Epidermal growth factor explained

Epidermal growth factor (EGF) is a protein that stimulates cell growth and differentiation by binding to its receptor, EGFR. Human EGF is 6-kDa[1] and has 53 amino acid residues and three intramolecular disulfide bonds.[2]

EGF was originally described as a secreted peptide found in the submaxillary glands of mice and in human urine. EGF has since been found in many human tissues, including platelets,[3] submandibular gland (submaxillary gland), and parotid gland. Initially, human EGF was known as urogastrone.[4]

Structure

In humans, EGF has 53 amino acids (sequence NSDSECPLSHDGYCLHDGVCMYIEALDKYACNCVVGYIGERCzYRDLKWWELR), with a molecular mass of around 6 kDa. It contains three disulfide bridges (Cys6-Cys20, Cys14-Cys31, Cys33-Cys42).

Function

EGF, via binding to its cognate receptor, results in cellular proliferation, differentiation, and survival.[5]

Salivary EGF, which seems to be regulated by dietary inorganic iodine, also plays an important physiological role in the maintenance of oro-esophageal and gastric tissue integrity. The biological effects of salivary EGF include healing of oral and gastroesophageal ulcers, inhibition of gastric acid secretion, stimulation of DNA synthesis as well as mucosal protection from intraluminal injurious factors such as gastric acid, bile acids, pepsin, and trypsin and to physical, chemical and bacterial agents.[6]

Biological sources

The Epidermal growth factor can be found in platelets, urine, saliva, milk, tears, and blood plasma.[7] It can also be found in the submandibular glands, and the parotid gland. The production of EGF has been found to be stimulated by testosterone.

Polypeptide growth factors

Polypeptide growth factors include:[8]

!Sr.No!Growth factor!Source!Major function
1Epidermal growth factor (EGF)Salivary glandStimulates growth of epidermal and epithelial cells
2Platelet derived growth factorPlateletsStimulates growth of mesenchymal cells, promotes wound healing
3Transforming growth factor-alpha (TGF-α)Epithelial cellSimilar to EGF
4Transforming growth factor-beta (TGF-β)Platelets, Kidney, PlacentaInhibitory effect on cultures tumor cell
5ErythropoietinKidneyStimulates development of erythropoietic cells
6Nerve growth factor (NGF)Salivary glandStimulates the growth of sensory nerves
7Insulin-like growth factorSerumStimulates incorporation of sulfates into cartilage, exerts insulin-like action on certain cells
8Tumor necrosis factorMonocytesNecrosis of tumor cells
9Interleukin-1Monocytes, Leukocytes Stimulates synthesis of IL-2
10Interleukin-2LymphocytesStimulates growth and maturation of T-cells

Mechanism

EGF acts by binding with high affinity to epidermal growth factor receptor (EGFR) on the cell surface. This stimulates ligand-induced dimerization,[9] activating the intrinsic protein-tyrosine kinase activity of the receptor (see the second diagram). The tyrosine kinase activity, in turn, initiates a signal transduction cascade that results in a variety of biochemical changes within the cell – a rise in intracellular calcium levels, increased glycolysis and protein synthesis, and increases in the expression of certain genes including the gene for EGFR – that ultimately lead to DNA synthesis and cell proliferation.[10]

EGF-family / EGF-like domain

See main article: EGF-like domain. EGF is the founding member of the EGF-family of proteins. Members of this protein family have highly similar structural and functional characteristics. Besides EGF itself other family members include:[11]

All family members contain one or more repeats of the conserved amino acid sequence:

CX7CX4-5CX10-13CXCX8GXRC

Where C is cysteine, G is glycine, R is arginine, and X represents any amino acid.[11]

This sequence contains six cysteine residues that form three intramolecular disulfide bonds. Disulfide bond formation generates three structural loops that are essential for high-affinity binding between members of the EGF-family and their cell-surface receptors.

