The Tat protein of human immunodeficiency virus type-1 promotes vascular cell growth and locomotion by engaging the alpha5beta1 and alphavbeta3 integrins and by mobilizing sequestered basic fibroblast growth factor.
The Tat protein of human immunodeficiency virus type-1 (HIV-1) has been shown to be released during acute infection of T cells by HIV-1 and to promote angiogenesis and Kaposi's sarcoma (KS) development in infected individuals. In this study, we investigated the molecular mechanisms responsible for the angiogenic effects of Tat. The results shown herein indicate that two different Tat domains cooperate to induce these effects by different pathways. The arginine-glycine-aspartic acid (RGD) sequence present at the carboxyterminal of Tat mediates vascular cell migration and invasion by binding to the alpha5beta1 and alphavbeta3 integrins. This interaction also provides endothelial cells with the adhesion signal they require to grow in response to mitogens. At the same time, the Tat basic sequence retrieves into a soluble form extracellular basic fibroblast growth factor (bFGF) bound to heparan sulfate proteoglycans by competing for heparin-binding sites. This soluble bFGF mediates Tat-induced vascular cell growth. These effects resemble those of extracellular matrix proteins, suggesting that Tat enhances angiogenesis and promotes KS progression by a molecular mimicry of these molecules.
Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy.
G
G
Barillari
C
C
Sgadari
V
V
Fiorelli
F
F
Samaniego
S
S
Colombini
V
V
Manzari
A
A
Modesti
B C
BC
Nair
A
A
Cafaro
M
M
Stürzl
B
B
Ensoli
D001667:Binding, Competitive; D002448:Cell Adhesion / Q000502:physiology; D002455:Cell Division; D002465:Cell Movement; D016207:Cytokines / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology*; D016326:Extracellular Matrix Proteins / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D015696:Gene Products, tat / Q000737:chemistry / Q000502:physiology*; D015756:Genes, tat; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances; D018716:Molecular Mimicry; D009389:Neovascularization, Pathologic / Q000821:virology*; D009842:Oligopeptides / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology; D011487:Protein Conformation; D017469:Receptors, Fibronectin / Q000502:physiology*; D019030:Receptors, Vitronectin / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012514:Sarcoma, Kaposi / Q000473:pathology; D012878:Skin Neoplasms / Q000473:pathology; D012995:Solubility; D054322:tat Gene Products, Human Immunodeficiency Virus
D016207:Cytokines; D016326:Extracellular Matrix Proteins; D015696:Gene Products, tat; D019812:Heparan Sulfate Proteoglycans; D046911:Macromolecular Substances; D009842:Oligopeptides; D010446:Peptide Fragments; D017469:Receptors, Fibronectin; D019030:Receptors, Vitronectin; D011994:Recombinant Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D016222:Fibroblast Growth Factor 2; C047981:arginyl-glycyl-aspartic acid