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

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

Chair of General Pathology and Immunology University of Brescia, 25123, Brescia, Italy; $Department of Human Anatomy and Histology, University of Bari, 70124, Bari, Italy; §Istituto Nazionale per la Ricerca sul Cancro, 16132 Genova, Italy; °Department of Internal Medicine II, University of Ulm, D-89081, Ulm, Germany


Erk1/2 activation by GST-Tat 
in endothelial cells
 
 


 

a: vehicle
b: GST-Tat
c:GST
 
 
 
 
 

Back to Presta's lab

 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 signalling 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.
 

Endothelium, in press

 

AIRC: Special Project Angiogenesis