EGF and NRG induce phosphorylation of HER3/ERBB3 by EGFR using distinct oligomeric mechanisms

Signaling by human epidermal growth factor receptor (HER) receptors relies on heteromeric interactions between four members of the family: EGF receptor, HER2, HER3, and HER4. These interactions remain remarkably poorly understood. Using super-resolution microscopy imaging and signaling assays, we demonstrate a rich scope of HER receptor organization patterns that are differentially influenced by ligands and coreceptor expression, resulting in unique phosphorylation signatures of HER receptors. We also show that there are fundamental differences in molecular mechanisms that govern HER receptor cross-activation, which do not always follow the canonical kinase dimerization mechanism. Our data underscore an emerging concept in the field that HER receptor signaling needs to be interpreted in the context of higher-order receptor oligomers, redefining the basic signaling unit relevant for receptor function.