AREG (amphiregulin (schwannoma-derived growth factor))

	Figure 2: Map of the human AR gene showing the exon organization and protein domains. The gene is drawn to scale in a 5'-to-3' orientation. Intron lengths in kilobase pairs are indicated between each exon. The six exons are shown, with the length in base pairs being listed directly under each exon. The corresponding position of each exon about the AR mRNA is shown below. Protein domains are represented by shaded boxes. The number of amino acid residues in each domain is indicated. The two dark filled boxes represent hydrophobic stretches that correspond to the signal peptide and transmembrane (TM) domains. Mature AR is represented by two boxes, the N-terminal hydrophilic heparin-binding domain and the C-terminal EGF-like motif (from Plowman et al., 1990).
Description	The AR/AREG human gene spans 10kb in the genomic DNA and it is composed of six exons.
Transcription	The transcription of the AR gene produces a 1.4 kb mRNA. AR gene shows broad constitutive expression, being more prevalent in human ovary and placenta although it is also expressed in pancreas, cardiac muscle, testis, colon, breast, lung, spleen and kidney, whereas it is undetectable in liver.

	AR is synthesized as a membrane-anchored precursor (Pro-AR) of 252 amino acids. Pro-AR encompasses a signal peptide, a Pro-region, a heparin-binding domain, an EGF-like domain, a transmembrane region (TM) and a carboxy-terminal cytosolic tail (CT-tail). The nuclear localization signal (NLS) and glycosylation sites are indicated.
Description	AR is synthesized as a 252-amino acids transmembrane glycoprotein, also known as transmembrane precursor or pro-form (Pro-AR). Pro-AR consists of a hydrophilic extracellular N-terminus (or ectodomain), a hydrophobic transmembrane domain (TM) and a hydrophilic cytoplasmic C-terminus (CT-tail). In the extracellular N-terminus we can distinguish an N-terminal pro-region containing glycosylation sites followed by a heparin-binding domain and an epidermal growth factor EGF-like region. The EGF-like region is shared by other members of the EGF family of ligands. At the plasma membrane Pro-AR undergoes proteolytic cleavage to release the mature soluble factor in a process known as "ectodomain shedding". Cleavage of Pro-AR at two N-terminal sites gives rise to two major soluble forms of ~19 and ~21 kDa. Alternatively Pro-AR cleavage can produce a larger 43-kDa soluble protein corresponding to the entire extracellular domain. Cleavage of Pro-AR at the cell surface can be mediated by tumor necrosis factor-alpha converting enzyme (TACE), a member of the disintegrin and metalloproteinase (ADAM) family also known as ADAM17. Shedding of AR allows the autocrine or paracrine interaction of the mature ligand with its cognate receptor, the EGFR (also known as ErbB1), a transmembrane protein endowed with tyrosine kinase activity, although juxtacine interaction between membrane-bound Pro-AR and the EGFR has also been observed.
Expression	AR is constitutively expressed in human ovary and placenta, in pancreas, cardiac muscle, testis, colon, breast, lung, spleen and kidney, whereas it is undetectable in liver. AR gene overexpression has been frequently demonstrated in cancerous tissues like colon, breast, bladder, prostate, pancreas, lung, ovary, squamous cell carcinomas, hepatocarcinoma and myeloma cells. Besides changes in AR gene expression, different stimuli can also influence the availability of this growth factor through the stimulation of Pro-AR cleavage at the cell membrane. This is achieved by the activation of TACE/ADAM17 in response to agonists acting through G-proteins coupled receptors (GPCRs) in a process termed EGFR transactivation.
Localisation	AR is synthesized as a transmembrane precursor which is proteolytically cleaved to produce the soluble factor.
Function	Binding of AR to the epidermal growth factor receptor (EGFR/ErbB1) triggers key intracellular signaling pathways, such as the mitogenic MAPK and survival PI3K/Akt pathways, which have been demonstrated to participate in the transduction of AR-effects. AR was originally identified as a factor capable of inhibiting the growth of certain carcinoma cell lines, while stimulating the proliferation of normal cells, a fact that motivated its denomination. Actually, depending on its concentration and the nature of the target cell AR promotes the growth and survival of most cell types, both normal and transformed.
	Figure 4: Cladogram Figure 5: from Sanderson et al., 2006.
Homology	The EGF-like region characterized by a six-cysteine consensus motif, XnCX7CX4-5CX10CXCX5GX2CXn is shared by other members of the EGF family of ligands. Mature HB-EGF and AR also have N-terminal extensions, composed of predominantly basic residues which are thought to confer their heparin-binding abilities.

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