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 10-JUN-2026, entry version 249. 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; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC 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; LYS-431; RP ARG-638; ILE-708; VAL-784; THR-842; VAL-920; GLU-981; PHE-1043 AND RP 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 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., 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 [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., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., 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., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., 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., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 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 project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP PROTEIN SEQUENCE OF 971-1023. RX PubMed=300079; DOI=10.1111/j.1399-3011.1977.tb03470.x; 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 N- and RT 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; DOI=10.1523/jneurosci.20-17-06355.2000; RA Hermann P.M., van Kesteren R.E., Wildering W.C., Painter S.D., Reno J.M., RA Smith J.S., Kumar S.B., Geraerts W.P., Ericsson L.H., Smit A.B., RA 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 CHARACTERIZATION RP 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., Hoenderop J.G., RA Knoers N.V., Bindels R.J.; RT "Impaired basolateral sorting of pro-EGF causes isolated recessive renal RT 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 to RT regulate intercellular signaling."; RL Cell 145:79-91(2011). RN [13] RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF 971-1021, AND DISULFIDE 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 dimerization."; RL J. Biol. Chem. 276:34913-34917(2001). RN [14] RP X-RAY CRYSTALLOGRAPHY (3.3 ANGSTROMS) OF 971-1023 IN COMPLEX WITH EGFR, AND RP 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 EGFR, AND RP 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 EGFR, AND RP 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., Springer T.A.; RT "Structural evidence for loose linkage between ligand binding and kinase RT 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 epithelial CC tissues in vivo and in vitro and of some fibroblasts in cell culture. CC Magnesiotropic hormone that stimulates magnesium reabsorption in the CC renal distal convoluted tubule via engagement of EGFR and activation of CC the magnesium channel TRPM6. Can induce neurite outgrowth in CC motoneurons of the pond snail Lymnaea stagnalis in vitro CC (PubMed:10964941). {ECO:0000269|PubMed:10964941, CC ECO:0000269|PubMed:17671655}. CC -!- SUBUNIT: Interacts with EGFR and promotes EGFR dimerization. Interacts CC with RHBDF2 (By similarity). Interacts with RHBDF1; may retain EGF in CC the endoplasmic reticulum and regulates its degradation through the CC endoplasmic reticulum-associated degradation (ERAD). {ECO:0000250, CC ECO:0000269|PubMed:12297050, ECO:0000269|PubMed:12620237, CC ECO:0000269|PubMed:20837704, ECO:0000269|PubMed:21029725, CC ECO:0000269|PubMed:21439629}. CC -!- INTERACTION: CC P01133; P00533: EGFR; NbExp=29; IntAct=EBI-640857, EBI-297353; CC P01133; P10620: MGST1; NbExp=3; IntAct=EBI-640857, EBI-2691601; CC P01133; Q01279: Egfr; Xeno; NbExp=3; IntAct=EBI-640857, EBI-6296235; CC PRO_0000007541; PRO_0000018520 [P28300]: LOX; NbExp=2; IntAct=EBI-9076336, EBI-20724846; CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane 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 -!- TISSUE SPECIFICITY: Expressed in kidney, salivary gland, cerebrum and CC prostate. {ECO:0000269|PubMed:17671655}. CC -!