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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.[1][2][3]

EGFR is expressed on vascular endothelial cells, HeLa cells, conjunctiva cells, vascular and uterine smooth muscle cells, keratinocytes, amniotic cells, placental membranes, and normal skin fibroblasts. It is no surprise that many cancers have been associated with the upregulation of EGFR, and overexpression has been identified in the majority of solid tumors. Associated cancers include breast, head-and-neck, non-small cell lung and squamous cell lung cancers, renal cell, ovarian, colon, bladder, pancreatic cancer, and gliomas. While normal cells express 40,000 to 100,000 EGFR receptors, cancer cells may express up to 2,000,000 receptors. Stimulation of overexpressed EGFR receptors may contribute to cancer pathology by inducing cancer-cell proliferation while simultaneously blocking apoptosis, activating invasion and metastasis of hyperproliferative cells, and stimulating tumor-induced neovascularization. The degree of overexpression correlates with tumor progression, resistance to chemotherapy, and a poor prognosis. In addition to their role in cancer cells, EGFR overexpression has been implicated in neurodegenerative diseases. In Alzheimer disease, mutations in presenilin 1 (PS1) contribute to the pathophysiology of the disease. PS1 is also involved in the transportation and production of EGFR. Neurites in proximity to the neuritic plaques found in Alzheimer disease show strong EGFR immunoreactivity, and excess EGF is known to induce neuronal death. Although the precise mechanism of this relationship is unclear, recent research indicates a role for EGFR overexpression in neurodegenerative disease.[19]