The EGF-receptor gene is amplified in 30-40% of malignant human gliomas. Some of them exhibit rearrangement of the EGF-receptor that deletes a portion of the extracellular domain. By analogy to the well- characterized oncogenic activation of chicken erbB/EGF-receptor gene in leukemia and sarcoma, the rearranged EGF-Rs in human gliomas are likely to carry constitutive kinase activity and are the underlying molecular basis for malignant transformation. The above findings strongly implicate EGF-receptor as one of the protooncogenes involved in the development of gliomas and astrocytomas. As EGF or TGF-alpha have diverse effects on different cell types, an understanding of the EGF- receptor mediated signal transduction in gliomas and astrocytes should provide knowledge about the transformation pathway. The PI's lab has been studying oncogenic activation of EGF-R and the tissue-specific transformation by erbB oncogenes. Using molecular genetics and tumor biology approaches, we wish to study (1) whether immortalized astrocytes can be transformed by various EGF-receptor mutants to directly test the hypothesis that EGF-R is the underlying oncogene of gliomas and astrocytomas. Other oncogenes will be tested as cooperating partners in the development of fully-malignant phenotype and (2) the EGF-receptor mediated signalling pathway in glial cells. Phosphorylation of defined and undefined substrates will be analyzed. The panel of EGF-receptor mutants will be used to dissect the pleiotropic pathway of EGF-receptor.
