ID EGFR_HUMAN Reviewed; 1210 AA. AC P00533; O00688; O00732; P06268; Q14225; Q68GS5; Q92795; Q9BZS2; AC Q9GZX1; Q9H2C9; Q9H3C9; Q9UMD7; Q9UMD8; Q9UMG5; DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1997, sequence version 2. DT 21-MAR-2012, entry version 181. DE RecName: Full=Epidermal growth factor receptor; DE EC=2.7.10.1; DE AltName: Full=Proto-oncogene c-ErbB-1; DE AltName: Full=Receptor tyrosine-protein kinase erbB-1; DE Flags: Precursor; GN Name=EGFR; Synonyms=ERBB, ERBB1, HER1; 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). RX MEDLINE=84219729; PubMed=6328312; DOI=10.1038/309418a0; RA Ullrich A., Coussens L., Hayflick J.S., Dull T.J., Gray A., Tam A.W., RA Lee J., Yarden Y., Libermann T.A., Schlessinger J., Downward J., RA Mayes E.L.V., Whittle N., Waterfield M.D., Seeburg P.H.; RT "Human epidermal growth factor receptor cDNA sequence and aberrant RT expression of the amplified gene in A431 epidermoid carcinoma cells."; RL Nature 309:418-425(1984). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RC TISSUE=Placenta; RX MEDLINE=95382957; PubMed=7654368; DOI=10.1002/mrd.1080410205; RA Ilekis J.V., Stark B.C., Scoccia B.; RT "Possible role of variant RNA transcripts in the regulation of RT epidermal growth factor receptor expression in human placenta."; RL Mol. Reprod. Dev. 41:149-156(1995). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 2). RC TISSUE=Placenta; RX MEDLINE=97078686; PubMed=8918811; DOI=10.1093/nar/24.20.4050; RA Reiter J.L., Maihle N.J.; RT "A 1.8 kb alternative transcript from the human epidermal growth RT factor receptor gene encodes a truncated form of the receptor."; RL Nucleic Acids Res. 24:4050-4056(1996). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RC TISSUE=Placenta; RX MEDLINE=97256547; PubMed=9103388; DOI=10.1006/gyno.1996.4526; RA Ilekis J.V., Gariti J., Niederberger C., Scoccia B.; RT "Expression of a truncated epidermal growth factor receptor-like RT protein (TEGFR) in ovarian cancer."; RL Gynecol. Oncol. 65:36-41(1997). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 3 AND 4). RC TISSUE=Placenta; RX MEDLINE=21100872; PubMed=11161793; DOI=10.1006/geno.2000.6341; RA Reiter J.L., Threadgill D.W., Eley G.D., Strunk K.E., Danielsen A.J., RA Schehl Sinclair C., Pearsall R.S., Green P.J., Yee D., Lampland A.L., RA Balasubramaniam S., Crossley T.D., Magnuson T.R., James C.D., RA Maihle N.J.; RT "Comparative genomic sequence analysis and isolation of human and RT mouse alternative EGFR transcripts encoding truncated receptor RT isoforms."; RL Genomics 71:1-20(2001). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RA Xu L., Hong A., He X.; RT "Cloning of the cDNA for a short EGF receptor from human placenta."; RL Submitted (JUL-2004) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS GLN-98; ARG-266; RP LYS-521; ILE-674; GLY-962 AND PRO-988. RG NIEHS SNPs program; RL Submitted (APR-2004) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 575-687. RA Reiter J.L., Threadgill D.W., Danielsen A.J., Schehl C.M., RA Lampland A.L., Balasubramaniam S., Crossley T.O., Magnuson T.R., RA Maihle N.J.; RT "Human and mouse alternative EGFR transcripts encoding only the RT extracellular domain of the receptor."; RL Submitted (FEB-1999) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [MRNA] OF 713-924. RX MEDLINE=84196372; PubMed=6326261; DOI=10.1126/science.6326261; RA Lin C.R., Chen W.S., Kruiger W., Stolarsky L.S., Weber W., Evans R.M., RA Verma I.M., Gill G.N., Rosenfeld M.G.; RT "Expression cloning of human EGF receptor complementary DNA: gene RT amplification and three related messenger RNA products in A431 RT cells."; RL Science 224:843-848(1984). RN [10] RP NUCLEOTIDE SEQUENCE [MRNA] OF 150-962. RX MEDLINE=84245835; PubMed=6330563; DOI=10.1038/309806a0; RA Xu Y.H., Ishii S., Clark A.J.L., Sullivan M., Wilson R.K., Ma D.P., RA Roe B.A., Merlino G.T., Pastan I.; RT "Human epidermal growth factor receptor cDNA is homologous to a RT variety of RNAs overproduced in A431 carcinoma cells."; RL Nature 309:806-810(1984). RN [11] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1028-1210. RX MEDLINE=85046483; PubMed=6093780; RA Simmen F.A., Gope M.L., Schulz T.Z., Wright D.A., Carpenter G., RA O'Malley B.W.; RT "Isolation of an evolutionarily conserved epidermal growth factor RT receptor cDNA from human A431 carcinoma cells."; RL Biochem. Biophys. Res. Commun. 