ID EGF_HUMAN Reviewed; 1207 AA. AC P01133; B4DRK7; E7EVD2; E9PBF0; Q52LZ6; DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot. DT 07-JUL-2009, sequence version 2. DT 13-FEB-2019, entry version 212. DE RecName: Full=Pro-epidermal growth factor; DE Short=EGF; DE Contains: DE RecName: Full=Epidermal growth factor; DE AltName: Full=Urogastrone; DE Flags: Precursor; GN Name=EGF; 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] (ISOFORM 1). RC TISSUE=Kidney; RX PubMed=3491360; DOI=10.1093/nar/14.21.8427; RA Bell G.I., Fong N.M., Stempien M.M., Wormsted M.A., Caput D., Ku L., RA Urdea M.S., Rall L.B., Sanchez-Pescador R.; RT "Human epidermal growth factor precursor: cDNA sequence, expression in RT vitro and gene organization."; RL Nucleic Acids Res. 14:8427-8446(1986). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ARG-16; HIS-257; RP LYS-431; ARG-638; ILE-708; VAL-784; THR-842; VAL-920; GLU-981; RP PHE-1043 AND GLY-1084. RG NIEHS SNPs program; RL Submitted (DEC-2003) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT RP VAL-920. RC TISSUE=Teratocarcinoma; 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=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J., RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., RA 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., RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., RA 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., RA Waterston R.H., Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 RT and 4."; RL Nature 434:724-731(2005). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Colon; 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 PROTEIN SEQUENCE OF 971-1023. RX PubMed=300079; RA Gregory H., Preston B.M.; RT "The primary structure of human urogastrone."; RL Int. J. Pept. Protein Res. 9:107-118(1977). RN [7] RP PROTEIN SEQUENCE OF 971-1023. RX PubMed=2789514; DOI=10.1016/0006-291X(89)92334-6; RA Furuya M., Akashi S., Hirayama K.; RT "The primary structure of human EGF produced by genetic engineering, RT studied by high-performance tandem mass spectrometry."; RL Biochem. Biophys. Res. Commun. 163:1100-1106(1989). RN [8] RP GLYCOSYLATION, STRUCTURE OF CARBOHYDRATES, AND IDENTIFICATION BY MASS RP 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 11:1-17(2012). RN [9] RP STRUCTURE BY NMR OF EGF. RX PubMed=1522591; DOI=10.1016/0022-2836(92)90697-I; RA Hommel U., Harvey T.S., Driscoll P.C., Campbell I.D.; RT "Human epidermal growth factor. High resolution solution structure and RT comparison with human transforming growth factor alpha."; RL J. Mol. Biol. 227:271-282(1992). RN [10] RP FUNCTION. RX PubMed=10964941; RA Hermann P.M., van Kesteren R.E., Wildering W.C., Painter S.D., RA Reno J.M., Smith J.S., Kumar S.B., Geraerts W.P., Ericsson L.H., RA Smit A.B., Bulloch A.G., Nagle G.T.; RT "Neurotrophic actions of a novel molluscan epidermal growth factor."; RL J. Neurosci. 20:6355-6364(2000). RN [11] RP FUNCTION, TISSUE SPECIFICITY, VARIANT HOMG4 LEU-1070, AND RP CHARACTERIZATION OF VARIANT HOMG4 LEU-1070. RX PubMed=17671655; DOI=10.1172/JCI31680; RA Groenestege W.M.T., Thebault S., van der Wijst J., van den Berg D., RA Janssen R., Tejpar S., van den Heuvel L.P., van Cutsem E., RA Hoenderop J.G., Knoers N.V., Bindels R.J.; RT "Impaired basolateral sorting of pro-EGF causes isolated recessive RT renal hypomagnesemia."; RL J. Clin. Invest. 