LIGAND INDEPENDENT ONCOGENIC SIGNALING BY ERBB1

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Transformation by v-ErbB is correlated with the expression of both tissue-specific and transformation-specific phosphorylation events. Moreover, recent evidence suggests that there are qualitative differences between ligand-dependent vs. ligand-independent ErbB signalling pathways. On the basis of these studies, we propose that v-ErbB oncoproteins are not simply constitutively activated EGF-receptors, but rather that these mutant receptors are capable of sending unique and specifically oncogenic signals. In this regard, we have identified a novel, transformation-associated complex of tyrosine phosphoproteins in v-ErbB transformed fibroblasts. This complex is composed of the signal adapter proteins Shc and Grb2, the guanine nucleotide exchange factor Sos, a novel tyrosine phosphorylated form of the cytoskeletal regulatory protein caldesmon, as well as two novel tyrosine phosphorylated proteins (i.e., pp75 and pp72) with no known homologues based on primary sequence information. In this application we propose to focus much of our effort on a careful dissection of the functional role of this complex in v-ErbB-mediated fibroblast transformation. These studies will allow us to determine if components of this novel transformation-associated complex are required for v-ErbB mediated stress fiber disassembly and/or transformation. We believe this intensive analysis of v-ErbB-mediated oncogenic signalling is warranted, based on the extensive body of information available regarding the molecular basis of oncogenic activation of the avian receptor, the stringency of the biological tests to be used in these analyses (transformation of primary cells in culture, and tumorigenicity assays using an avian gene in avian tissues), and based on the premise that oncogenic (i.e., ligand-independent) ErbB1 signalling pathways may be qualitatively distinct from mitogenic (i.e., ligand-dependent) ErbB1 signalling pathways. The ErbB family of proto-oncogenes has been implicated in the etiology and progression of a variety of human malignancies, and the results of these studies may, therefore, have important implications for the diagnosis and treatment of certain human cancers.