124:125-132(1984). RN [12] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-29. RX MEDLINE=88217333; PubMed=3329716; RA Haley J.D., Whittle N., Bennett P., Kinchington D., Ullrich A., RA Waterfield M.D.; RT "The human EGF receptor gene: structure of the 110 kb locus and RT identification of sequences regulating its transcription."; RL Oncogene Res. 1:375-396(1987). RN [13] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-29. RX MEDLINE=91107677; PubMed=1988448; RA Haley J.D., Waterfield M.D.; RT "Contributory effects of de novo transcription and premature RT transcript termination in the regulation of human epidermal growth RT factor receptor proto-oncogene RNA synthesis."; RL J. Biol. Chem. 266:1746-1753(1991). RN [14] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-29. RX MEDLINE=85270438; PubMed=2991899; DOI=10.1073/pnas.82.15.4920; RA Ishii S., Xu Y.H., Stratton R.H., Roe B.A., Merlino G.T., Pastan I.; RT "Characterization and sequence of the promoter region of the human RT epidermal growth factor receptor gene."; RL Proc. Natl. Acad. Sci. U.S.A. 82:4920-4924(1985). RN [15] RP NUCLEOTIDE SEQUENCE [MRNA] OF 25-49. RX MEDLINE=84172183; PubMed=6324343; DOI=10.1126/science.6324343; RA Weber W., Gill G.N., Spiess J.; RT "Production of an epidermal growth factor receptor-related protein."; RL Science 224:294-297(1984). RN [16] RP PROTEIN SEQUENCE OF 540. RA Kohda D.; RL Submitted (SEP-1997) to UniProtKB. RN [17] RP PROTEIN SEQUENCE OF 687-705; 986-998; 1000-1023; 1026-1030 AND RP 1068-1077, AND PHOSPHORYLATION AT THR-693; SER-695; SER-1070 AND RP SER-1071. RX MEDLINE=88330814; PubMed=3138233; RA Heisermann G.J., Gill G.N.; RT "Epidermal growth factor receptor threonine and serine residues RT phosphorylated in vivo."; RL J. Biol. Chem. 263:13152-13158(1988). RN [18] RP PROTEIN SEQUENCE OF 25-39. RX PubMed=15340161; DOI=10.1110/ps.04682504; RA Zhang Z., Henzel W.J.; RT "Signal peptide prediction based on analysis of experimentally RT verified cleavage sites."; RL Protein Sci. 13:2819-2824(2004). RN [19] RP PROTEIN SEQUENCE OF 740-744 AND 746-747. RX MEDLINE=85182650; PubMed=2985580; RA Russo M.W., Lukas T.J., Cohen S., Staros J.V.; RT "Identification of residues in the nucleotide binding site of the RT epidermal growth factor receptor/kinase."; RL J. Biol. Chem. 260:5205-5208(1985). RN [20] RP PROTEIN SEQUENCE OF 861-875 AND 914-932, UBIQUITINATION AT LYS-716; RP LYS-737; LYS-754; LYS-867; LYS-929 AND LYS-970, AND MASS SPECTROMETRY. RX PubMed=16543144; DOI=10.1016/j.molcel.2006.02.018; RA Huang F., Kirkpatrick D., Jiang X., Gygi S.P., Sorkin A.; RT "Differential regulation of EGF receptor internalization and RT degradation by multiubiquitination within the kinase domain."; RL Mol. Cell 21:737-748(2006). RN [21] RP PARTIAL PROTEIN SEQUENCE, AND DISULFIDE BONDS. RX MEDLINE=98225196; PubMed=9556602; DOI=10.1074/jbc.273.18.11150; RA Abe Y., Odaka M., Inagaki F., Lax I., Schlessinger J., Kohda D.; RT "Disulfide bond structure of human epidermal growth factor receptor."; RL J. Biol. Chem. 273:11150-11157(1998). RN [22] RP RECEPTOR ACTIVITY. RX MEDLINE=84191554; PubMed=6325948; DOI=10.1038/309270a0; RA Mroczkowski B., Mosig G., Cohen S.; RT "ATP-stimulated interaction between epidermal growth factor receptor RT and supercoiled DNA."; RL Nature 309:270-273(1984). RN [23] RP REVIEW. RX MEDLINE=87297456; PubMed=3039909; RX DOI=10.1146/annurev.bi.56.070187.004313; RA Carpenter G.; RT "Receptors for epidermal growth factor and other polypeptide RT mitogens."; RL Annu. Rev. Biochem. 56:881-914(1987). RN [24] RP LIGAND-BINDING. RX MEDLINE=90003233; PubMed=2790960; DOI=10.1016/0092-8674(89)90867-2; RA Chen W.S., Lazar C.S., Lund K.A., Welsh J.B., Chang C.P., Walton G.M., RA Der C.J., Wiley H.S., Gill G.N., Rosenfeld M.G.; RT "Functional independence of the epidermal growth factor receptor from RT a domain required for ligand-induced internalization and calcium RT regulation."; RL Cell 59:33-43(1989). RN [25] RP AUTOPHOSPHORYLATION AT TYR-1110. RX MEDLINE=89278137; PubMed=2543678; RA Margolis B.L., Lax I., Kris R., Dombalagian M., Honegger A.M., RA Howk R., Givol D., Ullrich A., Schlessinger J.; RT "All autophosphorylation sites of epidermal growth factor (EGF) RT receptor and HER2/neu are located in their carboxyl-terminal tails. RT Identification of a novel site in EGF receptor."; RL J. Biol. Chem. 264:10667-10671(1989). RN [26] RP IDENTIFICATION OF AMPHIREGULIN AS LIGAND. RX PubMed=7679104; RA Johnson G.R., Kannan B., Shoyab M., Stromberg K.; RT "Amphiregulin induces tyrosine phosphorylation of the epidermal growth RT factor receptor and p185erbB2. Evidence that amphiregulin acts RT exclusively through the epidermal growth factor receptor at the RT surface of human epithelial cells."; RL J. Biol. Chem. 268:2924-2931(1993). RN [27] RP PHOSPHORYLATION AT THR-678 AND THR-693. RX PubMed=10523301; DOI=10.1093/emboj/18.20.5567; RA Bagowski C.P., Stein-Gerlach M., Choidas A., Ullrich A.; RT "Cell-type specific phosphorylation of threonines T654 and T669 by PKD RT defines the signal capacity of the EGF receptor."; RL EMBO J. 18:5567-5576(1999). RN [28] RP IDENTIFICATION OF BETACELLULIN/BTC AS LIGAND. RX PubMed=8144591; RA Watanabe T., Shintani A., Nakata M., Shing Y., Folkman J., RA Igarashi K., Sasada R.; RT "Recombinant human betacellulin. Molecular structure, biological RT activities, and receptor interaction."; RL J. Biol. Chem. 269:9966-9973(1994). RN [29] RP FUNCTION IN PHOSPHORYLATION OF CBL, AND INTERACTION WITH CBL. RX PubMed=7657591; DOI=10.1074/jbc.270.35.20242; RA Galisteo M.L., Dikic I., Batzer A.G., Langdon W.Y., Schlessinger J.; RT "Tyrosine phosphorylation of the c-cbl proto-oncogene protein product RT and association with epidermal growth factor (EGF) receptor upon EGF RT stimulation."; RL J. Biol. Chem. 270:20242-20245(1995). RN [30] RP GLYCOSYLATION AT ASN-128; ASN-175; ASN-413; ASN-444 