- PTM: O-glycosylated with core 1-like and core 2-like glycans. It is CC uncertain if Ser-954 or Thr-955 is O-glycosylated. The modification CC here shows glycan heterogeneity: HexHexNAc (major) and Hex2HexNAc2 CC (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 tendon CC reflexes. {ECO:0000269|PubMed:17671655}. Note=The disease is caused by CC variants affecting the gene represented in this entry. CC -!- SEQUENCE CAUTION: CC Sequence=AAR84237.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305}; 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_001178130.3. [P01133-3] DR RefSeq; NP_001171602.1; NM_001178131.3. [P01133-2] DR RefSeq; NP_001954.2; NM_001963.6. [P01133-1] 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 PDB; 7OM4; X-ray; 6.05 A; C=971-1023. DR PDB; 7SYD; EM; 3.10 A; C/D=971-1023. DR PDB; 7SYE; EM; 3.30 A; C/D=971-1023. DR PDB; 7SZ0; EM; 3.30 A; C/D=971-1023. DR PDB; 7SZ1; EM; 3.40 A; C/D=971-1023. DR PDB; 8HGO; EM; 3.31 A; C=971-1023. DR PDB; 8HGS; EM; 3.81 A; C/D=971-1023. DR PDBsum; 1IVO; -. DR PDBsum; 1JL9; -. DR PDBsum; 1NQL; -. DR PDBsum; 1P9J; -. DR PDBsum; 2KV4; -. DR PDBsum; 3NJP; -. DR PDBsum; 7OM4; -. DR PDBsum; 7SYD; -. DR PDBsum; 7SYE; -. DR PDBsum; 7SZ0; -. DR PDBsum; 7SZ1; -. DR PDBsum; 8HGO; -. DR PDBsum; 8HGS; -. DR AlphaFoldDB; P01133; -. DR BMRB; P01133; -. DR EMDB; EMD-25522; -. DR EMDB; EMD-25523; -. DR EMDB; EMD-25558; -. DR EMDB; EMD-25559; -. DR EMDB; EMD-34744; -. DR EMDB; EMD-34746; -. DR SMR; P01133; -. DR BioGRID; 108270; 22. DR DIP; DIP-5767N; -. DR FunCoup; P01133; 1215. DR IntAct; P01133; 13. DR MINT; P01133; -. DR NDEx; IQUERY-CP-EGF; 59 NDEx IQuery Curated Pathways. DR STRING; 9606.ENSP00000265171; -. DR BindingDB; P01133; -. DR ChEMBL; CHEMBL5734; -. DR DrugBank; DB04454; Alpha-Aminobutyric Acid. DR DrugBank; DB08862; Cholecystokinin. DR DrugBank; DB12843; Oleandrin. DR DrugBank; DB00364; Sucralfate. DR DrugBank; DB11973; Tesevatinib. DR GlyConnect; P01133; 3 N-Linked glycans (1 site). DR GlyCosmos; P01133; 13 sites, 5 glycans. DR GlyGen; P01133; 15 sites, 8 N-linked glycans (2 sites), 4 O-linked glycans (6 sites). DR iPTMnet; P01133; -. DR PhosphoSitePlus; P01133; -. DR BioMuta; EGF; -. DR DMDM; 251757262; -. DR jPOST; P01133; -. DR MassIVE; P01133; -. DR PaxDb; 9606-ENSP00000265171; -. DR PeptideAtlas; P01133; -. DR ProteomicsDB; 18615; -. DR ProteomicsDB; 51330; -. [P01133-1] DR ProteomicsDB; 51331; -. [P01133-2] DR Antibodypedia; 4510; 1404 antibodies from 43 providers. DR DNASU; 1950; -. DR Ensembl; ENST00000265171.10; ENSP00000265171.5; ENSG00000138798.14. [P01133-1] DR Ensembl; ENST00000503392.1; ENSP00000421384.1; ENSG00000138798.14. [P01133-3] DR Ensembl; ENST00000509793.5; ENSP00000424316.1; ENSG00000138798.14. [P01133-2] DR GeneID; 1950; -. DR KEGG; hsa:1950; -. DR MANE-Select; ENST00000265171.10; ENSP00000265171.5; NM_001963.6; NP_001954.2. DR UCSC; uc003hzy.5; human. [P01133-1] DR AGR; HGNC:3229; -. DR CIViC; 1950; 1 evidence item across 1 molecular profile. DR ClinPGx; PA27664; -. DR CTD; 1950; -. DR DisGeNET; 1950; -. DR GeneCards; EGF; -. DR HGNC; HGNC:3229; EGF. DR HPA; ENSG00000138798; Group enriched (kidney, pancreas, skeletal muscle). DR MalaCards; EGF; -. DR MIM; 131530; gene. DR MIM; 611718; phenotype. DR OpenTargets; ENSG00000138798; -. DR Orphanet; 210159; Adult hepatocellular carcinoma. DR Orphanet; 620368; EGF-related primary hypomagnesemia with intellectual disability. DR VEuPathDB; HostDB:ENSG00000138798; -. DR eggNOG; KOG1215; Eukaryota. DR GeneTree; ENSGT00940000158366; -. DR HOGENOM; CLU_007857_0_0_1; -. DR InParanoid; P01133; -. DR OMA; YKEERIY; -. DR OrthoDB; 4062651at2759; -. DR PAN-GO; P01133; 5 GO annotations based on evolutionary models. DR PhylomeDB; P01133; -. DR PathwayCommons; P01133; -. 