O3a (Foxo3a) in osmotic stress response.

Main Methods:

  • Fibroblast cell culture and genetic deletion of erk5 and mek5 genes.
  • Sorbitol treatment to induce osmotic stress.
  • Analysis of cell viability, apoptosis markers, and protein activities (PKB, Foxo3a).
  • Western blotting and kinase assays to assess signaling pathway components.

Main Results:

  • ERK5 is essential for fibroblast survival under basal conditions and osmotic stress.
  • ERK5- and MEK5-deficient cells exhibit increased apoptosis under sorbitol treatment due to elevated FasL expression.
  • Reduced PKB activity and increased Foxo3a activity were observed in ERK5- or MEK5-deficient cells during osmotic stress.
  • The ERK5 pathway suppresses FasL expression, thereby promoting cell survival.

Conclusions:

  • The ERK5 signaling pathway is a key regulator of cell survival, particularly under osmotic stress.
  • ERK5 promotes cell survival by downregulating FasL expression.
  • This regulation involves PKB-dependent inhibition of Foxo3a, downstream of phosphoinositide 3 kinase, highlighting a novel survival mechanism.

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