EREG_HUMAN
ID EREG_HUMAN Reviewed; 169 AA.
AC O14944; B2RC66; Q6FH69;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1998, sequence version 1.
DT 03-AUG-2022, entry version 192.
DE RecName: Full=Proepiregulin;
DE Contains:
DE RecName: Full=Epiregulin;
DE Short=EPR;
DE Flags: Precursor;
GN Name=EREG;
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 [MRNA], SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RC TISSUE=Colon adenocarcinoma;
RX PubMed=9337852; DOI=10.1042/bj3260069;
RA Toyoda H., Komurasaki T., Uchida D., Morimoto S.;
RT "Distribution of mRNA for human epiregulin, a differentially expressed
RT member of the epidermal growth factor family.";
RL Biochem. J. 326:69-75(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S., Neubert P.,
RA Kstrang K., Schatten R., Shen B., Henze S., Mar W., Korn B., Zuo D., Hu Y.,
RA LaBaer J.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [6]
RP FUNCTION AS EGFR LIGAND, AND INTERACTION WITH EGFR AND ERBB4.
RX PubMed=9419975; DOI=10.1038/sj.onc.1201458;
RA Komurasaki T., Toyoda H., Uchida D., Morimoto S.;
RT "Epiregulin binds to epidermal growth factor receptor and ErbB-4 and
RT induces tyrosine phosphorylation of epidermal growth factor receptor, ErbB-
RT 2, ErbB-3 and ErbB-4.";
RL Oncogene 15:2841-2848(1997).
RN [7]
RP STRUCTURE BY NMR OF 63-108, AND DISULFIDE BONDS.
RX PubMed=14572630; DOI=10.1016/s0014-5793(03)01005-6;
RA Sato K., Nakamura T., Mizuguchi M., Miura K., Tada M., Aizawa T., Gomi T.,
RA Miyamoto K., Kawano K.;
RT "Solution structure of epiregulin and the effect of its C-terminal domain
RT for receptor binding affinity.";
RL FEBS Lett. 553:232-238(2003).
RN [8]
RP REVIEW.
RX PubMed=24631357; DOI=10.1016/j.semcdb.2014.03.005;
RA Riese D.J. II, Cullum R.L.;
RT "Epiregulin: roles in normal physiology and cancer.";
RL Semin. Cell Dev. Biol. 28:49-56(2014).
RN [9]
RP VARIANT [LARGE SCALE ANALYSIS] ALA-42.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Ligand of the EGF receptor/EGFR and ERBB4. Stimulates EGFR
CC and ERBB4 tyrosine phosphorylation (PubMed:9419975). Contributes to
CC inflammation, wound healing, tissue repair, and oocyte maturation by
CC regulating angiogenesis and vascular remodeling and by stimulating cell
CC proliferation (PubMed:24631357). {ECO:0000269|PubMed:9419975,
CC ECO:0000303|PubMed:24631357}.
CC -!- SUBUNIT: Interacts with EGFR and ERBB4. {ECO:0000269|PubMed:9419975}.
CC -!- INTERACTION:
CC O14944; Q07325: CXCL9; NbExp=3; IntAct=EBI-17272224, EBI-3911467;
CC O14944; P00533: EGFR; NbExp=3; IntAct=EBI-17272224, EBI-297353;
CC O14944; Q5J8X5: MS4A13; NbExp=3; IntAct=EBI-17272224, EBI-12070086;
CC O14944; Q9NZG7: NINJ2; NbExp=3; IntAct=EBI-17272224, EBI-10317425;
CC O14944; Q6UX06: OLFM4; NbExp=3; IntAct=EBI-17272224, EBI-2804156;
CC -!- SUBCELLULAR LOCATION: [Epiregulin]: Secreted, extracellular space
CC {ECO:0000269|PubMed:9337852}.
CC -!- SUBCELLULAR LOCATION: [Proepiregulin]: Cell membrane
CC {ECO:0000269|PubMed:9337852}; Single-pass type I membrane protein
CC {ECO:0000269|PubMed:9337852}.
