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

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/cancer-prone-explorer/