>EGFR Signaling Pathway
EGFR Signaling Pathway
EGFR Signaling Background
EGF (epidermal growth factor) is the founding member of the EGF family of proteins, which also include Amphiregulin (AREG), Betacellulin (BTC), Epiregulin (EPR), HB-EGF, Neuregulins, and others. Members of epidermal growth factor family have highly similar structural and functional characteristics. They have at least one common structural motif, the EGF domain, which consists of six conserved cysteine residues forming three disulfide bonds. The main structure of EGF domain is a two-stranded beta-sheet followed by a loop to a C-terminal short two-stranded sheet. In addition to their EGF domain, the epidermal growth factor family members are characterized by two features: Production of mitogenic responses in EGF-sensitive cells, and high affinity binding to the EGF receptor.
The activity of epidermal growth factor family members is mediated by the epidermal growth factor receptor tyrosine kinases (EGFR/ErbB). Members of the EGFR/ErbB family are made up of an extracellular region or ectodomain that contains approximately 620 amino acids, a single transmembrane spanning region and a cytoplasmic tyrosine kinase domain. The extracellular domain of the EGF receptor is characterized by its capacity to bind EGF and EGF-like ligands with high affinity. Chemically this portion of the receptor contains 10-11 N-linked oligosaccharide chains, high content of half-cystine residues (10%) that could give rise to as many as 25 disulfides. The region between the two half-cystine-rich clusters is involved in ligand binding. The hallmark of the cytoplasmic portion of epidermal growth factor receptor is the sequence defining the tyrosine kinase domain. Near the carboxyl terminus of the receptor are four sites of EGF-dependent autophosphorylation.
Epidermal growth factor plays an important role in the regulation of cell growth, proliferation, and differentiation. EGF acts by binding to EGF receptor (EGFR) on the cell surface and stimulating the intrinsic protein-tyrosine kinase activity of the receptor, and initiates a signal transduction cascade. As a result a variety of biochemical changes take place within the cell, including increased intracellular calcium levels, glycolysis and protein synthesis and transcription of certain genes, which ultimately lead to DNA synthesis and cell proliferation. Members of epidermal growth factor family are known to be involved in tumor formation. The mediations of EGF therapy are so far mainly based on inhibiting the EGF receptor.