The neu proto-oncogene encodes a receptor tyrosine kinase (RTK). The oncogenic allele neu* (p185*) bears a glutamic acid for valine substitution at position 664 within the predicted transmembrane domain. We have 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 correlation of dimerization with transformation. Both dimerization and transformation are dependent on a domain formed by the amino acids Val663-Glu664-Gly665 (VEG). However, movement of the VEG elsewhere within the transmembrane domain promoted weak dimerization but not transformation. Epidermal growth factor receptor (EGFR)/neu chimeras were used to determine if mutations that disrupt activation by Glu664 a ect hormone-regulated signal transduction as well. These mutations (of Val663 and Gly665) did not a ect regulation by EGF. Introduction of the known transmembrane dimerization domain from Glycophorin A (GpA) stimulated dimerization, but was not su cient for transformation. These results indicate that dimerization is necessary but not su cient for transforming activity. The homologous wild-type domain, VVG, is not required for hormone-regulated signaling.
The differences in workers who stayed at their shop compared to those who left, combined with the low asthma prevalence and high job turnover rate, all suggest that a healthy worker effect may exist in the auto body industry, and may in part account for the low prevalence of asthma noted in SPRAY and other cross-sectional studies of diisocyante workers.
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