Interactions

Epidermal growth factor has been shown to interact with epidermal growth factor receptors.[12] [13]

Medical uses

Recombinant human epidermal growth factor, sold under the brand name Heberprot-P, is used to treat diabetic foot ulcers. It can be given by injection into the wound site,[14] or may be used topically.[15] Tentative evidence shows improved wound healing.[16] Safety has been poorly studied.[16]

EGF is used to modify synthetic scaffolds for manufacturing of bioengineered grafts by emulsion electrospinning or surface modification methods.[17] [18]

Bone regeneration

EGF plays an enhancer role on the osteogenic differentiation of dental pulp stem cells (DPSCs) because it is capable of increasing extracellular matrix mineralization. A low concentration of EGF (10 ng/ml) is sufficient to induce morphological and phenotypic changes. These data suggests that DPSCs in combination with EGF could be an effective stem cell-based therapy to bone tissue engineering applications in periodontics and oral implantology.[19]

History

EGF was the second growth factor to be identified.[20] Initially, human EGF was known as urogastrone. Stanley Cohen discovered EGF while working with Rita Levi-Montalcini at the Washington University in St. Louis during experiments researching nerve growth factor. For these discoveries Levi-Montalcini and Cohen were awarded the 1986 Nobel Prize in Physiology or Medicine.

