GenomeNet

Database: UniProt
Entry: O14944
LinkDB: O14944
Original site: O14944 
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   13-FEB-2019, entry version 175.
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;
OC   Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC   Catarrhini; Hominidae; Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION, AND TISSUE
RP   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.,
RA   Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA   Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA   Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA   Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA   Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA   Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA   Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA   Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA   Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA   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.,
RA   Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA   Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA   Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA   Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA   Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA   Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA   Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA   Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA   Nakai K., Yada T., Nakamura Y., Ohara O., 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.,
RA   Neubert P., Kstrang K., Schatten R., Shen B., Henze S., Mar W.,
RA   Korn B., Zuo D., Hu Y., 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.,
RA   Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA   Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA   Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA   Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA   Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA   Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA   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
RT   project: 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,
RT   ErbB-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.,
RA   Gomi T., Miyamoto K., Kawano K.;
RT   "Solution structure of epiregulin and the effect of its C-terminal
RT   domain 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.,
RA   Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA   Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA   Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA   Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT   "The consensus coding sequences of human breast and colorectal
RT   cancers.";
RL   Science 314:268-274(2006).
CC   -!- FUNCTION: Ligand of the EGF receptor/EGFR and ERBB4. Stimulates
CC       EGFR and ERBB4 tyrosine phosphorylation (PubMed:9419975).
CC       Contributes to inflammation, wound healing, tissue repair, and
CC       oocyte maturation by regulating angiogenesis and vascular
CC       remodeling and by stimulating cell proliferation
CC       (PubMed:24631357). {ECO:0000269|PubMed:9419975,
CC       ECO:0000303|PubMed:24631357}.
CC   -!- SUBUNIT: Interacts with EGFR and ERBB4.
CC       {ECO:0000269|PubMed:9419975}.
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
CC       the placenta and peripheral blood leukocytes. High levels were
CC       detected in carcinomas of the bladder, lung, kidney and colon.
CC       {ECO:0000269|PubMed:9337852}.
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   UniGene; Hs.115263; -.
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   PDBsum; 1K36; -.
DR   PDBsum; 1K37; -.
DR   PDBsum; 5E8D; -.
DR   PDBsum; 5WB7; -.
DR   ProteinModelPortal; O14944; -.
DR   SMR; O14944; -.
DR   BioGrid; 108381; 5.
DR   IntAct; O14944; 3.
DR   STRING; 9606.ENSP00000244869; -.
DR   iPTMnet; O14944; -.
DR   PhosphoSitePlus; O14944; -.
DR   BioMuta; EREG; -.
DR   jPOST; O14944; -.
DR   MaxQB; O14944; -.
DR   PaxDb; O14944; -.
DR   PeptideAtlas; O14944; -.
DR   PRIDE; O14944; -.
DR   ProteomicsDB; 48327; -.
DR   DNASU; 2069; -.
DR   Ensembl; ENST00000244869; ENSP00000244869; ENSG00000124882.
DR   GeneID; 2069; -.
DR   KEGG; hsa:2069; -.
DR   UCSC; uc003hie.2; human.
DR   CTD; 2069; -.
DR   DisGeNET; 2069; -.
DR   EuPathDB; HostDB:ENSG00000124882.3; -.
DR   GeneCards; EREG; -.
DR   HGNC; HGNC:3443; EREG.
DR   HPA; HPA054373; -.
DR   MIM; 602061; gene.
DR   neXtProt; NX_O14944; -.
DR   OpenTargets; ENSG00000124882; -.
DR   PharmGKB; PA27856; -.
DR   eggNOG; ENOG410IXV0; Eukaryota.
DR   eggNOG; ENOG410YNFA; LUCA.
DR   GeneTree; ENSGT00510000048748; -.
DR   HOGENOM; HOG000059635; -.
DR   HOVERGEN; HBG005601; -.
DR   InParanoid; O14944; -.
DR   KO; K09784; -.
DR   OMA; CTALVQM; -.
DR   OrthoDB; 1420179at2759; -.
DR   PhylomeDB; O14944; -.
DR   TreeFam; TF336145; -.
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   SIGNOR; O14944; -.
DR   ChiTaRS; EREG; human.
DR   EvolutionaryTrace; O14944; -.
