DIMERIZATION OF THE P185(NEU) TRANSMEMBRANE DOMAIN IS NECESSARY BUT NOT SUFFICIENT FOR TRANSFORMATION

The neu proto-oncogene encodes a receptor tyrosine kinase (RTK). The o ncogenic allele neu (p185*) bears a glutamic acid for valine substitu tion at position 664 within the predicted transmembrane domain. We hav e used this mutant to explore the role of the transmembrane domain in signal transduction by RTKs. Analysis of a panel of neu proteins with second-site mutations in the transmembrane domain revealed a strong c orrelation of dimerization with transformation. Both dimerization and transformation are dependent on a domain formed by the amino acids Val 663-Glu664-Gly665 (VEG). However, movement of the VEG elsewhere within the transmembrane domain promoted weak dimerization but not transform ation, Epidermal growth factor receptor (EGFR)/neu chimeras were used to determine if mutations that disrupt activation by Glu664 affect hor mone-regulated signal transduction as well. These mutations (of Val663 and Gly665) did not affect regulation by EGF, Introduction of the kno wn transmembrane dimerization domain from Glycophorin A (GpA) stimulat ed dimerization, but was not sufficient for transformation. These resu lts indicate that dimerization is necessary but not sufficient for tra nsforming activity. The homologous wild-type domain, VVG, is not requi red for hormone-regulated signaling.