EGF & Receptor Background

EGF (Epidermal Growth Factor) Domain
Structurally, the EGF (Epidermal Growth Factor) domain is typically described as a small domain of 30–40 amino acids primarily stabilized by three disulfides with disulfide connectivity ababcc. The EGF domain consists of two β-sheets, usually referred to as the major (N-terminal) and minor (C-terminal) sheets. The half-cystines of the abc motif are arranged in a triangle on the major sheet. It is suggested that EGF-like domains in laminin, in other ECM proteins and in the extracellular portions of some membrane proteins are signals for cellular growth and differentiation. Because they are integral parts of large molecules and often of supramolecular assemblies these domains are well suited to stimulate neighboring cells in a specific and vectorial way. Learn more.

EGF (Epidermal Growth Factor) Molecular Weight
EGF (Epidermal Growth Factor) is a low-molecular-weight polypeptide. The molecular weight (MW) of EGF is approximately 6,400 daltons. However, in crude homogenates of the submaxillary gland of the male mouse, EGF exists almost entirely in a high molecular weight complex (about 74,000 daltons). This high molecular weight form may be reversibly dissociated into EGF and a protein of molecular weight 29,000. This EGF-binding protein is an esterase with an apparent high degree of specificity for arginine esters. Learn more.

EGF (Epidermal Growth Factor) Structure
The crystal structure of human epidermal growth factor (EGF) has been determined at pH 8.1. There are two human EGF molecules A and B in the asymmetric unit of the crystals, which form a potential dimer. Importantly, a number of residues known to be indispensable for EGF binding to its receptor are involved in the interface between the two EGF molecules, suggesting a crucial role of EGF dimerization in the EGF-induced dimerization of receptors. In addition, the crystal structure of EGF shares the main features of the NMR structure of mouse EGF determined at pH 2.0, but structural comparisons between different models have revealed new detailed features and properties of the EGF structure. Learn more.

EGF (Epidermal Growth Factor) and Cancer
Growth factors and their transmembrane receptor tyrosine kinases play important roles in cell proliferation, survival, migration and differentiation. One group of growth factors, comprising epidermal growth factor (EGF)-like proteins and neuregulins, stimulates cells to divide by activating members of the EGF receptor (EGFR) family, which consists of the EGFR itself and the receptors known as HER2-4. This highly conserved signalling module plays a fundamental role in the morphogenesis of a diverse spectrum of organisms, ranging from humans to nematodes, and has also been implicated in the development and growth of many types of human tumour cells. In humans, more than 30 ligands and the EGFR family of four receptors lie at the head of a complex, multi-layered signal-transduction network. Different activated receptor-ligand complexes vary in both the strength and type of cellular responses that they induce. Analysis of the multiple processes that modulate EGFR signal transduction, such as receptor heterodimerisation and endocytosis, has revealed new therapeutic opportunities and elucidated mechanisms contributing to the efficacy of existing anticancer treatments. Learn more.

EGF (Epidermal Growth Factor) Stimulation
In general, binding of its ligand, epidermal growth factor (EGF), results in stimulation of the EGFR tyrosine kinase, which in turn stimulates intracellular signal transduction, enhances transcription of growth related genes, and promotes cell growth. In vitro withdrawal of EGF leads to malignant transformation of human breast epithelial cell line HMT-3522, suggesting that EGF is important in the maintenance of normal cell phenotype. But in some tumor cell lines expressing high levels of EGFR, such as MDA-MB-468 breast cancer cells, EGF stimulation results in a decline in cell adhesion, apoptosis and inhibition of cell proliferation. In A431 epithelial carcinoma, low concentrations of EGF stimulate cell growth, while high concentrations inhibit proliferation in monolayer cultures. EGF is a potential growth stimulator of normal thyroid cells, but inhibits growth of the HTC-TSHr thyroid carcinoma cell line. Learn more.

EGF (Epidermal Growth Factor) Treatment
In the last two decades monoclonal antibodies (MAbs) which block activation of the EGFr and ErbB2 have been developed. These MAbs have shown promising preclinical activity and 'chimeric' and 'humanized' MAbs have been produced in order to obviate the problem of host immune reactions. Clinical activity with these antibodies has been documented: trastuzumab, a humanized anti-ErbB2 MAb, is active and was recently approved in combination with paclitaxel for the treatment of patients with metastatic ErbB2-overexpressing breast cancer; IMC-C225, a chimeric anti-EGFr MAb, has shown impressive activity when combined with radiation treatment and reverses resistance to chemotherapy. In addition to antibodies, compounds that directly inhibit receptor tyrosine kinases have shown preclinical activity and early clinical activity has been reported. A series of phase III studies with these antibodies and direct tyrosine kinase inhibitors are ongoing or planned, and will further address the role of these active anti-receptor agents in the treatment of patients with cancer. Learn more.

EGF (Epidermal Growth Factor) Inhibitor
In addition to antibodies which inhibit activation of the EGFr and ErbB2, compounds that directly inhibit receptor tyrosine kinases have shown preclinical activity and early clinical activity has been reported. A series of phase III studies with these antibodies and direct tyrosine kinase inhibitors are ongoing or planned, and will further address the role of these active anti-receptor agents in the treatment of patients with cancer. Learn more.

EGF & Receptor References
  1. Chen JX, et al. (2011) Involvement of c-Src/STAT3 signal in EGF-induced proliferation of rat spermatogonial stem cells. Mol Cell Biochem. 358(1-2):67-73.
  2. Guo Y, et al. (2012) Correlations among ERCC1, XPB, UBE2I, EGF, TAL2 and ILF3 revealed by gene signatures of histological subtypes of patients with epithelial ovarian cancer. Oncol Rep. 27(1):286-92.
  3. Kim S, et al. (2012) Smad7 acts as a negative regulator of the epidermal growth factor (EGF) signaling pathway in breast cancer cells. Cancer Lett. 314(2):147-54.
  4. Chatterton RT Jr, et al. (2010) Breast ductal lavage for assessment of breast cancer biomarkers. Horm Cancer. 1(4):197-204.
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