117:2260-2267(2007). RN [12] RP INTERACTION WITH RHBDF1. RX PubMed=21439629; DOI=10.1016/j.cell.2011.02.047; RA Zettl M., Adrain C., Strisovsky K., Lastun V., Freeman M.; RT "Rhomboid family pseudoproteases use the ER quality control machinery RT to regulate intercellular signaling."; RL Cell 145:79-91(2011). RN [13] RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF 971-1021, AND DISULFIDE RP BONDS. RX PubMed=11438527; DOI=10.1074/jbc.M102874200; RA Lu H.S., Chai J.J., Li M., Huang B.R., He C.H., Bi R.C.; RT "Crystal structure of human epidermal growth factor and its RT dimerization."; RL J. Biol. Chem. 276:34913-34917(2001). RN [14] RP X-RAY CRYSTALLOGRAPHY (3.3 ANGSTROMS) OF 971-1023 IN COMPLEX WITH RP EGFR, AND DISULFIDE BONDS. RX PubMed=12297050; DOI=10.1016/S0092-8674(02)00963-7; RA Ogiso H., Ishitani R., Nureki O., Fukai S., Yamanaka M., Kim J.H., RA Saito K., Sakamoto A., Inoue M., Shirouzu M., Yokoyama S.; RT "Crystal structure of the complex of human epidermal growth factor and RT receptor extracellular domains."; RL Cell 110:775-787(2002). RN [15] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 971-1023 IN COMPLEX WITH RP EGFR, AND DISULFIDE BONDS. RX PubMed=12620237; DOI=10.1016/S1097-2765(03)00047-9; RA Ferguson K.M., Berger M.B., Mendrola J.M., Cho H.S., Leahy D.J., RA Lemmon M.A.; RT "EGF activates its receptor by removing interactions that autoinhibit RT ectodomain dimerization."; RL Mol. Cell 11:507-517(2003). RN [16] RP STRUCTURE BY NMR OF 971-1023 IN COMPLEX WITH SURAMIN. RX PubMed=21029725; DOI=10.1016/j.bbrc.2010.10.089; RA Huang H.W., Mohan S.K., Yu C.; RT "The NMR solution structure of human epidermal growth factor (hEGF) at RT physiological pH and its interactions with suramin."; RL Biochem. Biophys. Res. Commun. 402:705-710(2010). RN [17] RP X-RAY CRYSTALLOGRAPHY (3.3 ANGSTROMS) OF 975-1021 IN COMPLEX WITH RP EGFR, AND DISULFIDE BONDS. RX PubMed=20837704; DOI=10.1128/MCB.00742-10; RA Lu C., Mi L.Z., Grey M.J., Zhu J., Graef E., Yokoyama S., RA Springer T.A.; RT "Structural evidence for loose linkage between ligand binding and RT kinase activation in the epidermal growth factor receptor."; RL Mol. Cell. Biol. 30:5432-5443(2010). CC -!- FUNCTION: EGF stimulates the growth of various epidermal and CC epithelial tissues in vivo and in vitro and of some fibroblasts in CC cell culture. Magnesiotropic hormone that stimulates magnesium CC reabsorption in the renal distal convoluted tubule via engagement CC of EGFR and activation of the magnesium channel TRPM6. Can induce CC neurite outgrowth in motoneurons of the pond snail Lymnaea CC stagnalis in vitro (PubMed:10964941). CC {ECO:0000269|PubMed:10964941, ECO:0000269|PubMed:17671655}. CC -!- SUBUNIT: Interacts with EGFR and promotes EGFR dimerization. CC Interacts with RHBDF2 (By similarity). Interacts with RHBDF1; may CC retain EGF in the endoplasmic reticulum and regulates its CC degradation through the endoplasmic reticulum-associated CC degradation (ERAD). {ECO:0000250, ECO:0000269|PubMed:12297050, CC ECO:0000269|PubMed:12620237, ECO:0000269|PubMed:20837704, CC ECO:0000269|PubMed:21029725, ECO:0000269|PubMed:21439629}. CC -!- INTERACTION: CC P00533:EGFR; NbExp=21; IntAct=EBI-640857, EBI-297353; CC Q01279:Egfr (xeno); NbExp=3; IntAct=EBI-640857, EBI-6296235; CC P28300:LOX; NbExp=2; IntAct=EBI-9076336, EBI-20724846; CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane CC protein. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=P01133-1; Sequence=Displayed; CC Name=2; CC IsoId=P01133-2; Sequence=VSP_041586; CC Name=3; CC IsoId=P01133-3; Sequence=VSP_047190; CC Note=No experimental confirmation available. Gene prediction CC based on cDNA data.; CC -!- TISSUE SPECIFICITY: Expressed in kidney, salivary gland, cerebrum CC and prostate. {ECO:0000269|PubMed:17671655}. CC -!- PTM: O-glycosylated with core 1-like and core 2-like glycans. It CC is uncertain if Ser-954 or Thr-955 is O-glycosylated. The CC modification here shows glycan heterogeneity: HexHexNAc (major) CC and Hex2HexNAc2 (minor). {ECO:0000269|PubMed:22171320}. CC -!- DISEASE: Hypomagnesemia 4 (HOMG4) [MIM:611718]: A disorder CC characterized by massive renal hypomagnesemia and normal levels of CC serum calcium and calcium excretion. Clinical features include CC seizures, mild-to moderate psychomotor retardation, and brisk CC tendon reflexes. {ECO:0000269|PubMed:17671655}. Note=The disease CC is caused by mutations affecting the gene represented in this CC entry. CC -!- SEQUENCE CAUTION: CC Sequence=AAR84237.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/egf/"; CC -!- WEB RESOURCE: Name=Wikipedia; Note=Epidermal growth factor entry; CC URL="https://en.wikipedia.org/wiki/Epidermal_growth_factor"; 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; X04571; CAA28240.1; -; mRNA. DR EMBL; AY506357; AAR84237.1; ALT_SEQ; Genomic_DNA. DR EMBL; AK299306; BAG61319.1; -; mRNA. DR EMBL; AC004050; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC005509; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC093731; AAH93731.1; -; mRNA. DR EMBL; BC113461; AAI13462.1; -; mRNA. DR CCDS; CCDS3689.1; -. [P01133-1] DR CCDS; CCDS54794.1; -. [P01133-3] DR CCDS; CCDS54795.1; -. [P01133-2] DR PIR; A25531; EGHU. DR RefSeq; NP_001171601.1; NM_001178130.2. [P01133-3] DR RefSeq; NP_001171602.1; NM_001178131.2. [P01133-2] DR RefSeq; NP_001954.2; NM_001963.5. [P01133-1] DR UniGene; Hs.419815; -. DR PDB; 1IVO; X-ray; 3.30 A; C/D=971-1023. DR PDB; 1JL9; X-ray; 3.00 A; A/B=971-1021. DR PDB; 1NQL; X-ray; 2.80 A; B=971-1023. DR PDB; 1P9J; NMR; -; A=976-1022. DR PDB; 2KV4; NMR; -; A=971-1023. DR PDB; 3NJP; X-ray; 3.30 A; C/D=975-1021. DR PDBsum; 1IVO; -. DR PDBsum; 1JL9; -. DR PDBsum; 1NQL; -. DR PDBsum; 1P9J; -. DR PDBsum; 2KV4; -. DR PDBsum; 3NJP; -. DR ProteinModelPortal; P01133; -. DR SMR; P01133; -. DR BioGrid; 108270; 16. DR DIP; DIP-5767N; -. DR IntAct; P01133; 10. DR MINT; P01133; -. DR STRING; 9606.ENSP00000265171; -. DR ChEMBL; CHEMBL5734; -. DR DrugBank; DB04454; Alpha-Aminobutyric Acid. DR DrugBank; DB00364; Sucralfate. DR DrugBank; DB05007; XL647. DR GlyConnect; 709; -. DR iPTMnet; P01133; -. DR PhosphoSitePlus; P01133; -. DR UniCarbKB; P01133; -. DR BioMuta; EGF; -. DR DMDM; 251757262; -. DR jPOST; P01133; -. DR PaxDb; P01133; -. DR PeptideAtlas; P01133; -. DR PRIDE; P01133; -. DR ProteomicsDB; 12632; -. [P01133-2] DR ProteomicsDB; 51330; -. DR ProteomicsDB; 51331; -. [P01133-2] DR Ensembl; ENST00000265171; ENSP00000265171; ENSG00000138798. [P01133-1] DR Ensembl; ENST00000503392; ENSP00000421384; ENSG00000138798. [P01133-3] DR Ensembl; ENST00000509793; ENSP00000424316; ENSG00000138798. [P01133-2] DR GeneID; 1950; -. DR KEGG; hsa:1950; -. DR UCSC; uc003hzy.5; human. [P01133-1] DR CTD; 1950; -. DR DisGeNET; 1950; -. DR EuPathDB; HostDB:ENSG00000138798.11; -. DR GeneCards; EGF; -. DR HGNC; HGNC:3229; EGF. DR MalaCards; EGF; -. DR MIM; 131530; gene. DR MIM; 611718; phenotype. DR neXtProt; NX_P01133; -. DR