Tumorigenesis induced by the HHV8-encoded chemokine receptor requires ligand modulation of high constitutive activity

International Union of Basic and Clinical Pharmacology. LXXXIX. Update on the Extended Family of Chemokine Receptors and Introducing a New Nomenclature for Atypical Chemokine Receptors

“…HHV8 ORF74 acts as a strong paracrine activator, because cells expressing this receptor secrete various growth, angiogenic, and proinflammatory cytokines (Montaner et al, 2001;Pati et al, 2001;Schwarz and Murphy, 2001;Shepard et al, 2001). These pharmacological features correlate with several in vivo studies placing HHV8 ORF74 centrally in relation to the oncogenic properties of HHV8 (Bais et al, 1998;Yang et al, 2000;Holst et al, 2001;Guo et al, 2003;Montaner et al, 2003;Jensen et al, 2005). No smallmolecule ligands exist for native HHV8 ORF74, yet by site-directed mutagenesis and incorporation of metalion binding sites it has been shown that both its constitutive and ligand-mediated activity can be modulated by small molecule ligands, indicating that it may be a good drug target (Rosenkilde et al, 1999(Rosenkilde et al, , 2000.…”

Neutralizing endogenous chemokines with small molecules

“…Spontaneous activity of chemokine receptors also exists. For herpesvirus-encoded receptors this activity is linked to transforming effects (Burger et al, 1999;Holst et al, 2001). Ligands of GPCRs almost never behave as neutral molecules, and most antagonists are either weak partial agonists (that increase the level of receptor activity) or are so called "inverse agonists" capable of diminishing the level of spontaneous activity of the receptor.…”

Constitutively Active Viral Chemokine Receptors: Tools for Immune Subversion and Pathogenesis

“…To delineate the role of the ligand-dependent and -independent ORF74-mediated angioproliferation, transgenic mice were generated carrying mutant ORF74 [125]. Transgenic mice with a mutant ORF74 capable of ligand-binding and activation, but deficient in constitutive signaling, did not develop any angiogenic lesions by 90 days of age, despite cell-surface expression of this mutant receptor.…”