Author: admin

Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated kaposi’s sarcoma. Science. 1994;266:1865–9. https://doi.org/10.1126/science.7997879.

Google Scholar 

Cesarman E, Damania B, Krown SE, Martin J, Bower M, Whitby D. Kaposi sarcoma. Nat Rev Dis Primers. 2019;5:9. https://doi.org/10.1038/s41572-019-0060-9.

Google Scholar 

Vischer HF, Siderius M, Leurs R, Smit MJ. Herpesvirus-encoded gpcrs: neglected players in inflammatory and proliferative diseases? Nat Rev Drug Discov. 2014;13:123–39. https://doi.org/10.1038/nrd4189.

Google Scholar 

De Groof TWM, Elder EG, Siderius M, Heukers R, Sinclair JH, Smit MJ. Viral G protein–coupled receptors: attractive targets for herpesvirus-associated diseases. Pharmacol Rev. 2021;73:828–46. https://doi.org/10.1124/pharmrev.120.000186.

Google Scholar 

Tsutsumi N, Kildedal DF, Hansen OK, Kong Q, Schols D, Van Loy T, et al. Insight into structural properties of viral G protein-coupled receptors and their role in the viral infection: IUPHAR Review 41. Br J Pharmacol. 2025;182:26–51. https://doi.org/10.1111/bph.17379.

Google Scholar 

Syrovatkina V, Alegre KO, Dey R, Huang X-Y. Regulation, signaling, and physiological functions of G-proteins. J Mol Biol. 2016;428:3850–68. https://doi.org/10.1016/j.jmb.2016.08.002.

Google Scholar 

Gurevich VV, Gurevich EV. GPCR signaling regulation: the role of GRKs and arrestins. Front Pharmacol. 2019;10:125. https://doi.org/10.3389/fphar.2019.00125.

Google Scholar 

Nagarsheth N, Wicha MS, Zou W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol. 2017;17:559–72. https://doi.org/10.1038/nri.2017.49.

Google Scholar 

Kohli K, Pillarisetty VG, Kim TS. Key chemokines direct migration of immune cells in solid tumors. Cancer Gene Ther. 2022;29:10–21. https://doi.org/10.1038/s41417-021-00303-x.

Google Scholar 

de Munnik SM, Smit MJ, Leurs R, Vischer HF. Modulation of cellular signaling by herpesvirus-encoded G protein-coupled receptors. Front Pharmacol. 2015. https://doi.org/10.3389/fphar.2015.00040.

Google Scholar 

Lyngaa R, Nørregaard K, Kristensen M, Kubale V, Rosenkilde MM, Kledal TN. Cell transformation mediated by the Epstein-Barr virus G protein-coupled receptor BILF1 is dependent on constitutive signaling. Oncogene. 2010;29:4388–98. https://doi.org/10.1038/onc.2010.173.

Google Scholar 

Maussang D, Verzijl D, Van Walsum M, Leurs R, Holl J, Pleskoff O, et al. Human cytomegalovirus-encoded chemokine receptor US28 promotes tumorigenesis. Proc Natl Acad Sci USA. 2006;103:13068–73. https://doi.org/10.1073/pnas.0604433103.

Google Scholar 

Bais C, Santomasso B, Coso O, Arvanitakis L. G-protein-coupled receptor of kaposi’s sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature. 1998;391:86–9. https://doi.org/10.1038/34193.

Google Scholar 

Yang T-Y, Chen S-C, Leach MW, Manfra D, Homey B, Wiekowski M, et al. Transgenic Expression of the Chemokine Receptor Encoded by Human Herpesvirus 8 Induces an Angioproliferative Disease Resembling Kaposi’s Sarcoma. J Exp Med. 2000;191:445–54. https://doi.org/10.1084/jem.191.3.445.

Google Scholar 

Holst PJ, Rosenkilde MM, Manfra D, Chen SC, Wiekowski MT, Holst B, et al. Tumorigenesis induced by the HHV8-encoded chemokine receptor requires ligand modulation of high constitutive activity. J Clin Invest. 2001;108:1789–96. https://doi.org/10.1172/JCI13622.

Google Scholar 

Jensen KK, Manfra DJ, Grisotto MG, Martin AP, Vassileva G, Kelley K, et al. The Human Herpes Virus 8-Encoded Chemokine Receptor Is Required for Angioproliferation in a Murine Model of Kaposi’s Sarcoma. J Immunol. 2005;174:3686–94. https://doi.org/10.4049/jimmunol.174.6.3686.