OpenTargets; ENSG00000138798; -. DR Orphanet; 210159; Adult hepatocellular carcinoma. DR Orphanet; 34527; Familial primary hypomagnesemia with normocalciuria and normocalcemia. DR PharmGKB; PA27664; -. DR eggNOG; ENOG410IPSY; Eukaryota. DR eggNOG; ENOG410ZVIM; LUCA. DR GeneTree; ENSGT00940000158366; -. DR HOGENOM; HOG000112345; -. DR HOVERGEN; HBG003858; -. DR InParanoid; P01133; -. DR KO; K04357; -. DR OMA; LPDRKTC; -. DR OrthoDB; 1174178at2759; -. DR PhylomeDB; P01133; -. DR TreeFam; TF315253; -. DR Reactome; R-HSA-114608; Platelet degranulation. DR Reactome; R-HSA-1227986; Signaling by ERBB2. DR Reactome; R-HSA-1236382; Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants. DR Reactome; R-HSA-1236394; Signaling by ERBB4. DR Reactome; R-HSA-1250196; SHC1 events in ERBB2 signaling. DR Reactome; R-HSA-1251932; PLCG1 events in ERBB2 signaling. 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-5637810; Constitutive Signaling by EGFRvIII. 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-9013507; NOTCH3 Activation and Transmission of Signal to the Nucleus. DR SignaLink; P01133; -. DR SIGNOR; P01133; -. DR ChiTaRS; EGF; human. DR EvolutionaryTrace; P01133; -. DR GeneWiki; Epidermal_growth_factor; -. DR GenomeRNAi; 1950; -. DR PMAP-CutDB; P01133; -. DR PRO; PR:P01133; -. DR Proteomes; UP000005640; Chromosome 4. DR Bgee; ENSG00000138798; Expressed in 147 organ(s), highest expression level in renal medulla. DR Genevisible; P01133; HS. DR GO; GO:0030665; C:clathrin-coated vesicle membrane; TAS:Reactome. DR GO; GO:0070062; C:extracellular exosome; IDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0005615; C:extracellular space; HDA:UniProtKB. DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW. DR GO; GO:0005765; C:lysosomal membrane; HDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central. DR GO; GO:0031093; C:platelet alpha granule lumen; TAS:Reactome. DR GO; GO:0043235; C:receptor complex; IBA:GO_Central. DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro. DR GO; GO:0005154; F:epidermal growth factor receptor binding; TAS:UniProtKB. DR GO; GO:0008083; F:growth factor activity; IDA:HGNC. DR GO; GO:0046934; F:phosphatidylinositol-4,5-bisphosphate 3-kinase activity; TAS:Reactome. DR GO; GO:0004713; F:protein tyrosine kinase activity; EXP:Reactome. DR GO; GO:0005088; F:Ras guanyl-nucleotide exchange factor activity; IDA:UniProtKB. DR GO; GO:0030297; F:transmembrane receptor protein tyrosine kinase activator activity; TAS:UniProtKB. DR GO; GO:0042813; F:Wnt-activated receptor activity; IBA:GO_Central. DR GO; GO:0017147; F:Wnt-protein binding; IBA:GO_Central. DR GO; GO:0000187; P:activation of MAPK activity; IEA:Ensembl. DR GO; GO:0000186; P:activation of MAPKK activity; IEA:Ensembl. DR GO; GO:0001525; P:angiogenesis; IDA:HGNC. DR GO; GO:0048754; P:branching morphogenesis of an epithelial tube; IEA:Ensembl. DR GO; GO:0060070; P:canonical Wnt signaling pathway; IBA:GO_Central. DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome. DR GO; GO:0038128; P:ERBB2 signaling pathway; TAS:Reactome. DR GO; GO:0070371; P:ERK1 and ERK2 cascade; IDA:UniProtKB. DR GO; GO:0060749; P:mammary gland alveolus development; IEA:Ensembl. DR GO; GO:0000165; P:MAPK cascade; TAS:Reactome. DR GO; GO:0061024; P:membrane organization; TAS:Reactome. DR GO; GO:0090370; P:negative regulation of cholesterol efflux; IEA:Ensembl. DR GO; GO:0042059; P:negative regulation of epidermal growth factor receptor signaling