Epidermal growth factor

EGF
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	1IVO, 1JL9, 1NQL, 1P9J, 2KV4, 3NJP
Identifiers
Aliases	EGF, HOMG4, URG, epidermal growth factor, Epidermal growth factor
External IDs	OMIM: 131530 MGI: 95290 HomoloGene: 1483 GeneCards: EGF
Gene location (Human)
Chr.	Chromosome 4 (human)[1]
End	110,013,766 bp[1]
Gene location (Mouse)
Chr.	Chromosome 3 (mouse)[2]
End	129,755,316 bp[2]
RNA expression pattern
	More reference expression data
Gene ontology
Molecular function	• calcium ion binding; • transmembrane receptor protein tyrosine kinase activator activity; • epidermal growth factor receptor binding; • Wnt-protein binding; • GO:0001948 protein binding; • growth factor activity; • Wnt-activated receptor activity; • protein tyrosine kinase activity; • Ras guanyl-nucleotide exchange factor activity; • phosphatidylinositol-4,5-bisphosphate 3-kinase activity;
Cellular component	• integral component of membrane; • membrane; • receptor complex; • extracellular region; • lysosomal membrane; • extracellular exosome; • platelet alpha granule lumen; • extracellular; • clathrin-coated vesicle membrane; • cell membrane;
Biological process	• negative regulation of epidermal growth factor receptor signaling pathway; • positive regulation of MAP kinase activity; • epidermal growth factor receptor signaling pathway; • regulation of protein localization to cell surface; • ERK1 and ERK2 cascade; • platelet degranulation; • regulation of calcium ion import; • mammary gland alveolus development; • MAPK cascade; • DNA replication; • positive regulation of transcription, DNA-templated; • activation of MAPK activity; • negative regulation of secretion; • positive regulation of hyaluronan biosynthetic process; • positive regulation of peptidyl-threonine phosphorylation; • positive regulation of protein ubiquitination involved in ubiquitin-dependent protein catabolic process; • angiogenesis; • Wnt signaling pathway involved in dorsal/ventral axis specification; • positive regulation of cell proliferation; • positive regulation of peptidyl-tyrosine phosphorylation; • positive regulation of cerebellar granule cell precursor proliferation; • canonical Wnt signaling pathway; • negative regulation of cholesterol efflux; • peptidyl-tyrosine phosphorylation; • positive regulation of DNA binding; • positive regulation of phosphorylation; • positive regulation of mitotic nuclear division; • branching morphogenesis of an epithelial tube; • signal transduction; • regulation of peptidyl-tyrosine phosphorylation; • ERBB2 signaling pathway; • phosphatidylinositol phosphorylation; • positive regulation of protein tyrosine kinase activity; • activation of transmembrane receptor protein tyrosine kinase activity; • regulation of cell motility; • activation of MAPKK activity; • positive regulation of receptor internalization; • positive regulation of epidermal growth factor-activated receptor activity; • membrane organization; • negative regulation of ERBB signaling pathway; • embryonic retina morphogenesis in camera-type eye; • positive regulation of gene expression; • positive regulation of cell migration; • positive regulation of protein kinase B signaling; • negative regulation of Notch signaling pathway; • regulation of JAK-STAT cascade; • positive regulation of canonical Wnt signaling pathway; • positive regulation of protein localization to early endosome;
	Sources:Amigo / QuickGO
Orthologs
	1950
	13645
	ENSG00000138798
	ENSMUSG00000028017
	P01133
	P01132
	NM_001178130; NM_001178131; NM_001963; NM_001357021
	NM_010113; NM_001310737; NM_001329594
	NP_001171601; NP_001171602; NP_001954; NP_001343950
	NP_001297666; NP_001316523; NP_034243
	Wikidata
View/Edit Human	View/Edit Mouse

Epidermal growth factor (EGF) is a protein that stimulates cell growth and differentiation by binding to its receptor, EGFR. Human EGF is 6-kDa[5] and has 53 amino acid residues and three intramolecular disulfide bonds.[6]

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 submandibular gland (submaxillary gland),[7] and parotid gland.[7] Initially, human EGF was known as urogastrone.[8]

Structure

In humans, EGF has 53 amino acids,[6] with a molecular mass of around 6 kDa.[5] It contains three disulfide bridges.[6]

Function

EGF, via binding to its cognate receptor, results in cellular proliferation, differentiation, and survival.[9]

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.[7]

Biological sources

Epidermal growth factor can be found in urine, saliva, milk, tears, and blood plasma.[10] It can also be found in the submandibular glands,[7][11] and the parotid gland.[7][11] The production of EGF has been found to be stimulated by testosterone.

