ID HBEGF_HUMAN Reviewed; 208 AA. AC Q99075; B2R821; DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-1994, sequence version 1. DT 11-NOV-2015, entry version 154. DE RecName: Full=Proheparin-binding EGF-like growth factor; DE Contains: DE RecName: Full=Heparin-binding EGF-like growth factor; DE Short=HB-EGF; DE Short=HBEGF; DE AltName: Full=Diphtheria toxin receptor; DE Short=DT-R; DE Flags: Precursor; GN Name=HBEGF; Synonyms=DTR, DTS, HEGFL; 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], AND PROTEIN SEQUENCE OF 73-93. RC TISSUE=Macrophage; RX PubMed=1840698; DOI=10.1126/science.1840698; RA Higashiyama S., Abraham J.A., Miller J., Fiddes J.C., Klagsbrun M.; RT "A heparin-binding growth factor secreted by macrophage-like cells RT that is related to EGF."; RL Science 251:936-939(1991). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NIEHS SNPs program; RL Submitted (OCT-2002) to the EMBL/GenBank/DDBJ databases. RN [3] 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 [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15372022; DOI=10.1038/nature02919; RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S., RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M., RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K., RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C., RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M., RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A., RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M., RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M., RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S., RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.; RT "The DNA sequence and comparative analysis of human chromosome 5."; RL Nature 431:268-274(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.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 (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Eye; 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 [7] RP PROTEIN SEQUENCE OF 63-141 AND 143-148, AND GLYCOSYLATION AT THR-75 RP AND THR-85. RC TISSUE=Histiocytic lymphoma; RX PubMed=1556128; RA Higashiyama S., Lau K., Besner G.E., Abraham J.A., Klagsbrun M.; RT "Structure of heparin-binding EGF-like growth factor. Multiple forms, RT primary structure, and glycosylation of the mature protein."; RL J. Biol. Chem. 267:6205-6212(1992). RN [8] RP DOMAIN TOXIN BINDING. RX PubMed=7836353; DOI=10.1074/jbc.270.3.1015; RA Mitamura T., Higashiyama S., Taniguchi N., Klagsbrun M., Mekada E.; RT "Diphtheria toxin binds to the epidermal growth factor (EGF)-like RT domain of human heparin-binding EGF-like growth factor/diphtheria RT toxin receptor and inhibits specifically its mitogenic activity."; RL J. Biol. Chem. 270:1015-1019(1995). RN [9] RP INTERACTION WITH ERBB4. RX PubMed=9135143; DOI=10.1093/emboj/16.6.1268; RA Elenius K., Paul S., Allison G., Sun J., Klagsbrun M.; RT "Activation of HER4 by heparin-binding EGF-like growth factor RT stimulates chemotaxis but not proliferation."; RL EMBO J. 16:1268-1278(1997). RN [10] RP REVIEW. RX PubMed=16508205; DOI=10.1247/csf.31.1; RA Iwamoto R., Mekada E.; RT "ErbB and HB-EGF signaling in heart development and function."; RL Cell Struct. Funct. 