pathway; TAS:Reactome. DR GO; GO:1901185; P:negative regulation of ERBB signaling pathway; TAS:Reactome. DR GO; GO:0045746; P:negative regulation of Notch signaling pathway; TAS:Reactome. DR GO; GO:0051048; P:negative regulation of secretion; IDA:BHF-UCL. DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome. DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; IDA:BHF-UCL. DR GO; GO:0030335; P:positive regulation of cell migration; IDA:UniProtKB. DR GO; GO:0008284; P:positive regulation of cell population proliferation; IDA:HGNC. DR GO; GO:0021940; P:positive regulation of cerebellar granule cell precursor proliferation; IEA:Ensembl. DR GO; GO:0043388; P:positive regulation of DNA binding; ISS:UniProtKB. DR GO; GO:0045741; P:positive regulation of epidermal growth factor-activated receptor activity; IDA:UniProtKB. DR GO; GO:0010628; P:positive regulation of gene expression; IDA:UniProtKB. DR GO; GO:1900127; P:positive regulation of hyaluronan biosynthetic process; IDA:UniProtKB. DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IDA:HGNC. DR GO; GO:0045840; P:positive regulation of mitotic nuclear division; IDA:HGNC. DR GO; GO:0010800; P:positive regulation of peptidyl-threonine phosphorylation; IDA:UniProtKB. DR GO; GO:0042327; P:positive regulation of phosphorylation; IDA:HGNC. DR GO; GO:0051897; P:positive regulation of protein kinase B signaling; TAS:Reactome. DR GO; GO:1902966; P:positive regulation of protein localization to early endosome; IDA:UniProtKB. DR GO; GO:0002092; P:positive regulation of receptor internalization; IDA:ParkinsonsUK-UCL. DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB. DR GO; GO:2000060; P:positive regulation of ubiquitin-dependent protein catabolic process; IEA:Ensembl. DR GO; GO:0090279; P:regulation of calcium ion import; IDA:BHF-UCL. DR GO; GO:2000145; P:regulation of cell motility; TAS:Reactome. DR GO; GO:2000008; P:regulation of protein localization to cell surface; IDA:BHF-UCL. DR GO; GO:0046425; P:regulation of receptor signaling pathway via JAK-STAT; ISS:UniProtKB. DR GO; GO:0007165; P:signal transduction; TAS:Reactome. DR Gene3D; 2.120.10.30; -; 2. DR InterPro; IPR011042; 6-blade_b-propeller_TolB-like. DR InterPro; IPR001881; EGF-like_Ca-bd_dom. DR InterPro; IPR013032; EGF-like_CS. DR InterPro; IPR000742; EGF-like_dom. DR InterPro; IPR000152; EGF-type_Asp/Asn_hydroxyl_site. DR InterPro; IPR018097; EGF_Ca-bd_CS. DR InterPro; IPR009030; Growth_fac_rcpt_cys_sf. DR InterPro; IPR000033; LDLR_classB_rpt. DR InterPro; IPR016317; Pro-epidermal_GF. DR Pfam; PF00008; EGF; 1. DR Pfam; PF07645; EGF_CA; 3. DR Pfam; PF00058; Ldl_recept_b; 4. DR PIRSF; PIRSF001778; Pro-epidermal_growth_factor; 1. DR SMART; SM00181; EGF; 9. DR SMART; SM00179; EGF_CA; 5. DR SMART; SM00135; LY; 9. DR SUPFAM; SSF57184; SSF57184; 2. DR PROSITE; PS00010; ASX_HYDROXYL; 3. DR PROSITE; PS00022; EGF_1; 1. DR PROSITE; PS01186; EGF_2; 7. DR PROSITE; PS50026; EGF_3; 5. DR PROSITE; PS01187; EGF_CA; 3. DR PROSITE; PS51120; LDLRB; 9. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Complete proteome; KW Direct protein sequencing; Disease mutation; Disulfide bond; KW EGF-like domain; Glycoprotein; Growth factor; Membrane; Polymorphism; KW Primary hypomagnesemia; Reference proteome; Repeat; Signal; KW Transmembrane; Transmembrane helix. FT SIGNAL 1 22 {ECO:0000255}. FT CHAIN 23 1207 Pro-epidermal growth factor. FT /FTId=PRO_0000007540. FT CHAIN 971 1023 Epidermal growth factor. FT /FTId=PRO_0000007541. FT TOPO_DOM 23 1032 Extracellular. {ECO:0000255}. FT TRANSMEM 1033 1053 Helical. {ECO:0000255}. FT TOPO_DOM 1054 1207 Cytoplasmic. {ECO:0000255}. FT REPEAT 86 127 LDL-receptor class B 1. FT REPEAT 128 169 LDL-receptor class B 2. FT REPEAT 170 211 LDL-receptor class B 3. FT REPEAT 212 258 LDL-receptor class B 4. FT DOMAIN 314 355 EGF-like 1. {ECO:0000255|PROSITE- FT ProRule:PRU00076}. FT DOMAIN 356 396 EGF-like 2; calcium-binding. FT {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DOMAIN 397 437 EGF-like 3. {ECO:0000255|PROSITE- FT ProRule:PRU00076}. FT DOMAIN 435 477 EGF-like 4. {ECO:0000255|PROSITE- FT ProRule:PRU00076}. FT REPEAT 483 523 LDL-receptor class B 5. FT REPEAT 524 566 LDL-receptor class B 6. FT REPEAT 567 609 LDL-receptor class B 7. FT REPEAT 610 653 LDL-receptor class B 8. FT REPEAT 654 696 LDL-receptor class B 9. FT DOMAIN 741 781 EGF-like 5. {ECO:0000255|PROSITE- FT ProRule:PRU00076}. FT DOMAIN 831 869 EGF-like 6. {ECO:0000255|PROSITE- FT ProRule:PRU00076}. FT DOMAIN 870 911 EGF-like 7; calcium-binding. FT {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DOMAIN 912 952 EGF-like 8; calcium-binding. FT {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DOMAIN 972 1013 EGF-like 9. {ECO:0000255|PROSITE- FT ProRule:PRU00076}. FT REGION 801 807 O-glycosylated at one site. FT CARBOHYD 38 38 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 104 104 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 117 117 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 148 148 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 324 324 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 404 404 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 596 596 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 815 815 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 926 926 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT DISULFID 318 330 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 325 339 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 341 354 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 360 371 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 367 380 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 382 395 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 401 412 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 408 421 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 423 436 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 439 451 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 447 461 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 463 476 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 745 756 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 752 765 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 767 780 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 835 846 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 840 855 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 857 868 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 874 888 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 881 897 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 899 910 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 916 929 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 923 938 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 940 951 {ECO:0000255|PROSITE-ProRule:PRU00076}. FT DISULFID 976 990 FT DISULFID 984 1001 FT DISULFID 1003 1012 FT VAR_SEQ 