AREG_HUMAN
ID AREG_HUMAN Reviewed; 252 AA.
AC P15514; Q5U026;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1991, sequence version 2.
DT 03-AUG-2022, entry version 196.
DE RecName: Full=Amphiregulin {ECO:0000303|PubMed:2325643};
DE Short=AR {ECO:0000303|PubMed:2325643};
DE AltName: Full=Colorectum cell-derived growth factor {ECO:0000303|PubMed:1333777};
DE Short=CRDGF {ECO:0000303|PubMed:1333777};
DE Flags: Precursor;
GN Name=AREG {ECO:0000312|HGNC:HGNC:651};
GN Synonyms=AREGB {ECO:0000312|HGNC:HGNC:651},
GN SDGF {ECO:0000312|HGNC:HGNC:651};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX PubMed=2325643; DOI=10.1128/mcb.10.5.1969-1981.1990;
RA Plowman G.D., Green J.M., McDonald V.L., Neubauer M.G., Disteche C.M.,
RA Todaro G.J., Shoyab M.;
RT "The amphiregulin gene encodes a novel epidermal growth factor-related
RT protein with tumor-inhibitory activity.";
RL Mol. Cell. Biol. 10:1969-1981(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS VAL-80 AND CYS-81.
RG NIEHS SNPs program;
RL Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP PROTEIN SEQUENCE OF 101-184.
RX PubMed=2466334; DOI=10.1126/science.2466334;
RA Shoyab M., Plowman G.D., McDonald V.L., Bradley J.G., Todaro G.J.;
RT "Structure and function of human amphiregulin: a member of the epidermal
RT growth factor family.";
RL Science 243:1074-1076(1989).
RN [8]
RP PROTEIN SEQUENCE OF 101-131.
RX PubMed=3413110; DOI=10.1073/pnas.85.17.6528;
RA Shoyab M., McDonald V.L., Bradley J.G., Todaro G.J.;
RT "Amphiregulin: a bifunctional growth-modulating glycoprotein produced by
RT the phorbol 12-myristate 13-acetate-treated human breast adenocarcinoma
RT cell line MCF-7.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:6528-6532(1988).
RN [9]
RP PROTEIN SEQUENCE OF 101-126.
RX PubMed=2017164; DOI=10.1128/mcb.11.5.2547-2557.1991;
RA Cook P.W., Mattox P.A., Keeble W.W., Pittelkow M.R., Plowman G.D.,
RA Shoyab M., Adelman J.P., Shipley G.D.;
RT "A heparin sulfate-regulated human keratinocyte autocrine factor is similar
RT or identical to amphiregulin.";
RL Mol. Cell. Biol. 11:2547-2557(1991).
RN [10]
RP PROTEIN SEQUENCE OF 101-122.
RX PubMed=1333777; DOI=10.3109/08977199209046924;
RA Culouscou J.-M., Remacle-Bonnet M., Carlton G.W., Plowman G.D., Shoyab M.;
RT "Colorectum cell-derived growth factor (CRDGF) is homologous to
RT amphiregulin, a member of the epidermal growth factor family.";
RL Growth Factors 7:195-205(1992).
RN [11]
RP PROTEIN SEQUENCE OF 188-194, AND CLEAVAGE SITE.
RX PubMed=22967896; DOI=10.1016/j.febslet.2012.07.078;
RA Levano K.S., Kenny P.A.;
RT "Clarification of the C-terminal proteolytic processing site of human
RT Amphiregulin.";
RL FEBS Lett. 586:3500-3502(2012).
RN [12]
RP IDENTIFICATION AS EGFR LIGAND.
RX PubMed=7679104; DOI=10.1016/s0021-9258(18)53862-x;
RA Johnson G.R., Kannan B., Shoyab M., Stromberg K.;
RT "Amphiregulin induces tyrosine phosphorylation of the epidermal growth
RT factor receptor and p185erbB2. Evidence that amphiregulin acts exclusively
RT through the epidermal growth factor receptor at the surface of human
RT epithelial cells.";
RL J. Biol. Chem. 268:2924-2931(1993).
RN [13]
RP INTERACTION WITH CNIH.
