Amphiregulin

Amphiregulin, also known as AREG, is a protein syntetized as a transmembrane glycoprotein with 252 aminoacids and it is encoded by the AREG gene.[5][6][7] in human.[8]

AREG
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2RNL
Identifiers
Aliases	AREG, AR, AREGB, CRDGF, SDGF, amphiregulin
External IDs	OMIM: 104640 MGI: 88068 HomoloGene: 1252 GeneCards: AREG
Gene location (Human) Chr. Chromosome 4 (human)[1] Band 4q13.3 Start 74,445,136 bp[1] End 74,455,005 bp[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)[2] Band 5 E1|5 44.78 cM Start 91,139,599 bp[2] End 91,148,432 bp[2]
Gene ontology Molecular function • cytokine activity • epidermal growth factor receptor binding • GO:0001948 protein binding • growth factor activity Cellular component • cytoplasm • integral component of membrane • endoplasmic reticulum membrane • membrane • intracellular • cell surface • ER to Golgi transport vesicle membrane • endoplasmic reticulum-Golgi intermediate compartment membrane • cell nucleus • Golgi membrane • extracellular • extracellular region • clathrin-coated vesicle membrane Biological process • dichotomous subdivision of terminal units involved in mammary gland duct morphogenesis • G-protein coupled receptor signaling pathway • response to estradiol • epidermal growth factor receptor signaling pathway • response to organic cyclic compound • cell-cell signaling • mammary gland branching involved in thelarche • response to peptide hormone • response to glucocorticoid • mammary gland alveolus development • negative regulation of osteoblast differentiation • ER to Golgi vesicle-mediated transport • epithelial cell proliferation involved in mammary gland duct elongation • COPII vesicle coating • glial cell proliferation • response to cAMP • positive regulation of phosphorylation • cellular proliferation • neuron projection development • response to hydrogen peroxide • positive regulation of peptidyl-tyrosine phosphorylation • regulation of receptor activity • positive regulation of cell proliferation • MAPK cascade • signal transduction • negative regulation of epidermal growth factor receptor signaling pathway • positive regulation of protein kinase B signaling • membrane organization • positive regulation of keratinocyte proliferation Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	374	11839
Ensembl	ENSG00000109321	ENSMUSG00000029378
UniProt	P15514	P31955
RefSeq (mRNA)	NM_001657	NM_009704
RefSeq (protein)	NP_001648	NP_033834
Location (UCSC)	Chr 4: 74.45 – 74.46 Mb	Chr 5: 91.14 – 91.15 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

The protein encoded by this gene is a member of the epidermal growth factor (EGF) family.[5]

It is a critical autocrine growth factor as well as a mitogen for astrocytes, Schwann cells, and fibroblasts. It is ligand for epidermal growth factor (EGF) and it is related to transforming growth factor alpha (TGF-alpha). This protein interacts with the Epidermal growth factor receptor (EGFR) to promote the growth of normal epithelial cells.

Biological role

AREG is a critical factor in estrogen action and ductal development of the mammary glands.[9][10][11][12][13] Amphiregulin has been found to be essential for mammary ductal development, as evidenced by absence of ductal growth in amphiregulin knockout mice.[12] This is similar to the phenotypes of EGFR and ERα knockout mice, which also show absence of ductal growth.[12] Amphiregulin is expressed in many parts of body such as ovaries, placenta, pancreas, breasts, lungs and spleen. Expression of amphiregulin can be induced by TGF-α, TNF-α, interleukin 1, and prostaglandins.[14][15]

Clinical significance

Psoriasis

Mutations in this encoded protein are associated with a psoriasis-like skin phenotype[16][5]. Higher circulating levels of amphiregulin are associated with AGVHD progression.[17] [18][19]

Cancer

Overexpression of amphiregulin is connected with cancer of the breast, prostate, colon, pancreas, lung, spleen, and bladder.[20][21][22]

Rheumatoid arthritis

It seems that expression of AREG is connected with proliferation of fibroblasts and production of proinflammatory cytokines interleukin 8 and vascular endothelial growth factor (VEGF).[23]

Inflammation

Amphiregulin is part of cellular response type 2.[24] It was found that the cell source of amphiregulin is innate lymphoid cells 2 (ILC2) which are dependent on interleukin 33. ILC2 expressed amphiregulin after tissue damage of the intestines and activation by IL-33. Moreover, endogenous AREG with IL-33 decreased the intestinal inflammation in mice with normal count of T-lymphocytes and in deficient mice.[25]