Polypeptide growth factors

Polypeptide growth factors include:[12]


Sr.No	Growth factor	Source	Major function
1	Epidermal growth factor	Salivary gland	Stimulate growth of epidermal and epithelial cell
2	Platelet derived growth factor	Platelets	Stimulate growth of mesenchymal cells, promotes wound healing
3	Transforming growth factor (Alpha)	Epithelial cell	Similar to Epidermal growth factor
4	Transforming growth factor (Beta)	Platelets, Kidney, Placenta	Inhibitory effect on cultures tumor cell
5	Erythropoietin	Kidney	Stimulate development of erythropoietic cells
6	Nerve growth factor (NGF)	Salivary gland	Stimulate the growth of sensory nerve
7	Insulin like growth factor	Serum	Stimulate incorporation of sulfates into cartilage, exerts insulin like action on certain cell
8	Tumor necrosis factor	Monocytes	Necrosis of tumor cells
9	Interleukin-1	Monocytes, Leukocytes	Stimulate synthesis of IL-2
10	Interleukin-2	Lymphocytes	Stimulate 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,[13] 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.[14]

EGF-family / 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:[15]

Heparin-binding EGF-like growth factor (HB-EGF)
transforming growth factor-α (TGF-α)
Amphiregulin (AR)
Epiregulin (EPR)
Epigen
Betacellulin (BTC)
neuregulin-1 (NRG1)
neuregulin-2 (NRG2)
neuregulin-3 (NRG3)
neuregulin-4 (NRG4).

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

CX₇CX_4-5CX_10-13CXCX₈GXRC

Where C is cysteine, G is glycine, R is arginine, and X represents any amino acid.[15]

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.[5]

Interactions

Epidermal growth factor has been shown to interact with epidermal growth factor receptor.[16][17]

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,[18] or may be used topically.[19] Tentative evidence shows improved wound healing.[20] Safety has been poorly studied.[20]

EGF is used to modify synthetic scaffolds for manufacturing of bioengineered grafts by emulsion electrospinning or surface modification methods.[21][22]

Bone regeneration

EGF plays an enhancer role on 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.[23]

History

EGF was the first growth factor to be identified.[24] Initially, human EGF was known as urogastrone.[8]

