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Gene Review

AREG  -  amphiregulin

Homo sapiens

Synonyms: AR, AREGB, Amphiregulin, CRDGF, Colorectum cell-derived growth factor, ...
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Disease relevance of AREG


Psychiatry related information on AREG

  • We also investigated the effects of chronic treatment with either typical or atypical antipsychotics on A2A AR binding parameters and receptors responsiveness in human platelets from patients affected by bipolar disorder [7].

High impact information on AREG

  • SDGF belongs to the epidermal growth factor family, and is an autocrine growth factor as well as a mitogen for astrocytes, Schwann cells and fibroblasts [8].
  • Moreover, H. pylori broth culture filtrates stimulated extracellular release of AR and HB-EGF protein by MKN 28 cells [9].
  • Our results indicate that transgene integration and subsequent expression of AR in basal keratinocytes correlated with a psoriasis-like skin phenotype [10].
  • Our observations also link the keratinocyte EGF receptor-ligand system to psoriatic inflammation, and suggest that aberrant expression of AR in the epidermis may represent a critical step in the development or propagation of psoriatic lesions [10].
  • To test the hypothesis that aberrant AR expression is central to the development of psoriatic lesions, we constructed a transgene (K14-ARGE) encoding a human keratin 14 promoter-driven AR gene [10].

Chemical compound and disease context of AREG


Biological context of AREG


Anatomical context of AREG

  • AREG stimulated IL-6 production and growth of BM stromal cells [1].
  • Using Affymetrix DNA microarrays, we show here that the AREG gene was expressed by purified primary myeloma cells from 65 patients and that the expression was higher than in normal bone marrow (BM) plasma cells or plasmablastic cells [1].
  • Northern blot analysis revealed that only one cell line and no tumor specimens expressed AR mRNA [5].
  • The mechanism of DCA-induced EGFR activation is ligand-dependent and is controlled, at least in part, at the level of AR release from the basolateral cell membrane [18].
  • A glycoprotein, termed amphiregulin (AR), inhibits growth of several human carcinoma cells in culture and stimulates proliferation of human fibroblasts and certain other tumor cells [17].

Associations of AREG with chemical compounds

  • AREG and TGFA are biomarkers for Gefitinib non-responders [2].
  • RESULTS: Basolateral delivery of DCA, but not CA, preferentially stimulated release of AR into the basolateral medium compared with cell lysates of polarized HCA-7 and HCT-8 cells [18].
  • Inhibiting cell surface cleavage of AR with WAY-022 before DCA treatment reduced AR (P < .05) and PGE2 (P < .05) levels in the basolateral medium [18].
  • In the absence of any N-terminal pro-region, secretion of the molecule is restored by deleting the N-terminal heparin-binding domain of mature AR [19].
  • Basal ErbB tyrosine phosphorylation and ERK phosphorylation were inhibited by two different ErbB receptor tyrosine kinase inhibitors, by the ErbB1-specific neutralizing monoclonal antibody 225 IgG, by two different metalloproteinase inhibitors, and by neutralizing antibodies against amphiregulin (AR) [20].

Physical interactions of AREG

  • EGFR truncation had no significant effect on AR binding to receptor but did result in defective GRB2 adaptor function [21].
  • Topical treatment of human skin with all-trans retinoic acid (tRA) induces EGFR ligands heparin-binding (HB)-EGF and amphiregulin (AR), and reduces betacellulin mRNA levels [22].

Regulatory relationships of AREG

  • AR is also functionally related to this family of growth regulatory molecules and is able to bind and activate the 170-kDa EGF receptor (EGFR) [23].
  • However, if the protein is fused with the AR heparin-binding domain, TGF-alpha secretion is inhibited unless the AR pro-region is also present [19].
  • In addition, AR can function as an autocrine and/or juxtacrine growth factor in human mammary epithelial cells that have been transformed by an activated c-Ha-ras proto-oncogene or by overexpression of c-erb B-2 [24].
  • Thus, AR can inhibit apoptosis in NSCLC cells through an IGF1-R-dependent pathway [25].
  • AR expression is also enhanced by mammotrophic hormones such as estrogens and other growth factors such as EGF [24].

Other interactions of AREG

  • Therefore, despite some functional redundancy among EGF family ligands, the present study reveals a distinct and essential role for AR in GPCR-triggered cellular responses [3].
  • With the exception of AR gene transcription, the CS-induced responses were blocked by the EGFR-selective kinase inhibitor AG1478 [26].
  • AR and BTC moieties were not evident by Northern blot analysis [27].
  • ERBB2 and AREG expression differed between early stage tumors (pTa grade 1) and normal samples [28].
  • Finally, PKCdelta, PKCzeta, or p90(rsk) small interfering RNAs block the antiapoptotic activity of AR/IGF1 combination but have no effect on partial apoptosis inhibition observed with each factor used alone [29].

Analytical, diagnostic and therapeutic context of AREG


  1. Expression of EGF-family receptors and amphiregulin in multiple myeloma. Amphiregulin is a growth factor for myeloma cells. Mahtouk, K., Hose, D., Rème, T., De Vos, J., Jourdan, M., Moreaux, J., Fiol, G., Raab, M., Jourdan, E., Grau, V., Moos, M., Goldschmidt, H., Baudard, M., Rossi, J.F., Cremer, F.W., Klein, B. Oncogene (2005) [Pubmed]
  2. Canonical WNT signaling pathway and human AREG. Katoh, Y., Katoh, M. Int. J. Mol. Med. (2006) [Pubmed]
  3. TACE cleavage of proamphiregulin regulates GPCR-induced proliferation and motility of cancer cells. Gschwind, A., Hart, S., Fischer, O.M., Ullrich, A. EMBO J. (2003) [Pubmed]
  4. Colorectum cell-derived growth factor (CRDGF) is homologous to amphiregulin, a member of the epidermal growth factor family. Culouscou, J.M., Remacle-Bonnet, M., Carlton, G.W., Plowman, G.D., Shoyab, M. Growth Factors (1992) [Pubmed]
  5. Heparin-binding epidermal growth factor-like growth factor stimulates mitogenic signaling and is highly expressed in human malignant gliomas. Mishima, K., Higashiyama, S., Asai, A., Yamaoka, K., Nagashima, Y., Taniguchi, N., Kitanaka, C., Kirino, T., Kuchino, Y. Acta Neuropathol. (1998) [Pubmed]
  6. Epidermal growth factor receptor pathway analysis identifies amphiregulin as a key factor for cisplatin resistance of human breast cancer cells. Eckstein, N., Servan, K., Girard, L., Cai, D., von Jonquieres, G., Jaehde, U., Kassack, M.U., Gazdar, A.F., Minna, J.D., Royer, H.D. J. Biol. Chem. (2008) [Pubmed]
  7. Upregulation of A2A adenosine receptors in platelets from patients affected by bipolar disorders under treatment with typical antipsychotics. Martini, C., Tuscano, D., Trincavelli, M.L., Cerrai, E., Bianchi, M., Ciapparelli, A., Alessio, L., Novelli, L., Catena, M., Lucacchini, A., Cassano, G.B., Dell'Osso, L. Journal of psychiatric research. (2006) [Pubmed]
  8. Structure, expression and function of a schwannoma-derived growth factor. Kimura, H., Fischer, W.H., Schubert, D. Nature (1990) [Pubmed]
  9. Helicobacter pylori upregulates expression of epidermal growth factor-related peptides, but inhibits their proliferative effect in MKN 28 gastric mucosal cells. Romano, M., Ricci, V., Di Popolo, A., Sommi, P., Del Vecchio Blanco, C., Bruni, C.B., Ventura, U., Cover, T.L., Blaser, M.J., Coffey, R.J., Zarrilli, R. J. Clin. Invest. (1998) [Pubmed]
  10. Transgenic expression of the human amphiregulin gene induces a psoriasis-like phenotype. Cook, P.W., Piepkorn, M., Clegg, C.H., Plowman, G.D., DeMay, J.M., Brown, J.R., Pittelkow, M.R. J. Clin. Invest. (1997) [Pubmed]
  11. Prostaglandin E2 synergistically enhances receptor tyrosine kinase-dependent signaling system in colon cancer cells. Shao, J., Evers, B.M., Sheng, H. J. Biol. Chem. (2004) [Pubmed]
  12. Characterization of a novel amphiregulin-related molecule in 12-O-tetradecanoylphorbol-13-acetate-treated breast cancer cells. Martinez-Lacaci, I., Johnson, G.R., Salomon, D.S., Dickson, R.B. J. Cell. Physiol. (1996) [Pubmed]
  13. Increased expression of schwannoma-derived growth factor (SDGF) mRNA in rat tumor cells: involvement of SDGF in the growth promotion of rat gliomas. Mishima, K., Asai, A., Sugiyama, A., Miyagi, Y., Kitanaka, C., Kagaya, S., Kirino, T., Kuchino, Y. Int. J. Cancer (1996) [Pubmed]
  14. Vitamin D-mediated growth inhibition of an androgen-ablated LNCaP cell line model of human prostate cancer. Yang, E.S., Maiorino, C.A., Roos, B.A., Knight, S.R., Burnstein, K.L. Mol. Cell. Endocrinol. (2002) [Pubmed]
  15. The CAG repeat polymorphism in the AR gene affects high density lipoprotein cholesterol and arterial vasoreactivity. Zitzmann, M., Brune, M., Kornmann, B., Gromoll, J., von Eckardstein, S., von Eckardstein, A., Nieschlag, E. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  16. Human airway trypsin-like protease induces amphiregulin release through a mechanism involving protease-activated receptor-2-mediated ERK activation and TNF alpha-converting enzyme activity in airway epithelial cells. Chokki, M., Eguchi, H., Hamamura, I., Mitsuhashi, H., Kamimura, T. FEBS J. (2005) [Pubmed]
  17. Amphiregulin: a bifunctional growth-modulating glycoprotein produced by the phorbol 12-myristate 13-acetate-treated human breast adenocarcinoma cell line MCF-7. Shoyab, M., McDonald, V.L., Bradley, J.G., Todaro, G.J. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  18. Ligand-dependent activation of the epidermal growth factor receptor by secondary bile acids in polarizing colon cancer cells. Merchant, N.B., Rogers, C.M., Trivedi, B., Morrow, J., Coffey, R.J. Surgery (2005) [Pubmed]
  19. The heparin-binding domain of amphiregulin necessitates the precursor pro-region for growth factor secretion. Thorne, B.A., Plowman, G.D. Mol. Cell. Biol. (1994) [Pubmed]
  20. Autocrine extracellular signal-regulated kinase (ERK) activation in normal human keratinocytes: metalloproteinase-mediated release of amphiregulin triggers signaling from ErbB1 to ERK. Kansra, S., Stoll, S.W., Johnson, J.L., Elder, J.T. Mol. Biol. Cell (2004) [Pubmed]
  21. A differential requirement for the COOH-terminal region of the epidermal growth factor (EGF) receptor in amphiregulin and EGF mitogenic signaling. Wong, L., Deb, T.B., Thompson, S.A., Wells, A., Johnson, G.R. J. Biol. Chem. (1999) [Pubmed]
  22. Retinoid-induced epidermal hyperplasia is mediated by epidermal growth factor receptor activation via specific induction of its ligands heparin-binding EGF and amphiregulin in human skin in vivo. Rittié, L., Varani, J., Kang, S., Voorhees, J.J., Fisher, G.J. J. Invest. Dermatol. (2006) [Pubmed]
  23. Differential expression of epidermal growth factor-related proteins in human colorectal tumors. Ciardiello, F., Kim, N., Saeki, T., Dono, R., Persico, M.G., Plowman, G.D., Garrigues, J., Radke, S., Todaro, G.J., Salomon, D.S. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  24. The role of amphiregulin in breast cancer. Salomon, D.S., Normanno, N., Ciardiello, F., Brandt, R., Shoyab, M., Todaro, G.J. Breast Cancer Res. Treat. (1995) [Pubmed]
  25. Inhibition of apoptosis by amphiregulin via an insulin-like growth factor-1 receptor-dependent pathway in non-small cell lung cancer cell lines. Hurbin, A., Dubrez, L., Coll, J.L., Favrot, M.C. Ann. N. Y. Acad. Sci. (2003) [Pubmed]
  26. Autocrine ligands for the epidermal growth factor receptor mediate interleukin-8 release from bronchial epithelial cells in response to cigarette smoke. Richter, A., O'Donnell, R.A., Powell, R.M., Sanders, M.W., Holgate, S.T., Djukanović, R., Davies, D.E. Am. J. Respir. Cell Mol. Biol. (2002) [Pubmed]
  27. Co-expression of heparin-binding EGF-like growth factor and related peptides in human gastric carcinoma. Naef, M., Yokoyama, M., Friess, H., Büchler, M.W., Korc, M. Int. J. Cancer (1996) [Pubmed]
  28. Gene expression profiling of ERBB receptors and ligands in human transitional cell carcinoma of the bladder. Amsellem-Ouazana, D., Bièche, I., Tozlu, S., Botto, H., Debré, B., Lidereau, R. J. Urol. (2006) [Pubmed]
  29. Cooperation of amphiregulin and insulin-like growth factor-1 inhibits Bax- and Bad-mediated apoptosis via a protein kinase C-dependent pathway in non-small cell lung cancer cells. Hurbin, A., Coll, J.L., Dubrez-Daloz, L., Mari, B., Auberger, P., Brambilla, C., Favrot, M.C. J. Biol. Chem. (2005) [Pubmed]
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