References

1. GRCh38: Ensembl release 89: ENSG00000109321 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000029378 - 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. "Entrez Gene: AREG amphiregulin (schwannoma-derived growth factor)".
6. Shoyab M, Plowman GD, McDonald VL, Bradley JG, Todaro GJ (February 1989). "Structure and function of human amphiregulin: a member of the epidermal growth factor family". Science. 243 (4894 Pt 1): 1074–6. Bibcode:1989Sci...243.1074S. doi:10.1126/science.2466334. PMID 2466334.
7. Plowman GD, Green JM, McDonald VL, Neubauer MG, Disteche CM, Todaro GJ, Shoyab M (May 1990). "The amphiregulin gene encodes a novel epidermal growth factor-related protein with tumor-inhibitory activity". Molecular and Cellular Biology. 10 (5): 1969–81. doi:10.1128/MCB.10.5.1969. PMC 360543. PMID 2325643.
8. "AREG (amphiregulin (schwannoma-derived growth factor))". atlasgeneticsoncology.org. Retrieved 2019-08-27.
9. Aupperlee MD, Leipprandt JR, Bennett JM, Schwartz RC, Haslam SZ (May 2013). "Amphiregulin mediates progesterone-induced mammary ductal development during puberty". Breast Cancer Research. 15 (3): R44. doi:10.1186/bcr3431. PMC 3738150. PMID 23705924.
10. LaMarca HL, Rosen JM (2007). "Estrogen regulation of mammary gland development and breast cancer: amphiregulin takes center stage". Breast Cancer Research. 9 (4): 304. doi:10.1186/bcr1740. PMC 2206713. PMID 17659070.
11. Kariagina A, Xie J, Leipprandt JR, Haslam SZ (October 2010). "Amphiregulin mediates estrogen, progesterone, and EGFR signaling in the normal rat mammary gland and in hormone-dependent rat mammary cancers". Hormones & Cancer. 1 (5): 229–44. doi:10.1007/s12672-010-0048-0. PMC 3000471. PMID 21258428.
12. McBryan J, Howlin J, Napoletano S, Martin F (June 2008). "Amphiregulin: role in mammary gland development and breast cancer". Journal of Mammary Gland Biology and Neoplasia. 13 (2): 159–69. doi:10.1007/s10911-008-9075-7. PMID 18398673.
13. Sternlicht MD, Sunnarborg SW (June 2008). "The ADAM17-amphiregulin-EGFR axis in mammary development and cancer". Journal of Mammary Gland Biology and Neoplasia. 13 (2): 181–94. doi:10.1007/s10911-008-9084-6. PMC 2723838. PMID 18470483.
14. "AREG (amphiregulin (schwannoma-derived growth factor))". atlasgeneticsoncology.org. Retrieved 2019-08-27.
15. Busser B, Sancey L, Brambilla E, Coll JL, Hurbin A (December 2011). "The multiple roles of amphiregulin in human cancer". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1816 (2): 119–31. doi:10.1016/j.bbcan.2011.05.003. PMID 21658434.
16. Bhagavathula N, Nerusu KC, Fisher GJ, Liu G, Thakur AB, Gemmell L, et al. (April 2005). "Amphiregulin and epidermal hyperplasia: amphiregulin is required to maintain the psoriatic phenotype of human skin grafts on severe combined immunodeficient mice". The American Journal of Pathology. 166 (4): 1009–16. doi:10.1016/S0002-9440(10)62322-X. PMC 1780140. PMID 15793282.
17. Bhagavathula N, Nerusu KC, Fisher GJ, Liu G, Thakur AB, Gemmell L, et al. (April 2005). "Amphiregulin and epidermal hyperplasia: amphiregulin is required to maintain the psoriatic phenotype of human skin grafts on severe combined immunodeficient mice". The American Journal of Pathology. 166 (4): 1009–16. doi:10.1016/S0002-9440(10)62322-X. PMC 1780140. PMID 15793282.
18. Holtan SG, DeFor TE, Panoskaltsis-Mortari A, Khera N, Levine JE, Flowers ME, et al. (August 2018). "Amphiregulin modifies the Minnesota Acute Graft-versus-Host Disease Risk Score: results from BMT CTN 0302/0802". Blood Advances. 2 (15): 1882–1888. doi:10.1182/bloodadvances.2018017343. PMC 6093743. PMID 30087106.
19. Piepkorn M (April 1996). "Overexpression of amphiregulin, a major autocrine growth factor for cultured human keratinocytes, in hyperproliferative skin diseases". The American Journal of Dermatopathology. 18 (2): 165–71. doi:10.1097/00000372-199604000-00010. PMID 8739992.
20. Busser B, Sancey L, Brambilla E, Coll JL, Hurbin A (December 2011). "The multiple roles of amphiregulin in human cancer". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1816 (2): 119–31. doi:10.1016/j.bbcan.2011.05.003. PMID 21658434.
21. "AREG (amphiregulin (schwannoma-derived growth factor))". atlasgeneticsoncology.org. Retrieved 2019-08-27.
22. McBryan J, Howlin J, Napoletano S, Martin F (June 2008). "Amphiregulin: role in mammary gland development and breast cancer". Journal of Mammary Gland Biology and Neoplasia. 13 (2): 159–69. doi:10.1007/s10911-008-9075-7. PMID 18398673.
23. Yamane S, Ishida S, Hanamoto Y, Kumagai K, Masuda R, Tanaka K, et al. (April 2008). "Proinflammatory role of amphiregulin, an epidermal growth factor family member whose expression is augmented in rheumatoid arthritis patients". Journal of Inflammation. 5: 5. doi:10.1186/1476-9255-5-5. PMC 2396620. PMID 18439312.
24. Zaiss DM, Yang L, Shah PR, Kobie JJ, Urban JF, Mosmann TR (December 2006). "Amphiregulin, a TH2 cytokine enhancing resistance to nematodes". Science. 314 (5806): 1746. Bibcode:2006Sci...314.1746Z. doi:10.1126/science.1133715. PMID 17170297.
25. Monticelli LA, Osborne LC, Noti M, Tran SV, Zaiss DM, Artis D (August 2015). "IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin-EGFR interactions". Proceedings of the National Academy of Sciences of the United States of America. 112 (34): 10762–7. Bibcode:2015PNAS..11210762M. doi:10.1073/pnas.1509070112. PMC 4553775. PMID 26243875.

