EPIDERMAL GROWTH FACTOR-RELATED PEPTIDES ACTIVATE DISTINCT SUBSETS OFERBB RECEPTORS AND DIFFER IN THEIR BIOLOGICAL-ACTIVITIES

Numerous epidermal growth factor (EGF)-related peptide binding members of the ErbB family of receptor tyrosine kinases have been described. While several EGF agonists bind and activate ErbB-1/EGF receptor, neu differentiation factor (NDF) functions as a ligand for ErbB-3 and ErbB -4. However, it is currently unknown which specific subsets of ErbB re ceptors become activated in response to each of these ligands. The pre sent study addresses this issue using the T47D breast tumor cell line, which expresses moderate levels of all the presently known ErbB recep tors. We show that all the EGF agonists, but not NDF, stimulated tyros ine phosphorylation of ErbB-1. In contrast, all the EGF-related factor s except amphiregulin were able to induce tyrosine phosphorylation of ErbB-2. The ability to induce tyrosine phosphorylation of ErbB-3 varie d dramatically among the different EGF-related peptides. While EGF, tr ansforming growth factor (TGF)-alpha, and amphiregulin only had a mode rate effect, NDF dramatically increased the ErbB-3 phosphotyrosine con tent. Most notably, heparin binding EGF-related growth factor (HB-EGF) and betacellulin (BTC) were more effective than other EGF agonists. C onsequently, only NDF, HB-EGF, and BTC significantly stimulated associ ation of phosphatidylinositol kinase activity with ErbB-3. Among the E GF agonists, HB-EGF induced a low level of ErbB-4 tyrosine phosphoryla tion, while BTC was as efficient as NDF in activating ErbB-4. The BTC activation of ErbB-4 appears to be independent of ErbB-1, as shown by pretreatment of cells with an antibody that inhibits binding of EGF ag onists to ErbB-1. As a result of the differential activation of ErbB r eceptors, most of the EGF-related growth factors had distinguishable b iological activities on cultured mammary epithelial cell lines.