Extracellular domains drive homo- but not hetero-dimerization of erbB receptors

Abstract

Many different growth factor ligands, including epidermal growth factor (EGF) and the neuregulins (NRGs), regulate members of the erbB/HER family of receptor tyrosine kinases. These growth factors induce erbB receptor oligomerization, and their biological specificity is thought to be defined by the combination of homo‐ and hetero‐oligomers that they stabilize upon binding. One model proposed for ligand‐induced erbB receptor hetero‐oligomerization involves simple heterodimerization; another suggests that higher order hetero‐oligomers are ‘nucleated’ by ligand‐induced homodimers. To distinguish between these possibilities, we compared the abilities of EGF and NRG1‐β1 to induce homo‐ and hetero‐oligomerization of purified erbB receptor extracellular domains. EGF and NRG1‐β1 induced efficient homo‐oligomerization of the erbB1 and erbB4 extracellular domains, respectively. In contrast, ligand‐induced erbB receptor extracellular domain hetero‐oligomers did not form (except for s‐erbB2–s‐erbB4 hetero‐oligomers). Our findings argue that erbB receptor extracellular domains do not recapitulate most heteromeric interactions of the erbB receptors, yet reproduce their ligand‐induced homo‐oligomerization properties very well. This suggests that mechanisms for homo‐ and hetero‐oligomerization of erbB receptors are different, and contradicts the simple heterodimerization hypothesis prevailing in the literature.