Epidermal Growth Factor Egf Receptor Proteins


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 Epidermal Growth Factor Egf Receptor Proteins Background

Epidermal Growth Factor Family of Ligands
The epidermal growth factor (EGF) family is comprised of polypeptides that share significant sequence homology and are involved with regulation of cell replication, cell movement, and cell survival. The EGF family of ligands can be divided into two groups based on their binding specificities to the EGFR/ErbB family of receptor tyrosine kinases (ErbB1, ErbB2, ErbB3, and ErbB4). The first group consists of EGF, transforming growth factor-α (TGF-α), and amphiregulin (AR), which bind preferentially to the EGFR/ErbB1 receptor. The second group consists of heparinbinding EGF (HB-EGF), betacellulin (BTC), and epiregulin (EPR), which exhibit dual specificity for ErbB1 and ErbB4. When ligand binds to ErbB receptors, homo- and hetero-dimers are formed, leading to activation of the intrinsic kinase domain and subsequent phosphorylation of specific tyrosine residues in the kinase domain of the cytoplasmic tail.
EGF produces a variety of biological responses, including enhanced proliferation and differentiation of epithelial cells. The biological actions of EGF are mediated through specific binding to EGFR, which is distributed throughout the fetal and neonatal intestinal tract. The major sources of EGF for the developing neonate are maternal colostrum, milk, and saliva. In adulthood, the salivary glands are the major producers of EGF; however, the kidneys, Brunner’s glands of the duodenum, and Paneth cells of the proximal jejunum are also capable of producing endogenous EGF.

Epidermal Growth Factor Receptor
Epidermal growth factor receptor (EGFR/ErbB) is a receptor tyrosine kinase and is a member of four receptor tyrosine kinases, collectively known as EGFR receptors that include EGFR (ErbB1/Her1), ErbB2 (Her2/neu), ErbB3 (Her3), and ErbB4 (Her4). EGFR was first discovered in 1978 when epidermal growth factor (EGF) was noted to bind to the cell membrane resulting in phosphorylation of intracellular proteins. All of these receptors contain an extracellular ligand binding region (620 amino acids) and a membrane spanning α helix. Intracellular region consists of juxtamembrane region (45 amino acids), followed by a tyrosine kinase domain (270 amino acids) and carboxyterminal regulatory sequences (230 amino acids). The ligands that regulate EGFR receptors are called as the EGF agonists. EGFR is known to activate Ras to lead to MAPK/ERK activation, activate JAK/STAT pathways and also activate PI-3K/Akt. Activation of these pathways seems to be context-specific and leads to proliferation, migration, or differentiation of enterocytes.
The extracellular region (residues 1-620), which is responsible for binding growth factors such as EGF via a 1:1 stoichiometry as a receptor dimer, consists of four sub-domains (I, II, III, IV). In the inactive receptor monomer, cysteine-rich domains II and IV interact to hold the extracellular region in a “tethered” conformation. To activate the receptor, domains I and III act as the growth factor binding-site. EGFR growth factors are thought to bind the extracellular domain in a negatively cooperative manner (meaning that the first growth factor binding event lowers the binding affinity for the second growth factor binding site). The “tether” between domains II and IV is broken due to the resulting conformational change, allowing domain II to act as a “dimerization arm” by interacting with domain II of a second receptor. Domain IV also appears to mildly facilitate stabilization of the active dimer via interactions with domain IV of the second receptor. In this way, the extracellular domain of EGFR (and other ErbB family members) forms the active conformation entirely through receptor-receptor interactions, unlike other activated RTKs in which the growth factor mediates the dimeric interface.
Most (about 95%) of the unliganded EGFR exists in a compact autoinhibited or tethered conformation, in which domains II and IV form an intramolecular interaction or tether. In the remaining 5% of the unliganded molecules, this tether is broken, and the EGFR can adopt a range of untethered conformations. Ligand binds preferentially to untethered molecules, and interacts simultaneously with domains I and III, stabilizing the particular extended form in which domain II is exposed and the receptor can dimerize. Dimerization is entirely receptor- mediated and dominated by domain II interactions. Ligand induced signaling from the receptor tyrosine kinase of the EGFR family regulates many cellular processes including, cell proliferation, cell motility and differentiation. Perturbation in these cellular signals can lead to malignant transformation and correlation between various cancers and EGFR is confirmed. Deregulation of EGFR through antibodies like Cetuximab correlates with the decrease disease-free and overall survival.