THE BOVINE PAPILLOMAVIRUS TYPE-1 E5 TRANSFORMING PROTEIN SPECIFICALLYBINDS AND ACTIVATES THE BETA-TYPE RECEPTOR FOR THE PLATELET-DERIVED GROWTH-FACTOR BUT NOT OTHER RELATED TYROSINE KINASE-CONTAINING RECEPTORS TO INDUCE CELLULAR-TRANSFORMATION

The 44-amino-acid E5 protein of bovine papillomavirus type 1 is a high ly hydrophobic protein which appears to transform cells through the ac tivation of growth factor receptors. To investigate the specificity of E5-growth factor receptor interactions required for mitogenic signali ng, we utilized a nontumorigenic, murine myeloid cell line (32D) which is strictly dependent on interleukin-3 (IL-3) for sustained prolifera tion in culture. This IL-3 dependence can be functionally substituted by the expression of a variety of surrogate growth factor receptors an d the addition of the corresponding ligand. Several receptor cDNAs for the alpha- and beta-type platelet-derived growth factor receptors [al pha PDGFR and beta PDGFR], the epidermal growth factor receptor, and t he colony-stimulating factor 1 receptor) were transfected into 32D cel ls constitutively expressing the E5 protein to test for IL-3-independe nt growth. Only beta PDGFR war capable of abrogating the IL-3 dependen ce of 32D cells. The proliferative signal induced by the coexpression of beta PDGFR and E5 was accompanied by stable complex formation betwe en these proteins, constitutive tyrosine phosphorylation of the recept or, and tumorigenicity in nude mice. The lack of cooperative interacti on between E5 and the epidermal growth factor receptor, the colony-sti mulating factor 1 receptor, and the highly related a PDGFR was paralle led by the inability of E5 to bind to these receptors and failure to i ncrease receptor tyrosine phosphorylation. Thus, these data indicate t hat the ability of ES to induce sustained proliferation and transforma tion of 32D cells is a direct consequence of specific interaction betw een the E5 protein and the beta PDGFR signaling complex and the subseq uent stimulation of receptor tyrosine phosphorylation.