EGFR forms ligand-independent oligomers that are distinct from the active state.

The human Epidermal Growth Factor Receptor (EGFR/ERBB1) is a Receptor Tyrosine Kinase (RTK) that forms activated oligomers in response to ligand.  Much evidence indicates that EGFR/ERBB1 also forms oligomers in the absence of ligand, but the structure and physiological role of these ligand-independent oligomers remain unclear. To examine these features, we use fluorescence microscopy to measure the oligomer stability and FRET efficiency for homo- and hetero-oligomers of fluorescent protein-labeled forms of EGFR and its paralog, Human Epidermal Growth Factor Receptor 2 (HER2/ERBB2) in vesicles derived from mammalian cell membranes. We observe that both receptors form ligand-independent oligomers at physiological plasma membrane concentrations.  Mutations introduced in the kinase region at the active state asymmetric kinase dimer interface alter but do not affect the stability of ligand-independent EGFR oligomers.  These results indicate that ligand-independent EGFR oligomers form using interactions that are distinct from the EGFR active state.