Biochemistry, Epidermal Growth Factor Receptor

Excerpt

The epidermal growth factor receptor (EGFR) family is a subclass of receptor tyrosine kinase (RTK) proteins and consists of 4 members: EGFR (ErbB1, HER1), ErbB2 (HER2, neu in rodents), ErbB3 (HER3) and ErbB4 (HER4). EGFRs are single-chain transmembrane glycoproteins consisting of an extracellular ligand-binding extracellular domain, a transmembrane domain, a short juxtamembrane domain, a tyrosine kinase domain, and a tyrosine-containing C-terminal tail. The binding of soluble EGF ligands to the extracellular domain promotes receptor activation.

EGFR and ErbB4 are fully functional receptors that bind ligands and undergo autophosphorylation (ie, tyrosine kinase activation). ErbB2 has no known ligand but is the preferred dimerization partner for EGFR, ErbB3, and ErbB4. ErbB3 has no intrinsic tyrosine kinase activity but can transduce signals through interaction with kinase-active receptors such as EGFR, ErbB2, and ErbB4. Seven known ligands bind and activate EGFRs: EGF, transforming growth factor alpha (TGFa), Amphiregulin (Areg), Betacellulin (Btc), Epiregulin (Ereg), heparin-binding EGF-like growth factor (HB-EGF), and Epigen (Epgn). Tyrosine phosphorylation of receptors stimulates various signaling pathways, including Ras/MAPK, PLCγ1/PKC, PI(3)kinase/Akt, and STAT pathways. Aberrant expression of EGF ligands and hyperactivation of EGFRs due to mutations are implicated in many human diseases ranging from various human cancers to psoriasis, Alzheimer disease, and schizophrenia. The pathologies associated with EGFRs have led to novel treatment modalities, including monoclonal antibodies designed to inhibit EGFR signaling.