Epidermal growth factor

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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Synonym(s)

EGF; epidermal growth factor; Epidermal growth factor

History
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The epidermal growth factor (EGF) was the first growth factor discovered. It was discovered in urine. This was also the original name "Urogastron".

Definition
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The Epidermal Growth Factor, or EGF for short, is a mitogenic, 6-kDa peptide growth factor that is an important signal molecule that activates the growth of epidermal and epithelial cells (Choi JS et al. 2008, Tanaka A et al. 2005, Hardwicke J et al. 2008). The Epidermal Growth Factor is the prototypical representative of a differentiated larger family of peptides that all act with different affinity as ligands for the complex Epidermal Growth Factor Receptor (EGFR).

Classification
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The EGF family consists of 12 different growth factors and can be divided into five groups according to binding affinities:

  1. Growth factors that mainly interact with the EGF receptor (EGFR also known as ERBB1 or HER1): These include: EGF - transforming growth factor α (TGFA), amphiregulin (AREG), vaccinia growth factor (VGF), shope fibroma growth factor (SFGF) and myxoma virus growth factor (MGF)
  2. The neuregulin or heregulin ligand family, which mainly interact with ErbB3 and ErbB4: Neuregulins 1 and 2 (NRG1, NRG2)
  3. Growth factors that interact equally with EGFR and ErbB4 (HER4): Betacellulin (BTC) and heparin-binding EGF-like growth factor (HBEGF)
  4. Growth factors that bind exclusively to ErbB4: Neuregulins 3 and 4 (NRG3, NRG4)
  5. Growth factors that bind to EGFR, ErbB3 or ErbB4 as pan- or broadband ligands: Epiregulin (EREG).

All these EGF-peptides can therefore only react in connection with the different receptor types of the "Epidermal Growth Factor Receptors", in short EGFRs. EGFRs are transmembrane binding proteins on the cell surface.

So far, four closely related receptor types are known, which are known as:

  1. EGFR also known as ERBB1 or HER1.
  2. Human Epidermal Growth Factor Receptor 2, ErbB-2 (HER2)
  3. Human Epidermal Growth Factor Receptor 3, ErbB-3 (HER3)
  4. Human Epidermal Growth Factor Receptor 4, ErbB-4 (HER4)

can be designated.

The different EGF ligands induce different combinations of receptors, probably because each ligand is divalent and has not only a site with high affinity but also a site with low or broad specificity that determines the dimerisation partner. The monomeric form of the receptor tyrosine kinases is inactive (see under EGFR). When a growth factor is bound, the oligomerization leads mainly by homodimerization to auto- and transphosphorylation of the receptor.

The divalent nature of EGF peptides enables the simultaneous binding of two identical(homodimerisation) or with different(heterodimerisation) ErbB receptors. The dimerization or juxtaposition of two ErbB receptors leads to the activation of the intrinsic tyrosine kinase activity and to the receptor auto and transphosphorylation of specific tyrosine residues. The transphosphorylation event creates docking sites at the activated receptor, which trigger a variety of intercellular signaling events through the recruitment of signal effectors. Recruitment is highly specific and is controlled by tyrosine-phosphorylated modules in the juxtamembrane and in the carboxyl tail of the receptor tyrosine kinase (RTK), which mainly contain either Src-homology 2 (SH2) - or phosphotyrosine-binding (PTB) motifs. As a result, several linear signalling cascades are initiated, culminating in the regulation of gene expression.

The EGF ligand family has a different mitogenic potency and a different signaling potential. Both factors are inseparably linked to the respective composition of the homo- or heterodimeric receptor complex, which determines the ligand dissociation rates, the receptor recycling/degradation and the temporal duration of the signal. In addition, the coupling of a given receptor to specific intracellular signal proteins is modulated by the EGF ligand dimerization partner and may indeed result from differential receptor transphosphorylation. Consequently, the different cellular responses to the EGF family of peptide growth factors are due to the arrangement of activated ErbB receptors and the repertoire of signalling pathways activated at the effector level.