RX PubMed=17607000; DOI=10.1242/jcs.004200;
RA Perez Castro C., Piscopo D., Nakagawa T., Derynck R.;
RT "Cornichon regulates transport and secretion of TGFalpha-related proteins
RT in metazoan cells.";
RL J. Cell Sci. 120:2454-2466(2007).
RN [14]
RP STRUCTURE BY NMR OF 142-184, AND DISULFIDE BONDS.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the EGF-like domain from human amphiregulin.";
RL Submitted (JAN-2009) to the PDB data bank.
CC -!- FUNCTION: Ligand of the EGF receptor/EGFR. Autocrine growth factor as
CC well as a mitogen for a broad range of target cells including
CC astrocytes, Schwann cells and fibroblasts.
CC -!- SUBUNIT: The immature precursor interacts with CNIH.
CC {ECO:0000269|PubMed:17607000}.
CC -!- INTERACTION:
CC P15514; A8MQ03: CYSRT1; NbExp=3; IntAct=EBI-953674, EBI-3867333;
CC P15514; P60410: KRTAP10-8; NbExp=3; IntAct=EBI-953674, EBI-10171774;
CC P15514; P26447: S100A4; NbExp=5; IntAct=EBI-953674, EBI-717058;
CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass membrane protein.
CC -!- INDUCTION: By phorbol 12-myristate 13-acetate (PMA).
CC -!- MISCELLANEOUS: AR is a protein containing cysteines in disulfide
CC linkage(s) that are essential for its biological activity. AR may
CC contain oligosaccharides and/or lipid moieties that are not obligatory
CC for the biological activity.
CC -!- SIMILARITY: Belongs to the amphiregulin family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/AREGID690ch4q13.html";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/areg/";
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DR EMBL; M30704; AAA51781.1; -; mRNA.
DR EMBL; M30702; AAA51773.1; -; Genomic_DNA.
DR EMBL; M30698; AAA51773.1; JOINED; Genomic_DNA.
DR EMBL; M30699; AAA51773.1; JOINED; Genomic_DNA.
DR EMBL; M30700; AAA51773.1; JOINED; Genomic_DNA.
DR EMBL; M30701; AAA51773.1; JOINED; Genomic_DNA.
DR EMBL; AY442340; AAR05438.1; -; Genomic_DNA.
DR EMBL; BT019866; AAV38669.1; -; mRNA.
DR EMBL; AC021180; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471057; EAX05710.1; -; Genomic_DNA.
DR EMBL; BC009799; AAH09799.1; -; mRNA.
DR EMBL; BC146953; AAI46954.1; -; mRNA.
DR EMBL; BC146967; AAI46968.1; -; mRNA.
DR CCDS; CCDS3565.1; -.
DR PIR; A34702; A34702.
DR RefSeq; NP_001648.1; NM_001657.3.
DR PDB; 2RNL; NMR; -; A=142-184.
DR PDBsum; 2RNL; -.
DR AlphaFoldDB; P15514; -.
DR SMR; P15514; -.
DR BioGRID; 106869; 21.
DR DIP; DIP-5766N; -.
DR IntAct; P15514; 18.
DR MINT; P15514; -.
DR STRING; 9606.ENSP00000379097; -.
DR BindingDB; P15514; -.
DR ChEMBL; CHEMBL3731; -.
DR GlyGen; P15514; 3 sites.
DR iPTMnet; P15514; -.
DR PhosphoSitePlus; P15514; -.
DR BioMuta; AREG; -.
DR DMDM; 113754; -.
DR EPD; P15514; -.
DR jPOST; P15514; -.
DR MassIVE; P15514; -.
DR PaxDb; P15514; -.
DR PeptideAtlas; P15514; -.
DR PRIDE; P15514; -.
DR ProteomicsDB; 53164; -.
DR ABCD; P15514; 1 sequenced antibody.
DR Antibodypedia; 1919; 522 antibodies from 35 providers.
DR DNASU; 374; -.
DR Ensembl; ENST00000395748.8; ENSP00000379097.3; ENSG00000109321.11.
DR GeneID; 374; -.
DR KEGG; hsa:374; -.
DR MANE-Select; ENST00000395748.8; ENSP00000379097.3; NM_001657.4; NP_001648.1.
DR UCSC; uc032tme.2; human.
