INHIBITION OF P185(NEU) KINASE-ACTIVITY AND CELLULAR-TRANSFORMATION BY COEXPRESSION OF A TRUNCATED NEU PROTEIN

The rat nea oncogene product encodes a 185 kDa receptor tyrosine kinas e which is constitutively activated as a result of a single amino acid substitution (Va1664-->Glu) within the transmembrane region. In this study, we show that the transforming activity of oncogenic p185(neu) ( also termed Tneu) can be inhibited by co-expression of a truncated nea protein with a large cytoplasmic deletion (termed T691stop) which inc ludes the tyrosine kinase domain. In cell lines co-expressing full-len gth and truncated nea proteins, we observed codimerization between ful l-length p185(neu) and truncated T691 stop, resulting in the formation of a kinase-inactive heteromeric complex. Phenotypic analysis of seve ral different clones showed that the degree of inhibition of transform ation in vitro and tumorigenicity in vivo was related to the ratio of full-length and truncated p185 proteins co-expressed in cells. These r esults provide evidence that expression of kinase-deficient nea protei ns leads to co-dimerization that results in suppression of kinase acti vation and oncogenicity of associated p185(neu)-activated receptors. T he mutant nea protein mediates inhibition in both transfected fibrobla sts expressing oncogenic p185(neu) and mammalian cancer cells derived from a rat primary neuroglioblastoma expressing oncogenic p185(neu). T his truncated peptide may be important for the design of future therap ies directed against erbB family oncoproteins.