EGF itself is formed as a non-active precursor protein. The EGF precursor protein is a transmembranous glycoprotein from which the actively active and binding EGF is cleaved by an endopeptidase. Like the other members of the epidermal growth factor family, EGF binds to its receptor (EGFR). After ligand binding, EGFR (ErbB-1) dimerises with itself or with the homologous receptor types ErbB-2 (HER2), ErbB-3 (HER3) or ErbB-4(HER4). Only dimerisation leads to an increase in intracellular tyrosine kinase activity with the activation of the downstream signalling cascades. This has effects on cell proliferation (cell proliferation is activated), apoptosis (apoptosis is reduced) and angiogenesis (angiogenesis is activated).

General information
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The EGF family shows different expression patterns. While EGF occurs in most body fluids, the other related family members are active as autocrine or paracrine peptides. Therefore, they generally only act over short distances.

The different expression patterns of EGF peptides are either developmentally regulated or tissue-specific. This is illustrated by the strongly regulated expression of HBEGF in the uterine lumen epithelium 6-7 hours before implantation of the egg into the uterus. In the adult organism, EGF peptides play an essential role in the proliferation and differentiation of the mammary gland (mammopoiesis) during puberty and the milk production of the mammary gland (lactogenesis) during pregnancy. A targeted inactivation of EGF ligands shows that they play both specific and overlapping roles in the development of the mammary glands. For example, the absence of AREG is associated with impaired ductal morphogenesis of the breast, while the inactivation of EGF and TGFA indicates that both factors are necessary for lactogenesis.

The virally encoded EGF-like factors are not required for viral replication. Genetic inactivation studies suggest that the virally encoded EGF ligands are required to enhance virulence and stimulate cell proliferation at the primary infection site. They may therefore play a role in inflammatory reactions. In general, controlled expression of the EGF ligand family seems to be one way to determine their signal specificity.

The importance of the regulated expression of the EGF ligand family is underlined by the fact that aberrant expression of EGF-related peptides underlies the pathogenesis of conditions such as cancer and inflammatory diseases. Co-overexpression of these peptides and their receptors frequently occurs in human breast, pancreatic, endometrial and ovarian cancer as well as in inflammatory diseases such as chronic pancreatitis. The deregulated expression of growth factors leads to an autocrine mechanism that drives uncontrolled cell growth and maintains neoplastic transformation.

Therapy
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The monoclonal antibody cetuximab binds to the receptor HER1 and thus prevents the binding of EGF. Cetuximab is used in the treatment of colon cancer. Gefitinib as a small molecule, blocks the EGF receptor. Geftinib is used in the treatment of lung cancer. Erlotinib inhibits downstream metabolic pathways of HER1 and HER2 and is used in the treatment of lung cancer and pancreatic cancer.

Overexpression of the receptor HER2 is an early event in the development of tumours, is found in about 20% of breast cancer cases and is associated with aggressive cancer growth and poor prognosis. Trastuzumab is a monoclonal antibody that binds to HER2, which is used in the treatment of breast cancer.

Overexpression of the receptor HER4 is a late event in tumour development, is found in about 40% of breast cancer cases and also indicates a poor prognosis.

Trastuzumab is a monoclonal antibody against HER2, which is used in the treatment of breast cancer.

Literature
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  1. Burstein HJ (2005) The New England Journal of Medicine 353: 1652-1564.
  2. Choi JS et al (2008) In vivo wound healing of diabetic ulcers using electrospun nanofibers immobilized with human epidermal growth factor (EGF) biomaterials 29:587.
  3. Coussens L et al (1085) Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 230: 1132-1139.
  4. Cunningham D et al (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337.
  5. Hardwicke J et al (2008) Epidermal growth factor therapy and wound healing-past, present and future perspectives. Surgeon 6:172.
  6. Mates M et al (2015) Systemic targeted therapy for her2-positive early female breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline". Current Oncology 22 (Suppl 1): 114-122.
  7. Pritchard C (2013) Epidermal Growth Factor. In: Brenner's Encyclopedia of Genetics (Second Edition)
  8. Roy Vet al (2009) Beyond trastuzumab: small molecule tyrosine kinase inhibitors in HER-2-positive breast cancer. The Oncologist 14: 1061-1069
  9. Rusnak Dwet al. (2001) The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer. Cancer Research 61: 7196-7203
  10. Tanaka A et al (2005) Acceleration of wound healing by gelatin film dressings with epidermal growth factor. J Vet Med Sci 67:909.

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Last updated on: 29.10.2020