Epidermal growth factor

Last updated

EGF
1a3p egf.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases EGF , HOMG4, URG, epidermal growth factor, epithelial growth factor
External IDs OMIM: 131530; MGI: 95290; HomoloGene: 1483; GeneCards: EGF; OMA:EGF - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1950

13645

Ensembl

ENSG00000138798

ENSMUSG00000028017

UniProt

P01133

P01132

RefSeq (mRNA)

NM_001178130
NM_001178131
NM_001963
NM_001357021

NM_010113
NM_001310737
NM_001329594

RefSeq (protein)

NP_001171601
NP_001171602
NP_001954
NP_001343950

NP_001297666
NP_001316523
NP_034243

Location (UCSC) Chr 4: 109.91 – 110.01 Mb Chr 3: 129.47 – 129.55 Mb
PubMed search [3] [4]
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]

Contents

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, [7] submandibular gland (submaxillary gland), [8] and parotid gland. [8] Initially, human EGF was known as urogastrone. [9]

Structure

In humans, EGF has 53 amino acids (sequence NSDSECPLSHDGYCLHDGVCMYIEALDKYACNCVVGYIGERCzYRDLKWWELR), [6] with a molecular mass of around 6 kDa. [5] It contains three disulfide bridges (Cys6-Cys20, Cys14-Cys31, Cys33-Cys42). [6]

Function

EGF, via binding to its cognate receptor, results in cellular proliferation, differentiation, and survival. [10]

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. [8]

Biological sources

The Epidermal growth factor can be found in platelets, [7] urine, saliva, milk, tears, and blood plasma. [11] It can also be found in the submandibular glands, [8] [12] and the parotid gland. [8] [12] The production of EGF has been found to be stimulated by testosterone.[ citation needed ]

Polypeptide growth factors

Polypeptide growth factors include: [13]

Sr.NoGrowth factorSourceMajor function
1Epidermal growth factor (EGF)Salivary glandStimulates growth of epidermal and epithelial cells
2 Platelet derived growth factor PlateletsStimulates growth of mesenchymal cells, promotes wound healing
3 Transforming growth factor-alpha (TGF-α) Epithelial cellSimilar to EGF
4 Transforming growth factor-beta (TGF-β) Platelets, Kidney, PlacentaInhibitory effect on cultures tumor cell
5ErythropoietinKidneyStimulates development of erythropoietic cells
6 Nerve growth factor (NGF) Salivary glandStimulates the growth of sensory nerves
7 Insulin-like growth factor SerumStimulates incorporation of sulfates into cartilage, exerts insulin-like action on certain cells
8Tumor necrosis factorMonocytesNecrosis of tumor cells
9Interleukin-1Monocytes, LeukocytesStimulates synthesis of IL-2
10Interleukin-2LymphocytesStimulates 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. MAPKpathway diagram.svg
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, [14] 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. [15]

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: [16]

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. [16]

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 receptors. [17] [18]

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, [19] or may be used topically. [20] Tentative evidence shows improved wound healing. [21] Safety has been poorly studied. [21]

EGF is used to modify synthetic scaffolds for manufacturing of bioengineered grafts by emulsion electrospinning or surface modification methods. [22] [23]

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. [24]

History

EGF was the second growth factor to be identified. [25] Initially, human EGF was known as urogastrone. [9] 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.

Related Research Articles

<span class="mw-page-title-main">Protein kinase</span> Enzyme that adds phosphate groups to other proteins

A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a functional change of the target protein (substrate) by changing enzyme activity, cellular location, or association with other proteins. The human genome contains about 500 protein kinase genes and they constitute about 2% of all human genes. There are two main types of protein kinase. The great majority are serine/threonine kinases, which phosphorylate the hydroxyl groups of serines and threonines in their targets. Most of the others are tyrosine kinases, although additional types exist. Protein kinases are also found in bacteria and plants. Up to 30% of all human proteins may be modified by kinase activity, and kinases are known to regulate the majority of cellular pathways, especially those involved in signal transduction.

<span class="mw-page-title-main">Epidermal growth factor receptor</span> Transmembrane protein

The epidermal growth factor receptor is a transmembrane protein that is a receptor for members of the epidermal growth factor family of extracellular protein ligands.

<span class="mw-page-title-main">Amphiregulin</span> Protein-coding gene in the species Homo sapiens

Amphiregulin, also known as AREG, is a protein synthesized as a transmembrane glycoprotein with 252 aminoacids and it is encoded by the AREG gene. in humans.

<span class="mw-page-title-main">HER2</span> Mammalian protein found in humans

Receptor tyrosine-protein kinase erbB-2 is a protein that normally resides in the membranes of cells and is encoded by the ERBB2 gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently referred to as HER2 or CD340.

