Tumorigenesis induced by the HHV8-encoded chemokine receptor requires ligand modulation of high constitutive activity
Peter J. Holst, … , Thue W. Schwartz, Sergio A. Lira
Peter J. Holst, … , Thue W. Schwartz, Sergio A. Lira
Published December 15, 2001
Citation Information: J Clin Invest. 2001;108(12):1789-1796. https://doi.org/10.1172/JCI13622.
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Article

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

Abstract

ORF74 (or KSHV-vGPCR) is a highly constitutively active G protein–coupled receptor encoded by HHV8 that is regulated both positively and negatively by endogenous chemokines. When expressed in transgenic mice, this chemokine receptor induces an angioproliferative disease closely resembling Kaposi sarcoma (KS). Here we demonstrate that several lines of mice carrying mutated receptors deficient in either constitutive activity or chemokine regulation fail to develop KS-like disease. In addition, animals expressing a receptor that preserves chemokine binding and constitutive activity but that does not respond to agonist stimulation have a much lower incidence of angiogenic lesions and tumors. These results indicate that induction of the KS-like disease in transgenic mice by ORF74 requires not only high constitutive signaling activity but also modulation of this activity by endogenous chemokines.

Authors

Peter J. Holst, Mette M. Rosenkilde, Denise Manfra, Shu-Cheng Chen, Maria T. Wiekowski, Birgitte Holst, Felix Cifire, Martin Lipp, Thue W. Schwartz, Sergio A. Lira

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Figure 1

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Regulation of ORF74 activity by human and murine CXC chemokines. (a) Dia...
Regulation of ORF74 activity by human and murine CXC chemokines. (a) Diagram of ORF74 and its mutant forms. (b) Phosphatidyl inositol turnover in transiently transfected COS-7 cells stimulated by human (open columns) or murine chemokines (filled columns). Values are given in percentage of specific basal activity. Three columns are shown for each peptide corresponding to 0, 1, and 100 nM of peptide (from left to right). WT-ORF74: Full, potent activation by the human agonist GROα as well as the murine homologue MIP-2, but not by KC, and potent, efficient inhibition by both the murine and human IP-10 and SDF-1α. Δ22-ORF74: No significant effect of any murine or human chemokine on the high constitutive signaling. L91D-ORF74: This mutant is fully and potently stimulated by both human GROα and the murine MIP2, but there is no effect of either human or murine inverse agonists. R208H;R212H-ORF74: No stimulation by either murine or human agonists, but inhibition of constitutive activity by both murine and human inverse agonists.