Amphiregulin

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

It is a critical autocrine growth factor as well as a mitogen for astrocytes, Schwann cells, and fibroblasts. It is a 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.

AREG is a critical factor in estrogen action and ductal development of the mammary glands.{{cite journal | vauthors = Aupperlee MD, Leipprandt JR, Bennett JM, Schwartz RC, Haslam SZ | title = Amphiregulin mediates progesterone-induced mammary ductal development during puberty | journal = Breast Cancer Research | volume = 15 | issue = 3 | pages = R44 | date = May 2013 | pmid = 23705924 | pmc = 3738150 | doi = 10.1186/bcr3431 | doi-access = free }}{{cite journal |author2-link=Jeffrey M. Rosen | vauthors = LaMarca HL, Rosen JM | title = Estrogen regulation of mammary gland development and breast cancer: amphiregulin takes center stage | journal = Breast Cancer Research | volume = 9 | issue = 4 | pages = 304 | year = 2007 | pmid = 17659070 | pmc = 2206713 | doi = 10.1186/bcr1740 | doi-access = free }}{{cite journal | vauthors = Kariagina A, Xie J, Leipprandt JR, Haslam SZ | title = Amphiregulin mediates estrogen, progesterone, and EGFR signaling in the normal rat mammary gland and in hormone-dependent rat mammary cancers | journal = Hormones & Cancer | volume = 1 | issue = 5 | pages = 229–244 | date = October 2010 | pmid = 21258428 | pmc = 3000471 | doi = 10.1007/s12672-010-0048-0 }}{{cite journal | vauthors = McBryan J, Howlin J, Napoletano S, Martin F | title = Amphiregulin: role in mammary gland development and breast cancer | journal = Journal of Mammary Gland Biology and Neoplasia | volume = 13 | issue = 2 | pages = 159–169 | date = June 2008 | pmid = 18398673 | doi = 10.1007/s10911-008-9075-7 | s2cid = 13229645 }}{{cite journal | vauthors = Sternlicht MD, Sunnarborg SW | title = The ADAM17-amphiregulin-EGFR axis in mammary development and cancer | journal = Journal of Mammary Gland Biology and Neoplasia | volume = 13 | issue = 2 | pages = 181–194 | date = June 2008 | pmid = 18470483 | pmc = 2723838 | doi = 10.1007/s10911-008-9084-6 }} Amphiregulin has been found to be essential for mammary ductal development, as evidenced by absence of ductal growth in amphiregulin knockout mice. This is similar to the phenotypes of EGFR and ERα knockout mice, which also show absence of ductal growth. 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.{{Cite web|url=http://atlasgeneticsoncology.org/Genes/GC_AREG.html|title=AREG (amphiregulin (schwannoma-derived growth factor))|website=atlasgeneticsoncology.org|access-date=2019-08-27|archive-date=2019-08-27|archive-url=https://web.archive.org/web/20190827181624/http://atlasgeneticsoncology.org/Genes/GC_AREG.html|url-status=dead}}{{cite journal | vauthors = Busser B, Sancey L, Brambilla E, Coll JL, Hurbin A | title = The multiple roles of amphiregulin in human cancer | journal = Biochimica et Biophysica Acta (BBA) - Reviews on Cancer | volume = 1816 | issue = 2 | pages = 119–131 | date = December 2011 | pmid = 21658434 | doi = 10.1016/j.bbcan.2011.05.003 }}

Generally, amphiregulin is considered to be a part of type 2 mediated resistance and tolerance, the latter of which occurs by promoting the reestablishment of tissue integrity after damage that is due to acute or chronic inflammation. Its involvement in tissue repair can be explained by its dual role, as amphiregulin can induce mitogenic signals, but it can also lead to cell differentiation of epithelial cells.{{cite journal | vauthors = Zaiss DM, Gause WC, Osborne LC, Artis D | title = Emerging functions of amphiregulin in orchestrating immunity, inflammation, and tissue repair | journal = Immunity | volume = 42 | issue = 2 | pages = 216–226 | date = February 2015 | pmid = 25692699 | pmc = 4792035 | doi = 10.1016/j.immuni.2015.01.020 }}

While epithelial-derived amphiregulin can promote tissue repair, several immune cells are found to express it in cases of tissue damage, so amphiregulin is part of the crosstalk between immune and epithelial cells. {{cite journal | vauthors = Singh SS, Chauhan SB, Kumar A, Kumar S, Engwerda CR, Sundar S, Kumar R | title = Amphiregulin in cellular physiology, health, and disease: Potential use as a biomarker and therapeutic target | journal = Journal of Cellular Physiology | volume = 237 | issue = 2 | pages = 1143–1156 | date = February 2022 | pmid = 34698381 | doi = 10.1002/jcp.30615 | s2cid = 239889516 }}