References

GRCh38: Ensembl release 89: ENSG00000138798 - Ensembl, May 2017
GRCm38: Ensembl release 89: ENSMUSG00000028017 - Ensembl, May 2017
"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
Harris RC, Chung E, Coffey RJ (March 2003). "EGF receptor ligands". Experimental Cell Research. 284 (1): 2–13. doi:10.1016/S0014-4827(02)00105-2. PMID 12648462.
Carpenter G, Cohen S (May 1990). "Epidermal growth factor". The Journal of Biological Chemistry. 265 (14): 7709–12. PMID 2186024.
Venturi S, Venturi M (2009). "Iodine in evolution of salivary glands and in oral health". Nutrition and Health. 20 (2): 119–34. doi:10.1177/026010600902000204. PMID 19835108. S2CID 25710052.
Hollenberg MD, Gregory H (May 1980). "Epidermal growth factor-urogastrone: biological activity and receptor binding of derivatives". Molecular Pharmacology. 17 (3): 314–20. PMID 6248761.
Herbst RS (2004). "Review of epidermal growth factor receptor biology". International Journal of Radiation Oncology, Biology, Physics. 59 (2 Suppl): 21–6. doi:10.1016/j.ijrobp.2003.11.041. PMID 15142631.
Kumar V, Abbas AK, Fausto N, Robbins SL, Cotran RS (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. ISBN 978-0-7216-0187-8.
Chao J (2013-01-01), Rawlings ND, Salvesen G (eds.), "Chapter 624 - Mouse Kallikrein 9, Epidermal Growth Factor-binding Protein", Handbook of Proteolytic Enzymes (Third ed.), Academic Press, pp. 2830–2831, doi:10.1016/b978-0-12-382219-2.00624-4, ISBN 978-0-12-382219-2
Satyanarayana U (2002). Biochemistry (2nd ed.). Kolkata, India: Books and Allied. ISBN 8187134801. OCLC 71209231.
Dawson JP, Berger MB, Lin CC, Schlessinger J, Lemmon MA, Ferguson KM (September 2005). "Epidermal growth factor receptor dimerization and activation require ligand-induced conformational changes in the dimer interface". Molecular and Cellular Biology. 25 (17): 7734–42. doi:10.1128/MCB.25.17.7734-7742.2005. PMC 1190273. PMID 16107719.
Fallon JH, Seroogy KB, Loughlin SE, Morrison RS, Bradshaw RA, Knaver DJ, Cunningham DD (June 1984). "Epidermal growth factor immunoreactive material in the central nervous system: location and development". Science. 224 (4653): 1107–9. doi:10.1126/science.6144184. PMID 6144184.
Dreux AC, Lamb DJ, Modjtahedi H, Ferns GA (May 2006). "The epidermal growth factor receptors and their family of ligands: their putative role in atherogenesis". Atherosclerosis. 186 (1): 38–53. doi:10.1016/j.atherosclerosis.2005.06.038. PMID 16076471.
Stortelers C, Souriau C, van Liempt E, van de Poll ML, van Zoelen EJ (July 2002). "Role of the N-terminus of epidermal growth factor in ErbB-2/ErbB-3 binding studied by phage display". Biochemistry. 41 (27): 8732–41. doi:10.1021/bi025878c. PMID 12093292.
Wong L, Deb TB, Thompson SA, Wells A, Johnson GR (March 1999). "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. doi:10.1074/jbc.274.13.8900. PMID 10085134.
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 (January 2013). "Heberprot-P: a novel product for treating advanced diabetic foot ulcer". MEDICC Review. 15 (1): 11–5. doi:10.1590/s1555-79602013000100004. PMID 23396236.
Yang S, Geng Z, Ma K, Sun X, Fu X (June 2016). "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. doi:10.1177/1534734616645444. PMID 27151755. S2CID 43897291.
Martí-Carvajal AJ, Gluud C, Nicola S, Simancas-Racines D, Reveiz L, Oliva P, Cedeño-Taborda J (October 2015). "Growth factors for treating diabetic foot ulcers". The Cochrane Database of Systematic Reviews. 10 (10): CD008548. doi:10.1002/14651858.CD008548.pub2. PMID 26509249.
Haddad T, Noel S, Liberelle B, El Ayoubi R, Ajji A, De Crescenzo G (January 2016). "Fabrication and surface modification of poly lactic acid (PLA) scaffolds with epidermal growth factor for neural tissue engineering". Biomatter. 6 (1): e1231276. doi:10.1080/21592535.2016.1231276. PMC 5098722. PMID 27740881.
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 (in Russian). 12 (4): 47–52. doi:10.23868/201707029.
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 (September 2015). "Epidermal growth factor enhances osteogenic differentiation of dental pulp stem cells in vitro". Head & Face Medicine. 11: 29. doi:10.1186/s13005-015-0086-5. PMC 4558932. PMID 26334535.
JC (2006-01-01). Laurent GJ, Shapiro SD (eds.). Epidermal growth factors. Encyclopedia of Respiratory Medicine. Oxford: Academic Press. pp. 129–133. doi:10.1016/b0-12-370879-6/00138-1. ISBN 978-0-12-370879-3. Retrieved 2020-11-30.

External links

Shaanxi Zhongbang Pharma-Tech Co., Ltd.-Supply of Epidermal Growth Factor
EGF at the Human Protein Reference Database.
Epidermal+growth+factor at the US National Library of Medicine Medical Subject Headings (MeSH)
EGF model in BioModels database

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[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000138798 - Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000028017 - Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid12648462-5] Harris RC, Chung E, Coffey RJ (March 2003). "EGF receptor ligands". Experimental Cell Research. 284 (1): 2–13. doi:10.1016/S0014-4827(02)00105-2. PMID 12648462.

[pmid2186024-6] Carpenter G, Cohen S (May 1990). "Epidermal growth factor". The Journal of Biological Chemistry. 265 (14): 7709–12. PMID 2186024.

[Venturi2009-7] Venturi S, Venturi M (2009). "Iodine in evolution of salivary glands and in oral health". Nutrition and Health. 20 (2): 119–34. doi:10.1177/026010600902000204. PMID 19835108. S2CID 25710052.

[:0-8] Hollenberg MD, Gregory H (May 1980). "Epidermal growth factor-urogastrone: biological activity and receptor binding of derivatives". Molecular Pharmacology. 17 (3): 314–20. PMID 6248761.