DR   GeneWiki; Epiregulin; -.
DR   GenomeRNAi; 2069; -.
DR   PRO; PR:O14944; -.
DR   Proteomes; UP000005640; Chromosome 4.
DR   Bgee; ENSG00000124882; Expressed in 122 organ(s), highest expression level in buccal mucosa cell.
DR   Genevisible; O14944; HS.
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:0046934; F:phosphatidylinositol-4,5-bisphosphate 3-kinase activity; TAS:Reactome.
DR   GO; GO:0004713; F:protein tyrosine kinase activity; TAS:Reactome.
DR   GO; GO:0005088; F:Ras guanyl-nucleotide exchange factor activity; TAS:Reactome.
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; ISS:UniProtKB.
DR   GO; GO:0038128; P:ERBB2 signaling pathway; TAS:Reactome.
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:0000165; P:MAPK cascade; TAS:Reactome.
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:0042108; P:positive regulation of cytokine biosynthetic process; IDA:UniProtKB.
DR   GO; GO:0001819; P:positive regulation of cytokine production; ISS: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:0045410; P:positive regulation of interleukin-6 biosynthetic process; 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:0051897; P:positive regulation of protein kinase B signaling; TAS:Reactome.
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:2000145; P:regulation of cell motility; TAS:Reactome.
DR   GO; GO:0043434; P:response to peptide hormone; IEA:Ensembl.
DR   GO; GO:0042060; P:wound healing; TAS:UniProtKB.
DR   InterPro; IPR013032; EGF-like_CS.
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; Complete proteome;
KW   Developmental protein; Differentiation; Disulfide bond;
KW   EGF-like domain; Glycoprotein; Growth factor; Membrane; Mitogen;
KW   Polymorphism; Reference proteome; Secreted; Signal; Transmembrane;
KW   Transmembrane helix.
FT   SIGNAL        1     29       {ECO:0000255}.
FT   CHAIN        30    169       Proepiregulin.
FT                                /FTId=PRO_0000302800.
FT   PROPEP       30     62       {ECO:0000250|UniProtKB:Q61521,
FT                                ECO:0000250|UniProtKB:Q9Z0L5}.
FT                                /FTId=PRO_0000007556.
FT   CHAIN        63    108       Epiregulin.
FT                                /FTId=PRO_0000007557.
FT   PROPEP      109    169       Removed in mature form. {ECO:0000250}.
FT                                /FTId=PRO_0000007558.
FT   TOPO_DOM     60    119       Extracellular. {ECO:0000255}.
FT   TRANSMEM    120    140       Helical. {ECO:0000255}.
FT   TOPO_DOM    141    169       Cytoplasmic. {ECO:0000255}.
FT   DOMAIN       64    104       EGF-like. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   COMPBIAS    145    152       Arg/Lys-rich (basic).
FT   CARBOHYD     47     47       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   DISULFID     68     81       {ECO:0000255|PROSITE-ProRule:PRU00076,
FT                                ECO:0000269|PubMed:14572630}.
FT   DISULFID     76     92       {ECO:0000255|PROSITE-ProRule:PRU00076,
FT                                ECO:0000269|PubMed:14572630}.
FT   DISULFID     94    103       {ECO:0000255|PROSITE-ProRule:PRU00076,
FT                                ECO:0000269|PubMed:14572630}.
FT   VARIANT      42     42       G -> A (in a breast cancer sample;
FT                                somatic mutation).
FT                                {ECO:0000269|PubMed:16959974}.
FT                                /FTId=VAR_035833.
FT   VARIANT     147    147       R -> Q (in dbSNP:rs35275884).
FT                                /FTId=VAR_033827.
FT   STRAND       65     67       {ECO:0000244|PDB:5WB7}.
FT   HELIX        70     72       {ECO:0000244|PDB:5E8D}.
FT   TURN         73     75       {ECO:0000244|PDB:5E8D}.
FT   STRAND       79     84       {ECO:0000244|PDB:5E8D}.
FT   TURN         85     88       {ECO:0000244|PDB:5E8D}.
FT   STRAND       89     94       {ECO:0000244|PDB:5E8D}.
FT   STRAND       98    100       {ECO:0000244|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
//
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