A population of immune cells that is found to increase its amphiregulin expression after tissue damage, is the innate lymphoid cell 2 (ILC2) population. This has been observed in several organs, such as the lung, the intestine, and the skin. The expression of amphiregulin by ILC2s can be induced by interleukin 33 (IL-33).{{cite journal | vauthors = Cox JR, Cruickshank SM, Saunders AE | title = Maintenance of Barrier Tissue Integrity by Unconventional Lymphocytes | journal = Frontiers in Immunology | volume = 12 | pages = 670471 | date = 2021 | pmid = 33936115 | pmc = 8079635 | doi = 10.3389/fimmu.2021.670471 | doi-access = free }} Also, in skin derived ILC2s, amphiregulin expression was regulated by the interaction of killer-cell lectin-like receptor G1 (KLRG1) with E-cadherin.{{cite journal | vauthors = Ochel A, Tiegs G, Neumann K | title = Type 2 Innate Lymphoid Cells in Liver and Gut: From Current Knowledge to Future Perspectives | journal = International Journal of Molecular Sciences | volume = 20 | issue = 8 | pages = 1896 | date = April 2019 | pmid = 30999584 | pmc = 6514972 | doi = 10.3390/ijms20081896 | doi-access = free }} After intestinal damage, activated intestinal ILC2s produce amphiregulin which enhances the production of mucin by epithelial cells, increases the expression of Claudin-1 and promotes the activity of goblet cells. These functions of amphiregulin lead to increased junction strength, as well as the strengthening of the mucus layer.

Tissue resident regulatory T cells (Tregs) can also express amphiregulin to promote tissue repair. In the skeletal muscle, the IL-33 receptor (ST2) expressing Tregs have a distinct T-cell receptor (TCR) repertoire,{{cite journal | vauthors = Burzyn D, Kuswanto W, Kolodin D, Shadrach JL, Cerletti M, Jang Y, Sefik E, Tan TG, Wagers AJ, Benoist C, Mathis D | title = A special population of regulatory T cells potentiates muscle repair | journal = Cell | volume = 155 | issue = 6 | pages = 1282–1295 | date = December 2013 | pmid = 24315098 | pmc = 3894749 | doi = 10.1016/j.cell.2013.10.054 }} and TCR signals don’t seem to be required for amphiregulin production, but this process can be dependent on the IL-33/ST2 (or IL-33 receptor) pathway and the expression of interleukin 18 receptor (IL-18R) on tissue resident Tregs.{{cite journal | vauthors = Zhang C, Li L, Feng K, Fan D, Xue W, Lu J | title = 'Repair' Treg Cells in Tissue Injury | journal = Cellular Physiology and Biochemistry | volume = 43 | issue = 6 | pages = 2155–2169 | date = 2017-10-25 | pmid = 29069643 | doi = 10.1159/000484295 | doi-access = free }} Also, amphiregulin that is expressed from these Tregs can further enhance their function, forming an autocrine positive feedback loop.{{cite journal | vauthors = Boothby IC, Cohen JN, Rosenblum MD | title = Regulatory T cells in skin injury: At the crossroads of tolerance and tissue repair | journal = Science Immunology | volume = 5 | issue = 47 | date = May 2020 | pmid = 32358172 | pmc = 7274208 | doi = 10.1126/sciimmunol.aaz9631 }} Amphiregulin-expressing tissue resident Tregs have been observed in the lung, where most of them are CD44^hiCD62L^lo and they express higher levels of CD103, programmed cell death protein 1 (PD-1), glucocorticoid-induced TNFR-related protein (GITR), cytotoxic T-lymphocyte antigen 4 (CTLA-4) and KLRG1. They have been found in injured muscles, where this population has been associated with eosinophil influx, and the production of amphiregulin could enhance the colony-forming efficiency and myogenic differentiation of skeletal muscle satellite cells in vitro, increasing muscle healing. In the inflamed colon, Gata3⁺Helios⁺ Tregs express high levels of amphiregulin too.{{cite journal | vauthors = Ito M, Komai K, Nakamura T, Srirat T, Yoshimura A | title = Tissue regulatory T cells and neural repair | journal = International Immunology | volume = 31 | issue = 6 | pages = 361–369 | date = May 2019 | pmid = 30893423 | doi = 10.1093/intimm/dxz031 | doi-access = free }} Moreover, Tregs that express amphiregulin, along with keratinocyte growth factor (KGF), CD39 and CD73, act on parenchymal cells to promote tissue repair and regeneration.