31:1-14(2006). RN [11] RP GLYCOSYLATION AT THR-44 AND THR-47, STRUCTURE OF CARBOHYDRATES, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=22171320; DOI=10.1074/mcp.M111.013649; RA Halim A., Nilsson J., Ruetschi U., Hesse C., Larson G.; RT "Human urinary glycoproteomics; attachment site specific analysis of RT N-and O-linked glycosylations by CID and ECD."; RL Mol. Cell. Proteomics 0:0-0(2011). RN [12] RP GLYCOSYLATION AT THR-37; SER-38 AND THR-44, AND IDENTIFICATION BY MASS RP SPECTROMETRY. RX PubMed=23234360; DOI=10.1021/pr300963h; RA Halim A., Ruetschi U., Larson G., Nilsson J.; RT "LC-MS/MS characterization of O-glycosylation sites and glycan RT structures of human cerebrospinal fluid glycoproteins."; RL J. Proteome Res. 12:573-584(2013). RN [13] RP X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) OF 73-147 IN COMPLEX WITH TOX. RX PubMed=9659904; DOI=10.1016/S1097-2765(00)80008-8; RA Louie G.V., Yang W., Bowman M.E., Choe S.; RT "Crystal structure of the complex of diphtheria toxin with an RT extracellular fragment of its receptor."; RL Mol. Cell 1:67-78(1997). CC -!- FUNCTION: Growth factor that mediates its effects via EGFR, ERBB2 CC and ERBB4. Required for normal cardiac valve formation and normal CC heart function. Promotes smooth muscle cell proliferation. May be CC involved in macrophage-mediated cellular proliferation. It is CC mitogenic for fibroblasts, but not endothelial cells. It is able CC to bind EGF receptor/EGFR with higher affinity than EGF itself and CC is a far more potent mitogen for smooth muscle cells than EGF. CC Also acts as a diphtheria toxin receptor. CC -!- SUBUNIT: Interacts with FBLN1 (By similarity). Interacts with EGFR CC and ERBB4. {ECO:0000250, ECO:0000269|PubMed:9135143, CC ECO:0000269|PubMed:9659904}. CC -!- SUBCELLULAR LOCATION: Heparin-binding EGF-like growth factor: CC Secreted, extracellular space. Note=Mature HB-EGF is released into CC the extracellular space and probably binds to a receptor. CC -!- SUBCELLULAR LOCATION: Proheparin-binding EGF-like growth factor: CC Cell membrane; Single-pass type I membrane protein. CC -!- PTM: Several N-termini have been identified by direct sequencing. CC The forms with N-termini 63, 73 and 74 have been tested and found CC to be biologically active. CC -!- PTM: O-glycosylated with core 1 or possibly core 8 glycans. Thr-47 CC is a minor glycosylation site compared to Thr-44. CC {ECO:0000269|PubMed:1556128, ECO:0000269|PubMed:22171320, CC ECO:0000269|PubMed:23234360}. CC -!- SIMILARITY: Contains 1 EGF-like domain. {ECO:0000255|PROSITE- CC ProRule:PRU00076}. CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/dtr/"; 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; M60278; AAA35956.1; -; mRNA. DR EMBL; AY164533; AAN46738.1; -; Genomic_DNA. DR EMBL; AK313202; BAG36018.1; -; mRNA. DR EMBL; AC004634; AAC15470.1; -; Genomic_DNA. DR EMBL; CH471062; EAW62069.1; -; Genomic_DNA. DR EMBL; BC033097; AAH33097.1; -; mRNA. DR CCDS; CCDS4223.1; -. DR PIR; A38432; A38432. DR RefSeq; NP_001936.1; NM_001945.2. DR UniGene; Hs.592942; -. DR UniGene; Hs.799; -. DR PDB; 1XDT; X-ray; 2.65 A; R=73-147. DR PDB; 2M8S; NMR; -; B=185-208. DR PDBsum; 1XDT; -. DR PDBsum; 2M8S; -. DR