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-9009391; Extra-nuclear estrogen signaling. DR Reactome; R-HSA-9013507; NOTCH3 Activation and Transmission of Signal to the Nucleus. 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-9665348; Signaling by ERBB2 ECD mutants. DR Reactome; R-HSA-9665686; Signaling by ERBB2 TMD/JMD mutants. DR Reactome; R-HSA-9725554; Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin. DR Reactome; R-HSA-9818030; NFE2L2 regulating tumorigenic genes. DR Reactome; R-HSA-9927418; Developmental Lineage of Mammary Gland Luminal Epithelial Cells. DR Reactome; R-HSA-9927432; Developmental Lineage of Mammary Gland Myoepithelial Cells. DR Reactome; R-HSA-9937080; Developmental Lineage of Multipotent Pancreatic Progenitor Cells. DR SignaLink; P01133; -. DR SIGNOR; P01133; -. DR Agora; ENSG00000138798; -. DR BioGRID-ORCS; 1950; 16 hits in 1165 CRISPR screens. DR ChiTaRS; EGF; human. DR EvolutionaryTrace; P01133; -. DR GeneWiki; Epidermal_growth_factor; -. DR GenomeRNAi; 1950; -. DR Pharos; P01133; Tbio. DR PRO; PR:P01133; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; P01133; protein. DR Bgee; ENSG00000138798; Expressed in renal medulla and 143 other cell types or tissues. DR ExpressionAtlas; P01133; baseline and differential. DR GO; GO:0030669; C:clathrin-coated endocytic 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; IDA:MGI. 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: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-UCL. DR GO; GO:0005085; F:guanyl-nucleotide exchange factor activity; IDA:UniProtKB. 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:0001525; P:angiogenesis; IDA:HGNC-UCL. DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0038134; P:ERBB2-EGFR signaling pathway; IDA:MGI. DR GO; GO:0070371; P:ERK1 and ERK2 cascade; IDA:UniProtKB. DR GO; GO:0090370; P:negative regulation of cholesterol efflux; IEA:Ensembl. DR GO; GO:0051048; P:negative regulation of secretion; IDA:BHF-UCL. 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-UCL. DR GO; GO:0043388; P:positive regulation of DNA binding; ISS:UniProtKB. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0010595; P:positive regulation of endothelial cell migration; IDA:BHF-UCL. DR GO; GO:0001938; P:positive regulation of endothelial cell proliferation; IDA:BHF-UCL. DR GO; GO:1905278; P:positive regulation of epithelial tube formation; IDA:BHF-UCL. 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:0043410; P:positive regulation of MAPK cascade; IDA:HGNC-UCL. DR GO; GO:0045840; P:positive regulation of mitotic nuclear division; IDA:HGNC-UCL. DR GO; GO:0010800; P:positive regulation of peptidyl-threonine phosphorylation; IDA:UniProtKB. DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IDA:BHF-UCL. DR GO; GO:0042327; P:positive regulation of phosphorylation; IDA:HGNC-UCL. 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: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: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 CDD; cd00054; EGF_CA; 2. DR FunFam; 2.10.25.10:FF:000010; Pro-epidermal growth factor; 1. DR FunFam; 2.10.25.10:FF:000219; Pro-epidermal growth factor; 1. DR FunFam; 2.10.25.10:FF:000254; Pro-epidermal growth factor; 1. DR FunFam; 2.10.25.10:FF:000300; Pro-epidermal growth factor; 1. DR FunFam; 2.10.25.10:FF:000345; Pro-epidermal growth factor; 1. DR FunFam; 2.10.25.10:FF:000362; Pro-epidermal growth factor; 1. DR FunFam; 2.10.25.10:FF:000409; Pro-epidermal growth factor; 1. DR FunFam; 2.120.10.30:FF:000028; Pro-epidermal growth factor; 1. DR FunFam; 2.120.10.30:FF:000036; Pro-epidermal growth factor; 1. DR Gene3D; 2.10.25.10; Laminin; 7. DR Gene3D; 2.120.10.30; TolB, C-terminal domain; 2. DR IDEAL; IID00263; -. DR InterPro; IPR011042; 6-blade_b-propeller_TolB-like. DR InterPro; IPR050778; Cueball_EGF_LRP_Nidogen. DR