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.

Important note: Information in this article was accurate in 1999. The state of the art may have changed since the publication date.

Blood. 1999 Jul 15;94(2):663-72. Unique Identifier : AIDSLINE MED/99326318
Barillari G; Sgadari C; Fiorelli V; Samaniego F; Colombini S; Manzari V; Modesti A; Nair BC; Cafaro A; Sturzl M; Ensoli B; Laboratory of Virology, Istituto Superiore di Sanita, Rome,; Italy.

Abstract: 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.

Keywords: JOURNAL ARTICLE Binding, Competitive Cell Adhesion/PHYSIOLOGY Cell Division Cell Movement Cytokines/PHARMACOLOGY Endothelium, Vascular/*CYTOLOGY Extracellular Matrix Proteins/PHYSIOLOGY Fibroblast Growth Factor, Basic/*METABOLISM Gene Products, tat/CHEMISTRY/*PHYSIOLOGY Genes, tat Heparan Sulfate Proteoglycan/METABOLISM Human HIV-1/GENETICS/*PHYSIOLOGY Macromolecular Systems Molecular Mimicry Neovascularization, Pathologic/*VIROLOGY Oligopeptides/PHYSIOLOGY Peptide Fragments/PHARMACOLOGY Protein Conformation Receptors, Fibronectin/*PHYSIOLOGY Receptors, Vitronectin/*PHYSIOLOGY Recombinant Proteins/PHARMACOLOGY Sarcoma, Kaposi/PATHOLOGY Skin Neoplasms/PATHOLOGY Solubility Support, Non-U.S. Gov't
991030
A99A0950

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