EPIDERMAL GROWTH-FACTOR AND BETACELLULIN MEDIATE SIGNAL-TRANSDUCTION THROUGH COEXPRESSED ERBB2 AND ERBB3 RECEPTORS

Interleukin-3 (IL-3)-dependent murine 32D cells do not detectably expr ess epidermal growth factor receptors (EGFRs) and do not proliferate i n response to EGF, heregulin (HRG) or other known EGF-like ligands, He re, we report that EGF specifically binds to and can be crosslinked to 32D transfectants co-expressing ErbB2 and ErbB3 (32D.E2/E3), but not to transfectants expressing either ErbB2 or ErbB3 individually. [I-125 ]EGF-crosslinked species detected in 32D.E2/E3 cells were displaced by HRG and betacellulin (ETC) but not by other EGF-like ligands that wer e analyzed. EGF, ETC and HRG also induced receptor tyrosine phosphoryl ation, activation of downstream signaling molecules and proliferation of 32D.E2/E3 cells. 32D transfectants were also generated which expres sed an ErbB3-EGFR chimera alone (32D.E3-E1) or in combination with Erb B2 (32D.E2/E3-E1). While HRG stimulation of 32D.E3-E1 cells resulted i n DNA synthesis and receptor phosphorylation, EGF and ETC were inactiv e. However, EGF and ETC were as effective as HRG in mediating signalin g when ErbB2 was co-expressed with the chimera in the 32D.E2/E3-E1 tra nsfectant. These results provide evidence that ErbB2/ErbB3 binding sit es for EGF and ETC are formed by a previously undescribed mechanism th at requires co-expression of two distinct receptors. Additional data u tilizing MDA MB134 human breast carcinoma cells, which naturally expre ss ErbB2 and ErbB3 in the absence of EGFRs, supported the results obta ined employing 32D cells and suggest that EGF and ETC may contribute t o the progression of carcinomas that co-express ErbB2 and ErbB3.