AND ASN-528. RX MEDLINE=96398132; PubMed=8962717; RA Smith K.D., Davies M.J., Bailey D., Renouf D.V., Hounsell E.F.; RT "Analysis of the glycosylation patterns of the extracellular domain of RT the epidermal growth factor receptor expressed in Chinese hamster RT ovary fibroblasts."; RL Growth Factors 13:121-132(1996). RN [31] RP IDENTIFICATION OF EPIREGULIN/EREG AS LIGAND. RX PubMed=9419975; DOI=10.1038/sj.onc.1201458; RA Komurasaki T., Toyoda H., Uchida D., Morimoto S.; RT "Epiregulin binds to epidermal growth factor receptor and ErbB-4 and RT induces tyrosine phosphorylation of epidermal growth factor receptor, RT ErbB-2, ErbB-3 and ErbB-4."; RL Oncogene 15:2841-2848(1997). RN [32] RP INTERACTION WITH AP2M1. RX PubMed=10228163; DOI=10.1093/emboj/18.9.2489; RA Nesterov A., Carter R.E., Sorkina T., Gill G.N., Sorkin A.; RT "Inhibition of the receptor-binding function of clathrin adaptor RT protein AP-2 by dominant-negative mutant mu2 subunit and its effects RT on endocytosis."; RL EMBO J. 18:2489-2499(1999). RN [33] RP INTERACTION WITH GRB2; NCK1 AND NCK2. RX PubMed=10026169; DOI=10.1074/jbc.274.9.5542; RA Braverman L.E., Quilliam L.A.; RT "Identification of Grb4/Nckbeta, a src homology 2 and 3 domain- RT containing adapter protein having similar binding and biological RT properties to Nck."; RL J. Biol. Chem. 274:5542-5549(1999). RN [34] RP GLYCOSYLATION AT ASN-56; ASN-352; ASN-361; ASN-568 AND ASN-603. RX MEDLINE=20198209; PubMed=10731668; RA Sato C., Kim J.-H., Abe Y., Saito K., Yokoyama S., Kohda D.; RT "Characterization of the N-oligosaccharides attached to the atypical RT Asn-X-Cys sequence of recombinant human epidermal growth factor RT receptor."; RL J. Biochem. 127:65-72(2000). RN [35] RP FUNCTION IN PHOSPHORYLATION OF RGS16. RX MEDLINE=21611229; PubMed=11602604; DOI=10.1074/jbc.M108862200; RA Derrien A., Druey K.M.; RT "RGS16 function is regulated by epidermal growth factor receptor- RT mediated tyrosine phosphorylation."; RL J. Biol. Chem. 276:48532-48538(2001). RN [36] RP FUNCTION IN CELL PROLIFERATION, INTERACTION WITH STAT3, AND RP PHOSPHORYLATION AT TYR-1092 AND TYR-1110. RX PubMed=12873986; RA Shao H., Cheng H.Y., Cook R.G., Tweardy D.J.; RT "Identification and characterization of signal transducer and RT activator of transcription 3 recruitment sites within the epidermal RT growth factor receptor."; RL Cancer Res. 63:3923-3930(2003). RN [37] RP ENZYME REGULATION, AND INTERACTION WITH LRIG1. RX PubMed=15282549; DOI=10.1038/sj.emboj.7600342; RA Gur G., Rubin C., Katz M., Amit I., Citri A., Nilsson J., RA Amariglio N., Henriksson R., Rechavi G., Hedman H., Wides R., RA Yarden Y.; RT "LRIG1 restricts growth factor signaling by enhancing receptor RT ubiquitylation and degradation."; RL EMBO J. 23:3270-3281(2004). RN [38] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-693, AND MASS RP SPECTROMETRY. RC TISSUE=Cervix carcinoma; RX PubMed=15302935; DOI=10.1073/pnas.0404720101; RA Beausoleil S.A., Jedrychowski M., Schwartz D., Elias J.E., Villen J., RA Li J., Cohn M.A., Cantley L.C., Gygi S.P.; RT "Large-scale characterization of HeLa cell nuclear phosphoproteins."; RL Proc. Natl. Acad. Sci. U.S.A. 101:12130-12135(2004). RN [39] RP FUNCTION IN EGFR SIGNALING, IDENTIFICATION IN A COMPLEX WITH PIK3C2A RP AND ERBB2, IDENTIFICATION IN A COMPLEX WITH PIK3C2B AND ERBB2, RP INTERACTION WITH PIK3C2B, AND MUTAGENESIS OF TYR-1016; TYR-1092; RP TYR-1110; TYR-1172 AND TYR-1197. RX PubMed=10805725; DOI=10.1128/MCB.20.11.3817-3830.2000; RA Arcaro A., Zvelebil M.J., Wallasch C., Ullrich A., Waterfield M.D., RA Domin J.; RT "Class II phosphoinositide 3-kinases are downstream targets of RT activated polypeptide growth factor receptors."; RL Mol. Cell. Biol. 20:3817-3830(2000). RN [40] RP FUNCTION IN NF-KAPPA-B ACTIVATION, AND INTERACTION WITH RIPK1. RX MEDLINE=21153697; PubMed=11116146; DOI=10.1074/jbc.M008458200; RA Habib A.A., Chatterjee S., Park S.-K., Ratan R.R., Lefebvre S., RA Vartanian T.; RT "The epidermal growth factor receptor engages receptor interacting RT protein and nuclear factor-kappa B (NF-kappa B)-inducing kinase to RT activate NF-kappa B. Identification of a novel receptor-tyrosine RT kinase signalosome."; RL J. Biol. Chem. 276:8865-8874(2001). RN [41] RP FUNCTION IN PHOSPHORYLATION OF MUC1, AND INTERACTION WITH MUC1. RX PubMed=11483589; DOI=10.1074/jbc.C100359200; RA Li Y., Ren J., Yu W., Li Q., Kuwahara H., Yin L., Carraway K.L. III, RA Kufe D.; RT "The epidermal growth factor receptor regulates interaction of the RT human DF3/MUC1 carcinoma antigen with c-Src and beta-catenin."; RL J. Biol. Chem. 276:35239-35242(2001). RN [42] RP ENZYME REGULATION, AND INTERACTION WITH SOCS5. RX PubMed=15590694; DOI=10.1074/jbc.M408575200; RA Kario E., Marmor M.D., Adamsky K., Citri A., Amit I., Amariglio N., RA Rechavi G., Yarden Y.; RT "Suppressors of cytokine signaling 4 and 5 regulate epidermal growth RT factor receptor signaling."; RL J. Biol. Chem. 280:7038-7048(2005). RN [43] RP IDENTIFICATION OF EPIGEN/EPGN AS A LIGAND. RX PubMed=15611079; DOI=10.1074/jbc.M413919200; RA Kochupurakkal B.S., Harari D., Di-Segni A., Maik-Rachline G., RA Lyass L., Gur