Virally Encoded GPCRs

GPCRs encoded by viruses of the herpes virus family have drawn considerable attention recently because some may provide causative links with respect to the onset or progression of cancer. Various herpes viruses and pox viruses contain DNA sequences encoding proteins with homologies to cellular chemokine receptors.156 Since GPCRs and chemokine receptors play key roles in cellular communications and appear to play roles in cancer, the virally encoded GPCRs are believed to be of great importance in subverting cellular signaling.

The Kaposi's sarcoma (KS)-associated herpes virus (KSHV or human herpes virus 8) implicated in the pathogenesis of KS, a highly vascularized tumor, encodes a GPCR designated ORF74 — one of the most studied viral chemokine receptors thought to be implicated in the pathology of KS.

ORF74 shows the highest homology to human CXCR2.157 158 However, in contrast to human chemokine receptors, ORF74 binds several CXC and some CC chemokines159-161 and is constitutively active.159 Through promiscuous G protein coupling, ORF74162-164 is able to constitutively activate a variety of signal transduction cascades in several cell types: activation of phosholipase C, kinase pathways including various MAPKs, Lyn kinase, related adhesion focal tyrosine kinase (RAFTK/Pyk2), phosphatidylinositol 3-kinase and Akt/protein kinase B, RhoA and transcription factors, including hypoxia-inducible factor 1a (HIF-1a), NF-kB, and AP-1 (Figure 5.3).156

NIH-3T3 cells transfected with ORF74 cause tumors when injected into nude mice.165 Moreover, transgenic mice expressing ORF74 within hematopoietic cells develop angioproliferative lesions that morphologically resemble KS lesions158166 via a paracrine effect through the expression of inflammatory cytokines and growth factors such as VEGF. Both the constitutive activity of ORF74 and its modulation by endogenous chemokines appear responsible for the induction of a KS-like disease in transgenic mice.167 It was recently shown that constitutive activation of Akt by ORF74 plays a crucial role in ORF74-mediated sarcomagenesis and pharmacological inhibition of Akt inhibited its oncogenic potential in vivo.168

These transgenic model systems clearly provide evidence that ORF74 possesses oncogenic potential and represents an important drug target against KS. KSHV has been pirating this gene from its host genome and has modified it both to bind a wide range of chemokines and also to constitutively activate a variety of signaling pathways for its own benefit.

We recently characterized a GPCR known as BILF1, encoded by the Epstein-Barr virus (EBV) associated with many lymphoproliferative diseases such as infectious mononucleosis, Burkitt's lymphoma (BL), and nasopharyngeal carcinoma (NPC).169 Like ORF74, BILF1 constitutively activates signaling to NF-kB and CRE, both implicated in proliferative signaling. BILF1-specific mRNA was detected in various EBV-positive lymphoblastoid B cell lines as well as in BL and NPC cell lines. Increased activation of signaling pathways was also observed in these cell lines. In addition, reduced levels of phosphorylated RNA-dependent PKR, which is known to function in the cellular antiviral response, were observed in BILF1-expressing cells. Neither of these effects required a ligand to interact with the BILF1

Autocrine signaling

Paracrine signaling

Paracrine signaling

FIGURE 5.3 The KSHV-encoded GPCR ORF74 as a viral oncogene. Through promiscuous G protein coupling, ORF74 constitutively activates a variety of signal transduction cascades in several cell-types, among which activation of phosholipase C, kinase pathways, including various MAPK, Lyn kinase, related adhesion focal tyrosine kinase (RAFTK/Pyk2), phosphatidyl-inositol 3-kinase and Akt/protein kinase B, RhoA and transcription factors, including hypoxia-inducible factor la (HIF-la), nuclear factor kappa-B (NF-kB) and AP-1.156 ORF74 can be further stimulated or inhibited by CXCL1 and CXCL10, respectively. Activation of these pathways can lead to activation of transcription factors and subsequent expression of VEGF, cytokines, chemo-kines, and adhesion molecules, resulting in angiogenesis and proliferation of adjacent cells. Activation of these pathways can be highly cell-type dependent and not all events might take place in the same cell as suggested in this picture. See text for details and references.

gene product. Taken together, these results indicate that BILF1 encodes a constitu-tively active viral GPCR, and that this EBV vGPCR plays a role in evasion from the PKR-mediated cellular antiviral response and may be implicated in lymphopro-liferative diseases caused by EBV.

Since other virally encoded GPCRs, for example, human cytomegalovirus (HCMV) -encoded receptors US28 and UL33,170-172 display constitutive activity and show promiscuous G protein coupling, other herpes viruses may contribute to the onset of transformation through expression of virally encoded GPCRs in their infected hosts.

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