Google Scholar 

Cesarman E, Nador RG, Bai F, Bohenzky RA, Russo JJ, Moore PS, et al. Kaposi’s sarcoma-associated herpesvirus contains G protein-coupled receptor and cyclin D homologs which are expressed in Kaposi’s sarcoma and malignant lymphoma. J Virol. 1996;70:8218–23. https://doi.org/10.1128/jvi.70.11.8218-8223.1996.

Google Scholar 

Chiou C-J, Poole LJ, Kim PS, Ciufo DM, Cannon JS, Ap Rhys CM, et al. Patterns of gene expression and a transactivation function exhibited by the vGCR (ORF74) chemokine receptor protein of Kaposi’s sarcoma-associated herpesvirus. J Virol. 2002;76:3421–39. https://doi.org/10.1128/JVI.76.7.3421-3439.2002.

Google Scholar 

Cannon M, Philpott NJ, Cesarman E. The kaposi’s Sarcoma-Associated herpesvirus G Protein-Coupled receptor has broad signaling effects in primary effusion lymphoma cells. J Virol. 2003;77:57–67. https://doi.org/10.1128/JVI.77.1.57-67.2003.

Google Scholar 

Cannon ML, Cesarman E. The KSHV G protein-coupled receptor signals via multiple pathways to induce transcription factor activation in primary effusion lymphoma cells. Oncogene. 2004;23:514–23. https://doi.org/10.1038/sj.onc.1207021.

Google Scholar 

Montaner S, Sodhi A, Servitja J-M, Ramsdell AK, Barac A, Sawai ET, et al. The small GTPase Rac1 links the Kaposi sarcoma–associated herpesvirus vGPCR to cytokine secretion and paracrine neoplasia. Blood. 2004;104:2903–11. https://doi.org/10.1182/blood-2003-12-4436.

Google Scholar 

Shepard LW, Yang M, Xie P, Browning DD, Voyno-Yasenetskaya T, Kozasa T, et al. Constitutive activation of NF-κB and secretion of interleukin-8 induced by the G protein-coupled receptor of Kaposi’s sarcoma-associated herpesvirus involve Gα13 and RhoA. J Biol Chem. 2001;276:45979–87. https://doi.org/10.1074/jbc.M104783200.

Google Scholar 

Boon K, Vanalken N, Szpakowska M, Chevigné A, Schols D, Van Loy T. Systematic assessment of chemokine ligand bias at the human chemokine receptor CXCR2 indicates G protein bias over β-arrestin recruitment and receptor internalization. Cell Commun Signal. 2024;22:43. https://doi.org/10.1186/s12964-023-01460-2.

Google Scholar 

Arvanitakis L, Geras-Raaka E, Varma A, Gershengorn MC, Cesarman E. Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation. Nature. 1997;385:347–50. https://doi.org/10.1038/385347a0.

Google Scholar 

Geras-Raaka E, Varma A, Ho H, Clark-Lewis I, Gershengorn MC. Human Interferon-γ–inducible protein 10 (IP-10) inhibits constitutive signaling of kaposi’s Sarcoma–associated herpesvirus G protein–coupled receptor. J Exp Med. 1998;188:405–8. https://doi.org/10.1084/jem.188.2.405.

Google Scholar 

Gershengorn MC, Geras-Raaka E, Varma A, Clark-Lewis I. Chemokines activate kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor in mammalian cells in culture. J Clin Invest. 1998;102:1469–72. https://doi.org/10.1172/JCI4461.

Google Scholar 

Geras-Raaka E, Varma A, Clark-Lewis I, Gershengorn MC. Kaposi’s sarcoma-associated herpesvirus (KSHV) chemokine vMIP-II and human SDF-1α inhibit signaling by KSHV G protein-coupled receptor. Biochem Biophys Res Commun. 1998;253:725–7. https://doi.org/10.1006/bbrc.1998.9557.

Google Scholar 

Rosenkilde MM, Kledal TN, Bräuner-Osborne H, Schwartz TW. Agonists and inverse agonists for the herpesvirus 8-encoded constitutively active seven-transmembrane oncogene product, ORF-74. J Biol Chem. 1999;274:956–61. https://doi.org/10.1074/jbc.274.2.956.

Google Scholar 

Ho HH, Du D, Gershengorn MC. The N terminus of Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor is necessary for high affinity chemokine binding but not for constitutive activity. J Biol Chem. 1999;274:31327–32. https://doi.org/10.1074/jbc.274.44.31327.

