Cytokine-mediated cPLA(2) phosphorylation is regulated by multiple MAPK family members

FEBS Lett. 2000 Apr 7;471(1):83-8. doi: 10.1016/s0014-5793(00)01373-9.

Abstract

Cytosolic phospholipase A(2) (cPLA(2)) plays a critical role in various neutrophil functions including the generation of leukotrienes and platelet-activating factor release. Enzyme activity is regulated both by translocation to the membrane in a Ca(2+)-dependent manner and serine phosphorylation by members of the mitogen-activated protein kinase (MAPK) family. In this report, we have investigated the role of granulocyte/macrophage colony-stimulating factor (GM-CSF)-mediated signalling pathways in the regulation of cPLA(2). GM-CSF-induced cPLA(2) phosphorylation was not affected by pharmacological inhibition of p38 MAPK, phosphatidylinositol 3-kinase or Src. However, inhibition of extracellular signal-regulated kinase (ERK) MAPK activation resulted in a partial inhibition of cPLA(2) phosphorylation, revealed in a slower onset of phosphorylation. A cell line stably transfected with the GM-CSF receptor was used to further analyze GM-CSF-mediated cPLA(2) phosphorylation. Mutation of tyrosine residues 577 and 612 resulted in a delayed cPLA(2) phosphorylation similar to the pharmacological ERK inhibition. Furthermore, inhibition of p38 MAPK in cells bearing the double mutant betac577/612 completely abrogated GM-CSF-induced cPLA(2) phosphorylation. We conclude that GM-CSF can mediate cPLA(2) phosphorylation through the redundant activation of both p38 and ERK MAP kinases.

MeSH terms

  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cytosol / enzymology
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
  • Humans
  • In Vitro Techniques
  • MAP Kinase Signaling System
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neutrophils / enzymology
  • Neutrophils / metabolism
  • Phospholipases A / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Transfection
  • Tyrosine / metabolism
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Tyrosine
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Phospholipases A
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)