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

Oncogene volume 24, pages 2067–2075 (2005)Cite this article

Abstract

The Kaposi’s sarcoma herpesvirus encodes a G-protein-coupled 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 Tyr705. 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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Acknowledgements

We are grateful to Barbara Rogalsky for excellent technical assistance. This paper was supported by the Deutsche Forschungsgemeinschaft (DFG) Grant No. BU/1159/3-1 (to MB), and NIH Grant HL55657 to IS.

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Authors and Affiliations

  1. Department of Internal Medicine, Freiburg University Hospital, Freiburg, Germany

    Meike Burger, Tanja Hartmann & Jan A Burger

  2. Department of Cancer Biology, La Jolla Institute for Molecular Medicine, San Diego, CA, USA

    Ingrid Schraufstatter

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Correspondence to Meike Burger.

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Burger, M., Hartmann, T., Burger, J. et al. KSHV-GPCR and CXCR2 transforming capacity and angiogenic responses are mediated through a JAK2-STAT3-dependent pathway. Oncogene 24, 2067–2075 (2005). https://doi.org/10.1038/sj.onc.1208442

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