CC -!- TISSUE SPECIFICITY: In normal adults, expressed predominantly in the
CC placenta and peripheral blood leukocytes. High levels were detected in
CC carcinomas of the bladder, lung, kidney and colon.
CC {ECO:0000269|PubMed:9337852}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; D30783; BAA22146.1; -; mRNA.
DR EMBL; AK314959; BAG37463.1; -; mRNA.
DR EMBL; CR541887; CAG46685.1; -; mRNA.
DR EMBL; CH471057; EAX05709.1; -; Genomic_DNA.
DR EMBL; BC136404; AAI36405.1; -; mRNA.
DR EMBL; BC136405; AAI36406.1; -; mRNA.
DR CCDS; CCDS3564.1; -.
DR RefSeq; NP_001423.1; NM_001432.2.
DR PDB; 1K36; NMR; -; A=63-108.
DR PDB; 1K37; NMR; -; A=63-108.
DR PDB; 5E8D; X-ray; 2.50 A; A=38-108.
DR PDB; 5WB7; X-ray; 2.94 A; E/F/G/H=56-116.
DR PDB; 7LEN; X-ray; 2.90 A; C/D=63-110.
DR PDB; 7LFR; X-ray; 3.20 A; C/D=63-110.
DR PDB; 7LFS; X-ray; 3.50 A; E/F/G/H=63-110.
DR PDBsum; 1K36; -.
DR PDBsum; 1K37; -.
DR PDBsum; 5E8D; -.
DR PDBsum; 5WB7; -.
DR PDBsum; 7LEN; -.
DR PDBsum; 7LFR; -.
DR PDBsum; 7LFS; -.
DR AlphaFoldDB; O14944; -.
DR BMRB; O14944; -.
DR SMR; O14944; -.
DR BioGRID; 108381; 12.
DR IntAct; O14944; 11.
DR STRING; 9606.ENSP00000244869; -.
DR ChEMBL; CHEMBL4662939; -.
DR GlyGen; O14944; 1 site.
DR iPTMnet; O14944; -.
DR PhosphoSitePlus; O14944; -.
DR BioMuta; EREG; -.
DR jPOST; O14944; -.
DR MassIVE; O14944; -.
DR MaxQB; O14944; -.
DR PaxDb; O14944; -.
DR PeptideAtlas; O14944; -.
DR PRIDE; O14944; -.
DR ProteomicsDB; 48327; -.
DR ABCD; O14944; 8 sequenced antibodies.
DR Antibodypedia; 24625; 287 antibodies from 30 providers.
DR DNASU; 2069; -.
DR Ensembl; ENST00000244869.3; ENSP00000244869.2; ENSG00000124882.4.
DR GeneID; 2069; -.
DR KEGG; hsa:2069; -.
DR MANE-Select; ENST00000244869.3; ENSP00000244869.2; NM_001432.3; NP_001423.1.
DR UCSC; uc003hie.2; human.
DR CTD; 2069; -.
DR DisGeNET; 2069; -.
DR GeneCards; EREG; -.
DR HGNC; HGNC:3443; EREG.
DR HPA; ENSG00000124882; Tissue enriched (bone).
DR MIM; 602061; gene.
DR neXtProt; NX_O14944; -.
DR OpenTargets; ENSG00000124882; -.
DR PharmGKB; PA27856; -.
DR VEuPathDB; HostDB:ENSG00000124882; -.
DR eggNOG; ENOG502S5DM; Eukaryota.
DR GeneTree; ENSGT00510000048748; -.
DR HOGENOM; CLU_138015_0_0_1; -.
DR InParanoid; O14944; -.
DR OMA; CTALVQM; -.
DR OrthoDB; 1420179at2759; -.
DR PhylomeDB; O14944; -.
DR TreeFam; TF336145; -.
DR PathwayCommons; O14944; -.
