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De novo selection of oncogenes

Significance Artificial proteins may have improved properties compared with proteins that arose during evolution, but approaches to construct active artificial proteins are cumbersome and often constrained by existing protein structures. Here, we used mouse cells to select proteins that formed tumors from a library of small transmembrane proteins with randomized hydrophobic amino acid sequences. The resulting oncoproteins lack amino acid sequences from any known protein and function by activating a cellular growth factor receptor. This approach can be used to generate structures not observed in nature, create prototypes for research and possibly clinical uses, and provide insight into cell biology, protein–protein interactions, and evolution. All cellular proteins are derived from preexisting ones by natural selection. Because of the random nature of this process, many potentially useful protein structures never arose or were discarded during evolution. Here, we used a single round of genetic selection in mouse cells to isolate chemically simple, biologically active transmembrane proteins that do not contain any amino acid sequences from preexisting proteins. We screened a retroviral library expressing hundreds of thousands of proteins consisting of hydrophobic amino acids in random order to isolate four 29-aa proteins that induced focus formation in mouse and human fibroblasts and tumors in mice. These proteins share no amino acid sequences with known cellular or viral proteins, and the simplest of them contains only seven different amino acids. They transformed cells by forming a stable complex with the platelet-derived growth factor β receptor transmembrane domain and causing ligand-independent receptor activation. We term this approach de novo selection and suggest that it can be used to generate structures and activities not observed in nature, create prototypes for novel research reagents and therapeutics, and provide insight into cell biology, transmembrane protein–protein interactions, and possibly virus evolution and the origin of life.