G., Kerber G., Citri A., Lavi S., Eilam R., RA Chalifa-Caspi V., Eshhar Z., Pikarsky E., Pinkas-Kramarski R., RA Bacus S.S., Yarden Y.; RT "Epigen, the last ligand of ErbB receptors, reveals intricate RT relationships between affinity and mitogenicity."; RL J. Biol. Chem. 280:8503-8512(2005). RN [44] RP GLYCOSYLATION AT ASN-56; ASN-128; ASN-175; ASN-196; ASN-352; ASN-361; RP ASN-413; ASN-444; ASN-528; ASN-568 AND ASN-603, PHOSPHORYLATION AT RP THR-693; SER-991 AND SER-1026, AND MASS SPECTROMETRY. RX PubMed=16083266; DOI=10.1021/pr050113n; RA Wu S.L., Kim J., Hancock W.S., Karger B.; RT "Extended Range Proteomic Analysis (ERPA): a new and sensitive LC-MS RT platform for high sequence coverage of complex proteins with extensive RT post-translational modifications-comprehensive analysis of beta-casein RT and epidermal growth factor receptor (EGFR)."; RL J. Proteome Res. 4:1155-1170(2005). RN [45] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-998; TYR-1069; TYR-1092; RP SER-1166 AND TYR-1172, AND MASS SPECTROMETRY. RC TISSUE=Mammary epithelium; RX PubMed=15951569; DOI=10.1074/mcp.M500089-MCP200; RA Zhang Y., Wolf-Yadlin A., Ross P.L., Pappin D.J., Rush J., RA Lauffenburger D.A., White F.M.; RT "Time-resolved mass spectrometry of tyrosine phosphorylation sites in RT the epidermal growth factor receptor signaling network reveals dynamic RT modules."; RL Mol. Cell. Proteomics 4:1240-1250(2005). RN [46] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-978, AND MASS RP SPECTROMETRY. RC TISSUE=Hepatoma; RX PubMed=16097034; DOI=10.1002/pmic.200401217; RA Gevaert K., Staes A., Van Damme J., De Groot S., Hugelier K., RA Demol H., Martens L., Goethals M., Vandekerckhove J.; RT "Global phosphoproteome analysis on human HepG2 hepatocytes using RT reversed-phase diagonal LC."; RL Proteomics 5:3589-3599(2005). RN [47] RP INTERACTION WITH PELP1. RX PubMed=16140940; DOI=10.1158/0008-5472.CAN-05-0614; RA Vadlamudi R.K., Manavathi B., Balasenthil S., Nair S.S., Yang Z., RA Sahin A.A., Kumar R.; RT "Functional implications of altered subcellular localization of PELP1 RT in breast cancer cells."; RL Cancer Res. 65:7724-7732(2005). RN [48] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-693; SER-991; SER-995; RP TYR-998; SER-1064; TYR-1069; TYR-1092; TYR-1110; TYR-1138; TYR-1172 RP AND TYR-1197, AND MASS SPECTROMETRY. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., RA Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in RT signaling networks."; RL Cell 127:635-648(2006). RN [49] RP FUNCTION IN CELL PROLIFERATION, FUNCTION IN PCNA PHOSPHORYLATION, RP INTERACTION WITH PCNA, AND SUBCELLULAR LOCATION. RX PubMed=17115032; DOI=10.1038/ncb1501; RA Wang S.C., Nakajima Y., Yu Y.L., Xia W., Chen C.T., Yang C.C., RA McIntush E.W., Li L.Y., Hawke D.H., Kobayashi R., Hung M.C.; RT "Tyrosine phosphorylation controls PCNA function through protein RT stability."; RL Nat. Cell Biol. 8:1359-1368(2006). RN [50] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-869; TYR-1092; TYR-1172 RP AND TYR-1197, AND MASS SPECTROMETRY. RC TISSUE=Lung carcinoma; RX PubMed=18083107; DOI=10.1016/j.cell.2007.11.025; RA Rikova K., Guo A., Zeng Q., Possemato A., Yu J., Haack H., Nardone J., RA Lee K., Reeves C., Li Y., Hu Y., Tan Z., Stokes M., Sullivan L., RA Mitchell J., Wetzel R., Macneill J., Ren J.M., Yuan J., RA Bakalarski C.E., Villen J., Kornhauser J.M., Smith B., Li D., Zhou X., RA Gygi S.P., Gu T.-L., Polakiewicz R.D., Rush J., Comb M.J.; RT "Global survey of phosphotyrosine signaling identifies oncogenic RT kinases in lung cancer."; RL Cell 131:1190-1203(2007). RN [51] RP TISSUE SPECIFICITY. 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 [52] RP INTERACTION WITH TNF2, AND SUBCELLULAR LOCATION. RX PubMed=17182860; DOI=10.1091/mbc.E06-02-0142; RA Shen F., Lin Q., Gu Y., Childress C., Yang W.; RT "Activated Cdc42-associated kinase 1 is a component of EGF receptor RT signaling complex and regulates EGF receptor degradation."; RL Mol. Biol. Cell 18:732-742(2007). RN [53] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-693, AND MASS RP SPECTROMETRY. RC TISSUE=Leukemic T-cell; RX PubMed=17192257; DOI=10.1074/mcp.T600062-MCP200; RA Wissing J., Jaensch L., Nimtz M., Dieterich G., Hornberger R., RA Keri G., Wehland J., Daub H.; RT "Proteomics analysis of protein kinases by target class-selective RT prefractionation and tandem mass spectrometry."; RL Mol. Cell. Proteomics 6:537-547(2007). RN [54] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-991; TYR-998; SER-1166; RP TYR-1069; TYR-1172 AND TYR-1197, AND MASS SPECTROMETRY. RC TISSUE=Mammary epithelium; RX PubMed=17389395; DOI=10.1073/pnas.0608638104; RA Wolf-Yadlin A., Hautaniemi S., Lauffenburger D.A., White F.M.; RT "Multiple reaction monitoring for robust quantitative proteomic RT analysis of cellular signaling networks."; RL Proc. Natl. Acad. Sci. U.S.A. 104:5860-5865(2007). RN [55] RP INTERACTION WITH GAB2. RX PubMed=19172738; DOI=10.1038/emboj.2008.159; RA Brummer T., Larance M., Herrera Abreu M.T., Lyons R.J., Timpson P., RA Emmerich C.H., Fleuren E.D.G., Lehrbach G.M., Schramek D., RA Guilhaus M., James D.E., Daly R.J.; RT "Phosphorylation-dependent binding of 14-3-3 terminates signalling by RT the Gab2 docking protein."; RL EMBO J. 27:2305-2316(2008). RN [56] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-693 AND SER-991, AND RP MASS SPECTROMETRY. RC TISSUE=Cervix carcinoma; RX PubMed=18220336; DOI=10.1021/pr0705441; RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., RA Yates J.R. III; RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for RT efficient phosphoproteomic analysis."; RL J. Proteome Res. 7:1346-1351(2008). RN [57] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-693; SER-695; THR-725; RP SER-991; SER-1025; SER-1026; SER-1037; SER-1039; SER-1042; SER-1064; RP SER-1081; SER-1166 AND TYR-1197, AND MASS SPECTROMETRY. