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

Meike Burger1, Tanja Hartmann, Jan A Burger

  • 1Department of Internal Medicine, Freiburg University Hospital, Freiburg, Germany. burgerm@mm11.uk1.uni-freiburg.de

Oncogene
|February 3, 2005
PubMed

Insights

Kaposi's sarcoma herpesvirus GPCR and its human homolog CXCR2 transform cells via JAK2-STAT3 signaling. This pathway is crucial for cell transformation, migration, and angiogenesis, offering potential therapeutic targets for Kaposi's sarcoma.

Area of Science:

  • Oncology
  • Virology
  • Cell Biology

Background:

  • Kaposi's sarcoma herpesvirus (KSHV) encodes KSHV-GPCR, a constitutively active G-protein-coupled receptor driving Kaposi's sarcoma.
  • The human homolog CXCR2 can also transform cells upon continuous stimulation or constitutive activation.
  • STAT3 activation is implicated in cellular transformation and oncogenesis.

Purpose of the Study:

  • To investigate the role of STAT3 activation in KSHV-GPCR and CXCR2-mediated cell transformation.
  • To determine if the JAK2-STAT3 pathway mediates the transforming and migratory functions of KSHV-GPCR and CXCR2.

Main Methods:

  • Transfection of NIH 3T3 cells with KSHV-GPCR, CXCR2, or a constitutively active CXCR2 mutant (D138V).
  • Assessment of STAT3 phosphorylation (Tyr705) in transfected cells and human microvascular endothelial cells (HMEC).
  • Inhibition of JAK2 using AG490 to evaluate its effect on cell transformation, migration, and angiogenesis.

Main Results:

  • STAT3 activation (constitutive or IL-8 stimulated) was a prerequisite for transformation in KSHV-GPCR and CXCR2 expressing cells.
  • JAK2 inhibition by AG490 blocked focus formation in NIH 3T3 cells.
  • AG490 also inhibited CXCR2-mediated functions like actin stress fiber formation, haptotaxis, and angiogenesis in HMEC.

Conclusions:

  • The transforming capacity of KSHV-GPCR and CXCR2 is dependent on JAK2-STAT3 signaling.
  • JAK2-STAT3 pathway mediates key cellular functions involved in tumor development, metastasis, and angiogenesis.
  • Targeting the JAK2-STAT3 pathway may offer a therapeutic strategy for KSHV-associated malignancies and other cancers involving CXCR2.

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