DR Reactome; R-HSA-1227986; Signaling by ERBB2.
DR Reactome; R-HSA-1236394; Signaling by ERBB4.
DR Reactome; R-HSA-1250196; SHC1 events in ERBB2 signaling.
DR Reactome; R-HSA-1250342; PI3K events in ERBB4 signaling.
DR Reactome; R-HSA-1250347; SHC1 events in ERBB4 signaling.
DR Reactome; R-HSA-1251985; Nuclear signaling by ERBB4.
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-1963640; GRB2 events in ERBB2 signaling.
DR Reactome; R-HSA-1963642; PI3K events in ERBB2 signaling.
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-6785631; ERBB2 Regulates Cell Motility.
DR Reactome; R-HSA-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
DR Reactome; R-HSA-8847993; ERBB2 Activates PTK6 Signaling.
DR Reactome; R-HSA-8856825; Cargo recognition for clathrin-mediated endocytosis.
DR Reactome; R-HSA-8856828; Clathrin-mediated endocytosis.
DR Reactome; R-HSA-8863795; Downregulation of ERBB2 signaling.
DR Reactome; R-HSA-9009391; Extra-nuclear estrogen signaling.
DR Reactome; R-HSA-9634638; Estrogen-dependent nuclear events downstream of ESR-membrane signaling.
DR Reactome; R-HSA-9664565; Signaling by ERBB2 KD Mutants.
DR Reactome; R-HSA-9665686; Signaling by ERBB2 TMD/JMD mutants.
DR SignaLink; O14944; -.
DR SIGNOR; O14944; -.
DR BioGRID-ORCS; 2069; 7 hits in 1081 CRISPR screens.
DR ChiTaRS; EREG; human.
DR EvolutionaryTrace; O14944; -.
DR GeneWiki; Epiregulin; -.
DR GenomeRNAi; 2069; -.
DR Pharos; O14944; Tbio.
DR PRO; PR:O14944; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; O14944; protein.
DR Bgee; ENSG00000124882; Expressed in buccal mucosa cell and 107 other tissues.
DR Genevisible; O14944; HS.
DR GO; GO:0030669; C:clathrin-coated endocytic 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:0005887; C:integral component of plasma membrane; TAS:UniProtKB.
DR GO; GO:0005154; F:epidermal growth factor receptor binding; ISS:UniProtKB.
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:0009653; P:anatomical structure morphogenesis; TAS:UniProtKB.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0009887; P:animal organ morphogenesis; TAS:UniProtKB.
DR GO; GO:0007267; P:cell-cell signaling; IDA:UniProtKB.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; IDA:UniProtKB.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; IDA:MGI.
DR GO; GO:0038134; P:ERBB2-EGFR signaling pathway; IDA:MGI.
DR GO; GO:0038135; P:ERBB2-ERBB4 signaling pathway; IDA:MGI.
DR GO; GO:0038138; P:ERBB4-ERBB4 signaling pathway; IDA:MGI.
DR GO; GO:0007143; P:female meiotic nuclear division; ISS:UniProtKB.
DR GO; GO:0030216; P:keratinocyte differentiation; TAS:UniProtKB.
DR GO; GO:0043616; P:keratinocyte proliferation; IDA:UniProtKB.
DR GO; GO:0042700; P:luteinizing hormone signaling pathway; ISS:UniProtKB.
DR GO; GO:0009299; P:mRNA transcription; IDA:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; ISS:UniProtKB.
DR GO; GO:0050680; P:negative regulation of epithelial cell proliferation; TAS:UniProtKB.
DR GO; GO:0051151; P:negative regulation of smooth muscle cell differentiation; IDA:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0001556; P:oocyte maturation; ISS:UniProtKB.
DR GO; GO:0001550; P:ovarian cumulus expansion; ISS:UniProtKB.
DR GO; GO:0030728; P:ovulation; ISS:UniProtKB.
DR GO; GO:0051781; P:positive regulation of cell division; IEA:UniProtKB-KW.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IDA:UniProtKB.
