Contents - College of Medical and Dental Sciences - University of ...
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Contents - College of Medical and Dental Sciences - University of ...
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The 11 th International Workshop on KSHV & Related Agents, Birmingham, UK<br />
Virus-Cell Interactions II Abstract 63<br />
FAK AND SHP2 ARE REQUIRED FOR KSHV VGPCR SIGNALING<br />
Thomas Bakken*, Chris Bosh<strong>of</strong>f**, Mark Cannon*<br />
*CIDMTR, Department <strong>of</strong> Medicine, <strong>University</strong> <strong>of</strong> Minnesota, ** C.R.U.K. Viral Oncology<br />
Group, <strong>University</strong> <strong>College</strong> London<br />
Abstract<br />
The KSHV vGPCR is a constitutively active homologue <strong>of</strong> CXCR1 <strong>and</strong> CXCR2. It shows<br />
potential both in vitro <strong>and</strong> in vivo to contribute to the proliferative, angiogenic <strong>and</strong><br />
inflammatory components <strong>of</strong> KS biology. In transgenic mice, vGPCR causes KS-like<br />
tumors <strong>and</strong> potentiates the tumorgenicity <strong>of</strong> other viral proteins. These effects are likely<br />
a combination <strong>of</strong> direct vGPCR signaling <strong>and</strong> paracrine effects via vGPCR-induced<br />
elaboration <strong>of</strong> various growth <strong>and</strong> angiogenic factors. Inhibition <strong>of</strong> vGPCR function is a<br />
promising anti-KSHV strategy.<br />
We focus on identifying host cell pathways that are disrupted by vGPCR <strong>and</strong> could be<br />
targeted to interfere with vGPCR function. The protein phosphatase, Shp2, <strong>and</strong> the focal<br />
adhesion-associated kinase (FAK) are signal integration proteins with adaptor <strong>and</strong><br />
enzymatic functions. Up-regulation <strong>of</strong> both is associated with various malignancies.<br />
Furthermore, both are the target <strong>of</strong> newly developed pharmacologic inhibitors (FAK<br />
inhibition in particular has shown promise in a mouse ovarian cancer model). Using<br />
shRNA knock-down <strong>and</strong> pharmacologic inhibition in HEK293, we find that vGPCR<br />
activation <strong>of</strong> MEK requires both FAK <strong>and</strong> Shp2. vGPCR-induced NFκB <strong>and</strong> AP-1 activation<br />
are also FAK-dependent, although only the former requires Shp2. These studies are<br />
being taken into primary endothelial cells in which the role <strong>of</strong> Shp2 <strong>and</strong> FAK in vGPCRmediated<br />
signaling <strong>and</strong> phenotypic changes will be assessed.<br />
Interfering with pathways that are upregulated by vGPCR is a promising anti-KSHV<br />
approach. We have identified two signaling integration proteins that are receiving<br />
attention in the medicinal chemistry field <strong>and</strong> that are required for important vGPCRmediated<br />
events.<br />
Presenting author Email: canno101@umn.edu<br />
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