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AREG (amphiregulin (schwannoma-derived growth factor))

Written2009-02Carmen Berasain, Matias A Avila
Division of Hepatology, Gene Therapy, CIMA, University of Navarra, Pamplona, Spain

(Note : for Links provided by Atlas : click)

Identity

Alias_namesSDGF
AREGB
schwannoma-derived growth factor
amphiregulin B
Other aliasAR
CRDGF
MGC13647
OTTHUMP00000160473
amphiregulin
HGNC (Hugo) AREG
LocusID (NCBI) 374
Atlas_Id 690
Location 4q13.3  [Link to chromosome band 4q13]
Location_base_pair Starts at 74445098 and ends at 74455009 bp from pter ( according to hg19-Feb_2009)  [Mapping AREG.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

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.

Protein

 
  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

Note
  
Entity 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 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 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

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Transforming growth factor alpha, amphiregulin and cripto-1 are frequently expressed in advanced human ovarian carcinomas.
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Citation

This paper should be referenced as such :
Berasain, C ; Avila, MA
AREG (amphiregulin (schwannoma-derived growth factor))
Atlas Genet Cytogenet Oncol Haematol. 2010;14(1):1-6.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/AREGID690ch4q13.html


External links

Nomenclature
HGNC (Hugo)AREG   651
Cards
AtlasAREGID690ch4q13
Entrez_Gene (NCBI)AREG  374  amphiregulin
AliasesAR; AREGB; CRDGF; SDGF
GeneCards (Weizmann)AREG
Ensembl hg19 (Hinxton)ENSG00000109321 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000109321 [Gene_View]  chr4:74445098-74455009 [Contig_View]  AREG [Vega]
ICGC DataPortalENSG00000109321
TCGA cBioPortalAREG
AceView (NCBI)AREG
Genatlas (Paris)AREG
WikiGenes374
SOURCE (Princeton)AREG
Genetics Home Reference (NIH)AREG
Genomic and cartography
GoldenPath hg38 (UCSC)AREG  -     chr4:74445098-74455009 +  4q13.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)AREG  -     4q13.3   [Description]    (hg19-Feb_2009)
EnsemblAREG - 4q13.3 [CytoView hg19]  AREG - 4q13.3 [CytoView hg38]
Mapping of homologs : NCBIAREG [Mapview hg19]  AREG [Mapview hg38]
OMIM104640   
Gene and transcription
Genbank (Entrez)AK023449 AW014754 BC009799 BC146953 BC146967
RefSeq transcript (Entrez)NM_001657
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)AREG
Cluster EST : UnigeneHs.645475 [ NCBI ]
CGAP (NCI)Hs.645475
Alternative Splicing GalleryENSG00000109321
Gene ExpressionAREG [ NCBI-GEO ]   AREG [ EBI - ARRAY_EXPRESS ]   AREG [ SEEK ]   AREG [ MEM ]
Gene Expression Viewer (FireBrowse)AREG [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)374
GTEX Portal (Tissue expression)AREG
Human Protein AtlasENSG00000109321-AREG [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP15514   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP15514  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP15514
Splice isoforms : SwissVarP15514
PhosPhoSitePlusP15514
Domaine pattern : Prosite (Expaxy)EGF_1 (PS00022)    EGF_3 (PS50026)   
Domains : Interpro (EBI)EGF-like_CS    EGF-like_dom    EGF_rcpt_ligand   
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)AREG
DMDM Disease mutations374
Blocks (Seattle)AREG
PDB (SRS)2RNL   
PDB (PDBSum)2RNL   
PDB (IMB)2RNL   
PDB (RSDB)2RNL   
Structural Biology KnowledgeBase2RNL   
SCOP (Structural Classification of Proteins)2RNL   
CATH (Classification of proteins structures)2RNL   
SuperfamilyP15514
Human Protein Atlas [tissue]ENSG00000109321-AREG [tissue]
Peptide AtlasP15514
HPRD00093
IPIIPI00012023   IPI00965669   
Protein Interaction databases
DIP (DOE-UCLA)P15514
IntAct (EBI)P15514
FunCoupENSG00000109321
BioGRIDAREG
STRING (EMBL)AREG
ZODIACAREG
Ontologies - Pathways
QuickGOP15514
