AREG (amphiregulin (schwannoma-derived growth factor))

2009-02-01 Carmen Berasain , Matias A Avila Affiliation

Division of Hepatology, Gene Therapy, CIMA, University of Navarra, Pamplona, Spain

Identity

HGNC

AREG

LOCATION

4q13.3

LOCUSID

374

ALIAS

AR,AREGB,CRDGF,SDGF

DNA/RNA

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.

Proteins

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.

Implicated in

Entity name

Various cancers

Note

AR gene overexpression has been demonstrated in a large variety of human cancerous tissues such as colon, breast, liver, prostate, pancreas, lung, squamous cell carcinoma, bladder, ovary, skin and myeloma cells. The genetic or epigenetic alterations responsible for this overexpression are unknown. However it has been documented that the expression of AR can be induced by hormones such as androgen or 17beta-estradiol, EGF-family growth factors, such as TGF-alpha or AR itself, pro-inflammatory cytokines, such as TNF-alpha or interleukin-1 beta, prostaglandins, aryl hydrocarbon receptor agonists, bile acids, or hypoxic conditions.
In addition to these changes in AR gene expression the availability of this growth factor may be increased through the stimulation of pro-AR cleavage at the cell membrane, which result in a process termed EGFR transactivation. This is achieved through the activation of TACE/ADAM17 in response to agonists acting through GPCRs. This process has been shown in different cancer cells upon treatment with lysophosphatidic acid, gastrin-releasing peptide, cigarette smoke, or the activation of cannabinoid receptors.
In vitro studies performed in tumour cell lines upon treatment with AR, or conversely with specific siRNAs to silence AR gene expression, have shown that AR plays an important role in the proliferation and survival of transformed cells. These assays have also demonstrated that AR participates in the maintenance of the metastatic and oncogenic properties of these cells as well as in their resistance to chemotherapy.
The role of AR in cancer development and progression is also supported by clinical data. It has been established a significant correlation between elevated AR mRNA levels in bladder tumour tissue and poor patient survival. In patients with advanced non-squamous non-small cell lung cancers increased levels of circulating AR in serum are predictors of poor response to gefitinib.

Entity name

Psoriasis

Note

AR is an autocrine growth factor for keratinocytes and the expression of AR is significantly induced in psoriatic epidermis. Transgenic mice which overexpress AR in the epidermis develop a psoriasis-like cutaneous phenotype and psoriatic arthritis. These results show that AR contributes to the pathogenesis of psoriasis and present AR as a target for anti-psoriatic therapy. Indeed the use of heparin, which binds and inhibits AR activity or the administration of glucosamine which induces the synthesis of heparan sulfates, physiological AR antagonists, provide therapeutic benefits in psoriasis.

Entity name

Rheumatoid arthritis

Note

The expression of AR is increased in rheumatoid arthritis patients. AR induces the proliferation of fibroblast-like synoviocytes and the production of proinflammatory cytokines such as interleukin-8 and vascular endothelial growth factor.