InterPro; IPR000742; EGF. DR InterPro; IPR001881; EGF-like_Ca-bd_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; IPR049883; NOTCH1_EGF-like. DR InterPro; IPR016317; Pro-epidermal_GF. DR PANTHER; PTHR46513:SF5; PRO-EPIDERMAL GROWTH FACTOR; 1. DR PANTHER; PTHR46513; VITELLOGENIN RECEPTOR-LIKE PROTEIN-RELATED-RELATED; 1. DR Pfam; PF00008; EGF; 2. DR Pfam; PF07645; EGF_CA; 3. DR Pfam; PF14670; FXa_inhibition; 1. DR Pfam; PF00058; Ldl_recept_b; 4. DR PIRSF; PIRSF001778; Pro-epidermal_growth_factor; 1. DR PRINTS; PR00009; EGFTGF. DR SMART; SM00181; EGF; 9. DR SMART; SM00179; EGF_CA; 5. DR SMART; SM00135; LY; 9. DR SUPFAM; SSF57196; EGF/Laminin; 4. DR SUPFAM; SSF57184; Growth factor receptor domain; 2. DR SUPFAM; SSF63825; YWTD domain; 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; Direct protein sequencing; KW Disease variant; Disulfide bond; EGF-like domain; Glycoprotein; KW Growth factor; Membrane; Primary hypomagnesemia; Proteomics identification; KW Reference proteome; Repeat; Signal; Transmembrane; Transmembrane helix. FT SIGNAL 1..22 FT /evidence="ECO:0000255" FT CHAIN 23..1207 FT /note="Pro-epidermal growth factor" FT /id="PRO_0000007540" FT CHAIN 971..1023 FT /note="Epidermal growth factor" FT /id="PRO_0000007541" FT TOPO_DOM 23..1032 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 1033..1053 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 1054..1207 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REPEAT 86..127 FT /note="LDL-receptor class B 1" FT REPEAT 128..169 FT /note="LDL-receptor class B 2" FT REPEAT 170..211 FT /note="LDL-receptor class B 3" FT REPEAT 212..258 FT /note="LDL-receptor class B 4" FT DOMAIN 314..355 FT /note="EGF-like 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 356..396 FT /note="EGF-like 2; calcium-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 397..437 FT /note="EGF-like 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 435..477 FT /note="EGF-like 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT REPEAT 483..523 FT /note="LDL-receptor class B 5" FT REPEAT 524..566 FT /note="LDL-receptor class B 6" FT REPEAT 567..609 FT /note="LDL-receptor class B 7" FT REPEAT 610..653 FT /note="LDL-receptor class B 8" FT REPEAT 654..696 FT /note="LDL-receptor class B 9" FT DOMAIN 741..781 FT /note="EGF-like 5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 831..869 FT /note="EGF-like 6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 870..911 FT /note="EGF-like 7; calcium-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 912..952 FT /note="EGF-like 8; calcium-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 972..1013 FT /note="EGF-like 9" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT REGION 801..807 FT /note="O-glycosylated at one site" FT REGION 1067..1093 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1108..1131 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1177..1207 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1070..1085 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT CARBOHYD 38 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 104 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 117 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 148 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 324 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 404 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 596 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 815 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 926 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 318..330 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 325..339 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 341..354 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 360..371 