Google Scholar 

Rosenkilde MM, Schwartz TW. Potency of ligands correlates with affinity measured against agonist and inverse agonists but not against neutral ligand in constitutively active chemokine receptor. Mol Pharmacol. 2000;57:602–9. https://doi.org/10.1124/mol.57.3.602.

Google Scholar 

Schwarz M, Murphy PM. Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor constitutively activates NF-κB and induces proinflammatory cytokine and chemokine production via a C-terminal signaling determinant. J Immunol. 2001;167:505–13. https://doi.org/10.4049/jimmunol.167.1.505.

Google Scholar 

Pati S, Cavrois M, Guo HG, Foulke JSJ, Kim J, Feldman RA, et al. Activation of NF-kappaB by the human herpesvirus 8 chemokine receptor ORF74: evidence for a paracrine model of kaposi’s sarcoma pathogenesis. J Virol United States. 2001;75:8660–73. https://doi.org/10.1128/jvi.75.18.8660-8673.2001.

Google Scholar 

Hensbergen PJ, Verzijl D, Balog CIA, Dijkman R, van der Schors RC, van der Raaij-Helmer EMH, et al. Furin is a chemokine-modifying enzyme: in vitro and in vivo processing of CXCL10 generates a C-terminally truncated chemokine retaining full activity. J Biol Chem United States. 2004;279:13402–11. https://doi.org/10.1074/jbc.M312814200.

Google Scholar 

de Munnik SM, van der Lee R, Velders DM, van Offenbeek J, de Smits- Vries L, Leurs R, et al. The viral G protein-coupled receptor ORF74 unmasks phospholipase C signaling of the receptor tyrosine kinase IGF-1R. Cell Signal. 2016;28:595–605. https://doi.org/10.1016/j.cellsig.2016.02.017.

Google Scholar 

Cornaby C, Tanner A, Stutz EW, Poole BD, Berges BK. Piracy on the molecular level: human herpesviruses manipulate cellular chemotaxis. J Gen Virol Microbiol Soc. 2016;97:543–60. https://doi.org/10.1099/jgv.0.000370.

Google Scholar 

Couty J-P, Lupu-Meiri M, Oron Y, Gershengorn MC. Kaposi’s sarcoma-associated herpesvirus-G protein-coupled receptor-expressing endothelial cells exhibit reduced migration and stimulated chemotaxis by chemokine inverse agonists. J Pharmacol Exp Ther. 2009;329:1142–7. https://doi.org/10.1124/jpet.108.147686.

Google Scholar 

Liu L, Doijen J, D’huys T, Verhaegen Y, Dehaen W, De Jonghe S, et al. Biological characterization of ligands targeting the human CC chemokine receptor 8 (CCR8) reveals the biased signaling properties of small molecule agonists. Biochem Pharmacol. 2021;188:114565. https://doi.org/10.1016/j.bcp.2021.114565.

Google Scholar 

Schoofs G, Van Hout A, D’huys T, Schols D, Van Loy T. A flow Cytometry-based assay to identify compounds that disrupt binding of Fluorescently-labeled CXC chemokine ligand 12 to CXC chemokine receptor 4. JoVE. 2018;57271. https://doi.org/10.3791/57271.

Claes S, D’huys T, Van Hout A, Schols D, Van Loy T. A kinetic Fluorescence-based Ca²⁺ mobilization assay to identify G Protein-coupled receptor Agonists, Antagonists, and allosteric modulators. JoVE. 2018;56780. https://doi.org/10.3791/56780.

Dixon AS, Schwinn MK, Hall MP, Zimmerman K, Otto P, Lubben TH, et al. Nanoluc complementation reporter optimized for accurate measurement of protein interactions in cells. ACS Chem Biol. 2016;11:400–8. https://doi.org/10.1021/acschembio.5b00753.

Google Scholar 

Liu C, Sandford G, Fei G, Nicholas J. Ga protein selectivity determinant specified by a viral chemokine receptor-conserved region in the C tail of the human herpesvirus 8 G protein-coupled receptor. J Virol. 2004. https://doi.org/10.1128/jvi.78.5.2460-2471.2004.

Google Scholar 

de Munnik SM, Kooistra AJ, van Offenbeek J, Nijmeijer S, de Graaf C, Smit MJ, et al. The viral G protein-coupled receptor ORF74 hijacks β-arrestins for endocytic trafficking in response to human chemokines. PLoS One. 2015;10:e0124486. https://doi.org/10.1371/journal.pone.0124486.

Google Scholar 

Bogacka J, Pawlik K, Ciapała K, Ciechanowska A, Mika J. CC chemokine receptor 4 (CCR4) as a possible new target for therapy. Int J Mol Sci. 2022;23:15638. https://doi.org/10.3390/ijms232415638.