ProteinModelPortal; Q99075; -. DR SMR; Q99075; 107-147. DR BioGrid; 108172; 9. DR DIP; DIP-114N; -. DR IntAct; Q99075; 1. DR MINT; MINT-1511911; -. DR STRING; 9606.ENSP00000230990; -. DR BindingDB; Q99075; -. DR ChEMBL; CHEMBL3286070; -. DR PhosphoSite; Q99075; -. DR BioMuta; HBEGF; -. DR DMDM; 544477; -. DR PaxDb; Q99075; -. DR PRIDE; Q99075; -. DR DNASU; 1839; -. DR Ensembl; ENST00000230990; ENSP00000230990; ENSG00000113070. DR GeneID; 1839; -. DR KEGG; hsa:1839; -. DR UCSC; uc003lfi.3; human. DR CTD; 1839; -. DR GeneCards; HBEGF; -. DR HGNC; HGNC:3059; HBEGF. DR HPA; HPA053243; -. DR MIM; 126150; gene. DR neXtProt; NX_Q99075; -. DR PharmGKB; PA27513; -. DR eggNOG; ENOG410IMHM; Eukaryota. DR eggNOG; ENOG41120D3; LUCA. DR GeneTree; ENSGT00530000063708; -. DR HOGENOM; HOG000026782; -. DR HOVERGEN; HBG053952; -. DR InParanoid; Q99075; -. DR KO; K08523; -. DR OMA; YSYDHTT; -. DR OrthoDB; EOG7VQJGP; -. DR PhylomeDB; Q99075; -. DR TreeFam; TF332773; -. 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-1963640; GRB2 events in ERBB2 signaling. DR Reactome; R-HSA-1963642; PI3K events in ERBB2 signaling. DR Reactome; R-HSA-2179392; EGFR Transactivation by Gastrin. DR Reactome; R-HSA-2219530; Constitutive Signaling by Aberrant PI3K in Cancer. DR Reactome; R-HSA-5336415; Uptake and function of diphtheria toxin. DR Reactome; R-HSA-5673001; RAF/MAP kinase cascade. DR SignaLink; Q99075; -. DR EvolutionaryTrace; Q99075; -. DR GeneWiki; Heparin-binding_EGF-like_growth_factor; -. DR GenomeRNAi; 1839; -. DR NextBio; 7529; -. DR PMAP-CutDB; Q99075; -. DR PRO; PR:Q99075; -. DR Proteomes; UP000005640; Chromosome 5. DR Bgee; Q99075; -. DR CleanEx; HS_HBEGF; -. DR Genevisible; Q99075; HS. DR GO; GO:0009986; C:cell surface; NAS:UniProtKB. DR GO; GO:0030669; C:clathrin-coated endocytic vesicle membrane; TAS:Reactome. DR GO; GO:0030666; C:endocytic vesicle membrane; TAS:Reactome. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0005615; C:extracellular space; TAS:UniProtKB. DR GO; GO:0005887; C:integral component of plasma membrane; TAS:UniProtKB. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0005154; F:epidermal growth factor receptor binding; TAS:ProtInc. DR GO; GO:0008083; F:growth factor activity; IDA:UniProtKB. DR GO; GO:0008201; F:heparin binding; IMP:UniProtKB. DR GO; GO:0000186; P:activation of MAPKK activity; TAS:Reactome. DR GO; GO:0007411; P:axon guidance; TAS:Reactome. DR GO; GO:0060326; P:cell chemotaxis; IMP:UniProtKB. DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; IMP:BHF-UCL. DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome. DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome. DR GO; GO:0045087; P:innate immune response; TAS:Reactome. DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome. DR GO; GO:0000165; P:MAPK cascade; TAS:Reactome. DR GO; GO:0007517; P:muscle organ development; TAS:ProtInc. DR GO; GO:0051545; P:negative regulation of elastin biosynthetic process; IEA:Ensembl. DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome. DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; TAS:Reactome. DR GO; GO:0030307; P:positive regulation of cell growth; IEA:Ensembl. DR GO; GO:0030335; P:positive regulation of cell migration; IMP:BHF-UCL. DR