TRANSFORMATION AND ALTERED SIGNAL-TRANSDUCTION BY A NATURALLY-OCCURRING MUTANT EGF RECEPTOR

An amino-truncated variant form of the epidermal growth factor recepto r (EGFRvIII) has been identified in human brain, breast, lung and ovar ian tumors, We have found that overexpression of this mutant EGF recep tor in NIH3T3 cells results in transformation as a result of the activ ation of the receptor kinase via ligand-independent dimerization, Tran sformation was correlated with tyrosine phosphorylation of only a subs et of the proteins observed in cells overexpressing the normal EGF rec eptor. This suggested that further studies on cells expressing the EGF RvIII might provide insights into the pathways most relevant to transf ormation, In clones expressing high levels of mutant EGF receptor, the levels of both Grb2 and SHC were decreased, Despite this decrease, mu ch of the endogenous Grb2 immunoprecipitated with EGFRvIII, Interestin gly, no increase in ras-GTP loading was found in clones expressing the EGFRvIII and MAP kinase assays indicated only a small increase in act ivity, These results indicate that high-level expression of the EGFRvI II induces downregulation of the ras-MAP kinase pathway and that other components involved in EGF receptor signal transduction may play a gr eater role in neoplastic transformation by the EGFRvIII.