Kaposi's Sarcoma-associated Herpesvirus Activation of Vascular Endothelial Growth Factor Receptor 3 Alters Endothelial Function and Enhances Infection

• Published in: The Journal of biological chemistry 2005-07, Vol.280 (28), p.26216-26224
• Main Authors: Zhang, Xuefeng, Wang, Jian Feng, Chandran, Bala, Persaud, Kris, Pytowski, Bronislaw, Fingeroth, Joyce, Groopman, Jerome E.
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; Binding, Competitive; Blotting, Western; Cell Line; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Cytokines - metabolism; DNA - metabolism; Electrophoresis, Polyacrylamide Gel; Endothelium, Vascular - metabolism; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Heparin - analogs & derivatives; Heparin - pharmacology; Herpesvirus 8, Human - metabolism; Human herpesvirus 8; Humans; Immunoprecipitation; Integrin alpha3beta1 - metabolism; Kaposi's sarcoma-associated herpesvirus; Ligands; Microcirculation - metabolism; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Mutation; Oligopeptides - chemistry; Open Reading Frames; Plasmids - metabolism; Polymerase Chain Reaction; Protein Binding; Protein Structure, Tertiary; Protein-Serine-Threonine Kinases - metabolism; Proteoglycans - pharmacology; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Reverse Transcriptase Polymerase Chain Reaction; Sarcoma, Kaposi - virology; Signal Transduction; Skin Neoplasms - virology; Time Factors; Transfection; Vascular Endothelial Growth Factor Receptor-3 - metabolism; Viral Envelope Proteins - chemistry; Viral Envelope Proteins - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M411392200

Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8) is the etiologic agent of Kaposi's sarcoma, an endothelial neoplasm. This γ-herpesvirus encodes for several unique proteins that alter target cell function, including the virion envelope-associated glycoprotein B (gB). Glycoprotein B has an RGD (Arg-Gly-Asp) motif at the extracellular amino terminus region and binds to the α3β1 surface integrin, which enhances virus entry. We now report that gB can activate the vascular endothelial growth factor receptor 3 (VEGFR-3) on the surface of microvascular endothelial cells and trigger receptor signaling, which can modulate endothelial migration and proliferation. Furthermore, we observed that VEGFR-3 expression and activation enhance KSHV infection and participate in KSHV-mediated transformation. These functional changes in the endothelium may contribute to the pathogenesis of Kaposi's sarcoma and suggest that interventions that inhibit gB activation of VEGFR-3 could be useful in the treatment of this neoplasm.