Google Scholar 

Liu A, Liu Y, Llinàs Del Torrent Masachs C, Zhang W, Pardo L, Ye RD. Structural insights into KSHV-GPCR constitutive activation and CXCL1 chemokine recognition. Proc Natl Acad Sci U S A. 2024;121:e2403217121. https://doi.org/10.1073/pnas.2403217121.

Google Scholar 

Park JB, Sahoo B, Sahoo AR, Kim D, Seo HD, Bowman J, et al. Structural basis for ligand promiscuity and high signaling activity of kaposi’s Sarcoma-associated Herpesvirus-encoded GPCR. Nat Commun. 2025;16:8403. https://doi.org/10.1038/s41467-025-63457-4.

Google Scholar 

Rosenkilde MM, Kledal TN, Holst PJ, Schwartz TW. Selective elimination of high constitutive activity or chemokine binding in the human herpesvirus 8 encoded seven transmembrane oncogene ORF74. J Biol Chem. 2000;275:26309–15. https://doi.org/10.1074/jbc.M003800200.

Google Scholar 

Feng H, Sun Z, Farzan MR, Feng P. Sulfotyrosines of the kaposi’s Sarcoma-Associated herpesvirus G Protein-Coupled receptor promote tumorigenesis through autocrine activation. J Virol. 2010;84:3351–61. https://doi.org/10.1128/JVI.01939-09.

Google Scholar 

Zhang R, Xie X. Tools for GPCR drug discovery. Acta Pharmacol Sin. 2012;33:372–84. https://doi.org/10.1038/aps.2011.173.

Google Scholar 

Zhang J, He S, Wang Y, Brulois K, Lan K, Jung JU, et al. Herpesviral G protein-coupled receptors activate NFAT to induce tumor formation via inhibiting the SERCA calcium ATPase. PLoS Pathog. 2015;11:e1004768. https://doi.org/10.1371/journal.ppat.1004768.

Google Scholar 

Machleidt T, Woodroofe CC, Schwinn MK, Méndez J, Robers MB, Zimmerman K, et al. NanoBRET—a novel BRET platform for the analysis of Protein–Protein interactions. ACS Chem Biol. 2015;10:1797–804. https://doi.org/10.1021/acschembio.5b00143.

Google Scholar 

Ma X, Leurs R, Vischer HF. NanoLuc-Based Methods to Measure β-Arrestin2 Recruitment to G Protein-Coupled Receptors. New York, NY: Springer US; 2021. pp. 233–48. https://doi.org/10.1007/978-1-0716-1221-7_16. G Protein-Coupled Receptor Screening Assays [Internet].

Luo J, Li D, Wei D, Wang X, Wang L, Zeng X. RhoA and RhoC are involved in stromal cell-derived factor-1-induced cell migration by regulating F-actin redistribution and assembly. Mol Cell Biochem. 2017;436:13–21. https://doi.org/10.1007/s11010-017-3072-3.

Google Scholar 

Michaelis UR. Mechanisms of endothelial cell migration. Cell Mol Life Sci. 2014;71:4131–48. https://doi.org/10.1007/s00018-014-1678-0.

Google Scholar 

Couty J-P, Geras-Raaka E, Weksler BB, Gershengorn MC. Kaposi’s Sarcoma-associated Herpesvirus G Protein-coupled Receptor Signals through Multiple Pathways in Endothelial Cells. J Biol Chem. 2001;276:33805–11. https://doi.org/10.1074/jbc.m104631200.

Google Scholar 

Smit MJ, Verzijl D, Casarosa P, Navis M, Timmerman H, Leurs R. Kaposi’s sarcoma-associated herpesvirus-encoded G protein-coupled receptor ORF74 constitutively activates p44/p42 MAPK and Akt via G(i) and phospholipase C-dependent signaling pathways. J Virol. 2002;76:1744–52. https://doi.org/10.1128/jvi.76.4.1744-1752.2002.

Google Scholar 

Boldajipour B, Mahabaleshwar H, Kardash E, Reichman-Fried M, Blaser H, Minina S, et al. Control of chemokine-guided cell migration by ligand sequestration. Cell. 2008;132:463–73. https://doi.org/10.1016/j.cell.2007.12.034.

Google Scholar 

Décaillot FM, Kazmi MA, Lin Y, Ray-Saha S, Sakmar TP, Sachdev P. CXCR7/CXCR4 heterodimer constitutively recruits β-arrestin to enhance cell migration. J Biol Chem. 2011;286:32188–97. https://doi.org/10.1074/jbc.M111.277038.

