Viral hijacking of G-protein-coupled-receptor signalling networks

Sodhi, Akrit; Montaner, Silvia; Gutkind, J. Silvio

doi:10.1038/nrm1529

Cited by 163 publications

(130 citation statements)

References 125 publications

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“…As the cellular receptors for HIV-1 are chemokine receptors, these could be directly involved. Gp120, the coat protein of the virus, binds to CCR5 and/or CXCR4 receptors, depending on the viral strain (Sodhi et al, 2004). It can also act as an agonist or antagonist of chemokine action depending on the circumstances, and prolonged treatment of DRG neurons in culture with gp120 produces apoptosis (Bodner et al, 2002;Keswani et al, 2003).…”

Section: Hiv-1 Associated Neuropathologymentioning

confidence: 99%

HIV-1, chemokines and neurogenesis

Tran

Miller

2005

neurotox res

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HIV-1 infection of the brain results in a large number of behavioural defecits accompanied by diverse neuropathological signs. However,it is not clear how the virus produces these effects or exactly how the neuropathology and behavioural defecits are related. In this article we discuss the possibility that HIV-1 infection may negatively impact the process of neurogenesis in the adult brain and that this may contribute to HIV-1 related effects on the nervous system. We have previously demonstrated that the development of the dentate gyrus during embryogenesis requires signaling by the chemokine SDF-1 via its receptor CXCR4. We demonstrated that neural progenitor cells that give rise to dentate granule neurons express CXCR4 and other chemokine receptors and migrate into the nascent dentate gyrus along SDF-1 gradients.

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Section: Hiv-1 Associated Neuropathologymentioning

confidence: 99%

HIV-1, chemokines and neurogenesis

Tran

Miller

2005

neurotox res

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“…Compelling data suggests that vGPCR induces sarcomagenesis through the release of pro-and antiangiogenic cytokines, chemokines, and growth factors that ultimately promote the proangiogenic and proexudative response induced by this viral receptor (8,13). In this regard, ANGPTL proteins have been previously shown to regulate multiple aspects of endothelial cell function, including endothelial cell proliferation, migration, differentiation, and endothelial cell adhesion (19).…”

Section: Vegf Is Not Sufficient For the Exudative Phenotype In Vgpcr mentioning

confidence: 99%

“…Indeed, VEGF and its receptor, VEGFR2 (KDR), are up-regulated in AIDS-KS primary lesions as well as in AIDS-KS spindle-cell cultures (9)(10)(11)(12). Interestingly, both VEGF and KDR are also up-regulated by the KSHV-encoded viral G protein-coupled receptor, (vGPCR; ORF74), the viral oncogene thought to play an essential role in the initiation and promotion of KS (13)(14)(15). Collectively, these observations have reinforced the assertion that VEGF is responsible for the increased vascular permeability observed in this tumor.…”

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confidence: 99%

Viral G protein-coupled receptor up-regulates Angiopoietin-like 4 promoting angiogenesis and vascular permeability in Kaposi's sarcoma

Jham

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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109

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Kaposi's sarcoma (KS) is an enigmatic vascular tumor thought to be a consequence of dysregulated expression of the human herpesvirus-8 (HHV-8 or KSHV)-encoded G protein-coupled receptor (vGPCR). Indeed, transgenic animals expressing vGPCR manifest vascular tumors histologically identical to human KS, with expression of the viral receptor limited to a few cells, suggestive of a paracrine mechanism for vGPCR tumorigenesis. Both human and vGPCR experimental KS lesions are characterized by prominent angiogenesis and vascular permeability attributed to the release of angiogenic molecules, most notably vascular endothelial growth factor. However, the relative contribution of these paracrine mediators to the angiogenic and exudative phenotype of KS lesions remains unclear. Here we show that vGPCR up-regulation of Angiopoietin-like 4 (ANGPTL4) plays a prominent role in promoting the angiogenesis and vessel permeability observed in KS. Indeed, ANGPTL4 expression is a hallmark of vGPCR experimental and human KS lesions. Inhibition of ANGPTL4 effectively blocks vGPCR promotion of the angiogenic switch and vascular leakage in vitro and tumorigenesis in vivo. These observations suggest that ANGPTL4 is a previously unrecognized target for the treatment of patients with KS. As angiogenesis and increased vessel permeability are common themes in all solid tumors, these findings may have a broad impact on our understanding and treatment of cancer.

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“…HHV8 vGPCR is a seven span transmembrane constitutively active receptor coupled to a heterotrimeric G protein, whose closest homologue is the chemokine receptor CXCR2 (Bais et al, 1998). At the molecular level, mitogenactivated protein kinases, Akt, Rac GTPase and NF-kB signaling pathways could be controlled by vGPCR without the need for further extracellular activation (Sodhi et al, 2000(Sodhi et al, , 2004aMontaner et al, 2001Montaner et al, , 2004. Of note, vGPCR expression triggers proliferation, survival and migration of endothelial cells in vitro, and is associated with paracrine secretion of diverse cytokines (Montaner et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

et al. 2010

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Kaposi Sarcoma (KS) are opportunistic tumors, associated with human herpes virus 8 (HHV8) infection. KS development is highly favored by immune-depression and remains the second most frequent tumor in acquired immune deficiency syndrome patients. Although it has been shown that experimental expression of the HHV8 G-proteincoupled receptor (vGPCR) in the endothelial compartment is alone sufficient to recapitulate the formation and progression of KS-like lesions, its functional effects on endothelial homeostasis are not fully understood. Here we show that vGPCR expression in endothelial cells induces an increase in paracellular permeability both in vivo and in vitro. By using pharmacological inhibitors and small interference RNA-based knockdown, we demonstrate an essential role for the PI(3)Kinase-c/Rac nexus in vGPCRmediated permeability. This was further accompanied by dramatic remodeling of VE-cadherin-dependent cell-cell junctions. Importantly, this in vitro vGPCR-initiated signaling signature was observed in a large panel of human KS. Altogether, our results support the hypothesis that endothelial vGPCR signaling is co-opted in KS, and unveil new key cellular targets for therapeutic intervention.

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Viral hijacking of G-protein-coupled-receptor signalling networks

Cited by 163 publications

References 125 publications

HIV-1, chemokines and neurogenesis

HIV-1, chemokines and neurogenesis

Viral G protein-coupled receptor up-regulates Angiopoietin-like 4 promoting angiogenesis and vascular permeability in Kaposi's sarcoma

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

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