Abstract
The Epidermal Growth Factor Receptor (EGFR) is the prototypical receptor tyrosine kinase (RTK). These cell surface receptors are integral membrane proteins that bind ligands on their extracellular domain and relay that information to within the cell. The activated EGFR regulates diverse cell fates such as growth, proliferation, differentiation, migration, and apoptosis. These signaling properties are important for the appropriate development and maintenance of an organism. However, when inappropriately controlled, due to EGFR overexpression or hyperactivation, these signaling events are characteristic of many cancers. It remains unclear whether the uncontrolled EGFR activity leads to cell transformation or is a consequence of cell transformation. Regardless of the cause, increased EGFR activity serves both as a biomarker in the diagnosis of some cancers and is a molecular target for anti-cancer therapies. The promising results with current anti-EGFR therapies suggest that the receptor is a viable molecular target for a limited number of applications. However, to become an effective therapeutic target for other cancers that have elevated levels of EGFR activity, current approaches for inhibiting EGFR signaling will need to be refined. Here we describe the molecular mechanisms that regulate EGFR inactivation and discuss their potential as therapeutic targets for inhibiting EGFR signaling.
Highlights
The Epidermal Growth Factor Receptor (EGFR) is the prototypical receptor tyrosine kinase (RTK)
Tyrosine phosphorylation is the essential activation step in EGFR signal transduction as these residues serve as docking sites for downstream signaling molecules containing Src homology 2 (SH2) or phosphotyrosine binding (PTB) domains
Clinical and experimental data indicate that the EGFR is a viable target to inhibit the growth of non-transformed and transformed cells
Summary
The EGFR, or ErbB-1, is one of four members of the ErbB family that includes ErbB-2, ErbB-3 and ErbB-4 (Carpenter, 2003; Citri et al 2003). There are six unique endogenous ligands for the EGFR helping generate diverse signals: EGF, transforming growth factor α (TGF-α) heparinbinding EGF (HB-EGF), amphiregulin, betacellulin, and epireglin (Harris et al 2003). These ligands differ from one another in their regulated secretion, tissue distribution, and binding properties. One of which was mammary gland development when amphiregulin was knocked out in conjunction with TGFα or EGF (Luetteke et al 1999) These findings suggest there are complementary roles for these ligands and underscore the difficulty in understanding receptor physiology in the context of a whole animal.
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