Further reading

• Culouscou JM, Remacle-Bonnet M, Carlton GW, Plowman GD, Shoyab M (1993). "Colorectum cell-derived growth factor (CRDGF) is homologous to amphiregulin, a member of the epidermal growth factor family". Growth Factors. 7 (3): 195–205. doi:10.3109/08977199209046924. PMID 1333777.
• Cook PW, Mattox PA, Keeble WW, Pittelkow MR, Plowman GD, Shoyab M, et al. (May 1991). "A heparin sulfate-regulated human keratinocyte autocrine factor is similar or identical to amphiregulin". Molecular and Cellular Biology. 11 (5): 2547–57. doi:10.1128/MCB.11.5.2547. PMC 360024. PMID 2017164.
• Kimura H, Fischer WH, Schubert D (November 1990). "Structure, expression and function of a schwannoma-derived growth factor". Nature. 348 (6298): 257–60. Bibcode:1990Natur.348..257K. doi:10.1038/348257a0. PMID 2234093.
• Plowman GD, Green JM, McDonald VL, Neubauer MG, Disteche CM, Todaro GJ, Shoyab M (May 1990). "The amphiregulin gene encodes a novel epidermal growth factor-related protein with tumor-inhibitory activity". Molecular and Cellular Biology. 10 (5): 1969–81. doi:10.1128/MCB.10.5.1969. PMC 360543. PMID 2325643.
• Shoyab M, Plowman GD, McDonald VL, Bradley JG, Todaro GJ (February 1989). "Structure and function of human amphiregulin: a member of the epidermal growth factor family". Science. 243 (4894 Pt 1): 1074–6. Bibcode:1989Sci...243.1074S. doi:10.1126/science.2466334. PMID 2466334.
• Shoyab M, McDonald VL, Bradley JG, Todaro GJ (September 1988). "Amphiregulin: a bifunctional growth-modulating glycoprotein produced by the phorbol 12-myristate 13-acetate-treated human breast adenocarcinoma cell line MCF-7". Proceedings of the National Academy of Sciences of the United States of America. 85 (17): 6528–32. Bibcode:1988PNAS...85.6528S. doi:10.1073/pnas.85.17.6528. PMC 282006. PMID 3413110.
• Chen CS, Bejcek BE, Kersey JH (1995). "A mapping study of 13 genes on human chromosome bands 4q11-->q25". Cytogenetics and Cell Genetics. 69 (3–4): 260–5. doi:10.1159/000133976. PMID 7698025.
• Cook PW, Piepkorn M, Clegg CH, Plowman GD, DeMay JM, Brown JR, Pittelkow MR (November 1997). "Transgenic expression of the human amphiregulin gene induces a psoriasis-like phenotype". The Journal of Clinical Investigation. 100 (9): 2286–94. doi:10.1172/JCI119766. PMC 508424. PMID 9410906.
• 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.
• Reddy KB, Krueger JS, Kondapaka SB, Diglio CA (July 1999). "Mitogen-activated protein kinase (MAPK) regulates the expression of progelatinase B (MMP-9) in breast epithelial cells". International Journal of Cancer. 82 (2): 268–73. doi:10.1002/(SICI)1097-0215(19990719)82:2<268::AID-IJC18>3.0.CO;2-4. PMID 10389762.
• Fernandes AM, Hamburger AW, Gerwin BI (July 1999). "Production of epidermal growth factor related ligands in tumorigenic and benign human lung epithelial cells". Cancer Letters. 142 (1): 55–63. doi:10.1016/S0304-3835(99)00166-4. PMID 10424781.
