Constitutively active Gq/11-coupled Receptors Enable Signaling by Co-expressed Gi/o-coupled Receptors

Bakker, Remko A.; Casarosa, Paola; Timmerman, Henk; Smit, Martine J.; Leurs, Rob

doi:10.1074/jbc.m309200200

Cited by 54 publications

(39 citation statements)

References 66 publications

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“…US28 has been shown to constitutively activate signaling pathways linked to proliferation and migration when expressed in vitro but also after HCMV infection (11,12). Moreover, US28 shows promiscuous G protein coupling, constitutively signaling, for example, through G␣ q proteins, and is able to potentiate signaling of cellular G␣ i -linked chemokine receptors (10,13,14). Hence, HCMV may effectively use US28 to orchestrate multiple signaling networks within infected cells.…”

Section: H Uman Cytomegalovirus (Hcmv) Is a Widely Spreadmentioning

confidence: 99%

Human cytomegalovirus-encoded chemokine receptor US28 promotes tumorigenesis

Maussang

Verzijl

Walsum

et al. 2006

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

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Human cytomegalovirus (HCMV) is a widely spread herpesvirus, suggested to play a role in tumor progression. US28, a chemokine receptor encoded by HCMV, binds a broad spectrum of chemokines and constitutively activates various pathways linked to proliferation. Our studies reveal that expression of US28 induces a proangiogenic and transformed phenotype by up-regulating the expression of vascular endothelial growth factor and enhancing cell growth and cell cycle progression. US28-expressing cells promote tumorigenesis when injected into nude mice. The G proteinuncoupled constitutively inactive mutant of US28, induces delayed and attenuated tumor formation, indicating the importance of constitutive receptor activity in the early onset of tumor development. Importantly, also in glioblastoma cells infected with the newly isolated clinical HCMV strain Titan, US28 was shown to be involved in the HCMV-induced angiogenic phenotype. Hence, the constitutively activated chemokine receptor US28 might act as a viral oncogene and enhance and͞or promote HCMV-associated tumor progression.cancer ͉ G protein-coupled receptor ͉ VEGF ͉ viral infection ͉ drug target

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Section: H Uman Cytomegalovirus (Hcmv) Is a Widely Spreadmentioning

confidence: 99%

Human cytomegalovirus-encoded chemokine receptor US28 promotes tumorigenesis

Maussang

Verzijl

Walsum

et al. 2006

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

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205

238

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“…For receptor studies, cells were stimulated with tetracycline (Invitrogen Q100-19) to induce receptor expression. For Western blotting, cells were lysed in radioimmunoprecipitation assay (RIPA) lysis buffer (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 1 mM EDTA, 1% NP-40, 0.25% sodium deoxycholate, 0.1% sodium dodecyl sulfate with the addition of protease inhibitors [phenylmethylsulfonyl fluoride, aprotinin, leupeptin, and pepstatin] and phosphatase inhibitors [activated Na 3 VO 4 and NaF]). For receptor glycosylation studies, cells were lysed in 0.1 M Tris-HCl-10 mM EDTA-1% Triton X-114-1 mM phenylmethylsulfonyl fluoride.…”

mentioning

confidence: 99%

Epstein-Barr Virus-Encoded BILF1 Is a Constitutively Active G Protein-Coupled Receptor

Paulsen

Rosenkilde

Eugen‐Olsen

et al. 2005

J Virol

114

124

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Both beta-and gammaherpesviruses encode G protein-coupled receptors (GPCRs) with unique pharmacological phenotypes and important biological functions. An example is ORF74, the ␥2-herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded GPCR, which is highly constitutively active and considered the key oncogene in Kaposi's sarcoma pathogenesis. In contrast, the current annotation of the Epstein-Barr virus (EBV) genome does not reveal any GPCR homolog encoded by this human oncogenic ␥1-herpesvirus. However, by employing bioinformatics, we recognized that the previously established EBV open reading frame BILF1 indeed encodes a GPCR. Additionally, BILF1 is a member of a new family of related GPCRs exclusively encoded by ␥1-herpesviruses. Expression of hemagglutinin-tagged BILF1 in the HEK293 epithelial cell line revealed that BILF1 is expressed as an approximately 50-kDa glycosylated protein. Immunocytochemistry and confocal microscopy revealed that BILF1 localizes predominantly to the plasma membrane, similar to the localization of KSHV ORF74. Using chimeric G proteins, we found that human and rhesus EBV-encoded BILF1 are highly potent constitutively active receptors, activating G␣ i . Furthermore, BILF1 is able to inhibit forskolin-triggered CREB activation via stimulation of endogenous G proteins in a pertussis toxin-sensitive manner, verifying that BILF1 signals constitutively through G␣ i . We suggest that EBV may use BILF1 to regulate G␣ i -activated pathways during viral lytic replication, thereby affecting disease progression.

