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.
Highlights
Specialty section: This article was submitted to Signaling, a section of the journal Frontiers in Cell and Developmental
One of the most intensely researched receptor tyrosine kinases (RTKs) families is that of the Epidermal Growth Factor Receptor (EGFR), which consists of four members, the archetypal epidermal growth factor receptor (EGFR), and ErbB2, ErbB3, and ErbB4
Whilst the structure, function and complex dimerisation mechanisms of this receptor family have been the subject of a number of seminal review papers (Rubin and Yarden, 2001; Yarden and Sliwkowski, 2001; Stern, 2003; Hubbard and Miller, 2007; Lemmon, 2009; Lemmon and Schlessinger, 2010), we will focus on the key aspects of the EGFR family necessary to appreciate the possibility and significance of this potential promiscuity
Summary
Receptor Tyrosine Kinases (RTKs) are cell surface receptors; all possessing an extracellular ligand binding domain, a single transmembrane domain and an intracellular tyrosine kinase domain (Lemmon and Schlessinger, 2010). RTKs are known to be key regulators of a diverse array of normal cellular functions including cellular metabolism, cell proliferation, migration and differentiation (Schlessinger, 2000) Given this central regulatory role, it is not surprising that mutation or atypical activation of RTKs has emerged as a driver of many diseases, including a variety of different cancers (Yarden and Sliwkowski, 2001; Stern, 2003; Lemmon and Schlessinger, 2010). One of the most intensely researched RTK families is that of the Epidermal Growth Factor Receptor (EGFR), which consists of four members, the archetypal EGFR, and ErbB2, ErbB3, and ErbB4 This family of receptors plays an important role in embryonal development of the nervous, gastrointestinal and cardiovascular system (Stern, 2003; Casalini et al, 2004). Whilst the structure, function and complex dimerisation mechanisms of this receptor family have been the subject of a number of seminal review papers (Rubin and Yarden, 2001; Yarden and Sliwkowski, 2001; Stern, 2003; Hubbard and Miller, 2007; Lemmon, 2009; Lemmon and Schlessinger, 2010), we will focus on the key aspects of the EGFR family necessary to appreciate the possibility and significance of this potential promiscuity
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