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of RT the kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [58] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-693; SER-695; SER-991; RP THR-993; SER-995; TYR-998; SER-1039; THR-1041; SER-1042; SER-1045; RP SER-1064 AND SER-1166, AND MASS SPECTROMETRY. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [59] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-693, AND MASS RP SPECTROMETRY. RC TISSUE=Embryonic kidney; RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., RA Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in RT a refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [60] RP ENZYME REGULATION BY PTPRJ AND PTPRK, PHOSPHORYLATION, RP DEPHOSPHORYLATION BY PTPRJ, SUBCELLULAR LOCATION, AND INTERACTION WITH RP CBL AND GRB2. RX PubMed=19836242; DOI=10.1016/j.cub.2009.09.048; RA Tarcic G., Boguslavsky S.K., Wakim J., Kiuchi T., Liu A., Reinitz F., RA Nathanson D., Takahashi T., Mischel P.S., Ng T., Yarden Y.; RT "An unbiased screen identifies DEP-1 tumor suppressor as a phosphatase RT controlling EGFR endocytosis."; RL Curr. Biol. 19:1788-1798(2009). RN [61] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-352; ASN-413 AND ASN-568, RP AND MASS SPECTROMETRY. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of RT multiple enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [62] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-998; TYR-1016; TYR-1092; RP TYR-1110; TYR-1138; TYR-1172 AND TYR-1197, AND MASS SPECTROMETRY. RC TISSUE=Mammary epithelium; RX PubMed=19534553; DOI=10.1021/pr900044c; RA Heibeck T.H., Ding S.-J., Opresko L.K., Zhao R., Schepmoes A.A., RA Yang F., Tolmachev A.V., Monroe M.E., Camp D.G. II, Smith R.D., RA Wiley H.S., Qian W.-J.; RT "An extensive survey of tyrosine phosphorylation revealing new sites RT in human mammary epithelial cells."; RL J. Proteome Res. 8:3852-3861(2009). RN [63] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-693, AND MASS RP SPECTROMETRY. RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200; RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., RA Mann M., Daub H.; RT "Large-scale proteomics analysis of the human kinome."; RL Mol. Cell. Proteomics 8:1751-1764(2009). RN [64] RP INTERACTION WITH COPG, SUBCELLULAR LOCATION, AND TOPOLOGY. RX PubMed=20674546; DOI=10.1016/j.bbrc.2010.07.096; RA Wang Y.N., Wang H., Yamaguchi H., Lee H.J., Lee H.H., Hung M.C.; RT "COPI-mediated retrograde trafficking from the Golgi to the ER RT regulates EGFR nuclear transport."; RL Biochem. Biophys. Res. Commun. 399:498-504(2010). RN [65] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [66] RP FUNCTION IN CELL PROLIFERATION AND CELL MIGRATION, METHYLATION AT RP ARG-1199 BY PRMT5, AND INTERACTION WITH PRMT5 AND PTPN6. RX PubMed=21258366; DOI=10.1038/ncb2158; RA Hsu J.M., Chen C.T., Chou C.K., Kuo H.P., Li L.Y., Lin C.Y., Lee H.J., RA Wang Y.N., Liu M., Liao H.W., Shi B., Lai C.C., Bedford M.T., RA Tsai C.H., Hung M.C.; RT "Crosstalk between Arg 1175 methylation and Tyr 1173 phosphorylation RT negatively modulates EGFR-mediated ERK activation."; RL Nat. Cell Biol. 13:174-181(2011). RN [67] RP INTERACTION WITH FER, AND PHOSPHORYLATION. RX PubMed=21518868; DOI=10.1073/pnas.1105369108; RA Guo C., Stark G.R.; RT "FER tyrosine kinase (FER) overexpression mediates resistance to RT quinacrine through EGF-dependent activation of NF-kappaB."; RL Proc. Natl. Acad. Sci. U.S.A. 108:7968-7973(2011). RN [68] RP X-RAY CRYSTALLOGRAPHY (3.3 ANGSTROMS) OF 25-646 IN COMPLEX WITH EGF, RP FUNCTION IN MAPK1 AND/OR MAPK3 ACTIVATION, SUBUNIT, SUBCELLULAR RP LOCATION, MUTAGENESIS OF TYR-275; PHE-287; ARG-309 AND ARG-429, RP DISULFIDE BONDS, AND GLYCOSYLATION AT ASN-56; ASN-175; ASN-196; RP ASN-352; ASN-361 AND ASN-444. 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 [69] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 25-642 IN COMPLEX WITH EGF, RP FUNCTION, SUBUNIT, MUTAGENESIS OF 587-ASP--HIS-590 AND LYS-609, RP DISULFIDE BONDS, AND GLYCOSYLATION AT ASN-352; ASN-361; ASN-444; RP ASN-528; ASN-568 AND ASN-603. 