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Protein

Amphiregulin

Gene

AREG

more
Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Ligand of the EGF receptor/EGFR. Autocrine growth factor as well as a mitogen for a broad range of target cells including astrocytes, Schwann cells and fibroblasts.

GO - Molecular functioni

  1. epidermal growth factor receptor binding Source: GO_Central
  2. growth factor activity Source: ProtInc

GO - Biological processi

  1. cell-cell signaling Source: ProtInc
  2. cell proliferation Source: ProtInc
  3. dichotomous subdivision of terminal units involved in mammary gland duct morphogenesis Source: Ensembl
  4. epidermal growth factor receptor signaling pathway Source: BHF-UCL
  5. epithelial cell proliferation involved in mammary gland duct elongation Source: Ensembl
  6. glial cell proliferation Source: Ensembl
  7. G-protein coupled receptor signaling pathway Source: BHF-UCL
  8. mammary gland alveolus development Source: Ensembl
  9. mammary gland branching involved in thelarche Source: Ensembl
  10. negative regulation of osteoblast differentiation Source: Ensembl
  11. neuron projection development Source: Ensembl
  12. positive regulation of cell proliferation Source: GO_Central
  13. positive regulation of DNA replication Source: BHF-UCL
  14. positive regulation of phosphorylation Source: Ensembl
  15. response to cAMP Source: Ensembl
  16. response to estradiol Source: Ensembl
  17. response to glucocorticoid Source: Ensembl
  18. response to hydrogen peroxide Source: Ensembl
  19. response to peptide hormone Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Cytokine, Growth factor

Enzyme and pathway databases

SignaLinkiP15514.

Names & Taxonomyi

Protein namesi
Recommended name:
Amphiregulin
Short name:
AR
Alternative name(s):
Colorectum cell-derived growth factor
Short name:
CRDGF
Gene namesi
Name:AREG
Synonyms:SDGF
AND
Name:AREGB
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640 Componenti: Chromosome 4

Organism-specific databases

HGNCiHGNC:651. AREG.
HGNC:34509. AREGB.

Subcellular locationi

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Transmembranei199 – 22123HelicalSequence AnalysisAdd
BLAST

GO - Cellular componenti

  1. cell surface Source: BHF-UCL
  2. cytoplasm Source: Ensembl
  3. extracellular space Source: BHF-UCL
  4. integral component of membrane Source: UniProtKB-KW
  5. nucleus Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Membrane

Pathology & Biotechi

Organism-specific databases

PharmGKBiPA162376851.

Polymorphism and mutation databases

BioMutaiAREG.
DMDMi113754.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 1919Sequence AnalysisAdd
BLAST
Propeptidei20 – 10081PRO_0000007473Add
BLAST
Chaini101 – 18787AmphiregulinPRO_0000007474Add
BLAST
Propeptidei188 – 25265PRO_0000007475Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi30 – 301N-linked (GlcNAc...)Sequence Analysis
Glycosylationi113 – 1131N-linked (GlcNAc...)Sequence Analysis
Glycosylationi119 – 1191N-linked (GlcNAc...)
Disulfide bondi146 ↔ 159PROSITE-ProRule annotation1 Publication
Disulfide bondi154 ↔ 170PROSITE-ProRule annotation1 Publication
Disulfide bondi172 ↔ 181PROSITE-ProRule annotation1 Publication

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

MaxQBiP15514.
PaxDbiP15514.
PeptideAtlasiP15514.
PRIDEiP15514.

PTM databases

PhosphoSiteiP15514.

Miscellaneous databases

PMAP-CutDBP15514.

Expressioni

Inductioni

By phorbol 12-myristate 13-acetate (PMA).

Gene expression databases

BgeeiP15514.
CleanExiHS_AREG.
ExpressionAtlasiP15514. baseline and differential.
GenevestigatoriP15514.

Organism-specific databases

HPAiCAB023519.
HPA008720.

Interactioni

Subunit structurei

The immature precursor interacts with CNIH.1 Publication

Binary interactionsi

WithEntry#Exp.IntActNotes
S100A4P264474EBI-953674,EBI-717058

Protein-protein interaction databases

BioGridi106869. 10 interactions.
608192. 1 interaction.
DIPiDIP-5766N.
IntActiP15514. 6 interactions.
MINTiMINT-105624.
STRINGi9606.ENSP00000264487.

Structurei

Secondary structure

1
252
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Turni145 – 1495Combined sources
Helixi150 – 1523Combined sources
Beta strandi155 – 1628Combined sources
Turni163 – 1664Combined sources
Beta strandi167 – 1715Combined sources
Beta strandi178 – 1803Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
2RNLNMR-A142-184[»]
ProteinModelPortaliP15514.
SMRiP15514. Positions 142-184.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP15514.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini142 – 18241EGF-likePROSITE-ProRule annotationAdd
BLAST

Sequence similaritiesi

Belongs to the amphiregulin family.Curated
Contains 1 EGF-like domain.PROSITE-ProRule annotation

Keywords - Domaini

EGF-like domain, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiNOG41450.
GeneTreeiENSGT00530000063708.
HOGENOMiHOG000034038.
HOVERGENiHBG060279.
InParanoidiP15514.
KOiK09782.
OMAiCKCHQDY.
OrthoDBiEOG7XDBH6.
PhylomeDBiP15514.
TreeFamiTF332773.

