The Under-Appreciated Promiscuity of the Epidermal Growth Factor Receptor Family

Abstract

Each member of the epidermal growth factor receptor (EGFR) family plays a key role in normal development, homeostasis, and a variety of pathophysiological conditions, most notably in cancer. According to the prevailing dogma, these four receptor tyrosine kinases (RTKs; EGFR, ERBB2, ERBB3, and ERBB4) function exclusively through the formation of homodimers and heterodimers within the EGFR family. These combinatorial receptor interactions are known to generate increased interactome diversity and therefore influence signaling output, subcellular localization and function of the heterodimer. This molecular plasticity is also thought to play a role in the development of resistance toward targeted cancer therapies aimed at these known oncogenes. Interestingly, many studies now challenge this dogma and suggest that the potential for EGFR family receptors to interact with more distantly related RTKs is much greater than currently appreciated. Here we discuss how the promiscuity of these oncogenic receptors may lead to the formation of many unexpected receptor pairings and the significant implications for the efficiency of many targeted cancer therapies.

Keywords: EGFR; ERBB2; ERBB3; ERBB4; cancer; heterodimerisation; receptor tyrosine kinase; therapeutic resistance.

Figure 1

The EGFR receptor family. (A) A schematic showing the structure of the four EGFR family receptors (EGFR, ErbB2, ErbB3, and ErbB4), including the four domains within the extracellular region, the intracellular tyrosine kinase domain and the ligands specific to each receptor. EGFR, ErbB3, and ErbB4 are shown in the unliganded, “closed” conformation. (B) The conformational change associated with ligand binding, receptor dimerisation and formation of an allosteric kinase domain dimer.