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 [70] RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 695-1022 IN COMPLEX WITH RP GW572016, CATALYTIC ACTIVITY, AND FUNCTION. RX PubMed=15374980; DOI=10.1158/0008-5472.CAN-04-1168; RA Wood E.R., Truesdale A.T., McDonald O.B., Yuan D., Hassell A., RA Dickerson S.H., Ellis B., Pennisi C., Horne E., Lackey K., RA Alligood K.J., Rusnak D.W., Gilmer T.M., Shewchuk L.; RT "A unique structure for epidermal growth factor receptor bound to RT GW572016 (Lapatinib): relationships among protein conformation, RT inhibitor off-rate, and receptor activity in tumor cells."; RL Cancer Res. 64:6652-6659(2004). RN [71] RP X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) OF 25-642 IN COMPLEX WITH RP CETUXIMAB. RX PubMed=15837620; DOI=10.1016/j.ccr.2005.03.003; RA Li S., Schmitz K.R., Jeffrey P.D., Wiltzius J.J., Kussie P., RA Ferguson K.M.; RT "Structural basis for inhibition of the epidermal growth factor RT receptor by cetuximab."; RL Cancer Cell 7:301-311(2005). RN [72] RP STRUCTURE BY NMR OF 669-721. RX PubMed=15840573; DOI=10.1074/jbc.M502698200; RA Choowongkomon K., Carlin C.R., Sonnichsen F.D.; RT "A structural model for the membrane-bound form of the juxtamembrane RT domain of the epidermal growth factor receptor."; RL J. Biol. Chem. 280:24043-24052(2005). RN [73] RP X-RAY CRYSTALLOGRAPHY (2.47 ANGSTROMS) OF 696-1022 OF WILD-TYPE AND RP VARIANTS SER-719 AND ARG-858 IN COMPLEXES WITH ATP ANALOGS AND RP SYNTHETIC INHIBITORS, CATALYTIC ACTIVITY, AUTOPHOSPHORYLATION, AND RP CHARACTERIZATION OF VARIANTS SER-719 AND ARG-858. RX PubMed=17349580; DOI=10.1016/j.ccr.2006.12.017; RA Yun C.H., Boggon T.J., Li Y., Woo M.S., Greulich H., Meyerson M., RA Eck M.J.; RT "Structures of lung cancer-derived EGFR mutants and inhibitor RT complexes: mechanism of activation and insights into differential RT inhibitor sensitivity."; RL Cancer Cell 11:217-227(2007). RN [74] RP X-RAY CRYSTALLOGRAPHY (2.90 ANGSTROMS) OF 702-1022 IN COMPLEX WITH RP ERRFI1, ENZYME REGULATION, CATALYTIC ACTIVITY, AUTOPHOSPHORYLATION, RP SUBUNIT, AND INTERACTION WITH ERRFI1. RX PubMed=18046415; DOI=10.1038/nature05998; RA Zhang X., Pickin K.A., Bose R., Jura N., Cole P.A., Kuriyan J.; RT "Inhibition of the EGF receptor by binding of MIG6 to an activating RT kinase domain interface."; RL Nature 450:741-744(2007). RN [75] RP X-RAY CRYSTALLOGRAPHY (3.05 ANGSTROMS) OF 695-1022 OF VARIANT MET-790, RP CATALYTIC ACTIVITY, AND CHARACTERIZATION OF VARIANT MET-790. RX PubMed=18227510; DOI=10.1073/pnas.0709662105; RA Yun C.H., Mengwasser K.E., Toms A.V., Woo M.S., Greulich H., RA Wong K.K., Meyerson M., Eck M.J.; RT "The T790M mutation in EGFR kinase causes drug resistance by RT increasing the affinity for ATP."; RL Proc. Natl. Acad. Sci. U.S.A. 105:2070-2075(2008). RN [76] RP X-RAY CRYSTALLOGRAPHY (2.96 ANGSTROMS) OF 696-1022, CATALYTIC RP ACTIVITY, PHOSPHORYLATION AT TYR-998; TYR-1016 AND TYR-1197, RP MUTAGENESIS OF LEU-688; GLU-690; LEU-692; ARG-977 AND RP 1005-GLU-ASP-1006, AND SUBUNIT. RX PubMed=19563760; DOI=10.1016/j.cell.2009.04.025; RA Jura N., Endres N.F., Engel K., Deindl S., Das R., Lamers M.H., RA Wemmer D.E., Zhang X., Kuriyan J.; RT "Mechanism for activation of the EGF receptor catalytic domain by the RT juxtamembrane segment."; RL Cell 137:1293-1307(2009). RN [77] RP X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 669-1022 OF MUTANT MET-745, RP CATALYTIC ACTIVITY, FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, RP AUTOPHOSPHORYLATION, AND MUTAGENESIS OF LEU-688; VAL-689; GLU-690; RP LEU-692; THR-693; PRO-694; PRO-699; ASN-700; LEU-704; ARG-705; ILE-706 RP AND LYS-745. RX PubMed=19560417; DOI=10.1016/j.molcel.2009.04.034; RA Red Brewer M., Choi S.H., Alvarado D., Moravcevic K., Pozzi A., RA Lemmon M.A., Carpenter G.; RT "The juxtamembrane region of the EGF receptor functions as an RT activation domain."; RL Mol. Cell 34:641-651(2009). RN [78] RP STRUCTURE BY NMR OF 634-677 IN COMPLEX WITH ERBB2, AND SUBUNIT. RX PubMed=20471394; DOI=10.1016/j.jmb.2010.05.016; RA Mineev K.S., Bocharov E.V., Pustovalova Y.E., Bocharova O.V., RA Chupin V.V., Arseniev A.S.; RT "Spatial structure of the transmembrane domain heterodimer of ErbB1 RT and ErbB2 receptor tyrosine kinases."; RL J. Mol. Biol. 400:231-243(2010). RN [79] RP X-RAY CRYSTALLOGRAPHY (3.3 ANGSTROMS) OF 25-638 IN COMPLEX WITH EGF, RP FUNCTION, SUBUNIT, DISULFIDE BONDS, AND GLYCOSYLATION AT ASN-56; RP ASN-73; ASN-175; ASN-196; ASN-352; ASN-361; ASN-444 AND ASN-528. 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). RN [80] RP VARIANTS SER-719 AND ARG-858, AND POSSIBLE INVOLVEMENT IN LUNG CANCER. RX PubMed=15118125; DOI=10.1126/science.1099314; RA Paez J.G., Janne P.A., Lee J.C., Tracy S., Greulich H., Gabriel S., RA Herman P., Kaye F.J., Lindeman N., Boggon T.J., Naoki K., Sasaki H., RA Fujii Y., Eck M.J., Sellers W.R., Johnson B.E., Meyerson M.; RT "EGFR mutations in lung cancer: correlation with clinical response to RT gefitinib therapy."; RL Science 304:1497-1500(2004). RN [81] RP VARIANTS ALA-709; LYS-709; ALA-719; ASP-719; CYS-719; SER-719; RP SER-724; LYS-734; GLU-746 DEL; PHE-747; 747-LEU--GLU-749 DEL; PRO-748; RP 752-SER--ILE-759 DEL; ARG-787; MET-790; VAL-833; LEU-834; MET-858; RP ARG-858; GLN-861 AND GLU-873, AND POSSIBLE INVOLVEMENT IN LUNG CANCER. RX PubMed=16533793; DOI=10.1158/1078-0432.CCR-05-1981; RA Tam I.Y.S., Chung L.P., Suen W.S., Wang E., Wong M.C.M., Ho K.K., RA