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 grow th factor (EGF)-related peptides in cell lines naturally expressing th e four :ErbB receptors, Down-regulation of cell surface ErbB-1 or ErbB -2 by intracellular expression of specific antibodies has allowed us t o 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 hete rodimerization 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 dimer ize 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 r ole in the lateral transmission of signals between other ErbB receptor s, 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 ow n ligands associates with and phosphorylates Cbl, These results provid e the first biochemical evidence that a given ErbB receptor has distin ct signaling properties depending on its dimerization.