title: The Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) K1 protein induces expression of angiogenic and invasion factors.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) has been linked to Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. In addition to endothelial cells and B lymphocytes, KSHV also has been shown to infect epithelial cells and keratinocytes. The transmembrane glycoprotein K1, encoded by the first open reading frame of KSHV, is a signaling protein capable of eliciting B-cell activation. We show that KSHV K1 can induce expression and secretion of vascular endothelial growth factor (VEGF) in epithelial and endothelial cells. Up-regulation of VEGF was mediated at the transcriptional level because expression of K1 resulted in VEGF promoter activation. We also show that K1 induces expression of matrix metalloproteinase-9 (MMP-9) in endothelial cells. Additional analyses with K1 mutant proteins revealed that the SH2 binding motifs present in the K1 cytoplasmic tail are necessary for VEGF secretion and MMP-9 induction. These results indicate that K1 signaling may contribute to KSHV-associated pathogenesis through a paracrine mechanism by promoting the secretion of VEGF and MMP-9 into the surrounding matrix.
authors.affiliation: Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Naohiro
authors.initials: N
authors.lastname: Wakisaka
authors.forename: Christine C
authors.initials: CC
authors.lastname: Tomlinson
authors.forename: Scott M
authors.initials: SM
authors.lastname: DeWire
authors.forename: Stuart
authors.initials: S
authors.lastname: Krall
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Pagano
authors.forename: Blossom
authors.initials: B
authors.lastname: Damania
mesh_terms: D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014764:Viral Proteins
chemical_list: D016222:Fibroblast Growth Factor 2; D020780:Matrix Metalloproteinase 9; D008565:Membrane Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D014759:Viral Envelope Proteins; C111600:K1 protein, Human herpesvirus 8; D014764:Viral Proteins