Lam W.K., Chiu S.W., Girard L., Minna J.D., Gazdar A.F., Wong M.P.; RT "Distinct epidermal growth factor receptor and KRAS mutation patterns RT in non-small cell lung cancer patients with different tobacco exposure RT and clinicopathologic features."; RL Clin. Cancer Res. 12:1647-1653(2006). RN [82] RP VARIANT 30-VAL--ARG-297 DEL, AND POSSIBLE INVOLVEMENT IN LUNG CANCER. RX PubMed=16672372; DOI=10.1073/pnas.0510284103; RA Ji H., Zhao X., Yuza Y., Shimamura T., Li D., Protopopov A., RA Jung B.L., McNamara K., Xia H., Glatt K.A., Thomas R.K., Sasaki H., RA Horner J.W., Eck M., Mitchell A., Sun Y., Al-Hashem R., Bronson R.T., RA Rabindran S.K., Discafani C.M., Maher E., Shapiro G.I., Meyerson M., RA Wong K.K.; RT "Epidermal growth factor receptor variant III mutations in lung RT tumorigenesis and sensitivity to tyrosine kinase inhibitors."; RL Proc. Natl. Acad. Sci. U.S.A. 103:7817-7822(2006). RN [83] RP VARIANTS [LARGE SCALE ANALYSIS] LYS-521; ARG-1034 AND VAL-1210. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E., RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). CC -!- FUNCTION: Receptor tyrosine kinase binding ligands of the EGF CC family and activating several signaling cascades to convert CC extracellular cues into appropriate cellular responses. Known CC ligands include EGF, TGFA/TGF-alpha, amphiregulin, epigen/EPGN, CC BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF. CC Ligand binding triggers receptor homo- and/or heterodimerization CC and autophosphorylation on key cytoplasmic residues. The CC phosphorylated receptor recruits adapter proteins like GRB2 which CC in turn activates complex downstream signaling cascades. Activates CC at least 4 major downstream signaling cascades including the RAS- CC RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules. May CC also activate the NF-kappa-B signaling cascade. Also directly CC phosphorylates other proteins like RGS16, activating its GTPase CC activity and probably coupling the EGF receptor signaling to the G CC protein-coupled receptor signaling. Also phosphorylates MUC1 and CC increases its interaction with SRC and CTNNB1/beta-catenin. CC -!- FUNCTION: Isoform 2 may act as an antagonist of EGF action. CC -!- CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a CC [protein]-L-tyrosine phosphate. CC -!- ENZYME REGULATION: Endocytosis and inhibition of the activated CC EGFR by phosphatases like PTPRJ and PTPRK constitute immediate CC regulatory mechanisms. Upon EGF-binding phosphorylates EPS15 that CC regulates EGFR endocytosis and activity. Moreover, inducible CC feedback inhibitors including LRIG1, SOCS4, SOCS5 and ERRFI1 CC constitute alternative regulatory mechanisms for the EGFR CC signaling. CC -!- SUBUNIT: Binding of the ligand triggers homo- and/or CC heterodimerization of the receptor triggering its CC autophosphorylation. Heterodimer with ERBB2. Interacts with CC ERRFI1; inhibits dimerization of the kinase domain and CC autophosphorylation. Part of a complex with ERBB2 and either CC PIK3C2A or PIK3C2B. Interacts with GRB2; an adapter protein CC coupling the receptor to downstream signaling pathways. Interacts CC with GAB2; involved in signaling downstream of EGFR. Interacts CC with STAT3; mediates EGFR downstream signaling in cell CC proliferation. Interacts with RIPK1; involved in NF-kappa-B CC activation. Interacts (autophosphorylated) with CBL; involved in CC EGFR ubiquitination and regulation. Interacts with SOCS5; CC regulates EGFR degradation through TCEB1- and TCEB2-mediated CC ubiquitination and proteasomal degradation. Interacts with PRMT5; CC methylates EGFR and enhances interaction with PTPN6. Interacts CC (phosphorylated) with PTPN6; inhibits EGFR-dependent activation of CC MAPK/ERK. Interacts with COPG; essential for regulation of EGF- CC dependent nuclear transport of EGFR by retrograde trafficking from CC the Golgi to the ER. Interacts with TNK2; this interaction is CC dependent on EGF stimulation and kinase activity of EGFR. CC Interacts with PCNA; positively regulates PCNA. Interacts with CC PELP1. Interacts with MUC1. Interacts with AP2M1. Interacts with CC FER. May interact with EPS8; mediates EPS8 phosphorylation. CC Interacts (via SH2 domains) with GRB2, NCK1 and NCK2. CC -!- INTERACTION: CC Self; NbExp=11; IntAct=EBI-297353, EBI-297353; CC Q02952:AKAP12; NbExp=2; IntAct=EBI-297353, EBI-2562430; CC P62158:CALM1; NbExp=3; IntAct=EBI-297353, EBI-397435; CC P62161:Calm1 (xeno); NbExp=6; IntAct=EBI-297353, EBI-397530; CC P22681:CBL; NbExp=4; IntAct=EBI-297353, EBI-518228; CC P22682:Cbl (xeno); NbExp=2; IntAct=EBI-297353, EBI-640919; CC Q99418:CYTH2; NbExp=5; IntAct=EBI-297353, EBI-448974; CC P01133:EGF; NbExp=3; IntAct=EBI-297353, EBI-640857; CC P04626:ERBB2; NbExp=9; IntAct=EBI-297353, EBI-641062; CC P21860:ERBB3; NbExp=3; IntAct=EBI-297353, EBI-720706; CC Q15303:ERBB4; NbExp=2; IntAct=EBI-297353, EBI-80371; CC Q9UJM3:ERRFI1; NbExp=2; IntAct=EBI-297353, EBI-2941912; CC P03372-4:ESR1; NbExp=4; IntAct=EBI-297353, EBI-4309277; CC Q14318:FKBP8; NbExp=3; IntAct=EBI-297353, EBI-724839; CC P60520:GABARAPL2; NbExp=2; IntAct=EBI-297353, EBI-720116; CC