DR GO; GO:0001819; P:positive regulation of cytokine production; IDA:UniProtKB.
DR GO; GO:0045740; P:positive regulation of DNA replication; IDA:UniProtKB.
DR GO; GO:0045741; P:positive regulation of epidermal growth factor-activated receptor activity; ISS:UniProtKB.
DR GO; GO:0048146; P:positive regulation of fibroblast proliferation; IDA:UniProtKB.
DR GO; GO:0045089; P:positive regulation of innate immune response; ISS:UniProtKB.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; ISS:UniProtKB.
DR GO; GO:0045840; P:positive regulation of mitotic nuclear division; ISS:UniProtKB.
DR GO; GO:0042327; P:positive regulation of phosphorylation; IDA:UniProtKB.
DR GO; GO:0045860; P:positive regulation of protein kinase activity; IDA:UniProtKB.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; ISS:UniProtKB.
DR GO; GO:0048160; P:primary follicle stage; ISS:UniProtKB.
DR GO; GO:0043434; P:response to peptide hormone; IEA:Ensembl.
DR GO; GO:0042060; P:wound healing; TAS:UniProtKB.
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; PS01186; EGF_2; 1.
DR PROSITE; PS50026; EGF_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Angiogenesis; Cell membrane; Developmental protein;
KW Differentiation; Disulfide bond; EGF-like domain; Glycoprotein;
KW Growth factor; Membrane; Mitogen; Reference proteome; Secreted; Signal;
KW Transmembrane; Transmembrane helix.
FT SIGNAL 1..29
FT /evidence="ECO:0000255"
FT CHAIN 30..169
FT /note="Proepiregulin"
FT /id="PRO_0000302800"
FT PROPEP 30..62
FT /evidence="ECO:0000250|UniProtKB:Q61521,
FT ECO:0000250|UniProtKB:Q9Z0L5"
FT /id="PRO_0000007556"
FT CHAIN 63..108
FT /note="Epiregulin"
FT /id="PRO_0000007557"
FT PROPEP 109..169
FT /note="Removed in mature form"
FT /evidence="ECO:0000250"
FT /id="PRO_0000007558"
FT TOPO_DOM 60..119
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 120..140
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 141..169
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 64..104
FT /note="EGF-like"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT CARBOHYD 47
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 68..81
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076,
FT ECO:0000269|PubMed:14572630"
FT DISULFID 76..92
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076,
FT ECO:0000269|PubMed:14572630"
FT DISULFID 94..103
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076,
FT ECO:0000269|PubMed:14572630"
FT VARIANT 42
FT /note="G -> A (in a breast cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_035833"
FT VARIANT 147
FT /note="R -> Q (in dbSNP:rs35275884)"
FT /id="VAR_033827"
FT STRAND 65..67
FT /evidence="ECO:0007829|PDB:7LEN"
FT HELIX 70..72
FT /evidence="ECO:0007829|PDB:5E8D"
FT TURN 73..75
FT /evidence="ECO:0007829|PDB:5E8D"
FT STRAND 79..84
FT /evidence="ECO:0007829|PDB:5E8D"
FT TURN 85..88
FT /evidence="ECO:0007829|PDB:5E8D"
FT STRAND 89..94
FT /evidence="ECO:0007829|PDB:5E8D"
FT STRAND 98..100
FT /evidence="ECO:0007829|PDB:5E8D"
SQ SEQUENCE 169 AA; 19044 MW; 17F3926ADFB2BDEE CRC64;
MTAGRRMEML CAGRVPALLL CLGFHLLQAV LSTTVIPSCI PGESSDNCTA LVQTEDNPRV
AQVSITKCSS DMNGYCLHGQ CIYLVDMSQN YCRCEVGYTG VRCEHFFLTV HQPLSKEYVA
LTVILIILFL ITVVGSTYYF CRWYRNRKSK EPKKEYERVT SGDPELPQV