Bibliography

Pubmed ID	Last Year	Title	Authors
8919027	1996	Induction of anchorage-independent growth by amphiregulin.	Adam RM et al
7835600	1995	Epidermal growth factor-related peptides and their relevance to gastrointestinal pathophysiology.	Barnard JA et al
17321672	2007	Amphiregulin: a new growth factor in hepatocarcinogenesis.	Berasain C et al
15793282	2005	Amphiregulin and epidermal hyperplasia: amphiregulin is required to maintain the psoriatic phenotype of human skin grafts on severe combined immunodeficient mice.	Bhagavathula N et al
12866037	2003	Prognostic value of ERBB family mRNA expression in breast carcinomas.	Bièche I et al
14633617	2003	Amphiregulin overexpression results in rapidly growing keratinocytic tumors: an in vivo xenograft model of keratoacanthoma.	Billings SD et al
14716741	2004	Amphiregulin expression in prostatic intraepithelial neoplasia and adenocarcinoma: a study of 93 cases.	Bostwick DG et al
16261397	2006	Bidirectional cross talk between ERalpha and EGFR signalling pathways regulates tamoxifen-resistant growth.	Britton DJ et al
11382759	2001	The proamphiregulin cytoplasmic domain is required for basolateral sorting, but is not essential for constitutive or stimulus-induced processing in polarized Madin-Darby canine kidney cells.	Brown CL et al
9642297	1998	Cell surface ectodomain cleavage of human amphiregulin precursor is sensitive to a metalloprotease inhibitor. Release of a predominant N-glycosylated 43-kDa soluble form.	Brown CL et al
9684287	1998	Growth control mechanisms in normal and transformed intestinal cells.	Burgess AW et al
19070973	2009	The increasing role of amphiregulin in non-small cell lung cancer.	Busser B et al
16778186	2006	Amphiregulin contributes to the transformed phenotype of human hepatocellular carcinoma cells.	Castillo J et al
15955087	2005	Amphiregulin causes functional downregulation of adherens junctions in psoriasis.	Chung E et al
2017164	1991	A heparin sulfate-regulated human keratinocyte autocrine factor is similar or identical to amphiregulin.	Cook PW et al
9410906	1997	Transgenic expression of the human amphiregulin gene induces a psoriasis-like phenotype.	Cook PW et al
10571748	1999	Overexpression of amphiregulin in the epidermis of transgenic mice induces a psoriasis-like cutaneous phenotype.	Cook PW et al
1333777	1992	Colorectum cell-derived growth factor (CRDGF) is homologous to amphiregulin, a member of the epidermal growth factor family.	Culouscou JM et al
12370739	2002	Transforming growth factor alpha, amphiregulin and cripto-1 are frequently expressed in advanced human ovarian carcinomas.	D'Antonio A et al
10024674	1999	Expression of cripto and amphiregulin in colon mucosa from high risk colon cancer families.	De Angelis E et al
11127817	2000	Simultaneous blockage of different EGF-like growth factors results in efficient growth inhibition of human colon carcinoma xenografts.	De Luca A et al
9335455	1997	Anti-sense oligonucleotides directed against EGF-related growth factors enhance anti-proliferative effect of conventional anti-tumor drugs in human colon-cancer cells.	De Luca A et al
16988945	2006	Impact of IGF-1R/EGFR cross-talks on hepatoma cell sensitivity to gefitinib.	Desbois-Mouthon C et al
15252843	2004	Clinical relevance of amphiregulin and VEGF in primary breast cancers.	Desruisseau S et al
10339571	1999	Metalloprotease-mediated ligand release regulates autocrine signaling through the epidermal growth factor receptor.	Dong J et al
8033121	1994	Induction and expression of amphiregulin in human pancreatic cancer.	Ebert M et al
17942395	2008	Epidermal growth factor receptor pathway analysis identifies amphiregulin as a key factor for cisplatin resistance of human breast cancer cells.	Eckstein N et al
9516978	1998	Evaluation of epidermal growth factor-related growth factors and receptors and of neoangiogenesis in completely resected stage I-IIIA non-small-cell lung cancer: amphiregulin and microvessel count are independent prognostic indicators of survival.	Fontanini G et al
11137396	2000	Regulation of keratinocyte function by growth factors.	Hashimoto K et al
16230376	2005	Increases of amphiregulin and transforming growth factor-alpha in serum as predictors of poor response to gefitinib among patients with advanced non-small cell lung cancers.	Ishikawa N et al
7929459	1994	Heparan sulfate is essential to amphiregulin-induced mitogenic signaling by the epidermal growth factor receptor.	Johnson GR et al
17168718	2006	Targeting the EGFR pathway for cancer therapy.	Johnston JB et al
15496427	2004	Prediction of sensitivity of advanced non-small cell lung cancers to gefitinib (Iressa, ZD1839).	Kakiuchi S et al
17664471	2007	Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab.	Khambata-Ford S et al
2234093	1990	Structure, expression and function of a schwannoma-derived growth factor.	Kimura H et al
8407551	1993	Expression of amphiregulin, a novel gene of the epidermal growth factor family, in human gastric carcinomas.	Kitadai Y et al
12814936	2003	TACE/ADAM17 processing of EGFR ligands indicates a role as a physiological convertase.	Lee DC et al
10490105	1999	The Wilms tumor suppressor WT1 encodes a transcriptional activator of amphiregulin.	Lee SB et al
10597254	1999	Antisense expression for amphiregulin suppresses tumorigenicity of a transformed human breast epithelial cell line.	Ma L et al
7561890	1995	Schwannoma-derived growth factor interacts with the epidermal growth factor receptor.	Maher PA et al
15735670	2005	Expression of EGF-family receptors and amphiregulin in multiple myeloma. Amphiregulin is a growth factor for myeloma cells.	Mahtouk K et al
18811692	2008	Clinical significance of pretreatment serum amphiregulin and transforming growth factor-alpha, and an epidermal growth factor receptor somatic mutation in patients with advanced non-squamous, non-small cell lung cancer.	Masago K et al
18398673	2008	Amphiregulin: role in mammary gland development and breast cancer.	McBryan J et al
9185133	1997	Glucosamine for psoriasis?	McCarty MF et al
15685562	2005	Liver regeneration, growth factors, and amphiregulin.	Michalopoulos GK et al
8621250	1996	Co-expression of heparin-binding EGF-like growth factor and related peptides in human gastric carcinoma.	Naef M et al
10225449	1999	Preneoplastic mammary tumor markers: Cripto and Amphiregulin are overexpressed in hyperplastic stages of tumor progression in transgenic mice.	Niemeyer CC et al
18097582	2008	Amphiregulin and epiregulin expression in neoplastic and inflammatory lesions in the colon.	Nishimura T et al
18049451	2008	The epidermal growth factor receptor system in skin repair and inflammation.	Pastore S et al
18634036	2008	The epidermal growth factor receptor ligand amphiregulin participates in the development of mouse liver fibrosis.	Perugorria MJ et al
8739992	1996	Overexpression of amphiregulin, a major autocrine growth factor for cultured human keratinocytes, in hyperproliferative skin diseases.	Piepkorn M et al
2325643	1990	The amphiregulin gene encodes a novel epidermal growth factor-related protein with tumor-inhibitory activity.	Plowman GD et al
7749138	1995	The role of amphiregulin in breast cancer.	Salomon DS et al
16801132	2006	Control of ErbB signaling through metalloprotease mediated ectodomain shedding of EGF-like factors.	Sanderson MP et al
11831905	2002	New strategy for antedrug application: development of metalloproteinase inhibitors as antipsoriatic drugs.	Sawa M et al
3413110	1988	Amphiregulin: a bifunctional growth-modulating glycoprotein produced by the phorbol 12-myristate 13-acetate-treated human breast adenocarcinoma cell line MCF-7.	Shoyab M et al
2466334	1989	Structure and function of human amphiregulin: a member of the epidermal growth factor family.	Shoyab M et al
8114701	1994	The heparin-binding domain of amphiregulin necessitates the precursor pro-region for growth factor secretion.	Thorne BA et al
18437539	2008	Amphiregulin as a novel target for breast cancer therapy.	Willmarth NE et al
18413824	2008	Amphiregulin is a promising prognostic marker for liver metastases of colorectal cancer.	Yamada M et al
15154665	2004	Amphiregulin and epidermal growth factor receptor expression in human malignant fibrous histiocytoma of soft tissues.	Yamamoto T et al
18980991	2008	Autocrine production of amphiregulin predicts sensitivity to both gefitinib and cetuximab in EGFR wild-type cancers.	Yonesaka K et al
18023415	2008	Validation of HB-EGF and amphiregulin as targets for human cancer therapy.	Yotsumoto F et al

