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Involvement of phosphatidylinositol 3'-kinase in stem-cell-factor-induced phospholipase D activation and arachidonic acid release

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Author

Summary, in English

We have shown previously that the stem cell factor (SCF) receptor undergoes phosphorylation on serine residues following ligand stimulation, and that this phopshorylation is dependent mainly on the activity of protein kinase C (PKC). In the present study, we have further investigated the molecular mechanisms behind SCF-stimulated activation of PKC, and found that SCF does not activate phosphatidylinositol-specific phospholipase C. In contrast, phospholipase D (PLD) is activated in response to SCF in a dose-dependent manner. Activation of PLD was not inhibited by calphostin C, an inhibitor of PKC. On the other hand, inhibitors of phosphatidylinositol PtdIns 3'-kinase (PtdIns 3'-kinase), i.e. wortmannin and LY294002, inhibited SCF-induced PLD activation. Moreover, a mutant SCF receptor in which Tyr721, which is responsible for activation of PtdIns 3'-kinase, is mutated to a phenylalanine residue was unable to mediate activation of PLD. Thus, PtdIns 3'-kinase appears to be essential for SCF-induced PLD activation. Furthermore, we demonstrate that phosphatidic acid (PtdH), generated through the action of PLD in response to SCF, is metabolized to diacylglycerol by dephosphorylation. Diacylglycerol can then activate PKC, and, moreover, after deacylation by a diacylglycerol lipase, yield arachidonic acid, an important second messenger in cell signaling.

Publishing year

1997

Language

English

Pages

149-155

Publication/Series

European Journal of Biochemistry

Volume

248

Issue

1

Document type

Journal article

Publisher

Wiley-Blackwell

Topic

  • Medicinal Chemistry

Keywords

  • Complementary/geneticsDiglycerides/biosynthesisEnzyme Activation/drug effectsHumansModels
  • Arachidonic Acid/*metabolismBase SequenceCell LineDNA
  • BiologicalMutagenesis
  • Site-DirectedPhosphatidylinositol 3-KinasesPhosphatidylinositol Diacylglycerol-LyasePhosphoinositide Phospholipase CPhospholipase D/*metabolismPhosphotransferases (Alcohol Group Acceptor)/*metabolismPropranolol/pharmacologyProto-Oncogene Proteins c-kit/genetics/metabolismSecond Messenger SystemsStem Cell Factor/metabolism/*pharmacologyTransfectionType C Phospholipases/metabolism

Status

Published

ISBN/ISSN/Other

  • ISSN: 0014-2956