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

Abstract

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.

Inhibition of Heme Oxygenase-1 Interferes with the Transforming Activity of the Kaposi Sarcoma Herpesvirusencoded G Protein-coupled Receptor

“…In addition, p38␣ regulates AP-1 transcriptional activity (61), and this transcription factor also controls vGPCR-driven vegf promoter activity (15,24). Interestingly, very recent studies have shown that STAT3 is required by vGPCR to induce transformation (62) and by several other oncogenes to induce VEGF secretion (63). We have also found that [Ru(CO) 3 Cl 2 ] 2 induces AKT (data not shown), and this kinase and p38␣ are required by CO to induce STAT3 and protect endothelial cells from apoptosis (64).…”

Berberine hydrochloride IL-8 dependently inhibits invasion and IL-8-independently promotes cell apoptosis in MDA-MB-231 cells

“…IL-8 can activate PI3K, protein kinase B (PKB and Akt), mammalian target of rapamycin (mTOR), ERK1/2, p38 MAPK and JAK2 pathways to regulate numerous gene and protein expressions involved in cell proliferation, survival, invasion and migration (25,45). Activation of PI3K and JAK2 pathways has been reported to modulate cell invasion and angiogenesis (25).…”

CCR1-Mediated STAT3 Tyrosine Phosphorylation and CXCL8 Expression in THP-1 Macrophage-like Cells Involve Pertussis Toxin-Insensitive Gα14/16 Signaling and IL-6 Release

“…In human macrophages and macrophage-derived foam cells, CCL15 is capable of inducing the production of MMP-9 (27), whose expression is regulated by STAT3 (28), whereas CXCL8 is apparently involved in the recruitment of human NK cells to sites of early viral infection by mast cells (61) and metastasis of colon cancer (62). The release of CXCL8 activates CXCR2, which is coexpressed with CCR1 in macrophages (39) and human mast cells (63,64), leading to STAT3 Tyr 705 phosphorylation (65). Hence, the production of CXCL8 mediated by CCR1/Ga 14/16 may create another loop of STAT3 activation, which synergizes with the effect on CXCL8 secretion.…”