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Journal of Virology, February 2002, p. 1744-1752, Vol. 76, No. 4
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.4.1744-1752.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Kaposi's Sarcoma-Associated Herpesvirus-Encoded G Protein-Coupled Receptor ORF74 Constitutively Activates p44/p42 MAPK and Akt via Gi and Phospholipase C-Dependent Signaling Pathways

Martine J. Smit, Dennis Verzijl, Paola Casarosa, Marjon Navis, Henk Timmerman, and Rob Leurs*

Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

Received 2 July 2001/ Accepted 30 October 2001

The G protein-coupled receptor encoded by Kaposi's sarcoma-associated herpesvirus, also referred to as ORF74, has been shown to stimulate oncogenic and angiogenic signaling pathways in a constitutively active manner. The biochemical routes linking ORF74 to these signaling pathways are poorly defined. In this study, we show that ORF74 constitutively activates p44/p42 mitogen-activated protein kinase (MAPK) and Akt via Gi- and phospholipase C (PLC)-mediated signaling pathways. Activation of Akt by ORF74 appears to be phosphatidylinositol 3-kinase (PI3-K) dependent but, interestingly, is also mediated by activation of protein kinase C (PKC) and p44/p42 MAPK. ORF74 may signal to Akt via p44/p42 MAPK, which can be activated by Gi, through activation of PI3-K or through PKC via the PLC pathway. Signaling of ORF74 to these proliferative and antiapoptotic signaling pathways can be further modulated positively by growth-related oncogene (GRO{alpha}/CXCL1) and negatively by human gamma interferon-inducible protein 10 (IP-10/CXCL10), thus acting as an agonist and an inverse agonist, respectively. Despite the ability of the cytomegalovirus-encoded chemokine receptor US28 to constitutively activate PLC, this receptor does not increase phosphorylation of p44/p42 MAPK or Akt in COS-7 cells. Hence, ORF74 appears to signal through a larger diversity of G proteins than US28, allowing it to couple to proliferative and antiapoptotic signaling pathways. ORF74 can therefore be envisioned as an attractive target for novel treatment of Kaposi's sarcoma.

* Corresponding author. Mailing address: Leiden/Amsterdam Center for Drug Research, Vrije Universiteit Amsterdam, Division of Medicinal Chemistry, Faculty of Chemistry, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands. Phone: 31-20-4447579. Fax: 31-20-4447610. E-mail: leurs{at}chem.vu.nl.

Journal of Virology, February 2002, p. 1744-1752, Vol. 76, No. 4
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.4.1744-1752.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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