Kaposi's sarcoma-associated herpesvirus activation of vascular endothelial growth factor receptor 3 alters endothelial function and enhances infection.
Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8) is the etiologic agent of Kaposi's sarcoma, an endothelial neoplasm. This gamma-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 alpha3beta1 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.
Zhang
Xuefeng
X
Division of Experimental Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
Wang
Jian Feng
JF
Chandran
Bala
B
Persaud
Kris
K
Pytowski
Bronislaw
B
Fingeroth
Joyce
J
Groopman
Jerome E
JE
D020816:Amino Acid Motifs; D001667:Binding, Competitive; D015153:Blotting, Western; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004730:Endothelium, Vascular / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006493:Heparin / Q000031:analogs & derivatives / Q000494:pharmacology; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D039201:Integrin alpha3beta1 / Q000378:metabolism; D008024:Ligands; D008833:Microcirculation / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009154:Mutation; D009842:Oligopeptides / Q000737:chemistry; D016366:Open Reading Frames; D010957:Plasmids / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012514:Sarcoma, Kaposi / Q000821:virology; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000821:virology; D013997:Time Factors; D014162:Transfection; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000378:metabolism
D016207:Cytokines; D039201:Integrin alpha3beta1; D008024:Ligands; D009842:Oligopeptides; D011509:Proteoglycans; D011518:Proto-Oncogene Proteins; D014759:Viral Envelope Proteins; C116207:glycoprotein B, human herpesvirus 8; C036090:heparin proteoglycan; C047981:arginyl-glycyl-aspartic acid; D006493:Heparin; D004247:DNA; D040321:Vascular Endothelial Growth Factor Receptor-3; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3