Some unconventional T cells have been associated with the promotion of tissue repair by amphiregulin in a direct or in an indirect manner. After intestinal damage, mucosal-associated invariant T (MAIT) cells produce amphiregulin that leads to epithelial cell turnover and enhances the activity of goblet cells. Also, a pro-repair response by amphiregulin produced by ILC2s and Tregs, that is dependent on IL-33 signaling, is induced by gamma delta (γδ) T cells that produce interleukin 17A (IL-17A). This correlation between IL-17A-producing γδ T cells and amphiregulin has been observed in the lungs and in the oral mucosa.

Mutations in this encoded protein are associated with a psoriasis-like skin phenotype.{{cite journal | vauthors = Bhagavathula N, Nerusu KC, Fisher GJ, Liu G, Thakur AB, Gemmell L, Kumar S, Xu ZH, Hinton P, Tsurushita N, Landolfi NF, Voorhees JJ, Varani J | title = Amphiregulin and epidermal hyperplasia: amphiregulin is required to maintain the psoriatic phenotype of human skin grafts on severe combined immunodeficient mice | journal = The American Journal of Pathology | volume = 166 | issue = 4 | pages = 1009–1016 | date = April 2005 | pmid = 15793282 | pmc = 1780140 | doi = 10.1016/S0002-9440(10)62322-X }} Higher circulating levels of amphiregulin are associated with AGVHD progression.{{cite journal | vauthors = Bhagavathula N, Nerusu KC, Fisher GJ, Liu G, Thakur AB, Gemmell L, Kumar S, Xu ZH, Hinton P, Tsurushita N, Landolfi NF, Voorhees JJ, Varani J | title = Amphiregulin and epidermal hyperplasia: amphiregulin is required to maintain the psoriatic phenotype of human skin grafts on severe combined immunodeficient mice | journal = The American Journal of Pathology | volume = 166 | issue = 4 | pages = 1009–1016 | date = April 2005 | pmid = 15793282 | pmc = 1780140 | doi = 10.1016/S0002-9440(10)62322-X }}{{cite journal | vauthors = Holtan SG, DeFor TE, Panoskaltsis-Mortari A, Khera N, Levine JE, Flowers ME, Lee SJ, Inamoto Y, Chen GL, Mayer S, Arora M, Palmer J, Cutler CS, Arai S, Lazaryan A, Newell LF, Jagasia MH, Pusic I, Wood WA, Renteria AS, Yanik G, Hogan WJ, Hexner E, Ayuk F, Holler E, Bunworasate U, Efebera YA, Ferrara JL, Pidala J, Howard A, Wu J, Bolaños-Meade J, Ho V, Alousi A, Blazar BR, Weisdorf DJ, MacMillan ML | title = Amphiregulin modifies the Minnesota Acute Graft-versus-Host Disease Risk Score: results from BMT CTN 0302/0802 | journal = Blood Advances | volume = 2 | issue = 15 | pages = 1882–1888 | date = August 2018 | pmid = 30087106 | pmc = 6093743 | doi = 10.1182/bloodadvances.2018017343 }}{{cite journal | vauthors = Piepkorn M | title = Overexpression of amphiregulin, a major autocrine growth factor for cultured human keratinocytes, in hyperproliferative skin diseases | journal = The American Journal of Dermatopathology | volume = 18 | issue = 2 | pages = 165–171 | date = April 1996 | pmid = 8739992 | doi = 10.1097/00000372-199604000-00010 }}

Overexpression of amphiregulin is connected with cancer of the breast, prostate, colon, pancreas, lung, spleen, and bladder.{{cite journal | vauthors = Busser B, Sancey L, Brambilla E, Coll JL, Hurbin A | title = The multiple roles of amphiregulin in human cancer | journal = Biochimica et Biophysica Acta (BBA) - Reviews on Cancer | volume = 1816 | issue = 2 | pages = 119–131 | date = December 2011 | pmid = 21658434 | doi = 10.1016/j.bbcan.2011.05.003 }}{{Cite web|url=http://atlasgeneticsoncology.org/Genes/GC_AREG.html|title=AREG (amphiregulin (schwannoma-derived growth factor))|website=atlasgeneticsoncology.org|access-date=2019-08-27|archive-date=2019-08-27|archive-url=https://web.archive.org/web/20190827181624/http://atlasgeneticsoncology.org/Genes/GC_AREG.html|url-status=dead}}

