Epidermal Growth Factor Receptor (EGFR): Revealing Activation and Signaling Mechanisms

Epidermal growth factor receptor (EGFR) is a cell-based signalling system, now a big player in molecular biology and oncology. It is a receptor tyrosine kinase, which is required for cell growth, survival and differentiation. EGFR is a transmembrane glycoprotein and one of four EGFR tyrosine kinase receptors. On signalling by its own ligand, EGFR autophosphorylates the receptor tyrosine kinase and fires off signal transduction pathways to control cell growth, differentiation and survival.

EGFR is not a feature of healthy cells, but in many cancer cell lines, EGFR is activated exogenously, leading to poor prognosis and low traceability. EGFR also regulates the failure of cancer cells to take up chemo and radiation.

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Epidermal Growth Factor Receptor Family

There's a large family of receptors called the epidermal growth factor receptor (EGFR) family that are principally responsible for cell proliferation, differentiation and survival. The EGFR family is dotted throughout cells of all types and tissues, and an ingredient in most physiological and pathological events (including the onset and spread of cancer). These members make up the EGFR family:

Fig. 1 Schematic diagram of EGFR (Jorissen, R.; et al. 2003).

EGFR is a monomer made up of 1186 amino acids. It has two cysteine-rich regions in its extracellular part (CR I and CRII). DER and Let-23 have another CRIII domain. DER and ErbB1 share a total amino acid identity of 29% with human ErbB1 and Let-23 proteins, and 38% with DER. The phosphorylable amino acids in EGFR are specified.

Excitation of EGFR Cytoplasmic PTK Domain

The cytoplasmic region of EGFR has three regions:

• A juxtamembrane domain, needed for PKC feedback;
• A non-catalytic carboxyl-terminal tail with six tyrosine transphosphorylation sites for attracting adaptor/effector proteins such as Grb2 and phospholipase C (PLC), respectively, with either SH2 (src homology domain 2) or PTB (phosphotyrosine binding) domains, and motif that is important for receptor internalisation and degradation;
• A single central domain of tyrosine kinase (src homology domain 1 (SH1)), transphosphorylating six carboxyl-terminal tyrosine residues.

Epidermal Growth Factor Receptor Signaling

The EGFR is a classic, universal signal-transmitter with a very long evolutionary shelf life. It's involved in everything from cell fate determination, proliferation, cell movement, and apoptosis. EGFR is controlled by several positive and negative regulators and then transmitted to the nucleus via several conserved signaling boxes.

This EGFR family signaling usually drives multiple downstream signaling circuits including the PI3K/Akt circuit and Ras/Raf/ERK circuit via dimerization (two receptors become a dimer). They are involved in these signaling systems, and they regulate cell proliferation, survival, migration, and more, so the EGFR family has now been a key therapeutic area for tumors. Monoclonal antibodies and EGFR-targeting TKI, for instance, have become standard treatments for cancers from lung cancer to breast cancer.

Epidermal Growth Factor Receptor and Cancer

Uncontrolled EGFR signaling is common in most types of cancers. EGFR gene mutations, receptor overexpression, and signaling abnormalities result in cells proliferating uncontrolled and spreading beyond therapy. EGFR is one of the ErbB-type receptor tyrosine kinases (RTKs). These transmembrane proteins are engaged when they attach to peptide growth factors from the EGF family of proteins.

Overexpression of EGFR and EGF-like peptides is common in human cancers, and these proteins have been used in both in vitro and live experiments to cause cellular change. It's the ErbB proteins and ligands in this intricate mechanism, whereby the interplay between receptor and ligand determines what intracellular signals result from receptor activation, and how long they last. As proteins from the ErbB family bind to ligands, they are either homodimers or heterodimers, each one having a different affinity for the ligand and a different signaling activity.

EGFR regulates cell proliferation, survival, and metastasis, and it's a popular molecular target since disruption of its function disrupts signaling. EGFR overexpression marks cancer cells as different from normal cells so that EGFR inhibitory molecules can target tumor cells more specifically and suppress their proliferative activity. EGFR is one of the first major targets that these new anti-tumor drugs identified. More than half of cases of TNBC and inflammatory breast cancer (IBC) overexpress EGFR. So, EGFR inhibitors have been studied for breast cancer in a number of studies.

Conclusion

Clarification of all the steps that are launched by EGFR activation has demonstrated definitively that EGFR is important to cellular function and that abnormal levels of its expression in cancer cells can affect prognosis and survival. This information also gives us the foundations of rational anticancer drug development. The two most studied pharmacological mechanisms of EGFR inhibition to date have been monoclonal antibodies that inhibit ligand binding to the extracellular part of EGFR, and low molecular weight inhibitory molecules that inhibit intracellular phosphorylation of EGFR tyrosine kinase within cells. Since the locations and mechanisms of action of these EGFR inhibitors differ from those of classical cytotoxic drugs, when EGFR is combined with chemotherapy and radiotherapy, additive or synergistic anticancer effects with toxicities that typically do not differ from those of classical cytotoxic drugs are achieved.

References

1. Herbst, R.; et al. Review of epidermal growth factor receptor biology. International Journal of Radiation Oncology* Biology* Physics. 2004, 59(2): S21-S26.
2. Jorissen, R.; et al. Epidermal growth factor receptor: mechanisms of activation and signalling. The EGF receptor family. 2003: 33-55.