<span class="mw-page-title-main">Receptor tyrosine kinase</span> Class of enzymes

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. The receptors are generally activated by dimerization and substrate presentation. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.

<span class="mw-page-title-main">TGF alpha</span> Protein

Transforming growth factor alpha (TGF-α) is a protein that in humans is encoded by the TGFA gene. As a member of the epidermal growth factor (EGF) family, TGF-α is a mitogenic polypeptide. The protein becomes activated when binding to receptors capable of protein kinase activity for cellular signaling.

<span class="mw-page-title-main">Cripto</span> Protein-coding gene in the species Homo sapiens

Cripto is an EGF-CFC or epidermal growth factor-CFC, which is encoded by the Cryptic family 1 gene. Cryptic family protein 1B is a protein that in humans is encoded by the CFC1B gene. Cryptic family protein 1B acts as a receptor for the TGF beta signaling pathway. It has been associated with the translation of an extracellular protein for this pathway. The extracellular protein which Cripto encodes plays a crucial role in the development of left and right division of symmetry.

The ErbB family of proteins contains four receptor tyrosine kinases, structurally related to the epidermal growth factor receptor (EGFR), its first discovered member. In humans, the family includes Her1, Her2 (ErbB2), Her3 (ErbB3), and Her4 (ErbB4). The gene symbol, ErbB, is derived from the name of a viral oncogene to which these receptors are homologous: erythroblastic leukemia viral oncogene. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's disease, while excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor.

<span class="mw-page-title-main">Heparin-binding EGF-like growth factor</span> Protein-coding gene in the species Homo sapiens

Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family of proteins that in humans is encoded by the HBEGF gene.

<span class="mw-page-title-main">Epiregulin</span> Protein found in humans

Epiregulin (EPR) is a protein that in humans is encoded by the EREG gene.

<span class="mw-page-title-main">Betacellulin</span> Protein-coding gene in humans

Betacellulin is a protein that in humans is encoded by the BTC gene located on chromosome 4 at locus 4q13-q21. Betacellulin was initially identified as a mitogen. Betacellulin, is a part of an Epidermal Growth Factor (EGF) family and functions as a ligand for the epidermal growth factor receptor (EGFR). The role of betacellulin as an EGF is manifested differently in various tissues, and it has a great effect on nitrogen signaling in retinal pigment epithelial cells and vascular smooth muscle cells. While many studies attest a role for betacellulin in the differentiation of pancreatic β-cells, the last decade witnessed the association of betacellulin with many additional biological processes, ranging from reproduction to the control of neural stem cells. Betacellulin is a member of the EGF family of growth factors. It is synthesized primarily as a transmembrane precursor, which is then processed to mature molecule by proteolytic events.

Argos is a secreted protein that is an inhibitor of the epidermal growth factor receptor (EGFR) pathway in Drosophila melanogaster. Argos inhibits the EGFR pathway by sequestering the EGFR ligand Spitz. Argos binds the epidermal growth factor domain of Spitz, preventing interaction between Spitz and EGFR. Argos does not directly interact with EGFR. Argos represents the first example of ligand sequestration as a mechanism of inhibition in the ErbB (EGFR) family.

<span class="mw-page-title-main">ERBB3</span> Protein found in humans

Receptor tyrosine-protein kinase erbB-3, also known as HER3, is a membrane bound protein that in humans is encoded by the ERBB3 gene.

<span class="mw-page-title-main">ERBB4</span> Protein-coding gene in the species Homo sapiens

Receptor tyrosine-protein kinase erbB-4 is an enzyme that in humans is encoded by the ERBB4 gene. Alternatively spliced variants that encode different protein isoforms have been described; however, not all variants have been fully characterized.

<span class="mw-page-title-main">EGF-like domain</span> Protein domain named after the epidermal growth factor protein

The EGF-like domain is an evolutionary conserved protein domain, which derives its name from the epidermal growth factor where it was first described. It comprises about 30 to 40 amino-acid residues and has been found in a large number of mostly animal proteins. Most occurrences of the EGF-like domain are found in the extracellular domain of membrane-bound proteins or in proteins known to be secreted. An exception to this is the prostaglandin-endoperoxide synthase. The EGF-like domain includes 6 cysteine residues which in the epidermal growth factor have been shown to form 3 disulfide bonds. The structures of 4-disulfide EGF-domains have been solved from the laminin and integrin proteins. The main structure of EGF-like domains is a two-stranded β-sheet followed by a loop to a short C-terminal, two-stranded β-sheet. These two β-sheets are usually denoted as the major (N-terminal) and minor (C-terminal) sheets. EGF-like domains frequently occur in numerous tandem copies in proteins: these repeats typically fold together to form a single, linear solenoid domain block as a functional unit.