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).{{cite journal | vauthors = Yamane S, Ishida S, Hanamoto Y, Kumagai K, Masuda R, Tanaka K, Shiobara N, Yamane N, Mori T, Juji T, Fukui N, Itoh T, Ochi T, Suzuki R | title = Proinflammatory role of amphiregulin, an epidermal growth factor family member whose expression is augmented in rheumatoid arthritis patients | journal = Journal of Inflammation | volume = 5 | pages = 5 | date = April 2008 | pmid = 18439312 | pmc = 2396620 | doi = 10.1186/1476-9255-5-5 | doi-access = free }}

Chronic elevation of amphiregulin levels has been associated with fibrosis in several organs. ILC2s are drivers of liver, skin, and pulmonary fibrosis, and their expression of interleukin 13 (IL-13) and amphiregulin is implicated in this process. Pathogenic memory Th2 cells that express amphiregulin are also involved in pulmonary fibrosis. Exposure to house dust mite leads to the increase of amphiregulin-expressing pathogenic memory Th2 cells. This increase might be related to the IL-33/ST2 signaling, as blocking this pathway causes less production of amphiregulin. The function of amphiregulin in airway fibrosis is related to eosinophils that express EGFR, in which amphiregulin binds to, resulting in the upregulation of inflammatory genes, including Spp1 that encodes osteopontin. The expression of osteopontin by eosinophils shapes the pathogenesis of pulmonary fibrosis.{{cite journal | vauthors = Hirahara K, Aoki A, Morimoto Y, Kiuchi M, Okano M, Nakayama T | title = The immunopathology of lung fibrosis: amphiregulin-producing pathogenic memory T helper-2 cells control the airway fibrotic responses by inducing eosinophils to secrete osteopontin | journal = Seminars in Immunopathology | volume = 41 | issue = 3 | pages = 339–348 | date = May 2019 | pmid = 30968186 | doi = 10.1007/s00281-019-00735-6 | s2cid = 106409455 }} Moreover, macrophage-derived amphiregulin is involved in the transforming growth factor beta (TGF-β)-induced fibrosis too, as it has been found to activate latent TGF-β through the activation of integrin-α_V complex.{{cite journal | vauthors = Huang H, Yin K, Tang H | title = Macrophage amphiregulin-pericyte TGF-β axis: a novel mechanism of the immune system that contributes to wound repair | journal = Acta Biochimica et Biophysica Sinica | volume = 52 | issue = 4 | pages = 463–465 | date = April 2020 | pmid = 32147698 | doi = 10.1093/abbs/gmaa001 | doi-access = free }}{{cite journal | vauthors = Zaiss DM, Minutti CM, Knipper JA | title = Immune- and non-immune-mediated roles of regulatory T-cells during wound healing | journal = Immunology | volume = 157 | issue = 3 | pages = 190–197 | date = July 2019 | pmid = 30866049 | pmc = 6600083 | doi = 10.1111/imm.13057 }} In the liver, ongoing necrosis leads to the activation of hepatic ILC2s which release amphiregulin along with IL-13. The release of them activates the hepatic stellate cells that transform into myofibroblasts, and ultimately promotes liver fibrosis.

Amphiregulin is part of cellular response type 2.{{cite journal | vauthors = Zaiss DM, Yang L, Shah PR, Kobie JJ, Urban JF, Mosmann TR | title = Amphiregulin, a TH2 cytokine enhancing resistance to nematodes | journal = Science | volume = 314 | issue = 5806 | pages = 1746 | date = December 2006 | pmid = 17170297 | doi = 10.1126/science.1133715 | s2cid = 27808704 | bibcode = 2006Sci...314.1746Z }} 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.{{cite journal | vauthors = Monticelli LA, Osborne LC, Noti M, Tran SV, Zaiss DM, Artis D | title = IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin-EGFR interactions | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 34 | pages = 10762–10767 | date = August 2015 | pmid = 26243875 | pmc = 4553775 | doi = 10.1073/pnas.1509070112 | doi-access = free | bibcode = 2015PNAS..11210762M }}

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{{refend}}

• {{UCSC gene info|AR}}
• {{UCSC gene info|AREG}}
• {{PDBe-KB2|P15514|Amphiregulin}}

{{Growth factor receptor modulators}}

Category:Estrogen regulation