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}. 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 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 //