Spontaneous autoactivation of the EGF receptor induced by mutations in its C‐terminal negatively charged residues

The epidermal growth factor receptor (EGFR) plays a crucial role in the development of organisms, and its aberrant activation is frequently implicated in cancers. EGFR consists of an extracellular ligand binding domain and an intracellular tyrosine kinase domain, which are separated by a transmembrane alpha helix. An accumulating number of studies demonstrate that EGFR exists as a preformed, yet inactive, dimer prior to ligand binding. Consistently, the EGFR kinase domain has determined by crystallography to have a back‐to‐back homodimeric structure as an inactive form. In the crystals, the homodimeric structure was stabilized by the C‐terminal tails, which consist of negatively charged residues. In the present study, we have found that mutations of the negatively charged residues spontaneously activate the receptor without bound ligand, and transform NIH 3T3 cells in the absence of bound ligand. These results are consistent with the hypothesis that the C‐terminal tails play an essential role in stabilizing the EGFR homodimeric structure prior to ligand binding. Therefore, the finding further provides insights into an understanding of how the activity of EGFR is regulated during the development and in cancers.