TRANSFORMATION SPECIFIC SIGNALING MEDIATED BY VERBS

禽红母细胞病病毒的v-erbB癌基因

DESCRIPTION: The v-erbB oncogene of the avian erythroblastosis virus encodes a truncated growth factor receptor with tyrosine kinase activity. Expression of this viral oncogene causes fibrosarcomas, erythroleukemias and hemangiosarcomas. Understanding the mechanisms of signal transduction by the v-ErbB oncoprotein will offer insights into tyrosine kinase signal transduction pathways, into the formation of transformation-specific multiprotein complexes, and has great potential to offer insights into the molecular biology of human malignancies. With these long-term goals in mind, the experiments outlined in this proposal will use well-characterized, transformation-specific, structural mutants of v-ErbB to dissect tyrosine kinase signaling pathways in transformed fibroblasts. This approach has already revealed the formation of a transformation-specific multiprotein signaling complex in v-ErbB transformed fibroblasts. This complex is composed of two signal adapter molecules (SHC and GRB2), a guanine nucleotide exchange factor (SOS), a tyrosine phosphorylated form of the cytoskeletal regulatory protein caldesmon, and a novel tyrosine phosphorylated protein (pp75). The hypothesis to be tested is that the oncogenic signals initiated by v-ErbB are transduced through the SHC-GRB2-SOS-caldesmon-pp75 complex, and that tyrosine phosphorylated caldesmon and pp75 participate in the regulation of anchorage-independent growth and tumorigenicity. The specific aims of this study are to (I) determine the mechanism of association of caldesmon with the multiprotein complex, (ii) define the functional role of caldesmon in v-ErbB mediated transformation, and (iii) characterize the novel 75 kd tyrosine phosphorylated protein in this signaling complex.