• Lee SB, Huang K, Palmer R, Truong VB, Herzlinger D, Kolquist KA, et al. (September 1999). "The Wilms tumor suppressor WT1 encodes a transcriptional activator of amphiregulin". Cell. 98 (5): 663–73. doi:10.1016/S0092-8674(00)80053-7. PMID 10490105.
• Tokumaru S, Higashiyama S, Endo T, Nakagawa T, Miyagawa JI, Yamamori K, et al. (October 2000). "Ectodomain shedding of epidermal growth factor receptor ligands is required for keratinocyte migration in cutaneous wound healing". The Journal of Cell Biology. 151 (2): 209–20. doi:10.1083/jcb.151.2.209. PMC 2192647. PMID 11038170.
• Ebert MP, Hernberg S, Fei G, Sokolowski A, Schulz HU, Lippert H, Malfertheiner P (July 2001). "Induction and expression of cyclin D3 in human pancreatic cancer". Journal of Cancer Research and Clinical Oncology. 127 (7): 449–54. doi:10.1007/s004320100235. PMID 11469683.
• Berquin IM, Dziubinski ML, Nolan GP, Ethier SP (July 2001). "A functional screen for genes inducing epidermal growth factor autonomy of human mammary epithelial cells confirms the role of amphiregulin". Oncogene. 20 (30): 4019–28. doi:10.1038/sj.onc.1204537. PMID 11494130.
• Thøgersen VB, Sørensen BS, Poulsen SS, Orntoft TF, Wolf H, Nexo E (August 2001). "A subclass of HER1 ligands are prognostic markers for survival in bladder cancer patients". Cancer Research. 61 (16): 6227–33. PMID 11507076.
• Wolfgang CD, Essand M, Lee B, Pastan I (November 2001). "T-cell receptor gamma chain alternate reading frame protein (TARP) expression in prostate cancer cells leads to an increased growth rate and induction of caveolins and amphiregulin". Cancer Research. 61 (22): 8122–6. PMID 11719440.
• Schiemann U, Konturek J, Assert R, Rembiasz K, Domschke W, Konturek S, Pfeiffer A (February 2002). "mRNA expression of EGF receptor ligands in atrophic gastritis before and after Helicobacter pylori eradication". Medical Science Monitor. 8 (2): CR53-8. PMID 11859273.
• Tørring N, Møller-Ernst Jensen K, Lund L, Nielsen JE, Djurhuus JC, Poulsen SS, Nexø E (April 2002). "Possible autocrine loop of the epidermal growth factor system in patients with benign prostatic hyperplasia treated with finasteride: a placebo-controlled randomized study". BJU International. 89 (6): 583–90. doi:10.1046/j.1464-410X.2002.02665.x. PMID 11942969.
• Hurbin A, Dubrez L, Coll JL, Favrot MC (December 2002). "Inhibition of apoptosis by amphiregulin via an insulin-like growth factor-1 receptor-dependent pathway in non-small cell lung cancer cell lines". The Journal of Biological Chemistry. 277 (51): 49127–33. doi:10.1074/jbc.M207584200. PMID 12356750.

External links

• Human AR genome location and AR gene details page in the UCSC Genome Browser.
• Human AREG genome location and AREG gene details page in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: P15514 (Amphiregulin) at the PDBe-KB.