ERBB-1 AND ERBB-2 ACQUIRE DISTINCT SIGNALING PROPERTIES DEPENDENT UPON THEIR DIMERIZATION PARTNER

The different epidermal growth factor (EGF)-related peptides elicit a diverse array of biological responses as the result of their ability t o activate distinct subsets of ErbB receptor dimers, leading to the re cruitment of different intracellular signaling networks. To specifical ly examine dimerization-dependent modulation of receptor signaling, we constructed NIH 3T3 cell lines expressing ErbB-1 and ErbB-2 singly an d in pairwise combinations with each other ErbB family member. This mo del system allowed the comparison of EGF-activated ErbB-1 with ErbB-1 activated by Neu differentiation factor (NDF)-induced heterodimerizati on with ErbB-4. In both cases, ErbB-1 coupled to the adaptor protein S hc, but only when activated by EGF was it able to interact with Grb2. Compared to the rapid internalization of EGF-activated ErbB-1, NDF-act ivated ErbB-1 showed delayed internalization characteristics. Furtherm ore, the p85 subunit of phosphatidylinositol kinase (PI3-K) associated with EGF-actavated ErbB-1 in a biphasic manner, whereas association w ith ErbB-1 transactivated by ErbB-4 was monophasic. The signaling prop erties of ErbB-2 following heterodimerization with the other ErbB rece ptors or homodimerization induced by point mutation or monoclonal anti body treatment were also analyzed. ErbB-2 binding to peptides containi ng the Src homology 2 domain of Grb2 or p85 and the phosphotyrosine bi nding domain of Shc varied according to the mode of receptor activatio n. Finally, tryptic phosphopeptide mapping of both ErbB-1 and ErbB-2 r evealed that receptor phosphorylation is dependent on the dimerization partner. Differential receptor phosphorylation may, therefore, be the basis for the differences in the signaling properties observed.