EGF_HUMAN
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 03-AUG-2022, entry version 231.
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=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";
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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 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 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 AlphaFoldDB; P01133; -.
DR BMRB; P01133; -.
DR SMR; P01133; -.
DR BioGRID; 108270; 21.
DR DIP; DIP-5767N; -.
DR IntAct; P01133; 13.
DR MINT; P01133; -.
DR STRING; 9606.ENSP00000265171; -.
DR BindingDB; P01133; -.
DR ChEMBL; CHEMBL5734; -.
DR DrugBank; DB04454; Alpha-Aminobutyric Acid.
DR DrugBank; DB08862; Cholecystokinin.
DR DrugBank; DB00364; Sucralfate.
DR DrugBank; DB11973; Tesevatinib.
DR GlyConnect; 709; 3 N-Linked glycans (1 site).
DR GlyGen; P01133; 13 sites, 2 N-linked glycans (1 site), 2 O-linked glycans (4 sites).
DR iPTMnet; P01133; -.
DR PhosphoSitePlus; P01133; -.
DR BioMuta; EGF; -.
DR DMDM; 251757262; -.
DR jPOST; P01133; -.
DR MassIVE; P01133; -.
DR PaxDb; P01133; -.
DR PeptideAtlas; P01133; -.
DR PRIDE; P01133; -.
DR ProteomicsDB; 18615; -.
DR ProteomicsDB; 51330; -. [P01133-1]
DR ProteomicsDB; 51331; -. [P01133-2]
DR Antibodypedia; 4510; 1422 antibodies from 44 providers.
DR DNASU; 1950; -.
DR Ensembl; ENST00000265171.10; ENSP00000265171.5; ENSG00000138798.13. [P01133-1]
DR Ensembl; ENST00000503392.1; ENSP00000421384.1; ENSG00000138798.13. [P01133-3]
DR Ensembl; ENST00000509793.5; ENSP00000424316.1; ENSG00000138798.13. [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 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 neXtProt; NX_P01133; -.
DR OpenTargets; ENSG00000138798; -.
DR Orphanet; 210159; Adult hepatocellular carcinoma.
DR Orphanet; 620368; EGF-related primary hypomagnesemia with intellectual disability.
DR PharmGKB; PA27664; -.
DR VEuPathDB; HostDB:ENSG00000138798; -.
DR eggNOG; KOG1215; Eukaryota.
DR GeneTree; ENSGT00940000158366; -.
DR HOGENOM; CLU_007857_0_0_1; -.
DR InParanoid; P01133; -.
DR OMA; CHELVSC; -.
DR OrthoDB; 1174178at2759; -.
DR PhylomeDB; P01133; -.
DR TreeFam; TF315253; -.
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 SignaLink; P01133; -.
DR SIGNOR; P01133; -.
DR BioGRID-ORCS; 1950; 15 hits in 1079 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 141 other tissues.
DR ExpressionAtlas; P01133; baseline and differential.
DR Genevisible; P01133; HS.
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: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: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:0048754; P:branching morphogenesis of an epithelial tube; IEA:Ensembl.
DR GO; GO:0021930; P:cerebellar granule cell precursor proliferation; IEA:Ensembl.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0038029; P:epidermal growth factor receptor signaling pathway via MAPK cascade; IMP:UniProtKB.
DR GO; GO:0050673; P:epithelial cell proliferation; IEA:Ensembl.
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:0060749; P:mammary gland alveolus development; IEA:Ensembl.
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:0018108; P:peptidyl-tyrosine phosphorylation; IEA:Ensembl.
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: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:0045740; P:positive regulation of DNA replication; IMP: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:0045741; P:positive regulation of epidermal growth factor-activated receptor activity; IDA:UniProtKB.
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:0043406; P:positive regulation of MAP kinase activity; IDA:HGNC-UCL.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:BHF-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:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; IGI:BHF-UCL.
DR GO; GO:0042327; P:positive regulation of phosphorylation; IDA:HGNC-UCL.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling; IDA:BHF-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: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: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 Gene3D; 2.120.10.30; -; 2.
DR IDEAL; IID00263; -.
DR InterPro; IPR011042; 6-blade_b-propeller_TolB-like.
DR InterPro; IPR001881; EGF-like_Ca-bd_dom.
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; Direct protein sequencing;
KW Disease variant; Disulfide bond; EGF-like domain; Glycoprotein;
KW Growth factor; Membrane; Primary hypomagnesemia; Reference proteome;
KW 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..1086
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
