title: The guanine exchange factor SWAP70 mediates vGPCR-induced endothelial plasticity.
abstract: BACKGROUND
  The viral G protein-coupled receptor (vGPCR) is proposed to act as one of the predominant mediators of Kaposi's sarcoma (KS), a human herpes virus 8 (HHV8)-elicited disease. The actions of vGPCR manifest pathogenesis, in part, through increased permeability of endothelial cells. Endothelial cell-cell junctions have indeed emerged as an instrumental target involved in the vasculature defects observed within the tumor microenvironment. The pathway leading to adherens junction destabilization has been shown to involve the activation of the small GTPase Rac, in the context of either latent infection or the sole expression of vGPCR. However, the precise molecular mechanisms governed by vGPCR in vascular leakage require further elucidation.
  
  
  RESULTS
  Guanine exchange factors (GEFs) function as critical molecular switches that control the activation of small GTPases. We therefore screened the effects of 80 siRNAs targeting GEFs on vGPCR-driven endothelial permeability and identified switch-associated protein 70 (SWAP70) as necessary for its elevating effects. Pull-down experiments further showed that Rac activation by vGPCR was dependent on SWAP70. Examination of tissues and cells from HHV8-positive patients revealed that SWAP70 was ubiquitously expressed. Furthermore, SWAP70 was found to be crucial for vGPCR-driven endothelial tube formation and endothelial sprouting in vitro.
  
  
  CONCLUSIONS
  SWAP70 appears to act as a molecular intermediate between vGPCR and endothelial activation. Because of the important role of vGPCR-mediated endothelial plasticity in KS pathogenesis, inhibition of SWAP70 function could be of interest for blocking vGPCR-driven activities in HHV8-defined diseases.
authors.affiliation: CNRS, UMR8104, 22 rue Mechain, 75014, Paris, France. juliedwyer@hotmail.com.|INSERM, U1016, 22 rue Mechain, 75014, Paris, France. juliedwyer@hotmail.com.|Universite Paris Descartes, Sorbonne Paris Cite, 6 rue de l'Ecole de Medecine, 75006, Paris, France. juliedwyer@hotmail.com.
authors.forename: Julie
authors.initials: J
authors.lastname: Dwyer
authors.affiliation: CNRS, UMR8104, 22 rue Mechain, 75014, Paris, France. sandy.azzi@inserm.fr.|INSERM, U1016, 22 rue Mechain, 75014, Paris, France. sandy.azzi@inserm.fr.|Universite Paris Descartes, Sorbonne Paris Cite, 6 rue de l'Ecole de Medecine, 75006, Paris, France. sandy.azzi@inserm.fr.
authors.forename: Sandy
authors.initials: S
authors.lastname: Azzi
authors.affiliation: CNRS, UMR8104, 22 rue Mechain, 75014, Paris, France. heloise.leclair@inserm.fr.|INSERM, U1016, 22 rue Mechain, 75014, Paris, France. heloise.leclair@inserm.fr.|Universite Paris Descartes, Sorbonne Paris Cite, 6 rue de l'Ecole de Medecine, 75006, Paris, France. heloise.leclair@inserm.fr.
authors.forename: Héloïse M
authors.initials: HM
authors.lastname: Leclair
authors.affiliation: CNRS, UMR8104, 22 rue Mechain, 75014, Paris, France. steven.georges@inserm.fr.|INSERM, U1016, 22 rue Mechain, 75014, Paris, France. steven.georges@inserm.fr.|Universite Paris Descartes, Sorbonne Paris Cite, 6 rue de l'Ecole de Medecine, 75006, Paris, France. steven.georges@inserm.fr.
authors.forename: Steven
authors.initials: S
authors.lastname: Georges
authors.affiliation: Service de Pathologie, Hopital Cochin-Tarnier, AP-HP, Paris, France. agnes.carlotti@cch.aphp.fr.
authors.forename: Agnès
authors.initials: A
authors.lastname: Carlotti
authors.affiliation: CNRS, UMR8104, 22 rue Mechain, 75014, Paris, France. lucas.treps@inserm.fr.|INSERM, U1016, 22 rue Mechain, 75014, Paris, France. lucas.treps@inserm.fr.|Universite Paris Descartes, Sorbonne Paris Cite, 6 rue de l'Ecole de Medecine, 75006, Paris, France. lucas.treps@inserm.fr.
authors.forename: Lucas
authors.initials: L
authors.lastname: Treps
authors.affiliation: CNRS, UMR8104, 22 rue Mechain, 75014, Paris, France. eva.galan@inserm.fr.|INSERM, U1016, 22 rue Mechain, 75014, Paris, France. eva.galan@inserm.fr.|Universite Paris Descartes, Sorbonne Paris Cite, 6 rue de l'Ecole de Medecine, 75006, Paris, France. eva.galan@inserm.fr.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Galan-Moya
authors.affiliation: Inserm UMR_753, Institut Gustave Roussy, Villejuif, 94800, France. catherine.alexia@inserm.fr.
authors.forename: Catherine
authors.initials: C
authors.lastname: Alexia
authors.affiliation: CNRS, UMR8104, 22 rue Mechain, 75014, Paris, France. nicolas.dupin@cch.aphp.fr.|INSERM, U1016, 22 rue Mechain, 75014, Paris, France. nicolas.dupin@cch.aphp.fr.|Universite Paris Descartes, Sorbonne Paris Cite, 6 rue de l'Ecole de Medecine, 75006, Paris, France. nicolas.dupin@cch.aphp.fr.|Service de Dermatologie, Hopital Cochin-Tarnier, Assistance Publique-Hôpitaux de Paris AP-HP, Paris, France. nicolas.dupin@cch.aphp.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dupin
authors.affiliation: CNRS, UMR8104, 22 rue Mechain, 75014, Paris, France. nicolas.bidere@inserm.fr.|INSERM, U1016, 22 rue Mechain, 75014, Paris, France. nicolas.bidere@inserm.fr.|Universite Paris Descartes, Sorbonne Paris Cite, 6 rue de l'Ecole de Medecine, 75006, Paris, France. nicolas.bidere@inserm.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bidère
authors.affiliation: CNRS, UMR8104, 22 rue Mechain, 75014, Paris, France. julie.gavard@inserm.fr.|INSERM, U1016, 22 rue Mechain, 75014, Paris, France. julie.gavard@inserm.fr.|Universite Paris Descartes, Sorbonne Paris Cite, 6 rue de l'Ecole de Medecine, 75006, Paris, France. julie.gavard@inserm.fr.
authors.forename: Julie
authors.initials: J
authors.lastname: Gavard
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; D043562:Receptors, G-Protein-Coupled; C491873:SWAP70 protein, human; D014764:Viral Proteins