title: Inhibiting the Recruitment of PLCγ1 to Kaposi's Sarcoma Herpesvirus K15 Protein Reduces the Invasiveness and Angiogenesis of Infected Endothelial Cells.
abstract: Kaposi's sarcoma (KS), caused by Kaposi's sarcoma herpesvirus (KSHV), is a highly vascularised tumour of endothelial origin. KSHV infected endothelial cells show increased invasiveness and angiogenesis. Here, we report that the KSHV K15 protein, which we showed previously to contribute to KSHV-induced angiogenesis, is also involved in KSHV-mediated invasiveness in a PLCγ1-dependent manner. We identified βPIX, GIT1 and cdc42, downstream effectors of PLCγ1 in cell migration, as K15 interacting partners and as contributors to KSHV-triggered invasiveness. We mapped the interaction between PLCγ1, PLCγ2 and their individual domains with two K15 alleles, P and M. We found that the PLCγ2 cSH2 domain, by binding to K15P, can be used as dominant negative inhibitor of the K15P-PLCγ1 interaction, K15P-dependent PLCγ1 phosphorylation, NFAT-dependent promoter activation and the increased invasiveness and angiogenic properties of KSHV infected endothelial cells. We increased the binding of the PLCγ2 cSH2 domain for K15P by substituting two amino acids, thereby creating an improved dominant negative inhibitor of the K15P-dependent PLCγ1 activation. Taken together, these results demonstrate a necessary role of K15 in the increased invasiveness and angiogenesis of KSHV infected endothelial cells and suggest the K15-PLCγ1 interaction as a possible new target for inhibiting the angiogenic and invasive properties of KSHV.
authors: Institute of Virology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Braunschweig, Germany.
authors: Silvia
authors: S
authors: Gramolelli
authors: Institute of Virology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Braunschweig, Germany.
authors: Magdalena
authors: M
authors: Weidner-Glunde
authors: Institute of Virology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Braunschweig, Germany.
authors: Bizunesh
authors: B
authors: Abere
authors: Institute of Virology, Hannover Medical School, Hannover, Germany.
authors: Abel
authors: A
authors: Viejo-Borbolla
authors: Institute of Virology, Hannover Medical School, Hannover, Germany.
authors: Kiran
authors: K
authors: Bala
authors: Institute of Virology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Braunschweig, Germany.
authors: Jessica
authors: J
authors: Rückert
authors: Institute of Molecular Immunology, Helmholtz Center Munich, German Research Center for Environmental Health (GmbH), Munich, Germany.
authors: Elisabeth
authors: E
authors: Kremmer
authors: Institute of Virology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Braunschweig, Germany.
authors: Thomas F
authors: TF
authors: Schulz
mesh_terms: D015153:Blotting, Western; D042783:Endothelial Cells; D005455:Fluorescent Antibody Technique; D019288:Herpesvirus 8, Human / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D051966:Phospholipase C gamma / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000378:metabolism / Q000473:pathology*; D020349:Surface Plasmon Resonance; D014162:Transfection; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: C402642:K15 protein, Human herpesvirus 8; D014764:Viral Proteins; C522157:PLCG1 protein, human; D051966:Phospholipase C gamma