POTENTIATION OF EPIDERMAL GROWTH-FACTOR RECEPTOR-MEDIATED ONCOGENESISBY C-SRC - IMPLICATIONS FOR THE ETIOLOGY OF MULTIPLE HUMAN CANCERS

c-Src is a nontransforming tyrosine kinase that participates in signal ing events mediated by a variety of polypeptide growth factor receptor s, including the epidermal growth factor receptor (EGFR). Overexpressi on and continual ligand stimulation of the EGFR results in morphologic al transformation of cells in vitro and tumor development in vivo, Ele vated levels of c-Src and the EGFR are found in a variety of human mal ignancies, raising the question of whether c-Src can functionally coop erate with the EGFR during tumorigenesis, To address this issue, we ge nerated c-Src/EGFR double overexpressors and compared their proliferat ive and biochemical characteristics to those of single overexpressors and control cells, We found that in cells expressing high levels of re ceptor, c-Src potentiated DNA synthesis, growth in soft agar, and tumo r formation in nude mice. Growth potentiation was associated with the formation of a heterocomplex between c-Src and activated EGFR, the app earance of a distinct tyrosyl phosphorylation on the receptor, and an enhancement of receptor substrate phosphorylation, These findings indi cate that c-Src is Capable of potentiating receptor-mediated tumorigen esis and suggest that synergism between c-Src and the EGFR may contrib ute to a more aggressive phenotype in multiple human tumors.