Family and domain databases

InterProiIPR000742. EG-like_dom.
IPR013032. EGF-like_CS.
IPR015497. EGF_rcpt_ligand.
[Graphical view]
PANTHERiPTHR10740. PTHR10740. 1 hit.
SMARTiSM00181. EGF. 1 hit.
[Graphical view]
PROSITEiPS00022. EGF_1. 1 hit.
PS50026. EGF_3. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P15514-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MRAPLLPPAP VVLSLLILGS GHYAAGLDLN DTYSGKREPF SGDHSADGFE
60 70 80 90 100
VTSRSEMSSG SEISPVSEMP SSSEPSSGAD YDYSEEYDNE PQIPGYIVDD
110 120 130 140 150
SVRVEQVVKP PQNKTESENT SDKPKRKKKG GKNGKNRRNR KKKNPCNAEF
160 170 180 190 200
QNFCIHGECK YIEHLEAVTC KCQQEYFGER CGEKSMKTHS MIDSSLSKIA
210 220 230 240 250
LAAIAAFMSA VILTAVAVIT VQLRRQYVRK YEGEAEERKK LRQENGNVHA

IA
Length:252
Mass (Da):27,895
Last modified:February 1, 1991 - v2
Checksum:i68C1FA6BCD4D2BED
GO

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti80 – 801D → V.1 Publication
VAR_018918
Natural varianti81 – 811Y → C.1 Publication
VAR_018919

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M30704 mRNA. Translation: AAA51781.1.
M30702
, M30698, M30699, M30700, M30701 Genomic DNA. Translation: AAA51773.1.
AY442340 Genomic DNA. Translation: AAR05438.1.
BT019866 mRNA. Translation: AAV38669.1.
CH471057 Genomic DNA. Translation: EAX05710.1.
BC009799 mRNA. Translation: AAH09799.1.
BC146953 mRNA. Translation: AAI46954.1.
BC146967 mRNA. Translation: AAI46968.1.
CCDSiCCDS3565.1.
PIRiA34702.
RefSeqiNP_001648.1. NM_001657.3.
UniGeneiHs.270833.
Hs.645475.

Genome annotation databases

EnsembliENST00000395748; ENSP00000379097; ENSG00000109321.
GeneIDi374.
KEGGihsa:374.
UCSCiuc021xpc.1. human.

Polymorphism and mutation databases

BioMutaiAREG.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Web resourcesi

Atlas of Genetics and Cytogenetics in Oncology and Haematology
NIEHS-SNPs

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M30704 mRNA. Translation: AAA51781.1.
M30702
, M30698, M30699, M30700, M30701 Genomic DNA. Translation: AAA51773.1.
AY442340 Genomic DNA. Translation: AAR05438.1.
BT019866 mRNA. Translation: AAV38669.1.
CH471057 Genomic DNA. Translation: EAX05710.1.
BC009799 mRNA. Translation: AAH09799.1.
BC146953 mRNA. Translation: AAI46954.1.
BC146967 mRNA. Translation: AAI46968.1.
CCDSiCCDS3565.1.
PIRiA34702.
RefSeqiNP_001648.1. NM_001657.3.
UniGeneiHs.270833.
Hs.645475.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
2RNLNMR-A142-184[»]
ProteinModelPortaliP15514.
SMRiP15514. Positions 142-184.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi106869. 10 interactions.
608192. 1 interaction.
DIPiDIP-5766N.
IntActiP15514. 6 interactions.
MINTiMINT-105624.
STRINGi9606.ENSP00000264487.

Chemistry

BindingDBiP15514.
ChEMBLiCHEMBL3731.

PTM databases

PhosphoSiteiP15514.

Polymorphism and mutation databases

BioMutaiAREG.
DMDMi113754.

Proteomic databases

MaxQBiP15514.
PaxDbiP15514.
PeptideAtlasiP15514.
PRIDEiP15514.

Protocols and materials databases

DNASUi374.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000395748; ENSP00000379097; ENSG00000109321.
GeneIDi374.
KEGGihsa:374.
UCSCiuc021xpc.1. human.

Organism-specific databases

CTDi374.
GeneCardsiGC04P075300.
GC04P075480.
HGNCiHGNC:651. AREG.
HGNC:34509. AREGB.
HPAiCAB023519.
HPA008720.
MIMi104640. gene.
neXtProtiNX_P15514.
PharmGKBiPA162376851.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiNOG41450.
GeneTreeiENSGT00530000063708.
HOGENOMiHOG000034038.
HOVERGENiHBG060279.
InParanoidiP15514.
KOiK09782.
OMAiCKCHQDY.
OrthoDBiEOG7XDBH6.
PhylomeDBiP15514.
TreeFamiTF332773.