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 367..380 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 382..395 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 401..412 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 408..421 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 423..436 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 439..451 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 447..461 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 463..476 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 745..756 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 752..765 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 767..780 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 835..846 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 840..855 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 857..868 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 874..888 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 881..897 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 899..910 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 916..929 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 923..938 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 940..951 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DISULFID 976..990 FT DISULFID 984..1001 FT DISULFID 1003..1012 FT VAR_SEQ 314..355 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_041586" FT VAR_SEQ 912..952 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000305" FT /id="VSP_047190" FT VARIANT 16 FT /note="S -> R (in dbSNP:rs11568849)" FT /evidence="ECO:0000269|Ref.2" FT /id="VAR_020161" FT VARIANT 151 FT /note="H -> Y (in dbSNP:rs9991664)" FT /id="VAR_033825" FT VARIANT 257 FT /note="D -> H (in dbSNP:rs11568911)" FT /evidence="ECO:0000269|Ref.2" FT /id="VAR_020968" FT VARIANT 292 FT /note="L -> H (in dbSNP:rs35191533)" FT /id="VAR_033826" FT VARIANT 431 FT /note="R -> K (in dbSNP:rs11568943)" FT /evidence="ECO:0000269|Ref.2" FT /id="VAR_020162" FT VARIANT 638 FT /note="S -> R (in dbSNP:rs11568992)" FT /evidence="ECO:0000269|Ref.2" FT /id="VAR_020969" FT VARIANT 708 FT /note="M -> I (in dbSNP:rs2237051)" FT /evidence="ECO:0000269|Ref.2" FT /id="VAR_002275" FT VARIANT 723 FT /note="G -> R (in dbSNP:rs6413481)" FT /id="VAR_020163" FT VARIANT 784 FT /note="D -> V (in dbSNP:rs11569017)" FT /evidence="ECO:0000269|Ref.2" FT /id="VAR_020164" FT VARIANT 842 FT /note="M -> T (in dbSNP:rs11569046)" FT /evidence="ECO:0000269|Ref.2" FT /id="VAR_020165" FT VARIANT 920 FT /note="E -> V (in dbSNP:rs4698803)" FT /evidence="ECO:0000269|PubMed:14702039, ECO:0000269|Ref.2" FT /id="VAR_020970" FT VARIANT 981 FT /note="D -> E (in dbSNP:rs11569086)" FT /evidence="ECO:0000269|Ref.2" FT /id="VAR_020971" FT VARIANT 1043 FT /note="L -> F (in dbSNP:rs11569098)" FT /evidence="ECO:0000269|Ref.2" FT /id="VAR_020166" FT VARIANT 1070 FT /note="P -> L (in HOMG4; affects basolateral sorting of FT pro-EGF preventing the hormone to stimulate EGFR; lack of FT TRPM6 activation; dbSNP:rs121434567)" FT /evidence="ECO:0000269|PubMed:17671655" FT /id="VAR_039474" FT VARIANT 1084 FT /note="A -> G (in dbSNP:rs11569111)" FT /evidence="ECO:0000269|Ref.2" FT /id="VAR_020972" FT CONFLICT 302 FT /note="A -> T (in Ref. 3; BAG61319)" FT /evidence="ECO:0000305" FT STRAND 979..981 FT /evidence="ECO:0007829|PDB:1JL9" FT STRAND 982..984 FT /evidence="ECO:0007829|PDB:1P9J" FT TURN 985..987 FT /evidence="ECO:0007829|PDB:1JL9" FT STRAND 989..993 FT /evidence="ECO:0007829|PDB:1NQL" FT TURN 994..997 FT /evidence="ECO:0007829|PDB:1NQL" FT STRAND 998..1003 FT /evidence="ECO:0007829|PDB:1NQL" FT STRAND 1007..1009 FT /evidence="ECO:0007829|PDB:1NQL" FT HELIX 1017..1019 FT /evidence="ECO:0007829|PDB:7SYE" 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 //