Biology:Epidermal growth factor

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Short description: Protein that stimulates cell division and differentiation


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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),[4] and parotid gland.[4] Initially, human EGF was known as urogastrone.[5]

Structure

In humans, EGF has 53 amino acids (sequence NSDSECPLSHDGYCLHDGVCMYIEALDKYACNCVVGYIGERCzYRDLKWWELR),[2] with a molecular mass of around 6 kDa.[1] It contains three disulfide bridges (Cys6-Cys20, Cys14-Cys31, Cys33-Cys42).[2]

Function

EGF, via binding to its cognate receptor, results in cellular proliferation, differentiation, and survival.[6]

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.[4]

Biological sources

The Epidermal growth factor can be found in platelets,[3] urine, saliva, milk, tears, and blood plasma.[7] It can also be found in the submandibular glands,[4][8] and the parotid gland.[4][8] The production of EGF has been found to be stimulated by testosterone.[citation needed]

Polypeptide growth factors

Polypeptide growth factors include:[9]

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

Mechanism

Diagram showing key components of the MAPK/ERK pathway. In the diagram, "P" represents phosphate. Note EGF at the very top.

EGF acts by binding with high affinity to epidermal growth factor receptor (EGFR) on the cell surface. This stimulates ligand-induced dimerization,[10] 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.[11]

EGF-family / EGF-like domain

Main page: Biology: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:[12]

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.[12]

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.[1]

Interactions

Epidermal growth factor has been shown to interact with epidermal growth factor receptors.[13][14]

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,[15] or may be used topically.[16] Tentative evidence shows improved wound healing.[17] Safety has been poorly studied.[17]

EGF is used to modify synthetic scaffolds for manufacturing of bioengineered grafts by emulsion electrospinning or surface modification methods.[18][19]

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.[20]

History

EGF was the second growth factor to be identified.[21] Initially, human EGF was known as urogastrone.[5] Stanly 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.

References

  1. ↑ 1.0 1.1 1.2 "EGF receptor ligands". Experimental Cell Research 284 (1): 2–13. March 2003. doi:10.1016/S0014-4827(02)00105-2. PMID 12648462. 
  2. ↑ 2.0 2.1 2.2 "Epidermal growth factor". The Journal of Biological Chemistry 265 (14): 7709–12. May 1990. doi:10.1016/S0021-9258(19)38983-5. PMID 2186024. 
  3. ↑ 3.0 3.1 Custo, S; Baron, B; Felice, A; Seria, E (5 July 2022). "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. doi:10.3205/iprs000167. PMID 35909816. PMC 9284722. https://www.egms.de/static/en/journals/iprs/2022-11/iprs000167.shtml#block5. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 "Iodine in evolution of salivary glands and in oral health". Nutrition and Health 20 (2): 119–34. 2009. doi:10.1177/026010600902000204. PMID 19835108. 
  5. ↑ 5.0 5.1 "Epidermal growth factor-urogastrone: biological activity and receptor binding of derivatives". Molecular Pharmacology 17 (3): 314–20. May 1980. PMID 6248761. http://molpharm.aspetjournals.org/content/17/3/314. 
  6. ↑ "Review of epidermal growth factor receptor biology". International Journal of Radiation Oncology, Biology, Physics 59 (2 Suppl): 21–6. 2004. doi:10.1016/j.ijrobp.2003.11.041. PMID 15142631. 
  7. ↑ Kumar, Vinay; Abbas, Abul K; Fausto, Nelson; Robbins, Stanley L; Cotran, Ramzi S (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. ISBN 978-0-7216-0187-8. 
  8. ↑ 8.0 8.1 "Chapter 624 - Mouse Kallikrein 9, Epidermal Growth Factor-binding Protein", Handbook of Proteolytic Enzymes (Academic Press): pp. 2830–2831, 2013-01-01, doi:10.1016/b978-0-12-382219-2.00624-4, ISBN 978-0-12-382219-2 
  9. ↑ Biochemistry (2nd ed.). Kolkata, India: Books and Allied. 2002. ISBN 8187134801. OCLC 71209231. 
  10. ↑ "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. doi:10.1128/MCB.25.17.7734-7742.2005. PMID 16107719. 
  11. ↑ "Epidermal growth factor immunoreactive material in the central nervous system: location and development". Science 224 (4653): 1107–9. June 1984. doi:10.1126/science.6144184. PMID 6144184. Bibcode: 1984Sci...224.1107F. 
  12. ↑ 12.0 12.1 "The epidermal growth factor receptors and their family of ligands: their putative role in atherogenesis". Atherosclerosis 186 (1): 38–53. May 2006. doi:10.1016/j.atherosclerosis.2005.06.038. PMID 16076471. 
  13. ↑ "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. doi:10.1021/bi025878c. PMID 12093292. 
  14. ↑ "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. doi:10.1074/jbc.274.13.8900. PMID 10085134. 
  15. ↑ "Heberprot-P: a novel product for treating advanced diabetic foot ulcer". MEDICC Review 15 (1): 11–5. January 2013. doi:10.1590/s1555-79602013000100004. PMID 23396236. 
  16. ↑ "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. doi:10.1177/1534734616645444. PMID 27151755. 
  17. ↑ 17.0 17.1 "Growth factors for treating diabetic foot ulcers". The Cochrane Database of Systematic Reviews 2015 (10): CD008548. October 2015. doi:10.1002/14651858.CD008548.pub2. PMID 26509249. 
  18. ↑ "Fabrication and surface modification of poly lactic acid (PLA) scaffolds with epidermal growth factor for neural tissue engineering". Biomatter 6 (1): e1231276. January 2016. doi:10.1080/21592535.2016.1231276. PMID 27740881. 
  19. ↑ "Modification of biodegradable fibrous scaffolds with Epidermal Growth Factor by emulsion electrospinning for promotion of epithelial cells proliferation" (in ru). Гены и клетки 12 (4): 47–52. 2017. doi:10.23868/201707029. https://zenodo.org/record/1175806. 
  20. ↑ "Epidermal growth factor enhances osteogenic differentiation of dental pulp stem cells in vitro". Head & Face Medicine 11: 29. September 2015. doi:10.1186/s13005-015-0086-5. PMID 26334535. 
  21. ↑ Pache, JC (2006-01-01). "Epidermal growth factors" (in en). Oxford: Academic Press. pp. 129–133. doi:10.1016/b0-12-370879-6/00138-1. ISBN 978-0-12-370879-3. http://www.sciencedirect.com/science/article/pii/B0123708796001381. Retrieved 2020-11-30. 

Further reading

External links



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