Enzyme and pathway databases

SignaLinkiP15514.

Miscellaneous databases

EvolutionaryTraceiP15514.
GeneWikiiAmphiregulin.
GenomeRNAii374.
NextBioi1565.
PMAP-CutDBP15514.
PROiP15514.
SOURCEiSearch...

Gene expression databases

BgeeiP15514.
CleanExiHS_AREG.
ExpressionAtlasiP15514. baseline and differential.
GenevestigatoriP15514.

Family and domain databases

InterProiIPR000742. EG-like_dom.
IPR013032. EGF-like_CS.
IPR015497. EGF_rcpt_ligand.
[Graphical view]
PANTHERiPTHR10740. PTHR10740. 1 hit.
SMARTiSM00181. EGF. 1 hit.
[Graphical view]
PROSITEiPS00022. EGF_1. 1 hit.
PS50026. EGF_3. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "The amphiregulin gene encodes a novel epidermal growth factor-related protein with tumor-inhibitory activity."
    Plowman G.D., Green J.M., McDonald V.L., Neubauer M.G., Disteche C.M., Todaro G.J., Shoyab M.
    Mol. Cell. Biol. 10:1969-1981(1990) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
  2. NIEHS SNPs program
    Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS VAL-80 AND CYS-81.
  3. "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."
    Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A.
    Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
  4. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  5. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Tissue: Brain.
  6. "Structure and function of human amphiregulin: a member of the epidermal growth factor family."
    Shoyab M., Plowman G.D., McDonald V.L., Bradley J.G., Todaro G.J.
    Science 243:1074-1076(1989) [PubMed] [Europe PMC] [Abstract]
    Cited for: PROTEIN SEQUENCE OF 101-184.
  7. "Amphiregulin: a bifunctional growth-modulating glycoprotein produced by the phorbol 12-myristate 13-acetate-treated human breast adenocarcinoma cell line MCF-7."
    Shoyab M., McDonald V.L., Bradley J.G., Todaro G.J.
    Proc. Natl. Acad. Sci. U.S.A. 85:6528-6532(1988) [PubMed] [Europe PMC] [Abstract]
    Cited for: PROTEIN SEQUENCE OF 101-131.
  8. "A heparin sulfate-regulated human keratinocyte autocrine factor is similar or identical to amphiregulin."
    Cook P.W., Mattox P.A., Keeble W.W., Pittelkow M.R., Plowman G.D., Shoyab M., Adelman J.P., Shipley G.D.
    Mol. Cell. Biol. 11:2547-2557(1991) [PubMed] [Europe PMC] [Abstract]
    Cited for: PROTEIN SEQUENCE OF 101-126.
  9. "Colorectum cell-derived growth factor (CRDGF) is homologous to amphiregulin, a member of the epidermal growth factor family."
    Culouscou J.-M., Remacle-Bonnet M., Carlton G.W., Plowman G.D., Shoyab M.
    Growth Factors 7:195-205(1992) [PubMed] [Europe PMC] [Abstract]
    Cited for: PROTEIN SEQUENCE OF 101-122.
  10. "Clarification of the C-terminal proteolytic processing site of human Amphiregulin."
    Levano K.S., Kenny P.A.
    FEBS Lett. 586:3500-3502(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: PROTEIN SEQUENCE OF 188-194, CLEAVAGE SITE.
  11. "Amphiregulin induces tyrosine phosphorylation of the epidermal growth factor receptor and p185erbB2. Evidence that amphiregulin acts exclusively through the epidermal growth factor receptor at the surface of human epithelial cells."
    Johnson G.R., Kannan B., Shoyab M., Stromberg K.
    J. Biol. Chem. 268:2924-2931(1993) [PubMed] [Europe PMC] [Abstract]
    Cited for: IDENTIFICATION AS EGFR LIGAND.
  12. "Cornichon regulates transport and secretion of TGFalpha-related proteins in metazoan cells."
    Perez Castro C., Piscopo D., Nakagawa T., Derynck R.
    J. Cell Sci. 120:2454-2466(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH CNIH.
  13. "Solution structure of the EGF-like domain from human amphiregulin."
    RIKEN structural genomics initiative (RSGI)
    Submitted (JAN-2009) to the PDB data bank
    Cited for: STRUCTURE BY NMR OF 142-184, DISULFIDE BONDS.

Entry informationi

Entry nameiAREG_HUMAN
AccessioniPrimary (citable) accession number: P15514
Secondary accession number(s): Q5U026
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 1, 1990
Last sequence update: February 1, 1991
Last modified: April 29, 2015
This is version 145 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Miscellaneous

AR is a protein containing cysteines in disulfide linkage(s) that are essential for its biological activity. AR may contain oligosaccharides and/or lipid moieties that are not obligatory for the biological activity.

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 4
    Human chromosome 4: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.