Small transmembrane protein inhibitors of the platelet-derived growth factor β receptor (LB215)

The platelet-derived growth factor β receptor (PDGFβR) tyrosine kinase has been implicated in several cancers and is normally activated by binding of ligand to its extracellular domain. In addition, the small E5 transmembrane protein of bovine papillomavirus transforms cells by binding to the transmembrane domain of the PDGFβR and inducing receptor dimerization and activation. By screening retroviral libraries expressing hundreds of thousands of small proteins with randomized transmembrane domains, we identified artificial small transmembrane proteins termed “traptamers”, which specifically activate the PDGFβR and transform cells even though they have little or no sequence similarity to E5. A single conservative amino acid substitution in two traptamers converts them into inhibitors of the PDGFβR. The mutant traptamers bind to the PDGFβR and inhibit the mitogenic and transforming effects of PDGF and its homologue v-sis by preventing phosphorylation of the receptor at particular tyrosine residues, suggesti...