GO; GO:0008284; P:positive regulation of cell proliferation; IBA:GO_Central. DR GO; GO:0051549; P:positive regulation of keratinocyte migration; IEA:Ensembl. DR GO; GO:0051897; P:positive regulation of protein kinase B signaling; IMP:BHF-UCL. DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IEA:Ensembl. DR GO; GO:0090303; P:positive regulation of wound healing; IMP:BHF-UCL. DR GO; GO:0007265; P:Ras protein signal transduction; TAS:Reactome. DR GO; GO:0008016; P:regulation of heart contraction; IEA:Ensembl. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR GO; GO:0007264; P:small GTPase mediated signal transduction; TAS:Reactome. DR GO; GO:0048010; P:vascular endothelial growth factor receptor signaling pathway; TAS:Reactome. DR GO; GO:0035313; P:wound healing, spreading of epidermal cells; IEA:Ensembl. DR InterPro; IPR013032; EGF-like_CS. DR InterPro; IPR000742; EGF-like_dom. DR InterPro; IPR015497; EGF_rcpt_ligand. DR PANTHER; PTHR10740; PTHR10740; 1. DR Pfam; PF00008; EGF; 1. DR SMART; SM00181; EGF; 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; Cell membrane; Complete proteome; KW Direct protein sequencing; Disulfide bond; EGF-like domain; KW Glycoprotein; Growth factor; Heparin-binding; Membrane; Receptor; KW Reference proteome; Secreted; Signal; Transmembrane; KW Transmembrane helix. FT SIGNAL 1 19 {ECO:0000255}. FT CHAIN 20 208 Proheparin-binding EGF-like growth FT factor. FT /FTId=PRO_0000302803. FT PROPEP 20 62 Or 72, or 73, or 76, or 81. FT {ECO:0000269|PubMed:1556128}. FT /FTId=PRO_0000007611. FT CHAIN 63 148 Heparin-binding EGF-like growth factor. FT /FTId=PRO_0000007612. FT PROPEP 149 208 C-terminal. {ECO:0000255}. FT /FTId=PRO_0000007613. FT TOPO_DOM 20 160 Extracellular. {ECO:0000255}. FT TRANSMEM 161 184 Helical. {ECO:0000255}. FT TOPO_DOM 185 208 Cytoplasmic. {ECO:0000255}. FT DOMAIN 104 144 EGF-like. {ECO:0000255|PROSITE- FT ProRule:PRU00076}. FT SITE 141 141 Plays a critical role in diphtheria toxin FT binding and toxin sensitivity. FT {ECO:0000250}. FT CARBOHYD 37 37 O-linked (GalNAc...). FT {ECO:0000305|PubMed:23234360}. FT CARBOHYD 38 38 O-linked (GalNAc...). FT {ECO:0000305|PubMed:23234360}. FT CARBOHYD 44 44 O-linked (GalNAc...). FT {ECO:0000269|PubMed:22171320, FT ECO:0000269|PubMed:23234360}. FT CARBOHYD 47 47 O-linked (GalNAc...). FT {ECO:0000269|PubMed:22171320}. FT CARBOHYD 75 75 O-linked (GalNAc...). FT {ECO:0000269|PubMed:1556128}. FT CARBOHYD 85 85 O-linked (GalNAc...). FT {ECO:0000269|PubMed:1556128}. FT DISULFID 108 121 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 116 132 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 134 143 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT TURN 108 114 {ECO:0000244|PDB:1XDT}. FT STRAND 117 121 {ECO:0000244|PDB:1XDT}. FT TURN 125 128 {ECO:0000244|PDB:1XDT}. FT STRAND 132 134 {ECO:0000244|PDB:1XDT}. FT STRAND 138 140 {ECO:0000244|PDB:1XDT}. FT STRAND 188 195 {ECO:0000244|PDB:2M8S}. SQ SEQUENCE 208 AA; 23067 MW; 2C43C9D1D8291B51 CRC64; MKLLPSVVLK LFLAAVLSAL VTGESLERLR RGLAAGTSNP DPPTVSTDQL LPLGGGRDRK VRDLQEADLD LLRVTLSSKP QALATPNKEE HGKRKKKGKG LGKKRDPCLR KYKDFCIHGE CKYVKELRAP SCICHPGYHG ERCHGLSLPV ENRLYTYDHT TILAVVAVVL SSVCLLVIVG LLMFRYHRRG GYDVENEEKV KLGMTNSH //