Google Scholar 

Desnoyer A, Dupin N, Assoumou L, Carlotti A, Gaudin F, Deback C, et al. Expression pattern of the CXCL12/CXCR4-CXCR7 trio in Kaposi sarcoma skin lesions. Br J Dermatol. 2016;175:1251–62. https://doi.org/10.1111/bjd.14748.

Google Scholar 

Kwon E-K, Min C-K, Kim Y, Lee J-W, Aigerim A, Schmidt S, et al. Constitutive activation of T cells by γ2-herpesviral GPCR through the interaction with cellular CXCR4. Biochimica et Biophysica Acta (BBA) – Molecular Cell Research. 2017;1864:1–11. https://doi.org/10.1016/j.bbamcr.2016.10.008.

Google Scholar 

Nijmeijer S, Leurs R, Smit MJ, Vischer HF. The Epstein-Barr virus-encoded G protein-coupled receptor BILF1 hetero-oligomerizes with human CXCR4, scavenges Gαi proteins, and constitutively impairs CXCR4 functioning. J Biol Chem. 2010;285:29632–41. https://doi.org/10.1074/jbc.M110.115618.

Google Scholar 

Gouwy M, Struyf S, Noppen S, Schutyser E, Springael J-Y, Parmentier M, et al. Synergy between coproduced CC and CXC chemokines in monocyte chemotaxis through Receptor-Mediated events. Mol Pharmacol. 2008;74:486–96. https://doi.org/10.1124/mol.108.045146.

Google Scholar 

Lane BR, Liu J, Bock PJ, Schols D, Coffey MJ, Strieter RM, et al. Interleukin-8 and growth-regulated oncogene alpha mediate angiogenesis in Kaposi’s sarcoma. J Virol. 2002;76:11570–83. https://doi.org/10.1128/JVI.76.22.11570-11583.2002.

Google Scholar 

Xu Y, Ganem D. Induction of chemokine production by latent kaposi’s sarcoma-associated herpesvirus infection of endothelial cells. J Gen Virol. 2007;88:46–50. https://doi.org/10.1099/vir.0.82375-0.

Google Scholar 

Lee M, Lee J, Kang S, Wirth D, Yoo S, Park C. CXCL1 confers a survival advantage in Kaposi’s sarcoma-associated herpesvirus‐infected human endothelial cells through STAT3 phosphorylation. J Med Virol. 2023;95:jmv.28020. https://doi.org/10.1002/jmv.28020.

Google Scholar 

Korbecki J, Bosiacki M, Szatkowska I, Kupnicka P, Chlubek D, Baranowska-Bosiacka I. The clinical significance and involvement in molecular cancer processes of chemokine CXCL1 in selected tumors. IJMS. 2024;25:4365. https://doi.org/10.3390/ijms25084365.

Google Scholar 

Li X, Ohler ZW, Day A, Bassel L, Grosskopf A, Afsari B et al. Mapping herpesvirus-driven impacts on the cellular milieu and transcriptional profile of Kaposi sarcoma in patient-derived mouse models. BioRxiv. 2024. https://doi.org/10.1101/2024.09.27.615429. Cited 2025 Sep 9.

Knowlton ER, Rappocciolo G, Piazza P, Lepone LM, Nadgir SV, Bullotta A, et al. Human herpesvirus 8 induces polyfunctional B lymphocytes that drive Kaposi’s sarcoma. mBio. 2014;5:e01277-14. https://doi.org/10.1128/mBio.01277-14.

Google Scholar 

Pontejo SM, Murphy PM, Pease JE. Chemokine subversion by human herpesviruses. J Innate Immun. 2018;10:465–78. https://doi.org/10.1159/000492161.

Google Scholar 

Palande V, Roden RBS, Choi YB. Nano-luciferase complementation assay of human herpesvirus 8 chemo/cytokine-receptor interactions. Sci Rep. 2025;15:35365. https://doi.org/10.1038/s41598-025-19281-3.

Google Scholar 

West J, Damania B. Upregulation of the TLR3 pathway by kaposi’s sarcoma-associated herpesvirus during primary infection. J Virol. 2008;82:5440–9. https://doi.org/10.1128/JVI.02590-07.

Google Scholar 

Neumeyer S, Tagawa T. The Kaposi sarcoma herpesvirus control of monocytes, macrophages, and the tumour microenvironment. Virology. 2025;601:110286. https://doi.org/10.1016/j.virol.2024.110286.

Google Scholar