Abstract
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.
Highlights
Kaposi’s sarcoma-associated herpesvirus (KSHV; known as human herpesvirus 8) is the etiologic agent of Kaposi’s sarcoma, an endothelial neoplasm
The glycoprotein B (gB)-induced Activation of vascular endothelial growth factor receptor 3 (VEGFR-3) Is Inhibited by Blocking VEGFR-3 or Integrin ␣3—Engagement of integrins by extracellular matrix proteins can induce the activation of growth factor receptors in the absence of their cognate ligands [47,48,49] and thereby modulate a variety of cell functions including migration and growth
Recent reports indicate that the gB protein of KSHV, which spans the viral membrane, can interact with the specific cell surface integrin ␣31 that is expressed on target endothelial cells [17], thereby mimicking the extracellular matrix protein fibronectin
Summary
Cells—Primary human dermal microvascular endothelial cells (HMVEC; adult) were purchased from Clonetics Inc. (San Diego, CA) and maintained in endothelial basal medium 2 (EBM-2) with EGM-2MV SingleQuots. Cells were washed twice with 1ϫ PBS and one time with migration medium, pre-incubated with anti-␣3 and anti-VEGFR-3 (hF4-3C5) or with their isotype controls for 30 min at 4 °C, and loaded into the upper chamber of the inserts (0.1 ml, 2 ϫ 105 cells/ml). After green fluorescent cells were counted, cells were fixed with 4% paraformaldehyde solution, and immunoperoxidase staining was performed with anti-LANA-1 (ORF-73; Advanced Biotechnology Inc., Columbia, MD) antibody by using the VECTASTAIN® ABC system and the DAB substrate kit (Vector Laboratories). Statistical significance was determined using the analysis of variance test (p Ͻ 0.05)
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