The phosphatase Shp2 is required for signaling by the Kaposi's sarcoma-associated herpesvirus viral GPCR in primary endothelial cells.
Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), an AIDS-related endothelial cell malignancy that is the most common cancer in central and southern Africa. The KSHV viral G protein-coupled receptor (vGPCR) is a viral oncogene that conveys a survival advantage to endothelial cells and causes KS-like tumors in mouse models. In this study we investigate the role of Shp2, a protein tyrosine phosphatase in vGPCR signaling. Shp2 is vital to many cytokine-induced signaling pathways and is dysregulated in various infections and malignancies. It has also recently been implicated in angiogenesis. We find that vGPCR activity results in phosphorylation of regulatory tyrosines in Shp2 and that in turn, Shp2 is required for vGPCR-mediated activation of MEK, NFkappaB, and AP-1. Furthermore, both genetic and chemical inhibition of Shp2 abrogate vGPCR-induced enhancement of endothelial cell migration. This establishes Shp2 as an important point of convergence of KSHV vGPCR signaling and a potential molecular target in the design of an anti-KSHV therapeutic regimen.
Bakken
Thomas
T
The Department of Medicine, The University of Minnesota, 2001 6(th) St SE, MTRF Room 3-216, Minneapolis, MN 55455, USA.
He
Meilan
M
Cannon
Mark L
ML
D002460:Cell Line; D002465:Cell Movement; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000821:virology*; D019288:Herpesvirus 8, Human / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism
C115448:G protein-coupled receptor, Human herpesvirus 8; D016328:NF-kappa B; D019707:Receptors, Chemokine; D018808:Transcription Factor AP-1; D020930:MAP Kinase Kinase Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11