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“…This constitutive activation cannot be further stimulated by chemokine binding to US28 (Bakker et al, 2004). However, coexpression of US28 with the human chemokine receptor CCR1 unmasks the activation of NF-B transcription factors in response to CCL5 (Bakker et al, 2004).…”

Section: Signaling Cross-talkmentioning

confidence: 99%

“…Hence, CCL5 binding to CCR1 induces NF-B activation in a pertussis toxin-sensitive manner via G␣ i/o proteins. However, this CCR1-mediated activation of NF-B signaling is strictly dependent on the constitutive activity of US28, because the signaling-impaired US28 mutant R 129 A failed to reveal this CCL5-induced signaling (Waldhoer et al, 2003;Bakker et al, 2004). Whether this effect of the constitutively active US28 on CCR1 signaling involves direct physical interactions between these GPCRs or is at the level of intracellular signal networks is currently under investigation.…”

Section: Signaling Cross-talkmentioning

confidence: 99%

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Herpesvirus-Encoded G Protein-Coupled Receptors as Modulators of Cellular Function

Maussang¹,

Vischer²,

Leurs³

et al. 2009

Mol Pharmacol

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Human herpesviruses (HHVs) are widespread pathogens involved in proliferative diseases, inflammatory conditions, and cardiovascular diseases. During evolution, homologs of human chemokine receptors were integrated into the HHV genomes. In addition to binding endogenous chemokines, these viral G protein-coupled receptors (vGPCRs) have acquired the ability to signal in a constitutive manner. Ligand-induced and ligandindependent and autocrine and paracrine signaling properties of vGPCRs modify the functions of the expressing cells and lead to transformation and escape from immune surveillance. Furthermore, cross-talk or heterodimerization with endogenous chemokine receptors represent other ways for vGPCRs to modify intracellular signaling and cellular functions. As such, these viral receptors seem to play a prominent role during viral pathogenesis and life cycle and thus represent innovative antiviral therapies.G protein-coupled receptors (GPCRs) are essential mediators of cellular communication. Their cell surface expression allows easy access and activation by their extracellular ligands to initiate intracellular signaling cascades. The physiological role of GPCR activation ranges from gene transcription to cellular migration and proliferation. Besides being activated by their cognitive ligands, GPCRs can signal independently from ligand activation. This so-called constitutive activity is the molecular basis of various pathologies (Smit et al., 2007). It is noteworthy that, during evolution, human herpesviruses (HHV) of the ␤ and ␥ families hijacked human GPCR while coexisting with their host (Brunovskis and Kung, 1995). These viral GPCRs (vGPCRs) show considerable homology to chemokine receptors, which are essential in the development of the hematopoietic system and regulation of cellular homeostasis (Mackay, 2001). In addition, chemokine receptors play a prominent role in cancer development (e.g., by inducing cellular proliferation or by modifying cellular migration patterns), resulting in cancer metastasis (Balkwill, 2004). Although human chemokine receptors require ligand activation to exert a physiological function, most of the vGPCRs show high levels of constitutive activity (Vischer et al., 2006b). As for human GPCRs, the constitutive modulation of signaling pathways by vGPCRs may play a role in the development of HHV-related diseases. As such, these vGPCRs may serve as therapeutic targets for the intervention of viral pathogenesis. ␥-Herpesvirus-Encoded G Protein-Coupled ReceptorsThe Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) and the Epstein-Barr virus (EBV or HHV-4) are lymphotropic viruses that are involved in proliferative dis- Article, publication date, and citation information can be found at

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Constitutively active Gq/11-coupled Receptors Enable Signaling by Co-expressed Gi/o-coupled Receptors

Cited by 54 publications

References 66 publications

Human cytomegalovirus-encoded chemokine receptor US28 promotes tumorigenesis

Human cytomegalovirus-encoded chemokine receptor US28 promotes tumorigenesis

Epstein-Barr Virus-Encoded BILF1 Is a Constitutively Active G Protein-Coupled Receptor

Herpesvirus-Encoded G Protein-Coupled Receptors as Modulators of Cellular Function

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