Epidermal Growth Factor (EGF) Receptor (EGFR, HER-1, c-ErbB-1) is a member of the Epidermal Growth Factor Receptor family of Receptor Tyrosine Kinases. These cell surface receptors play an important role in the flow of information from the outside of a cell to the inside. Upon binding of EGF to the extracellular domain, the receptor undergoes dimerization and becomes phosphorylated on several tyrosine residues within the cytoplasmic domain. This results in EGFR activation and increased tyrosine kinase activity toward a variety of intracellular substrates. Autophosphorylation of tyrosine 845, 992 and 1173 are critical to EGFR signaling. Phosphorylation at tyrosine 992 creates a direct binding site for phospholipase C-g (PLC-g). PLC-g binding to EGFR (Y992) results in the activation of protein kinase C and the subsequent activation of downstream signaling cascades. Phosphorylation at 1173 creates a major binding site for the protein tyrosine phosphatase SHP-1, which can dephosphorylate the EGFR and thereby block EGFR-induced activation of the ERK1/2 signaling pathway. Tyrosine 845 phosphorylation is mediated by integrin engagement and Src, and regulates receptor function and tumor progression. Aberrant regulation of EGFR signaling has been associated with many types of cancer including mammary, ovarian, non-small cell lung, glioblastoma, prostate, pancreas and head and neck. Thus, methods to rapidly quantify receptor activation are in high demand.

The Epidermal Growth Factor Receptor (EGFR, HER-1, c-ErbB-1) is a 170 kDa member of the Epidermal Growth Factor (EGF) Receptor family of Receptor Tyrosine Kinases (RTKs) which includes ErbB-2 (Her2/neu), ErbB-3 (HER3) and ErbB-4 (HER4). These cell-surface receptors are glycoproteins comprised of an extracellular ligand-binding domain, a single transmembrane domain and an intracellular domain with ligand-activated tyrosine kinase activity. These proteins modulate critical cellular processes such as mitogenesis, cell death, angiogenesis and cell differentiation.

Proteins of the EGFR family of RTKs are activated by ligand binding. This results in receptor dimerization, autophosphorylation, activation of downstream signaling molecules and ultimately, lysosomal degradation of the receptor. Natural ligands that activate EGFR are EGF and TGF-alpha.

EGFR activity is modulated to a large extent through phosphorylation of several phosphorylation and autophosphorylation sites. Autophosphorylation at Tyr992 creates a direct binding site for the SH2 domain of phospholipase C-g (PLC-g). PLC-g binding to EGFR Y992 results in the activation of protein kinase C (PKC) and subsequent activation of the MAP kinase/ERK signaling cascades. These cascades in turn regulate a variety of proteins, including cytosolic proteins involved in protein translation and nuclear proteins such as the transcription factors Elk-1, c-Jun, STAT1 and 3, Ets-1, c-Myc, ER, CREB and PPARg. Phosphorylation at Tyr1173 permits binding of the N-terminal SH2 domain for the protein tyrosine phosphatase SHP-1. SHP-1 has the capacity to activate the cytoplasmic tyrosine kinase c-Src by dephosphorylation of the inhibitory phosphotyrosine at the C-terminus, an event that may be related to SHP-1-dependent activation of the MAP kinase cascade. Tyrosine 845, a major autophosphorylation site in EGFR, is mediated by integrin engagement and Src, and regulates receptor function and tumor progression. Phosphorylation of Tyr845 in the kinase domain may stabilize the activation loop, maintain the enzyme in an active state and provide a binding surface for substrate proteins. c-Src is involved in phosphorylation of Tyr845.

Aberrant control of EGFR is implicated in development, progression and severity of several human cancers. For example, EGFR overexpression correlates with poor prognosis in breast, ovarian and head/neck cancers. Several mutant forms of the coding gene have also been found. DEGFR, a deletion mutation lacking exons 2-7, is most common and is associated with glioblastoma.

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