DR CTD; 374; -.
DR DisGeNET; 374; -.
DR GeneCards; AREG; -.
DR HGNC; HGNC:651; AREG.
DR HPA; ENSG00000109321; Tissue enhanced (bone marrow, placenta, urinary bladder).
DR MIM; 104640; gene.
DR neXtProt; NX_P15514; -.
DR OpenTargets; ENSG00000109321; -.
DR VEuPathDB; HostDB:ENSG00000109321; -.
DR eggNOG; ENOG502S0KA; Eukaryota.
DR GeneTree; ENSGT00940000160696; -.
DR HOGENOM; CLU_096527_1_0_1; -.
DR InParanoid; P15514; -.
DR OMA; CHHDYFG; -.
DR OrthoDB; 1444868at2759; -.
DR PhylomeDB; P15514; -.
DR TreeFam; TF332773; -.
DR PathwayCommons; P15514; -.
DR Reactome; R-HSA-1257604; PIP3 activates AKT signaling.
DR Reactome; R-HSA-177929; Signaling by EGFR.
DR Reactome; R-HSA-179812; GRB2 events in EGFR signaling.
DR Reactome; R-HSA-180292; GAB1 signalosome.
DR Reactome; R-HSA-180336; SHC1 events in EGFR signaling.
DR Reactome; R-HSA-182971; EGFR downregulation.
DR Reactome; R-HSA-204005; COPII-mediated vesicle transport.
DR Reactome; R-HSA-212718; EGFR interacts with phospholipase C-gamma.
DR Reactome; R-HSA-2219530; Constitutive Signaling by Aberrant PI3K in Cancer.
DR Reactome; R-HSA-5638303; Inhibition of Signaling by Overexpressed EGFR.
DR Reactome; R-HSA-5673001; RAF/MAP kinase cascade.
DR Reactome; R-HSA-5694530; Cargo concentration in the ER.
DR Reactome; R-HSA-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
DR Reactome; R-HSA-8856825; Cargo recognition for clathrin-mediated endocytosis.
DR Reactome; R-HSA-8856828; Clathrin-mediated endocytosis.
DR Reactome; R-HSA-9009391; Extra-nuclear estrogen signaling.
DR Reactome; R-HSA-9634638; Estrogen-dependent nuclear events downstream of ESR-membrane signaling.
DR SignaLink; P15514; -.
DR SIGNOR; P15514; -.
DR BioGRID-ORCS; 374; 8 hits in 995 CRISPR screens.
DR ChiTaRS; AREG; human.
DR EvolutionaryTrace; P15514; -.
DR GeneWiki; Amphiregulin; -.
DR GenomeRNAi; 374; -.
DR Pharos; P15514; Tchem.
DR PRO; PR:P15514; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; P15514; protein.
DR Bgee; ENSG00000109321; Expressed in mucosa of urinary bladder and 130 other tissues.
DR ExpressionAtlas; P15514; baseline and differential.
DR Genevisible; P15514; HS.
DR GO; GO:0009986; C:cell surface; IDA:BHF-UCL.
DR GO; GO:0030669; C:clathrin-coated endocytic vesicle membrane; TAS:Reactome.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0033116; C:endoplasmic reticulum-Golgi intermediate compartment membrane; TAS:Reactome.
DR GO; GO:0012507; C:ER to Golgi transport vesicle membrane; TAS:Reactome.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005634; C:nucleus; IEA:Ensembl.
DR GO; GO:0005125; F:cytokine activity; IEA:UniProtKB-KW.
DR GO; GO:0005154; F:epidermal growth factor receptor binding; IBA:GO_Central.
DR GO; GO:0008083; F:growth factor activity; IBA:GO_Central.
DR GO; GO:0048018; F:receptor ligand activity; IDA:MGI.
DR GO; GO:0030297; F:transmembrane receptor protein tyrosine kinase activator activity; IDA:MGI.
DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc.
DR GO; GO:0060598; P:dichotomous subdivision of terminal units involved in mammary gland duct morphogenesis; IEA:Ensembl.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0060750; P:epithelial cell proliferation involved in mammary gland duct elongation; IEA:Ensembl.
