title: Kaposi's sarcoma-associated herpesvirus induces rapid release of angiopoietin-2 from endothelial cells.
abstract: Kaposi sarcoma-associated herpesvirus (KSHV) stimulates proliferation, angiogenesis, and inflammation to promote Kaposi sarcoma (KS) tumor growth, which involves various growth factors and cytokines. Previously, we found that KSHV infection of human umbilical vein endothelial cells (HUVECs) induces a transcriptional induction of the proangiogenic and proinflammatory cytokine angiopoietin-2 (Ang-2). Here, we report that KSHV induces rapid release of Ang-2 that is presynthesized and stored in the Weibel-Palade bodies (WPB) of endothelial cells upon binding to its integrin receptors. Blocking viral binding to integrins inhibits Ang-2 release. KSHV binding activates the integrin tyrosine kinase receptor signaling pathways, leading to tyrosine phosphorylation of focal adhesion kinase (FAK), the tyrosine kinase Src, and the Calα2 subunit of the l-type calcium channel to trigger rapid calcium (Ca(2+)) influx. Pretreatment of endothelial cells with specific inhibitors of protein tyrosine kinases inhibits KSHV-induced Ca(2+) influx and Ang-2 release. Inhibition of Ca(2+) mobilization with calcium channel blockers also inhibits Ang-2 release. Thus, the interaction between KSHV and its integrin receptors plays a key role in regulating rapid Ang-2 release from endothelial cells. This finding highlights a novel mechanism of viral induction of angiogenesis and inflammation, which might play important roles in the early event of KS tumor development.
authors.affiliation: Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, Ohio, USA. fxy63@case.edu
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Ye
authors.forename: Fu-Chun
authors.initials: FC
authors.lastname: Zhou
authors.forename: Stanley
authors.initials: S
authors.lastname: Nithianantham
authors.forename: Bala
authors.initials: B
authors.lastname: Chandran
authors.forename: Xiao-Lan
authors.initials: XL
authors.lastname: Yu
authors.forename: Aaron
authors.initials: A
authors.lastname: Weinberg
authors.forename: Shou-Jiang
authors.initials: SJ
authors.lastname: Gao
mesh_terms: D042702:Angiopoietin-2 / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism* / Q000821:virology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D016023:Integrins / Q000378:metabolism; D010766:Phosphorylation; D012514:Sarcoma, Kaposi / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000821:virology
chemical_list: D042702:Angiopoietin-2; D016023:Integrins; D051416:Focal Adhesion Protein-Tyrosine Kinases; D002118:Calcium
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