Other Information

Locus ID:

NCBI: 374
MIM: 104640
HGNC: 651
Ensembl: ENSG00000109321

Variants:

dbSNP: 374
ClinVar: 374
TCGA: ENSG00000109321
COSMIC: AREG

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000109321	ENST00000395748	P15514
ENSG00000109321	ENST00000502307	D6RFX5

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
ErbB signaling pathway	KEGG	ko04012
ErbB signaling pathway	KEGG	hsa04012
Hippo signaling pathway	KEGG	hsa04390
Hippo signaling pathway	KEGG	ko04390
Metabolism of proteins	REACTOME	R-HSA-392499
Post-translational protein modification	REACTOME	R-HSA-597592
Asparagine N-linked glycosylation	REACTOME	R-HSA-446203
Transport to the Golgi and subsequent modification	REACTOME	R-HSA-948021
ER to Golgi Anterograde Transport	REACTOME	R-HSA-199977
COPII (Coat Protein 2) Mediated Vesicle Transport	REACTOME	R-HSA-204005
Vesicle-mediated transport	REACTOME	R-HSA-5653656
Membrane Trafficking	REACTOME	R-HSA-199991
Cargo concentration in the ER	REACTOME	R-HSA-5694530

Protein levels (Protein atlas)

Not detected

Low

Medium

High

PharmGKB

Entity ID	Name	Type	Evidence	Association	PD	PMIDs
PA10040	cetuximab	Chemical	ClinicalAnnotation, Pathway	associated	PD	23959273
PA162373091	panitumumab	Chemical	ClinicalAnnotation, Pathway	associated	PD	23959273
PA166122986	radiotherapy	Chemical	ClinicalAnnotation	associated	PD	25026457
PA445503	Rectal Neoplasms	Disease	ClinicalAnnotation	associated	PD	25026457
PA446108	Colorectal Neoplasms	Disease	ClinicalAnnotation	associated	PD	23959273
PA448771	capecitabine	Chemical	ClinicalAnnotation	associated	PD	25026457
PA450085	irinotecan	Chemical	ClinicalAnnotation	associated	PD	23959273

References

Pubmed ID	Year	Title	Citations
19935651	2009	YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway.	172
21514161	2011	Amphiregulin exosomes increase cancer cell invasion.	124
12743035	2003	TACE cleavage of proamphiregulin regulates GPCR-induced proliferation and motility of cancer cells.	104
12711607	2003	Tobacco smoke-induced lung cell proliferation mediated by tumor necrosis factor alpha-converting enzyme and amphiregulin.	67
16641105	2006	Phosphorylation of TNF-alpha converting enzyme by gastrin-releasing peptide induces amphiregulin release and EGF receptor activation.	61
15685553	2005	Amphiregulin: an early trigger of liver regeneration in mice.	57
17035230	2006	Autocrine and juxtacrine effects of amphiregulin on the proliferative, invasive, and migratory properties of normal and neoplastic human mammary epithelial cells.	55
17962208	2008	ErbB/HER ligands in human breast cancer, and relationships with their receptors, the bio-pathological features and prognosis.	46
15735670	2005	Expression of EGF-family receptors and amphiregulin in multiple myeloma. Amphiregulin is a growth factor for myeloma cells.	45
22825057	2012	TAZ induces growth factor-independent proliferation through activation of EGFR ligand amphiregulin.	39

Citation

Carmen Berasain ; Matias A Avila

AREG (amphiregulin (schwannoma-derived growth factor))

Atlas Genet Cytogenet Oncol Haematol. 2009-02-01

Online version: http://atlasgeneticsoncology.org/gene/690/areg