The oncoprotein ErbB2 is frequently overexpressed in human tumours, but no activating ErbB2-specific ligand has yet been identified. Here we analyse the catalytic and oligomeric behaviour of ErbB2 using phosphorylation-state-specific antibodies which distinguish kinase-active and -inactive ErbB2 receptor subsets. Heregulin-α (HRG) activates ErbB2 in G8/DHFR 3T3 cells by selectively inducing hetero-oligomerization with kinase-defective ErbB3, indicating that heterologous transphosphorylation is an unlikely prerequisite for ErbB2 activation. HRG also triggers association of epidermal-growth-factor receptors (EGFR) with a kinase-inactive ErbB2 subset while reducing EGFR association with active ErbB2. Similarly, EGF treatment of A431 cells induces concomitant hetero-oligomerization of active ErbB2 with inactive EGFR, of active EGFR with inactive ErbB2, and of inactive ErbB2 with kinase-defective ErbB3. These combinatorial patterns of ligand-dependent oligomerization suggest a multivalent model of receptor tyrosine kinase interaction in which liganded homodimers provide stable oligomerization interfaces for unliganded ErbB2 or other bystander receptors. We submit that ErbB2 may be physiologically activated via a ‘proxy ’ ligand-inducible heterotetrameric mechanism similar to that already established for transforming-growth-factor-β type I receptors.

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