Further reading

External links

Notes and References

  1. Harris RC, Chung E, Coffey RJ . EGF receptor ligands . Experimental Cell Research . 284 . 1 . 2–13 . March 2003 . 12648462 . 10.1016/S0014-4827(02)00105-2 .
  2. Carpenter G, Cohen S . Epidermal growth factor . The Journal of Biological Chemistry . 265 . 14 . 7709–12 . May 1990 . 10.1016/S0021-9258(19)38983-5 . 2186024 . free .
  3. Custo S, Baron B, Felice A, Seria E . A comparative profile of total protein and six angiogenically-active growth factors in three platelet products . GMS Interdisciplinary Plastic and Reconstructive Surgery DGPW . 11 . Doc06 . Doc06 . 5 July 2022 . 35909816 . 9284722 . 10.3205/iprs000167 .
  4. Hollenberg MD, Gregory H . Epidermal growth factor-urogastrone: biological activity and receptor binding of derivatives . Molecular Pharmacology . 17 . 3 . 314–320 . May 1980 . 6248761 .
  5. Herbst RS . Review of epidermal growth factor receptor biology . International Journal of Radiation Oncology, Biology, Physics . 59 . 2 Suppl . 21–6 . 2004 . 15142631 . 10.1016/j.ijrobp.2003.11.041 . free .
  6. Venturi S, Venturi M . Iodine in evolution of salivary glands and in oral health . Nutrition and Health . 20 . 2 . 119–34 . 2009 . 19835108 . 10.1177/026010600902000204 . 25710052 .
  7. Book: Kumar V, Abbas AK, Fausto N, Robbins SL, Cotran RS . Robbins and Cotran pathologic basis of disease . 7th . Elsevier Saunders . St. Louis, Mo . 2005 . 978-0-7216-0187-8 .
  8. Book: Biochemistry. Satyanarayana U . 2002. Books and Allied. 8187134801. 2nd. Kolkata, India. 71209231.
  9. Dawson JP, Berger MB, Lin CC, Schlessinger J, Lemmon MA, Ferguson KM . Epidermal growth factor receptor dimerization and activation require ligand-induced conformational changes in the dimer interface . Molecular and Cellular Biology . 25 . 17 . 7734–42 . September 2005 . 16107719 . 1190273 . 10.1128/MCB.25.17.7734-7742.2005 .
  10. Fallon JH, Seroogy KB, Loughlin SE, Morrison RS, Bradshaw RA, Knaver DJ, Cunningham DD . Epidermal growth factor immunoreactive material in the central nervous system: location and development . Science . 224 . 4653 . 1107–9 . June 1984 . 6144184 . 10.1126/science.6144184 . 1984Sci...224.1107F .
  11. Dreux AC, Lamb DJ, Modjtahedi H, Ferns GA . The epidermal growth factor receptors and their family of ligands: their putative role in atherogenesis . Atherosclerosis . 186 . 1 . 38–53 . May 2006 . 16076471 . 10.1016/j.atherosclerosis.2005.06.038 .
  12. Stortelers C, Souriau C, van Liempt E, van de Poll ML, van Zoelen EJ . Role of the N-terminus of epidermal growth factor in ErbB-2/ErbB-3 binding studied by phage display . Biochemistry . 41 . 27 . 8732–41 . July 2002 . 12093292 . 10.1021/bi025878c .
  13. Wong L, Deb TB, Thompson SA, Wells A, Johnson GR . A differential requirement for the COOH-terminal region of the epidermal growth factor (EGF) receptor in amphiregulin and EGF mitogenic signaling . The Journal of Biological Chemistry . 274 . 13 . 8900–9 . March 1999 . 10085134 . 10.1074/jbc.274.13.8900 . free .
  14. Berlanga J, Fernández JI, López E, López PA, del Río A, Valenzuela C, Baldomero J, Muzio V, Raíces M, Silva R, Acevedo BE, Herrera L . Heberprot-P: a novel product for treating advanced diabetic foot ulcer . MEDICC Review . 15 . 1 . 11–5 . January 2013 . 23396236 . 10.1590/s1555-79602013000100004 . free .
  15. Yang S, Geng Z, Ma K, Sun X, Fu X . Efficacy of Topical Recombinant Human Epidermal Growth Factor for Treatment of Diabetic Foot Ulcer: A Systematic Review and Meta-Analysis . The International Journal of Lower Extremity Wounds . 15 . 2 . 120–5 . June 2016 . 27151755 . 10.1177/1534734616645444 . 43897291 .
  16. Martí-Carvajal AJ, Gluud C, Nicola S, Simancas-Racines D, Reveiz L, Oliva P, Cedeño-Taborda J . Growth factors for treating diabetic foot ulcers . The Cochrane Database of Systematic Reviews . 2015 . 10 . CD008548 . October 2015 . 26509249 . 10.1002/14651858.CD008548.pub2 . 8665376 .
  17. Haddad T, Noel S, Liberelle B, El Ayoubi R, Ajji A, De Crescenzo G . Fabrication and surface modification of poly lactic acid (PLA) scaffolds with epidermal growth factor for neural tissue engineering . Biomatter . 6 . 1 . e1231276 . January 2016 . 27740881 . 5098722 . 10.1080/21592535.2016.1231276 .
  18. Tenchurin T, Lyundup A, Demchenko A, Krasheninnikov M, Balyasin M, Klabukov I, Shepelev AD, Mamagulashvili VG, Orehov AS . 2017. Modification of biodegradable fibrous scaffolds with Epidermal Growth Factor by emulsion electrospinning for promotion of epithelial cells proliferation. Гены и клетки . ru. 12. 4. 47–52. 10.23868/201707029. 90593089 .
  19. Del Angel-Mosqueda C, Gutiérrez-Puente Y, López-Lozano AP, Romero-Zavaleta RE, Mendiola-Jiménez A, Medina-De la Garza CE, Márquez-M M, De la Garza-Ramos MA . Epidermal growth factor enhances osteogenic differentiation of dental pulp stem cells in vitro . Head & Face Medicine . 11 . 29 . September 2015 . 26334535 . 4558932 . 10.1186/s13005-015-0086-5 . free .
  20. Book: Pache JC . Epidermal growth factors . 2006-01-01. http://www.sciencedirect.com/science/article/pii/B0123708796001381. Encyclopedia of Respiratory Medicine. 129–133. Laurent GJ, Shapiro SD . Oxford. Academic Press. en. 10.1016/b0-12-370879-6/00138-1. 978-0-12-370879-3. 2020-11-30 .

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