activity, which leads to the phosphorylation of tyrosine residues in the intracellular domain of the receptors (van 1 Corresponding author der Geer et al., 1994). These serve as docking sites for a number of SH2-and PTB-domain containing proteins We have analyzed ErbB receptor interplay induced by (Kavanaugh and Williams, 1994;Cohen,G.B. et al., 1995 Riese et al. 1996); neu ErbB-2, suggesting that ErbB-2 has a role in the lateral differentiation factors (NDFs)/heregulins (Peles and transmission of signals between other ErbB receptors. Yarden, 1993), which are ligands of ErbB-3 and ErbB-4 Finally, ErbB-1 activated by all EGF-related peptides (Plowman et al., 1993b;, the (EGF, HB-EGF, BTC and NDF) couples to SHC, respective low and high affinity receptors (Tzahar et al., whereas only ErbB-1 activated by its own ligands 1994). associates with and phosphorylates Cbl. These results By binding to the ECD of their respective receptors, provide the first biochemical evidence that a given ErbB EGF-related peptides induce not only receptor homodimers receptor has distinct signaling properties depending on but also heterodimers. Consequently, although none of its dimerization.these peptides directly bind ErbB-2, all of them induce its

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