Analyses of 11 new erbB transducing viruses had previously correlated differences in disease potential with deletions or truncations in sequences encoding the carboxy-terminal domain of the chicken EGF receptor. erbB sequences of two of these viruses, one inducing only erythroblastosis (AEV-5005) and the other inducing only angiosarcoma (AAV-5005), were molecularly cloned. Sequence analysis confirmed the presence of an internal deletion in AAV-5005. The deletion was found to be inframe and to have removed 177 nucleotides. The deleted sequence had encoded a region between the kinase domain and the autophosphorylation sites of the EGF receptor. To establish that the deletion was responsible for the change in disease potential two recombinant viruses were constructed. One recombinant virus (srE) contained erbB sequences from AEV-5005. The other recombinant virus (srE/A) was identical to srE except that a restriction fragment from AAV-5005 which contained the deletion was substituted for the homologous fragment of AEV-5005. The srE virus induced only erythroblastosis, while the srE/A virus induced angiosarcoma as well as erythroblastosis. This demonstrated that the deletion was sufficient to induce angiosarcoma. Metabolic labelling did not reveal any difference in the expression or processing of these proteins and both became phosphorylated in an in vitro kinase assay. The biochemical basis for the difference in disease potential of these two related proteins remains to be determined.

Eleven recently isolated erbB-transducing viruses as well as avian erythroblastosis virus (AEV)-R (ES4) and AEV-H have been characterized for the type of disease they cause, their ability to transform fibroblasts in culture, their ability to cause disease in pedigrees of chicken that differ in susceptibility to erbB-induced erythroblastosis, and the structure of their erbB genes. Differences in each of the biological parameters correlated with differences in erbB sequences encoding the C-terminal domain of the epidermal growth factor receptor (EGFR). Seven viruses were strain restricted in their ability to induce erythroblastosis and did not transform fibroblasts. These seven viruses contained v-erbB genes encoding the complete C terminus of the EGFR. AEV-R and AEV-H were not pedigree restricted in their ability to induce erythroblastosis and could transform fibroblasts. These viruses contain v-erbB genes that lack codons for the immediate C terminus of the EGFR. Three viruses caused angiosarcoma and one caused fibrosarcoma. The angiosarcoma and fibrosarcoma-inducing viruses were not strain restricted and did not cause erythroblastosis. The v-erbB genes of each of these viruses contained extensive internal deletions or 3' truncations in sequences encoding the C-terminal domain of the EGFR.

Recently, 12 new transductions of c-erbB have been identified in a series of Rous-associated virus type 1-induced erythroleukemias. During the passage of these new transducing viruses it has become apparent that the erythroleukemia in chicken 5005 contained two different c-erbB transducing viruses. One induces erythroblastosis, whereas the second induces angiosarcoma. The angiosarcoma- and erythroblastosis-inducing viruses appear to have had a common ancestor, since tumors induced by each contain a novel, 4.3-kilobase c-erbB-related EcoRI fragment. The angiosarcoma-inducing virus has been named avian angiosarcoma virus and is designated for the chicken in which it originated.