DR GO; GO:0038134; P:ERBB2-EGFR signaling pathway; IDA:MGI.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0014009; P:glial cell proliferation; IEA:Ensembl.
DR GO; GO:0060749; P:mammary gland alveolus development; IEA:Ensembl.
DR GO; GO:0060744; P:mammary gland branching involved in thelarche; IEA:Ensembl.
DR GO; GO:0045668; P:negative regulation of osteoblast differentiation; IEA:Ensembl.
DR GO; GO:0031175; P:neuron projection development; IEA:Ensembl.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IMP:BHF-UCL.
DR GO; GO:0045741; P:positive regulation of epidermal growth factor-activated receptor activity; IBA:GO_Central.
DR GO; GO:0010838; P:positive regulation of keratinocyte proliferation; TAS:GO_Central.
DR GO; GO:0051591; P:response to cAMP; IEA:Ensembl.
DR GO; GO:0032355; P:response to estradiol; IEA:Ensembl.
DR GO; GO:0051384; P:response to glucocorticoid; IEA:Ensembl.
DR GO; GO:0042542; P:response to hydrogen peroxide; IEA:Ensembl.
DR GO; GO:0043434; P:response to peptide hormone; IEA:Ensembl.
DR InterPro; IPR000742; EGF-like_dom.
DR InterPro; IPR015497; EGF_rcpt_ligand.
DR PANTHER; PTHR10740; PTHR10740; 1.
DR PROSITE; PS00022; EGF_1; 1.
DR PROSITE; PS50026; EGF_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cytokine; Direct protein sequencing; Disulfide bond;
KW EGF-like domain; Glycoprotein; Growth factor; Membrane; Reference proteome;
KW Signal; Transmembrane; Transmembrane helix.
FT SIGNAL 1..19
FT /evidence="ECO:0000255"
FT PROPEP 20..100
FT /id="PRO_0000007473"
FT CHAIN 101..187
FT /note="Amphiregulin"
FT /id="PRO_0000007474"
FT PROPEP 188..252
FT /id="PRO_0000007475"
FT TRANSMEM 199..221
FT /note="Helical"
FT /evidence="ECO:0000255"
FT DOMAIN 142..182
FT /note="EGF-like"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT REGION 38..92
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 108..143
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 51..79
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 126..142
FT /note="Basic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 30
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 113
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 119
FT /note="N-linked (GlcNAc...) asparagine"
FT DISULFID 146..159
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076,
FT ECO:0000269|Ref.14"
FT DISULFID 154..170
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076,
FT ECO:0000269|Ref.14"
FT DISULFID 172..181
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076,
FT ECO:0000269|Ref.14"
FT VARIANT 80
FT /note="D -> V (in dbSNP:rs373527160)"
FT /evidence="ECO:0000269|Ref.2"
FT /id="VAR_018918"
FT VARIANT 81
FT /note="Y -> C (in dbSNP:rs28364979)"
FT /evidence="ECO:0000269|Ref.2"
FT /id="VAR_018919"
FT TURN 145..149
FT /evidence="ECO:0007829|PDB:2RNL"
FT HELIX 150..152
FT /evidence="ECO:0007829|PDB:2RNL"
FT STRAND 155..162
FT /evidence="ECO:0007829|PDB:2RNL"
FT TURN 163..166
FT /evidence="ECO:0007829|PDB:2RNL"
FT STRAND 167..171
FT /evidence="ECO:0007829|PDB:2RNL"
FT STRAND 178..180
FT /evidence="ECO:0007829|PDB:2RNL"
SQ SEQUENCE 252 AA; 27895 MW; 68C1FA6BCD4D2BED CRC64;
MRAPLLPPAP VVLSLLILGS GHYAAGLDLN DTYSGKREPF SGDHSADGFE VTSRSEMSSG
SEISPVSEMP SSSEPSSGAD YDYSEEYDNE PQIPGYIVDD SVRVEQVVKP PQNKTESENT
SDKPKRKKKG GKNGKNRRNR KKKNPCNAEF QNFCIHGECK YIEHLEAVTC KCQQEYFGER
CGEKSMKTHS MIDSSLSKIA LAAIAAFMSA VILTAVAVIT VQLRRQYVRK YEGEAEERKK
LRQENGNVHA IA
