TRANSMEMBRANE SIGNALING IN VIRAL ONCOGENESIS

Albany Medical College, Albany NY

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Abstract

DESCRIPTION: The long range goal of this research is to assess the molecular mechanisms of cell growth transformation by viral transmembrane (TM) proteins as a means of investigating cell signaling through growth factor receptor tyrosine kinases. The interaction between the bovine papillomavirus E5 protein and the cellular beta receptor for platelet-derived growth factor (PDGF) will be used as a model for understanding mechanisms by which TM proteins alter the activity of growth factor receptors. In this application, the nature of the E5/PDGF receptor (PDGFR) interaction will be more clearly defined. Site-directed mutagenesis of the PDGFR followed by gene transfer experiments will be performed using heterologous cells which lack PDGFR. The information gained from these studies may reveal a role for small TM proteins in regulating the activity of growth factor receptors. The E5/PDGFR interaction promises to be a model for characterizing other TM viral oncoproteins and a useful tool for exploring the role of PDGFR signaling in tumorigenesis. Ligand-independent activation of the PDGFR can also be induced by replacing its TM domain with that of the p185neu* receptor. The mechanism by which this TM substitution activates the PDGFR will be explored by assessing dimerization status of the constitutively activated receptor, PR/neu*. PR/neu* may allow identification of novel PDGFR substrates and intracellular signaling pathways. Therefore, the components of the activated PR/neu* complex will be examined by biochemical and genetic assays.