J. Exp. Med., Volume 187, Number 5, March 2, 1998 801-806

BRIEF DEFINITIVE REPORT:
Inhibition of Constitutive Signaling of Kaposi's Sarcoma-associated Herpesvirus G Protein-Coupled Receptor by Protein Kinases in Mammalian Cells in Culture

By Elizabeth Geras-Raaka,^* Leandros Arvanitakis, Carlos Bais,^§ Ethel Cesarman, Enrique A. Mesri,^§ and Marvin C. Gershengorn^*

From the ^* Division of Molecular Medicine, the Department of Medicine, the  Department of Pathology, and the ^§ Division of Hematology-Oncology, the Department of Medicine, Cornell University Medical College, New York 10021

Kaposi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8, which is consistently present in tissues of patients with Kaposi's sarcoma and primary effusion lymphomas, contains a gene that encodes a G protein-coupled receptor (KSHV-GPCR). We recently showed that KSHV-GPCR exhibits constitutive signaling via activation of phosphoinositide-specific phospholipase C and stimulates cell proliferation and transformation. In this study, we determined whether normal cellular mechanisms could inhibit constitutive signaling by KSHV-GPCR and thereby KSHV-GPCR-stimulated proliferation. We show that coexpression of GPCR-specific kinases (GRKs) and activation of protein kinase C inhibit constitutive signaling by KSHV-GPCR in COS-1 monkey kidney cells and in mouse NIH 3T3 cells. Moreover, GRK-5 but not GRK-2 inhibits KSHV-GPCR-stimulated proliferation of rodent fibroblasts. These data provide evidence that cell regulatory pathways of receptor desensitization may be therapeutic targets in human diseases involving constitutively active receptors.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Neve, K. A. (2006). Novel Features of G Protein-Coupled Receptor Kinase 4. Mol. Pharmacol. 69: 673-676 [Abstract] [Full Text]  
• Cannon, M., Cesarman, E., Boshoff, C. (2006). KSHV G protein-coupled receptor inhibits lytic gene transcription in primary-effusion lymphoma cells via p21-mediated inhibition of Cdk2. Blood 107: 277-284 [Abstract] [Full Text]  
• Paulsen, S. J., Rosenkilde, M. M., Eugen-Olsen, J., Kledal, T. N. (2005). Epstein-Barr Virus-Encoded BILF1 Is a Constitutively Active G Protein-Coupled Receptor. J. Virol. 79: 536-546 [Abstract] [Full Text]  
• Hecht, I., Hershkoviz, R., Shivtiel, S., Lapidot, T., Cohen, I. R., Lider, O., Cahalon, L. (2004). Heparin-disaccharide affects T cells: inhibition of NF-{kappa}B activation, cell migration, and modulation of intracellular signaling. J. Leukoc. Biol. 75: 1139-1146 [Abstract] [Full Text]  
• Poole, L. J., Yu, Y., Kim, P. S., Zheng, Q.-Z., Pevsner, J., Hayward, G. S. (2002). Altered Patterns of Cellular Gene Expression in Dermal Microvascular Endothelial Cells Infected with Kaposi's Sarcoma-Associated Herpesvirus. J. Virol. 76: 3395-3420 [Abstract] [Full Text]  
• Chiou, C.-J., Poole, L. J., Kim, P. S., Ciufo, D. M., Cannon, J. S., ap Rhys, C. M., Alcendor, D. J., Zong, J.-C., Ambinder, R. F., Hayward, G. S. (2002). Patterns of Gene Expression and a Transactivation Function Exhibited by the vGCR (ORF74) Chemokine Receptor Protein of Kaposi's Sarcoma-Associated Herpesvirus. J. Virol. 76: 3421-3439 [Abstract] [Full Text]  
• Shepard, L. W., Yang, M., Xie, P., Browning, D. D., Voyno-Yasenetskaya, T., Kozasa, T., Ye, R. D. (2001). Constitutive Activation of NF-kappa B and Secretion of Interleukin-8 Induced by the G Protein-coupled Receptor of Kaposi's Sarcoma-associated Herpesvirus Involve Galpha 13 and RhoA. J. Biol. Chem. 276: 45979-45987 [Abstract] [Full Text]  
