Constitutive Activation of NF-κB and Secretion of Interleukin-8 Induced by the G Protein-coupled Receptor of Kaposi's Sarcoma-associated Herpesvirus Involve Gα13 and RhoA

Shepard, Larry W.; Yang, Ming; Xie, Ping; Browning, Darren D.; Voyno-Yasenetskaya, Tatyana A.; Kozasa, Tohru; Ye, Richard D.

doi:10.1074/jbc.m104783200

Cited by 101 publications

(99 citation statements)

References 61 publications

(101 reference statements)

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“…Figures 1c-f show that vGPCR-induced AP-1, NFAT, and CREB activation is inhibited by small amounts of pcDNA3.1-a t (as little as 1/10th the amount of input transcription factor-luciferase reporter plasmid). In contrast to the work by Shepard et al (2001) in HeLa cells, vGPCR activation of NFkB is unaffected by pcDNA3.1-a t . Since it is now known that Gq proteins can signal via their bg subunits, it is possible that the dramatic inhibition of AP-1, CREB, and NFAT caused by a t signifies a contribution of both Gq and Gi proteins.…”

Section: Kshv Vgpcr Signals Via Both Gq and Gi In Pel Cells To Activacontrasting

confidence: 45%

The KSHV G protein-coupled receptor signals via multiple pathways to induce transcription factor activation in primary effusion lymphoma cells

Cannon

Cesarman

2004

Oncogene

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Section: Kshv Vgpcr Signals Via Both Gq and Gi In Pel Cells To Activacontrasting

confidence: 45%

The KSHV G protein-coupled receptor signals via multiple pathways to induce transcription factor activation in primary effusion lymphoma cells

Cannon

Cesarman

2004

Oncogene

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“…To further confirm the relationship between LGR5 and the G 12/13 -Rho pathway, we tested whether LGR5 regulates NF-κB reporter activity. NF-κB has long been known to be activated by the Rho pathway, although the underlying molecular mechanism remains unclear (Iguchi et al, 2008;Montaner et al, 1998;Perona et al, 1993;Shepard et al, 2001). As shown in Figs.…”

Section: Resultsmentioning

confidence: 99%

Leucine-Rich Repeat-Containing G-Protein Coupled Receptor 5/GPR49 Activates G12/13-Rho GTPase Pathway

Kwon

Park

Kim

et al. 2013

Molecules and Cells

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Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5/GPR49) is highly expressed in adult stem cells of various tissues, such as intestine, hair follicles, and stomach.LGR5 is also overexpressed in some colon and ovarian tumors. Recent reports show that R-spondin (RSPO) family ligands bind to and activate LGR5, enhancing canonical Wnt signaling via the interaction with LRP5/6 and Frizzled. The identity of heterotrimeric G-proteins coupled to LGR5, however, remains unclear. Here, we show that Rho GTPase is a downstream target of LGR5. Overexpression of LGR5 induced SRF-RE luciferase activity, a reporter of Rho signaling. RSPOs, ligands for LGR4, LGR5, and LGR6, however, did not induce SRF-RE reporter activity in the presence of LGR5. Consistently, LGR5-induced activity of the SRF-RE reporter was inhibited by Rho inhibitor C3 transferase and RhoA N19 mutant, and knockdown of Gα 12/13 genes blocked the reporter activity induced by LGR5. In addition, focal adhesion kinase, NF-κB and c-fos, targets of Rho GTPase, were shown to be regulated by LGR5. Here, we have demonstrated, for the first time, that LGR5 is coupled to the Rho pathway through G 12/13 signaling.

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“…Cells transfected with CXCR2 or KSHV-GPCR have been described to secrete higher levels of IL-8 (Shepard et al, 2001;Schraufstatter et al, 2003). Thus in tumors, which express CXCR2, the cascade from ELR chemokine activation to increased IL-8/gro a production may serve as an autocrine loop leading to continuous STAT3 activation that augments the motility and anchorage independent growth of the cancer cells.…”

Section: Kshv-gpcr and Cxcr2 Signal Through Jak2-stat3mentioning

confidence: 99%

KSHV-GPCR and CXCR2 transforming capacity and angiogenic responses are mediated through a JAK2-STAT3-dependent pathway

et al. 2005

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The Kaposi's sarcoma herpesvirus encodes a G-proteincoupled chemokine receptor termed KSHV-GPCR. Expression of this constitutively active GPCR leads to cell transformation and vascular overgrowth characteristic of Kaposi's sarcoma. Previously, we have shown that CXCR2, the closest human homolog, is similarly able to transform cells if continuously stimulated or constitutively activated by amino-acid exchange D138V of the DRY sequence. Here, we demonstrate that STAT3 activation is a prerequisite for transformation in KSHV-GPCR and CXCR2 transfected NIH 3T3 cells. In KSHV-GPCR and D138V transfected cells, STAT-3 is constitutively phosphorylated on Tyr 705 . In CXCR2 transfected NIH 3T3 cells and human microvascular endothelial cells (HMEC), which express the CXCR2 constitutively, STAT3 is phosphorylated upon stimulation with IL-8 (CXCL8). Focus formation in NIH 3T3 cells transfected with the KSHV-GPCR, CXCR2, or the D138V mutant, was blocked by the specific JAK2 inhibitor AG490. Typical functions of the CXCR2 including actin stress fiber formation, haptotaxis, and the angiogenic response in HMEC shown by tube formation in Matrigel were blocked by AG490. These data suggest that the transforming capacity and migratory responses that are involved in tumor development, metastasis, and angiogenesis in KSHV or CXCR2-expressing cells is at least partially mediated through a JAK2-STAT3 dependent pathway.

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Constitutive Activation of NF-κB and Secretion of Interleukin-8 Induced by the G Protein-coupled Receptor of Kaposi's Sarcoma-associated Herpesvirus Involve Gα13 and RhoA

Cited by 101 publications

References 61 publications

The KSHV G protein-coupled receptor signals via multiple pathways to induce transcription factor activation in primary effusion lymphoma cells

The KSHV G protein-coupled receptor signals via multiple pathways to induce transcription factor activation in primary effusion lymphoma cells

Leucine-Rich Repeat-Containing G-Protein Coupled Receptor 5/GPR49 Activates G12/13-Rho GTPase Pathway

KSHV-GPCR and CXCR2 transforming capacity and angiogenic responses are mediated through a JAK2-STAT3-dependent pathway

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