[Herbst-9] Herbst RS (2004). "Review of epidermal growth factor receptor biology". International Journal of Radiation Oncology, Biology, Physics. 59 (2 Suppl): 21–6. doi:10.1016/j.ijrobp.2003.11.041. PMID 15142631.

[isbn0-7216-0187-1-10] Kumar V, Abbas AK, Fausto N, Robbins SL, Cotran RS (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. ISBN 978-0-7216-0187-8.

[:1-11] Chao J (2013-01-01), Rawlings ND, Salvesen G (eds.), "Chapter 624 - Mouse Kallikrein 9, Epidermal Growth Factor-binding Protein", Handbook of Proteolytic Enzymes (Third ed.), Academic Press, pp. 2830–2831, doi:10.1016/b978-0-12-382219-2.00624-4, ISBN 978-0-12-382219-2

[12] Satyanarayana U (2002). Biochemistry (2nd ed.). Kolkata, India: Books and Allied. ISBN 8187134801. OCLC 71209231.

[pmid16107719-13] Dawson JP, Berger MB, Lin CC, Schlessinger J, Lemmon MA, Ferguson KM (September 2005). "Epidermal growth factor receptor dimerization and activation require ligand-induced conformational changes in the dimer interface". Molecular and Cellular Biology. 25 (17): 7734–42. doi:10.1128/MCB.25.17.7734-7742.2005. PMC 1190273. PMID 16107719.

[pmid6144184-14] Fallon JH, Seroogy KB, Loughlin SE, Morrison RS, Bradshaw RA, Knaver DJ, Cunningham DD (June 1984). "Epidermal growth factor immunoreactive material in the central nervous system: location and development". Science. 224 (4653): 1107–9. doi:10.1126/science.6144184. PMID 6144184.

[dreux-15] Dreux AC, Lamb DJ, Modjtahedi H, Ferns GA (May 2006). "The epidermal growth factor receptors and their family of ligands: their putative role in atherogenesis". Atherosclerosis. 186 (1): 38–53. doi:10.1016/j.atherosclerosis.2005.06.038. PMID 16076471.

[pmid12093292-16] Stortelers C, Souriau C, van Liempt E, van de Poll ML, van Zoelen EJ (July 2002). "Role of the N-terminus of epidermal growth factor in ErbB-2/ErbB-3 binding studied by phage display". Biochemistry. 41 (27): 8732–41. doi:10.1021/bi025878c. PMID 12093292.

[pmid10085134-17] Wong L, Deb TB, Thompson SA, Wells A, Johnson GR (March 1999). "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. doi:10.1074/jbc.274.13.8900. PMID 10085134.

[Ber2013-18] 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 (January 2013). "Heberprot-P: a novel product for treating advanced diabetic foot ulcer". MEDICC Review. 15 (1): 11–5. doi:10.1590/s1555-79602013000100004. PMID 23396236.

[19] Yang S, Geng Z, Ma K, Sun X, Fu X (June 2016). "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. doi:10.1177/1534734616645444. PMID 27151755. S2CID 43897291.

[Mar2015-20] Martí-Carvajal AJ, Gluud C, Nicola S, Simancas-Racines D, Reveiz L, Oliva P, Cedeño-Taborda J (October 2015). "Growth factors for treating diabetic foot ulcers". The Cochrane Database of Systematic Reviews. 10 (10): CD008548. doi:10.1002/14651858.CD008548.pub2. PMID 26509249.

[21] Haddad T, Noel S, Liberelle B, El Ayoubi R, Ajji A, De Crescenzo G (January 2016). "Fabrication and surface modification of poly lactic acid (PLA) scaffolds with epidermal growth factor for neural tissue engineering". Biomatter. 6 (1): e1231276. doi:10.1080/21592535.2016.1231276. PMC 5098722. PMID 27740881.

[22] 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 (in Russian). 12 (4): 47–52. doi:10.23868/201707029.

[23] 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 (September 2015). "Epidermal growth factor enhances osteogenic differentiation of dental pulp stem cells in vitro". Head & Face Medicine. 11: 29. doi:10.1186/s13005-015-0086-5. PMC 4558932. PMID 26334535.

[24] JC (2006-01-01). Laurent GJ, Shapiro SD (eds.). Epidermal growth factors. Encyclopedia of Respiratory Medicine. Oxford: Academic Press. pp. 129–133. doi:10.1016/b0-12-370879-6/00138-1. ISBN 978-0-12-370879-3. Retrieved 2020-11-30.