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

• Published in: FEBS letters 2000-04, Vol.471 (1), p.83-88
• Main Authors: Geijsen, N, Dijkers, P F, Lammers, J J, Koenderman, L, Coffer, P J
• Format: Article
• Language: English
• Subjects: 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; p38 Mitogen-Activated Protein Kinases; Phospholipases A - metabolism; Phosphorylation; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Transfection; Tyrosine - metabolism
• ISSN: 0014-5793
• DOI: 10.1016/S0014-5793(00)01373-9

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.