The laboratory is interested in determining the mechanism of action of viral oncogenes, with the belief that these studies will provide new insight into signal transduction and the control of cell proliferation. For many years, we have studied the E5 oncoprotein of bovine papillomavirus (BPV), a small DNA tumor virus closely related to the human papillomaviruses that cause a variety of human cancers. The forty-four amino acid BPV E5 protein is the shortest protein known to cause tumorigenic transformation of cells . In transformed cells, the E5 protein exists as a dimeric transmembrane protein with a very hydrophobic central domain that spans the membranes of the Golgi apparatus and endoplasmic reticulum (Figure E5.1).

We showed that the E5 protein specifically binds to and activates the platelet-derived growth factor ß receptor, a cellular transmembrane receptor tyrosine kinase that normally transduces signals from PDGF, a soluble ligand. The E5/PDGF receptor interaction results in growth stimulation and tumorigenic transformation of cells. These findings demonstrated that receptor tyrosine kinases can be activated by proteins that do not resemble their normal ligands. We also showed that direct interactions involving specific transmembrane and juxtamembrane amino acids in the E5 protein and the PDGF ß receptor result in dimerization and trans-phosphorylation of the receptor, and recruitment of cellular signaling molecules into a signal transduction complex. Thus, the E5 protein acts as a specific, intramembrane crosslinker of the PDGF ß receptor (Figure E5.2). We are conducting genetic and biochemical experiments to define the structure of this unique complex, in the belief that it will provide new insight into the assembly of transmembrane protein complexes in general. Experiments are also underway to determine whether the same intracellular pathways are mobilized when the PDGF ß receptor is activated by PDGF, by the E5 protein, or by activating mutations in the receptor.

Figure E5.2 Schematic model of PDGF ß receptor activated by PDGF (left) and by the BPV E5 protein (right). The horizontal lines represent the lipid bilayer of cell membranes.