Human amphiregulin is a glycoprotein containing 84 amino acids and is a ligand for epidermal growth factor receptor (EGFR). In recent years, with the gradual revelation of the relationship between amphiregulin and tumorigenesis and progression, the study of amphiregulin has become a hot research topic in both basic and clinical medicine.
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Discovery of Amphiregulin
Human amphiregulin was first discovered and isolated from human breast cancer cells. Amphiregulin was named after its discovery that it could mediate both the proliferation and differentiation of fibroblasts in vitro and inhibit normal epidermal cells and invasive tumor cell lines. Murine-derived amphiregulin was discovered in mice in 1990.
Structure of Amphiregulin
The human amphiregulin gene is approximately 10 kb in length and is located in the q13-q21 region of chromosome 4. Its 3' end is adjacent to the B-cellulin gene, while the 5' end is adjacent to the genes for epiregulin and epidermal growth factor receptor. The amphiregulin gene consists of 6 exons, encoding a 1.4 kb mRNA transcript that can synthesize a transmembrane amphiregulin precursor (Pro. AREG) consisting of 252 amino acids.
The amphiregulin precursor has several structural domains, including a hydrophobic signal peptide (aa1-20), an N-terminal hydrophilic protein domain containing glycosylation sites (aa 20-101), a heparin-binding domain containing glycosylation sites and a nuclear localization signal (aa 141-181), an EGF-like region (aa 141-181), a membrane-proximal structure containing protein cleavage sites (aa 182-198) for extracellular dissociation. In addition, it contains a transmembrane hydrophobic region (aa 199-221) and an intracellular region (aa 222-252), the latter of which includes a nuclear localization signal, a basolateral single leucine amino acid sorting motif, and a ubiquitination site.
The N-terminus of amphiregulin is hydrophilic and contains an N-acetylated heparin-binding region, while the C-terminus has an epidermal growth factor (EGF) structural domain. Therefore, structurally, it is highly homologous to other members of the EGF family, with 38% homology to EGF and 32% homology to tumor growth factor-alpha.
Physiological Functions of Amphiregulin
Amphiregulin is expressed in various tissues and organs, with the highest expression in the reproductive and urinary systems (breast, uterus, ovaries, placenta, and prostate). It is also expressed in the pancreas, circulatory system (vascular walls, bone marrow, blood, and lymph), respiratory tract, and digestive tract (lungs, spleen, kidneys, trachea, esophagus, stomach, small intestine, and colon). Recent findings indicate that amphiregulin is also expressed in colostrum and the serum of healthy individuals.
Experimental results from various cell types suggest that amphiregulin can promote cell proliferation. Mice with a knockout of the amphiregulin exhibit normal survival and reproductive capacity, suggesting that the function of amphiregulin can be compensated by other EGFR ligands. However, despite the almost nonexistent expression of amphiregulin in the liver of both humans and mice, adult mice with knockout of amphiregulin show chronic liver damage, underdeveloped mammary glands, and difficulty nursing their offspring, resulting in malnutrition and death in the second generation.
Relationship between Amphiregulin and Female Reproductive System Development
Amphiregulin is involved in several crucial processes in developing the female reproductive system. During the proliferative phase of the endometrium, EGFR and its ligands such as amphiregulin and TGF-α exhibit periodic expression. Under the influence of estrogen and progesterone, leukemia inhibitory factor is highly expressed, promoting the expression of amphiregulin. Amphiregulin is a key paracrine signal secreted by cumulus cells to promote the development of oocytes into embryos. Amphiregulin is also involved in the preparation of the uterus for embryo implantation. In early pregnancy, ovarian prolactin receptor signaling induces the expression of leukemia inhibitory factors, promoting the expression of implantation-specific genes, including amphiregulin. Luteinizing hormone can also locally and transiently regulate the expression of several members of the EGF family, including amphiregulin, thereby promoting follicle maturation.
Relationship between Amphiregulin and Branch Morphogenesis in the Lung, Kidney, and Prostate
The involvement of amphiregulin is required for branch morphogenesis in the lung, kidney, and prostate. In the lungs, both epithelial cells and stromal cells can secrete amphiregulin, and stromal-cell-secreted amphiregulin promotes the growth of epithelial cells.
Relationship between Amphiregulin and Neurogenesis
Amphiregulin also participates in the development of neurons and bone tissue. During the differentiation of bone marrow stromal stem cells into neurons, the expression of amphiregulin and various other genes is upregulated. These genes are involved in synaptic growth, early neuronal proliferation, and synthesis of neuropeptides, and neurotransmitters, suggesting that amphiregulin plays an important role in neurodevelopment. Amphiregulin acts as a mitogen in adult neural stem cells and is involved in neurogenesis in the adult brain.
Relationship between Amphiregulin and Mammary Gland Development
During puberty and pregnancy, amphiregulin plays a central role in mammary gland development. Under the influence of estrogen and progesterone, amphiregulin induces the proliferation of normal mammary epithelial cells and activates the intracellular ERK and AKT signaling pathways. During pregnancy, amphiregulin mediates progesterone-induced mammary gland hyperplasia. Overexpression of amphiregulin may be associated with abnormalities in adult mammary epithelial cells, such as abnormal proliferation or breast cancer.
Relationship between Amphiregulin and the Immune System
Amphiregulin also has a significant impact on the immune system. Various immune cells express amphiregulin under inflammatory conditions, including eosinophils, basophils, mast cells, type 2 innate lymphoid cells, dendritic cells, and activated CD4+ T cells. Amphiregulin plays a crucial role in maintaining skin homeostasis, and during skin injury, it strongly stimulates the proliferation of keratinocytes. Amphiregulin also plays an important role in the secretion of antimicrobial peptides. Studies suggest that amphiregulin plays a key role in host resistance and tolerance, tissue repair and homeostasis, fibrosis, local inflammation inhibition, and tumor microenvironment immune suppression.
References
- McBryan J.; et al. Amphiregulin: role in mammary gland development and breast cancer. Journal of Mammary Gland Biology and Neoplasia. 2008, 13: 159-169.
- Berasain C.; Avila M. A. Amphiregulin[C]//Seminars in cell & developmental biology. Academic Press. 2014, 28: 31-41.
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