The papillomavirus E5 proteins are short, hydrophobic transforming proteins. The transmembrane E5 protein encoded by bovine papillomavirus transforms cells by activating the platelet-derived growth factor beta receptor tyrosine kinase in a ligand-independent fashion. The bovine papillomavirus E5 protein forms a stable complex with the receptor, thereby inducing receptor dimerization and activation, trans-phosphorylation, and recruitment of cellular signaling proteins to the receptor. The E5 proteins of the human papillomaviruses also appear to affect the activity of growth factor receptors and their signaling pathways. The interaction of papillomavirus E5 proteins with a subunit of the vacuolar ATPase may also contribute to transformation. Further analysis of these unique mechanisms of viral transformation will yield new insight into the regulation of growth factor receptor activity and cellular signal transduction pathways.