314 355 Missing (in isoform 2). FT {ECO:0000303|PubMed:14702039}. FT /FTId=VSP_041586. FT VAR_SEQ 912 952 Missing (in isoform 3). {ECO:0000305}. FT /FTId=VSP_047190. FT VARIANT 16 16 S -> R (in dbSNP:rs11568849). FT {ECO:0000269|Ref.2}. FT /FTId=VAR_020161. FT VARIANT 151 151 H -> Y (in dbSNP:rs9991664). FT /FTId=VAR_033825. FT VARIANT 257 257 D -> H (in dbSNP:rs11568911). FT {ECO:0000269|Ref.2}. FT /FTId=VAR_020968. FT VARIANT 292 292 L -> H (in dbSNP:rs35191533). FT /FTId=VAR_033826. FT VARIANT 431 431 R -> K (in dbSNP:rs11568943). FT {ECO:0000269|Ref.2}. FT /FTId=VAR_020162. FT VARIANT 638 638 S -> R (in dbSNP:rs11568992). FT {ECO:0000269|Ref.2}. FT /FTId=VAR_020969. FT VARIANT 708 708 M -> I (in dbSNP:rs2237051). FT {ECO:0000269|Ref.2}. FT /FTId=VAR_002275. FT VARIANT 723 723 G -> R (in dbSNP:rs6413481). FT /FTId=VAR_020163. FT VARIANT 784 784 D -> V (in dbSNP:rs11569017). FT {ECO:0000269|Ref.2}. FT /FTId=VAR_020164. FT VARIANT 842 842 M -> T (in dbSNP:rs11569046). FT {ECO:0000269|Ref.2}. FT /FTId=VAR_020165. FT VARIANT 920 920 E -> V (in dbSNP:rs4698803). FT {ECO:0000269|PubMed:14702039, FT ECO:0000269|Ref.2}. FT /FTId=VAR_020970. FT VARIANT 981 981 D -> E (in dbSNP:rs11569086). FT {ECO:0000269|Ref.2}. FT /FTId=VAR_020971. FT VARIANT 1043 1043 L -> F (in dbSNP:rs11569098). FT {ECO:0000269|Ref.2}. FT /FTId=VAR_020166. FT VARIANT 1070 1070 P -> L (in HOMG4; affects basolateral FT sorting of pro-EGF preventing the hormone FT to stimulate EGFR; lack of TRPM6 FT activation; dbSNP:rs121434567). FT {ECO:0000269|PubMed:17671655}. FT /FTId=VAR_039474. FT VARIANT 1084 1084 A -> G (in dbSNP:rs11569111). FT {ECO:0000269|Ref.2}. FT /FTId=VAR_020972. FT CONFLICT 302 302 A -> T (in Ref. 3; BAG61319). FT {ECO:0000305}. FT STRAND 979 981 {ECO:0000244|PDB:1JL9}. FT STRAND 982 984 {ECO:0000244|PDB:1P9J}. FT TURN 985 987 {ECO:0000244|PDB:1JL9}. FT STRAND 989 993 {ECO:0000244|PDB:1NQL}. FT TURN 994 997 {ECO:0000244|PDB:1NQL}. FT STRAND 998 1003 {ECO:0000244|PDB:1NQL}. FT STRAND 1007 1009 {ECO:0000244|PDB:1NQL}. FT TURN 1018 1021 {ECO:0000244|PDB:1P9J}. SQ SEQUENCE 1207 AA; 133994 MW; 3C787F1D405CFAF1 CRC64; MLLTLIILLP VVSKFSFVSL SAPQHWSCPE GTLAGNGNST CVGPAPFLIF SHGNSIFRID TEGTNYEQLV VDAGVSVIMD FHYNEKRIYW VDLERQLLQR VFLNGSRQER VCNIEKNVSG MAINWINEEV IWSNQQEGII TVTDMKGNNS HILLSALKYP ANVAVDPVER FIFWSSEVAG SLYRADLDGV GVKALLETSE KITAVSLDVL DKRLFWIQYN REGSNSLICS CDYDGGSVHI SKHPTQHNLF AMSLFGDRIF YSTWKMKTIW IANKHTGKDM VRINLHSSFV PLGELKVVHP LAQPKAEDDT WEPEQKLCKL RKGNCSSTVC GQDLQSHLCM CAEGYALSRD RKYCEDVNEC AFWNHGCTLG CKNTPGSYYC TCPVGFVLLP DGKRCHQLVS CPRNVSECSH DCVLTSEGPL CFCPEGSVLE RDGKTCSGCS SPDNGGCSQL CVPLSPVSWE CDCFPGYDLQ LDEKSCAASG PQPFLLFANS QDIRHMHFDG TDYGTLLSQQ MGMVYALDHD PVENKIYFAH TALKWIERAN MDGSQRERLI EEGVDVPEGL AVDWIGRRFY WTDRGKSLIG RSDLNGKRSK IITKENISQP RGIAVHPMAK RLFWTDTGIN PRIESSSLQG LGRLVIASSD LIWPSGITID FLTDKLYWCD AKQSVIEMAN LDGSKRRRLT QNDVGHPFAV AVFEDYVWFS DWAMPSVMRV NKRTGKDRVR LQGSMLKPSS LVVVHPLAKP GADPCLYQNG GCEHICKKRL GTAWCSCREG FMKASDGKTC LALDGHQLLA GGEVDLKNQV TPLDILSKTR VSEDNITESQ HMLVAEIMVS DQDDCAPVGC SMYARCISEG EDATCQCLKG FAGDGKLCSD IDECEMGVPV CPPASSKCIN TEGGYVCRCS EGYQGDGIHC LDIDECQLGE HSCGENASCT NTEGGYTCMC AGRLSEPGLI CPDSTPPPHL REDDHHYSVR NSDSECPLSH DGYCLHDGVC MYIEALDKYA CNCVVGYIGE RCQYRDLKWW ELRHAGHGQQ QKVIVVAVCV VVLVMLLLLS LWGAHYYRTQ KLLSKNPKNP YEESSRDVRS RRPADTEDGM SSCPQPWFVV IKEHQDLKNG GQPVAGEDGQ AADGSMQPTS WRQEPQLCGM GTEQGCWIPV SSDKGSCPQV MERSFHMPSY GTQTLEGGVE KPHSLLSANP LWQQRALDPP HQMELTQ //