The angiogenesis induced by HIV-1 tat protein is mediated by the Flk-1/KDR receptor on vascular endothelial cells.
The HIV-1 Tat protein transactivates HIV, viral and some host cell genes. Tat can be released by infected cells and acts extracellularly in the microenvironment, regulating functions of immunocompetent and mesenchymal cells. One of the most striking effects of Tat is the induction of a functional program in vascular cells related to angiogenesis and inflammation (migration, proliferation and expression of plasminogen activator inhibitor-1 and E selectin). Tat induces growth of Kaposi's sarcoma (KS) spindle cells and is angiogenic in vivo and in transgenic mice10-12. We previously reported that Tat is a direct angiogenic factor and noted the Tat arginine- and lysine-rich sequence is similar to that of other potent angiogenic growth factors, such as vascular endothelial growth factor-A (VEGF-A). It is possible that Tat mimics one of these factors by interacting with its growth factor tyrosine kinase receptor. Here we demonstrate that Tat specifically binds and activates the Flk-1/kinase insert domain receptor (Flk-1/KDR), a VEGF-A tyrosine kinase receptor (for review see ref. 13), and that Tat-induced angiogenesis is blocked by agents blocking the Flk-1/KDR receptor. Endothelial cell stimulation by Tat occurs in the absence of activation of FLT-1, another VEGF-A tyrosine kinase receptor.
Albini
A
A
Dipartimento di Genetica, Biologia e Chimica Medica, Università di Torino, Turin, Italy.
Soldi
R
R
Giunciuglio
D
D
Giraudo
E
E
Benelli
R
R
Primo
L
L
Noonan
D
D
Salio
M
M
Camussi
G
G
Rockl
W
W
Bussolino
F
F
D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002633:Chemotaxis / Q000187:drug effects; D003094:Collagen; D004338:Drug Combinations; D016228:Endothelial Growth Factors / Q000378:metabolism / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D015696:Gene Products, tat / Q000378:metabolism* / Q000494:pharmacology; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D007797:Laminin; D008222:Lymphokines / Q000378:metabolism / Q000494:pharmacology; D009389:Neovascularization, Pathologic; D010766:Phosphorylation; D011509:Proteoglycans; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D054322:tat Gene Products, Human Immunodeficiency Virus
D004338:Drug Combinations; D016228:Endothelial Growth Factors; D015696:Gene Products, tat; D007797:Laminin; D008222:Lymphokines; D011509:Proteoglycans; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D054322:tat Gene Products, Human Immunodeficiency Virus; C059485:matrigel; D003094:Collagen; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor