Alternative titles; symbols
HGNC Approved Gene Symbol: AREG
Cytogenetic location: 4q13.3 Genomic coordinates (GRCh38): 4:74,445,136-74,455,005 (from NCBI)
Shoyab et al. (1988) isolated a novel glycoprotein termed amphiregulin (AREG) that inhibits growth of certain human tumor cells and stimulates proliferation of human fibroblasts and other normal and tumor cells. Shoyab et al. (1989) determined the complete amino acid sequence. The truncated form contains 78 amino acids, whereas a larger form contains 6 additional amino acids at the N-terminal end. The C-terminal half, residues 46 to 84, exhibited striking homology to the epidermal growth factor (EGF; 131530) family of proteins. Amphiregulin binds to the EGF receptor but not as well as EGF does.
To identify new growth factors important to the development of the nervous system, Kimura et al. (1990) screened serum-free growth-conditioned media from many clonal cell lines for the presence of mitogens for CNS glial cells. A cell line secreting a potent glial mitogen was established from a schwannoma of the sciatic nerve. The cells of the tumor, named JS1 cells, were adapted to clonal culture and identified as Schwann cells. Schwann cells secrete an autocrine mitogen and human schwannoma extracts have mitogenic activity on glial cells. Kimura et al. (1990) reported the purification and characterization of the mitogenic molecule, designated schwannoma-derived growth factor (SDGF), from the growth-conditioned medium of the JS1 Schwann cell line. 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.
Amphiregulin is a heparin-binding, heparin-inhibited member of the epidermal growth factor family and an autocrine growth factor for human keratinocytes. AREG expression is increased in psoriatic epidermis. To test the hypothesis that aberrant AREG expression is central to the development of psoriatic lesions, Cook et al. (1997) constructed a transgene encoding the human AREG gene driven by the promoter of human keratin 14 (148066). They found that transgene integration and subsequent expression of AREG in basal keratinocytes correlated with a psoriasis-like skin phenotype. Afflicted mice demonstrated shortened life spans, prominent scaling and erythematous skin with alopecia, and occasional papillomatous epidermal growths. Histologic examination revealed extensive areas of marked hyperkeratosis with focal parakeratosis, acanthosis, dermal and epidermal lymphocytic and neutrophilic infiltration, and dilated blood vessels within the papillary dermis. The skin pathology was considered to be strikingly similar to psoriasis. The observations of Cook et al. (1997) linked the keratinocyte EGF receptor-ligand system to psoriatic inflammation and suggested that aberrant expression of AREG in the epidermis may represent a critical step in the development or propagation of psoriatic lesions.
Before ovulation in mammals, a cascade of events resembling an inflammatory and/or tissue remodeling process is triggered by luteinizing hormone (LH; see 152780) in the ovarian follicle. Many LH effects, however, are thought to be indirect because of the restricted expression of its receptor (LHR; 152790) to mural granulosa cells (Peng et al., 1991). Park et al. (2004) demonstrated that LH stimulation in wildtype mouse ovaries induces the transient and sequential expression of the epidermal growth factor family members amphiregulin, epiregulin (602061), and betacellulin (600345). Incubation of follicles with these growth factors recapitulates the morphologic and biochemical events triggered by LH, including cumulus expansion and oocyte maturation. Thus, Park et al. (2004) concluded that these EGF-related growth factors are paracrine mediators that propagate the LH signal throughout the follicle.
Protection against nematodes is mediated mainly by a type 2-biased immune responses, characterized by T helper 2 (Th2) lymphocytes and other cells secreting a set of cytokines, including interleukin IL4 (147780), IL5 (147850), IL10 (124092), and IL13 (147683). Zaiss et al. (2006) found that amphiregulin enhanced resistance to nematodes. The authors infected C57BL/6 mice with Trichuris muris and 14 days later analyzed cDNA from mesenteric lymph nodes. Amphiregulin expression was increased in parallel with typical Th2 cytokines. Trichuris clearance was significantly delayed in amphiregulin-deficient mice compared to wildtype. Zaiss et al. (2006) found that clearance of Trichuris is independent of mast cells, gamma-delta T cells, eosinophils, and natural killer T cells. To test whether lymphoid cell-derived amphiregulin was sufficient to accelerate parasite clearance, they infected bone marrow chimeras between amphiregulin-deficient and wildtype mice with Trichuris and measured the worm burdens 14 days later. Amphiregulin-expressing bone marrow cells significantly restored parasite clearance in amphiregulin-deficient mice. Thus, although other pathways (possibly IL13-dependent) can ultimately expel worms, amphiregulin secreted by hematopoietic (probably Th2) cells significantly enhances the expulsion of this intestinal parasite.
Ciarloni et al. (2007) demonstrated that amphiregulin was the only member of the EGF family to be transcriptionally induced by estrogen in the mammary glands of pubertal mice at a time of exponential expansion of the ductal system. Estrogens induced amphiregulin through the estrogen receptor-alpha (ESRA; 133430). Amphiregulin was required in the epithelium of pubertal mice for epithelial proliferation, terminal end bud formation, and ductal elongation; subsequent stages such as side branching and alveologenesis were not affected. When in close proximity to wildtype cells, Areg-null mammary epithelial cells proliferated and contributed to all cell compartments of ductal outgrowth. Ciarloni et al. (2007) concluded that amphiregulin is an important paracrine mediator of estrogen function specifically required for puberty-induced ductal elongation but not for any earlier or later developmental stages.
Disteche et al. (1989) used a combination of in situ hybridization and somatic cell hybrid methods to map the amphiregulin gene to human chromosome 4q13-q21. Pathak et al. (1995) demonstrated that the Areg gene maps to mouse chromosome 5, where it is tightly linked to the gene for Btc (600345).
Ciarloni, L., Mallepell, S., Brisken, C. Amphiregulin is an essential mediator of estrogen receptor alpha function in mammary gland development. Proc. Nat. Acad. Sci. 104: 5455-5460, 2007. [PubMed: 17369357] [Full Text: https://doi.org/10.1073/pnas.0611647104]
Cook, P. W., Piepkorn, M., Clegg, C. H., Plowman, G. D., DeMay, J. M., Brown, J. R., Pittelkow, M. R. Transgenic expression of the human amphiregulin gene induces a psoriasis-like phenotype. J. Clin. Invest. 100: 2286-2294, 1997. [PubMed: 9410906] [Full Text: https://doi.org/10.1172/JCI119766]
Disteche, C. M., Plowman, G. D., Gronwald, R. G. K., Kelly, J., Bowen-Pope, D., Adler, D. A., Murray, J. C. Mapping of the amphiregulin and the platelet-growth factor receptor alpha genes to the proximal long arm of chromosome 4. (Abstract) Cytogenet. Cell Genet. 51: 990 only, 1989.
Kimura, H., Fischer, W. H., Schubert, D. Structure, expression and function of a schwannoma-derived growth factor. Nature 348: 257-260, 1990. [PubMed: 2234093] [Full Text: https://doi.org/10.1038/348257a0]
Park, J.-Y., Su, Y.-Q., Ariga, M., Law, E., Jin, S.-L. C., Conti, M. EGF-like growth factors as mediators of LH action in the ovulatory follicle. Science 303: 682-684, 2004. [PubMed: 14726596] [Full Text: https://doi.org/10.1126/science.1092463]
Pathak, B. G., Gilbert, D. J., Harrison, C. A., Luetteke, N. C., Chen, X., Klagsbrun, M., Plowman, G. D., Copeland, N. G., Jenkins, N. A., Lee, D. C. Mouse chromosomal location of three EGF receptor ligands: amphiregulin (Areg), betacellulin (Btc), and heparin-binding EGF (Hegfl). Genomics 28: 116-118, 1995. [PubMed: 7590736] [Full Text: https://doi.org/10.1006/geno.1995.1116]
Peng, X.-R., Hsueh, A. J. W., LaPolt, P. S., Bjersing, L., Ny, T. Localization of luteinizing hormone receptor messenger ribonucleic acid expression in ovarian cell types during follicle development and ovulation. Endocrinology 129: 3200-3207, 1991. [PubMed: 1954899] [Full Text: https://doi.org/10.1210/endo-129-6-3200]
Shoyab, M., McDonald, V. L., Bradley, J. G., Todaro, G. J. Amphiregulin: a bifunctional growth-modulating glycoprotein produced by the phorbol 12-myristate 13-acetate-treated human breast adenocarcinoma cell line MCF-7. Proc. Nat. Acad. Sci. 85: 6528-6532, 1988. [PubMed: 3413110] [Full Text: https://doi.org/10.1073/pnas.85.17.6528]
Shoyab, M., Plowman, G. D., McDonald, V. L., Bradley, J. G., Todaro, G. J. Structure and function of human amphiregulin: a member of the epidermal growth factor family. Science 243: 1074-1076, 1989. [PubMed: 2466334] [Full Text: https://doi.org/10.1126/science.2466334]
Zaiss, D. M., Yang, L., Shah, P. R., Kobie, J. J., Urban, J. F., Mosmann, T. R. Amphiregulin, a T(H)2 cytokine enhancing resistance to nematodes. Science 314: 1746 only, 2006. [PubMed: 17170297] [Full Text: https://doi.org/10.1126/science.1133715]