• Schwarz, M., Murphy, P. M. (2001). Kaposi's Sarcoma-Associated Herpesvirus G Protein-Coupled Receptor Constitutively Activates NF-{{kappa}}B and Induces Proinflammatory Cytokine and Chemokine Production Via a C-Terminal Signaling Determinant. J. Immunol. 167: 505-513 [Abstract] [Full Text]  
• Afonso, C. L., Tulman, E. R., Lu, Z., Zsak, L., Rock, D. L., Kutish, G. F. (2001). The Genome of Turkey Herpesvirus. J. Virol. 75: 971-978 [Abstract] [Full Text]  
• Tulman, E. R., Afonso, C. L., Lu, Z., Zsak, L., Rock, D. L., Kutish, G. F. (2000). The Genome of a Very Virulent Marek's Disease Virus. J. Virol. 74: 7980-7988 [Abstract] [Full Text]  
• Belperio, J. A., Keane, M. P., Arenberg, D. A., Addison, C. L., Ehlert, J. E., Burdick, M. D., Strieter, R. M. (2000). CXC chemokines in angiogenesis. J. Leukoc. Biol. 68: 1-8 [Abstract] [Full Text]  
• Rosenkilde, M. M., Schwartz, T. W. (2000). Potency of Ligands Correlates with Affinity Measured against Agonist and Inverse Agonists but Not against Neutral Ligand in Constitutively Active Chemokine Receptor. Mol. Pharmacol. 57: 602-609 [Abstract] [Full Text]  
• Murphy, P. M., Baggiolini, M., Charo, I. F., Hebert, C. A., Horuk, R., Matsushima, K., Miller, L. H., Oppenheim, J. J., Power, C. A. (2000). International Union of Pharmacology. XXII. Nomenclature for Chemokine Receptors. Pharmacol. Rev. 52: 145-176 [Abstract] [Full Text]  
• Yang, T.-Y., Chen, S.-C., Leach, M. W., Manfra, D., Homey, B., Wiekowski, M., Sullivan, L., Jenh, C.-H., Narula, S. K., Chensue, S. W., Lira, S. A. (2000). Transgenic Expression of the Chemokine Receptor Encoded by Human Herpesvirus 8 Induces an Angioproliferative Disease Resembling Kaposi's Sarcoma. J. Exp. Med. 191: 445-454 [Abstract] [Full Text]  
• Camarda, G., Spinetti, G., Bernardini, G., Mair, C., Davis-Poynter, N., Capogrossi, M. C., Napolitano, M. (1999). The Equine Herpesvirus 2 E1 Open Reading Frame Encodes a Functional Chemokine Receptor. J. Virol. 73: 9843-9848 [Abstract] [Full Text]  
• Munshi, N., Ganju, R. K., Avraham, S., Mesri, E. A., Groopman, J. E. (1999). Kaposi's Sarcoma-associated Herpesvirus-encoded G Protein-coupled Receptor Activation of c-Jun Amino-terminal Kinase/Stress-activated Protein Kinase and Lyn Kinase Is Mediated by Related Adhesion Focal Tyrosine Kinase/Proline-rich Tyrosine Kinase 2. J. Biol. Chem. 274: 31863-31867 [Abstract] [Full Text]  
• Rosenkilde, M. M., Kledal, T. N., Brauner-Osborne, H., Schwartz, T. W. (1999). Agonists and Inverse Agonists for the Herpesvirus 8-encoded Constitutively Active Seven-transmembrane Oncogene Product, ORF-74. J. Biol. Chem. 274: 956-961 [Abstract] [Full Text]  
• Lupu-Meiri, M., Silver, R. B., Simons, A. H., Gershengorn, M. C., Oron, Y. (2001). Constitutive Signaling by Kaposi's Sarcoma-associated Herpesvirus G-protein-coupled Receptor Desensitizes Calcium Mobilization by Other Receptors. J. Biol. Chem. 276: 7122-7128 [Abstract] [Full Text]  
• Couty, J.-P., Geras-Raaka, E., Weksler, B. B., Gershengorn, M. C. (2001). Kaposi's Sarcoma-associated Herpesvirus G Protein-coupled Receptor Signals through Multiple Pathways in Endothelial Cells. J. Biol. Chem. 276: 33805-33811 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS