Platelet-activating factor (PAF) induces the early tyrosine phosphorylation of focal adhesion kinase (p125(FAK)) in human endothelial cells

R. Soldi, F. Sanavio, M. Aglietta, L. Primo, P. Defilippi, P. C. Marchisio, F. Bussolino

Research output: Contribution to journalArticle

Abstract

Platelet-activating factor (PAF) is a potent activator of angiogenesis and controls the motility and the shape of vascular endothelium. The mechanism(s) whereby PAF exerts its action are in part known. Here we report that the biological active (R)PAF enantiomer administrated to cultured endothelial cells induces the early phosphorylation in tyrosine residues of focal adhesion kinase (p125(FAK)) and paxillin, two molecules involved in the early signaling and cytoskeleton assembly in cells that undergo integrin-mediated adhesion or are challenged by neuropeptides or lysophosphatidic acid. The phenomenon is rapidly turned on, lasts for a few minutes and is adhesion-independent indicating that the chain of events induced by (R)PAF, including p125(FAK) activation, precedes adhesion. The inhibitory effect of WEB2086, a PAF receptor antagonist, and the lack of activity exerted by the (S)PAF enantiomer, indicate that (R)PAF-mediated p125(FAK) activation, is PAF receptor-dependent. Calphostin C, an inhibitor of protein kinase C blocks the effect of (R)PAF on p125(FAK) phosphorylation suggesting that protein kinase C activation is up-stream the activation of this tyrosine kinase. When endothelial cells are exposed to a substratum that allows adhesion and spreading. (R)PAF-stimulated cells, change their adhesive phenotype and start migrating. Inhibitors of tyrosine kinases, like 3-(1,4,-dihydroxytetralyl) methylen-2-oxindole and herbimycin A, reduce the cells migration, the transendothelial flux of albumin and the enhancement of p125(FAK) activity induced by (R)PAF. The observation that increased tyrosine phosphorylation of p125(FAK) and its ensuing association with focal adhesion occurs rapidly upon (R)PAF challenge indicates that this signaling molecule has a primary and independent role also in the signaling cascade initiated by (R)PAF.

Original languageEnglish
Pages (from-to)515-525
Number of pages11
JournalOncogene
Volume13
Issue number3
Publication statusPublished - 1996

Keywords

  • Cell motility
  • Cytoskeleton
  • Endothelial cells
  • FAK
  • PAF

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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