Ontology : AmiGOGolgi membrane  cytokine activity  epidermal growth factor receptor binding  protein binding  extracellular space  extracellular space  nucleus  endoplasmic reticulum membrane  ER to Golgi vesicle-mediated transport  epidermal growth factor receptor signaling pathway  epidermal growth factor receptor signaling pathway  G-protein coupled receptor signaling pathway  cell-cell signaling  growth factor activity  cell proliferation  positive regulation of cell proliferation  cell surface  ER to Golgi transport vesicle membrane  glial cell proliferation  integral component of membrane  neuron projection development  response to estradiol  endoplasmic reticulum-Golgi intermediate compartment membrane  response to hydrogen peroxide  response to peptide hormone  negative regulation of osteoblast differentiation  positive regulation of DNA replication  COPII vesicle coating  positive regulation of peptidyl-tyrosine phosphorylation  response to glucocorticoid  response to cAMP  dichotomous subdivision of terminal units involved in mammary gland duct morphogenesis  mammary gland branching involved in thelarche  mammary gland alveolus development  epithelial cell proliferation involved in mammary gland duct elongation  
Ontology : EGO-EBIGolgi membrane  cytokine activity  epidermal growth factor receptor binding  protein binding  extracellular space  extracellular space  nucleus  endoplasmic reticulum membrane  ER to Golgi vesicle-mediated transport  epidermal growth factor receptor signaling pathway  epidermal growth factor receptor signaling pathway  G-protein coupled receptor signaling pathway  cell-cell signaling  growth factor activity  cell proliferation  positive regulation of cell proliferation  cell surface  ER to Golgi transport vesicle membrane  glial cell proliferation  integral component of membrane  neuron projection development  response to estradiol  endoplasmic reticulum-Golgi intermediate compartment membrane  response to hydrogen peroxide  response to peptide hormone  negative regulation of osteoblast differentiation  positive regulation of DNA replication  COPII vesicle coating  positive regulation of peptidyl-tyrosine phosphorylation  response to glucocorticoid  response to cAMP  dichotomous subdivision of terminal units involved in mammary gland duct morphogenesis  mammary gland branching involved in thelarche  mammary gland alveolus development  epithelial cell proliferation involved in mammary gland duct elongation  
Pathways : KEGGErbB signaling pathway    Hippo signaling pathway   
NDEx NetworkAREG
Atlas of Cancer Signalling NetworkAREG
Wikipedia pathwaysAREG
Orthology - Evolution
OrthoDB374
GeneTree (enSembl)ENSG00000109321
Phylogenetic Trees/Animal Genes : TreeFamAREG
HOVERGENP15514
HOGENOMP15514
Homologs : HomoloGeneAREG
Homology/Alignments : Family Browser (UCSC)AREG
Gene fusions - Rearrangements
Tumor Fusion PortalAREG
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerAREG [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)AREG
dbVarAREG
ClinVarAREG
1000_GenomesAREG 
Exome Variant ServerAREG
ExAC (Exome Aggregation Consortium)ENSG00000109321
GNOMAD BrowserENSG00000109321
Genetic variants : HAPMAP374
Genomic Variants (DGV)AREG [DGVbeta]
DECIPHERAREG [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisAREG 
Mutations
ICGC Data PortalAREG 
TCGA Data PortalAREG 
Broad Tumor PortalAREG
OASIS PortalAREG [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICAREG  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDAREG
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch AREG
DgiDB (Drug Gene Interaction Database)AREG
DoCM (Curated mutations)AREG (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)AREG (select a term)
intoGenAREG
NCG5 (London)AREG
Cancer3DAREG(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM104640   
Orphanet
DisGeNETAREG
MedgenAREG
Genetic Testing Registry AREG
NextProtP15514 [Medical]
TSGene374
GENETestsAREG
Target ValidationAREG
Huge Navigator AREG [HugePedia]
snp3D : Map Gene to Disease374
BioCentury BCIQAREG
ClinGenAREG
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD374
Chemical/Pharm GKB GenePA24933
Clinical trialAREG
Miscellaneous
canSAR (ICR)AREG (select the gene name)
Probes
Litterature
PubMed154 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineAREG
EVEXAREG
GoPubMedAREG
iHOPAREG
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Tue Nov 21 14:44:10 CET 2017

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