Differences in sequences encoding the carboxyl-terminal domain of the epidermal growth factor receptor correlate with differences in the disease potential of viral erbB genes.

Abstract

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.

Protein tyrosine kinase activities of the epidermal growth factor receptor and ErbB proteins: correlation of oncogenic activation with altered kinetics.

“…Many also contain point mutations, truncations, or internal deletions in the cytoplasmic domain of the receptor. These mutations determine differences in the potential to induce erythroblastosis, angiosarcoma, hemangioma, or fibrosarcoma (7,21,22,24,27).…”

“…Many also contain point mutations, truncations, or internal deletions in the cytoplasmic domain of the receptor. These mutations determine differences in the potential to induce erythroblastosis, angiosarcoma, hemangioma, or fibrosarcoma (7,21,22,24,27).The tyrosine kinase activity of the EGFR is required for its mitogenic activity (28). Analysis of the transformation potential of a series of linker insertion mutations in ErbB suggests that kinase activity is required for transformation (20).…”

“…The first, AEV-5005 ErbB, represented a nonmutated, C-terminal complete ErbB that causes only erythroblastosis (7,27). The second, AAV-5005 ErbB, served as an example of an ErbB that transforms erythroid as well as endothelial cells (7,27). The ability of…”

Epidermal growth factor receptor cytoplasmic domain mutations trigger ligand-independent transformation.

“…Furthermore, during or after the recombination event, other structural alterations that include cytoplasmic C-terminal truncations, internal deletions, and point mutations were introduced into the virus-acquired CER sequences which differ among AEV strains (6,9,12,25,34,35). These alterations are likely to be responsible for the characteristic properties of distinct virus isolates with respect to pathogenic potential in vivo and transforming activity in cultured cells (3,12,25). Therefore, naturally selected v-erbB variants represent an excellent system with which to evaluate the structural basis for altered biochemical properties and biological signaling activities of growth factor receptor derivatives involved in a variety of distinct neoplastic phenotypes.…”

“…When compared with EGF receptor, the erbB proteins of all currently characterized AEV strains have lost most of their amino-terminal, extracellular ligand-binding domain, which is thought to result in constitutive activation of its cytoplasmic tyrosine kinase activity (6,9,25,34). Furthermore, during or after the recombination event, other structural alterations that include cytoplasmic C-terminal truncations, internal deletions, and point mutations were introduced into the virus-acquired CER sequences which differ among AEV strains (6,9,12,25,34,35). These alterations are likely to be responsible for the characteristic properties of distinct virus isolates with respect to pathogenic potential in vivo and transforming activity in cultured cells (3,12,25).…”