Activation of endothelial cell mitogen activated protein kinase ERK1/2 by extracellular HIV-1 Tat protein

M. Rusnati, C. Urbinati, B. Musulin, D. Ribatti, A. Albini, D. Noonan, C. Marchisone, J. Waltenberger, M. Presta

Research output: Contribution to journalArticlepeer-review

Abstract

Extracellular Tat protein, the transactivating factor of the human immunodeficiency virus type 1 (HIV-1), modulates gene expression, growth, and angiogenic activity in endothelial cells by interacting with the vascular endothelial growth factor (VEGF) receptor-2 (Flk-1/KDR). Recombinant Tat protein, produced as glutathione-S-transferase chimera (GST-Tat), activates mitogen-activated protein kinase (MAPK) ERK1/2 in human, murine, and bovine endothelial cells whereas GST is ineffective. In bovine aortic endothelial cells, GST-Tat and the 165 amino acid VEGF isoform (VEGF165) induce transient ERK1/2 phosphorylation with similar potency and kinetics. The synthetic peptide Tat(41-60), but not peptides Tat(1-21) and Tat(71-86), causes ERK1/2 phosphorylation, thus implicating Tat/KDR interaction in the activation of this signaling pathway. Accordingly, GST-Tat induces ERK1/2 phosphorylation in KDR-transfected porcine aortic endothelial cells but not in parental cells. MAPK kinase inhibitors PD098059 and U0126 prevent ERK1/2 phosphorylation by Tat. However, they do not affect the angiogenic activity exerted by Tat in the murine Matrigel plug and chick embryo chorioallantoic membrane assays. Blocking of MAPK kinase activity impairs instead the angiogenic response to VEGF165 and to fibroblast growth factor-2 (FGF-2). Our data demonstrate that ERK1/2 activation following the interaction of HIV-1 Tat protein with endothelial cell Flk-1/KDR receptor does not represent an absolute requirement for a full angiogenic response to this growth factor that appears to utilize mechanism(s) at least in part distinct from those triggered by other prototypic angiogenic growth factors.

Original languageEnglish
Pages (from-to)65-74
Number of pages10
JournalEndothelium: Journal of Endothelial Cell Research
Volume8
Issue number1
Publication statusPublished - 2001

Keywords

  • AIDS
  • Angiogenesis
  • ERK
  • KDR
  • Signal transduction
  • Tat

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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