ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling

We have analyzed ErbB receptor interplay induced by the epidermal growth factor (EGF)-related peptides in cell lines naturally expressing the four :ErbB receptors, Down-regulation of cell surface ErbB-1 or ErbB-2 by intracellular expression of specific antibodies has allowed us to delineate the role of these receptors during signaling elicited by: EGF and heparin binding EGF (HB-EGF), ligands of ErbB-1; betacellulin (ETC), a ligand of ErbB-1 and ErbB-4; and neu differentiation factor (NDF), a ligand of ErbB-3 and ErbB-4, Ligand-induced ErbB receptor heterodimerization follows a strict hierarchy and ErbB-2 is the preferred heterodimerization partner of all ErbB proteins, NDF-activated ErbB-3 or ErbB-4 heterodimerize with ErbB-1 only when no ErbB-2 is available, If ail ErbB receptors are present, NDF receptors preferentially dimerize with ErbB-2, Furthermore, EGF- and ETC-induced activation of ErbB-3 is impaired in the absence of ErbB-2, suggesting that ErbB-2 has a role in the lateral transmission of signals between other ErbB receptors, Finally, ErbB-1 activated by all EGF-related peptides (EGF, HB-EGF, ETC and NDF) couples to SHC, whereas only ErbB-1 activated by fits own ligands associates with and phosphorylates Cbl, These results provide the first biochemical evidence that a given ErbB receptor has distinct signaling properties depending on its dimerization.