<span class="mw-page-title-main">TNFRSF12A</span> Protein-coding gene in the species Homo sapiens

Tumor necrosis factor receptor superfamily member 12A also known as the TWEAK receptor (TWEAKR) is a protein that in humans is encoded by the TNFRSF12A gene.

<span class="mw-page-title-main">Neuregulin 3</span> Protein-coding gene in Homo sapiens

Neuregulin 3, also known as NRG3, is a neural-enriched member of the neuregulin protein family which in humans is encoded by the NRG3 gene. The NRGs are a group of signaling proteins part of the superfamily of epidermal growth factor, EGF like polypeptide growth factor. These groups of proteins possess an 'EGF-like domain' that consists of six cysteine residues and three disulfide bridges predicted by the consensus sequence of the cysteine residues.

<span class="mw-page-title-main">TMEM8A</span> Protein-coding gene in the species Homo sapiens

Transmembrane protein 8A is a protein that in humans is encoded by the TMEM8A gene (16p13.3.). Evolutionarily, TMEM8A orthologs are found in primates and mammals and in a few more distantly related species. TMEM8A contains five transmembrane domains and one EGF-like domain which are all highly conserved in the ortholog space. Although there is no confirmed function of TMEM8A, through analyzing expression and experimental data, it is predicted that TMEM8A is an adhesion protein that plays a role in keeping T-cells in their resting state.

<span class="mw-page-title-main">Spitz (protein)</span> Protein in Drosophila melanogaster

Spitz is a protein in Drosophila species which is the major activator of their epidermal growth factor receptor (EGFR).

Nepidermin, also known as recombinant human epidermal growth factor (rhEGF), is a recombinant form of human epidermal growth factor (EGF) and a cicatrizant. As a recombinant form of EGF, nepidermin is an agonist of the epidermal growth factor receptor (EGFR), and is the first EGFR agonist to be marketed. It was developed by Cuban Center for Genetic Engineering and Biotechnology (CIBG), and has been marketed by Heber Biotech as an intralesional injection for diabetic foot ulcer under the trade name Heberprot-P since 2006. As of 2016, Heberprot-P had been marketed in 23 countries, but remains unavailable in the United States. In 2015, preparations were made to conduct the Phase III trials required for FDA approval, however as of 2023 developments in U.S.-Cuba relations have stymied importation of the drug from Cuba.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000138798 – Ensembl, May 2017
  2. 1 2 3 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.
  5. 1 2 3 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.
  6. 1 2 3 Carpenter G, Cohen S (May 1990). "Epidermal growth factor". The Journal of Biological Chemistry. 265 (14): 7709–12. doi: 10.1016/S0021-9258(19)38983-5 . PMID   2186024.
  7. 1 2 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. PMC   9284722 . PMID   35909816.
  8. 1 2 3 4 5 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.
  9. 1 2 Hollenberg MD, Gregory H (May 1980). "Epidermal growth factor-urogastrone: biological activity and receptor binding of derivatives". Molecular Pharmacology. 17 (3): 314–320. PMID   6248761.
  10. ↑ 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.
  11. ↑ 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.
  12. 1 2 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
  13. ↑ Satyanarayana U (2002). Biochemistry (2nd ed.). Kolkata, India: Books and Allied. ISBN   8187134801. OCLC   71209231.
  14. ↑ 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.
  15. ↑ Fallon JH, Seroogy KB, Loughlin SE, Morrison RS, Bradshaw RA, Knaver DJ, et al. (June 1984). "Epidermal growth factor immunoreactive material in the central nervous system: location and development". Science. 224 (4653): 1107–9. Bibcode:1984Sci...224.1107F. doi:10.1126/science.6144184. PMID   6144184.
  16. 1 2 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ Berlanga J, Fernández JI, López E, López PA, del Río A, Valenzuela C, et al. (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.
  20. ↑ 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.
  21. 1 2 Martí-Carvajal AJ, Gluud C, Nicola S, Simancas-Racines D, Reveiz L, Oliva P, et al. (October 2015). "Growth factors for treating diabetic foot ulcers". The Cochrane Database of Systematic Reviews. 2015 (10): CD008548. doi:10.1002/14651858.CD008548.pub2. PMC   8665376 . PMID   26509249.
  22. ↑ 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.
  23. ↑ Tenchurin T, Lyundup A, Demchenko A, Krasheninnikov M, Balyasin M, Klabukov I, et al. (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. S2CID   90593089.
  24. ↑ Del Angel-Mosqueda C, Gutiérrez-Puente Y, López-Lozano AP, Romero-Zavaleta RE, Mendiola-Jiménez A, Medina-De la Garza CE, et al. (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.
  25. ↑ Pache JC (2006-01-01). "Epidermal growth factors". In Laurent GJ, Shapiro SD (eds.). 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.

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