P04406:GAPDH; NbExp=4; IntAct=EBI-297353, EBI-354056; CC P62993:GRB2; NbExp=12; IntAct=EBI-297353, EBI-401755; CC Q9UBN7:HDAC6; NbExp=8; IntAct=EBI-297353, EBI-301697; CC P08107:HSPA1A; NbExp=4; IntAct=EBI-297353, EBI-629985; CC Q9Y2H9:MAST1; NbExp=2; IntAct=EBI-297353, EBI-3385920; CC P08581:MET; NbExp=4; IntAct=EBI-297353, EBI-1039152; CC O00750:PIK3C2B; NbExp=7; IntAct=EBI-297353, EBI-641107; CC Q9UJ41:RABGEF1; NbExp=4; IntAct=EBI-297353, EBI-913954; CC Q13671:RIN1; NbExp=3; IntAct=EBI-297353, EBI-366017; CC P29353:SHC1; NbExp=5; IntAct=EBI-297353, EBI-78835; CC P13866:SLC5A1; NbExp=3; IntAct=EBI-297353, EBI-1772443; CC P12931:SRC; NbExp=5; IntAct=EBI-297353, EBI-621482; CC P31948:STIP1; NbExp=2; IntAct=EBI-297353, EBI-1054052; CC Q8K424:Trpv3 (xeno); NbExp=2; IntAct=EBI-297353, EBI-2650739; CC P09936:UCHL1; NbExp=2; IntAct=EBI-297353, EBI-714860; CC Q9P0L0:VAPA; NbExp=2; IntAct=EBI-297353, EBI-1059156; CC P27348:YWHAQ; NbExp=4; IntAct=EBI-297353, EBI-359854; CC P63104:YWHAZ; NbExp=4; IntAct=EBI-297353, EBI-347088; CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane CC protein. Endoplasmic reticulum membrane; Single-pass type I CC membrane protein. Golgi apparatus membrane; Single-pass type I CC membrane protein. Nucleus membrane; Single-pass type I membrane CC protein. Endosome. Endosome membrane. Note=In response to EGF, CC translocated from the cell membrane to the nucleus via Golgi and CC ER. Endocytosed upon activation by ligand. CC -!- SUBCELLULAR LOCATION: Isoform 2: Secreted. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; Synonyms=p170; CC IsoId=P00533-1; Sequence=Displayed; CC Name=2; Synonyms=p60, Truncated, TEGFR; CC IsoId=P00533-2; Sequence=VSP_002887, VSP_002888; CC Name=3; Synonyms=p110; CC IsoId=P00533-3; Sequence=VSP_002889, VSP_002890; CC Name=4; CC IsoId=P00533-4; Sequence=VSP_002891, VSP_002892; CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. Isoform 2 is also CC expressed in ovarian cancers. CC -!- PTM: Phosphorylation at Ser-695 is partial and occurs only if Thr- CC 693 is phosphorylated. Phosphorylation at Thr-678 and Thr-693 by CC PRKD1 inhibits EGF-induced MAPK8/JNK1 activation. CC Dephosphorylation by PTPRJ prevents endocytosis and stabilizes the CC receptor at the plasma membrane. Autophosphorylation at Tyr-1197 CC is stimulated by methylation at Arg-1199 and enhances interaction CC with PTPN6. Autophosphorylation at Tyr-1092 and/or Tyr-1110 CC recruits STAT3. CC -!- PTM: Monoubiquitinated and polyubiquitinated upon EGF stimulation; CC which does not affect tyrosine kinase activity or signaling CC capacity but may play a role in lysosomal targeting. Polyubiquitin CC linkage is mainly through 'Lys-63', but linkage through 'Lys-48', CC 'Lys-11' and 'Lys-29' also occur. CC -!- PTM: Methylated. Methylation at Arg-1199 by PRMT5 positively CC stimulates phosphorylation at Tyr-1197. CC -!- DISEASE: Defects in EGFR are associated with lung cancer (LNCR) CC [MIM:211980]. LNCR is a common malignancy affecting tissues of the CC lung. The most common form of lung cancer is non-small cell lung CC cancer (NSCLC) that can be divided into 3 major histologic CC subtypes: squamous cell carcinoma, adenocarcinoma, and large cell CC lung cancer. NSCLC is often diagnosed at an advanced stage and has CC a poor prognosis. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein CC kinase family. EGF receptor subfamily. CC -!- SIMILARITY: Contains 1 protein kinase domain. CC -!- WEB RESOURCE: Name=GeneReviews; CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/EGFR"; CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/egfr/"; CC -!- WEB RESOURCE: Name=Wikipedia; Note=EGFR entry; CC URL="http://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor"; 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; X00588; CAA25240.1; -; mRNA. DR EMBL; U95089; AAB53063.1; -; mRNA. DR EMBL; U48722; AAC50802.1; -; mRNA. DR EMBL; U48723; AAC50804.1; -; Genomic_DNA. DR EMBL; U48724; AAC50796.1; -; Genomic_DNA. DR EMBL; U48725; AAC50797.1; -; Genomic_DNA. DR EMBL; U48726; AAC50798.1; -; Genomic_DNA. DR EMBL; U48727; AAC50799.1; -; Genomic_DNA. DR EMBL; U48728; AAC50800.1; -; Genomic_DNA. DR EMBL; U48729; AAC50801.1; -; Genomic_DNA. DR EMBL; AF288738; AAG35786.1; -; Genomic_DNA. DR EMBL; AF288738; AAG35787.1; -; Genomic_DNA. DR EMBL; AF288738; AAG35788.1; -; Genomic_DNA. DR EMBL; AF288738; AAG35789.1; -; Genomic_DNA. DR EMBL; AF288738; AAG35790.1; -; Genomic_DNA. DR EMBL; AY698024; AAT97979.1; -; mRNA. DR EMBL; AY588246; AAS83109.1; -; Genomic_DNA. DR EMBL; AF277897; AAK01080.1; -; mRNA. DR EMBL; AF125253; AAG43240.1; -; mRNA. DR EMBL; AF125539; AAG43243.1; -; Genomic_DNA. DR EMBL; AF125538; AAG43243.1; JOINED; Genomic_DNA. DR EMBL; X06370; CAA29668.1; -; Genomic_DNA. DR EMBL; X00663; CAA25282.1; -; mRNA. DR EMBL; M38425; AAA63171.1; -; Genomic_DNA. DR EMBL; M11234; AAA52370.1; -; Genomic_DNA. DR IPI; IPI00018274; -. DR IPI; IPI00221346; -. DR IPI; IPI00221347; -. DR IPI; IPI00221348; -. DR PIR; A00641; GQHUE. DR RefSeq; NP_005219.2; NM_005228.3. DR RefSeq; NP_958439.1; NM_201282.1. DR RefSeq; NP_958440.1; NM_201283.1. DR RefSeq; NP_958441.1; NM_201284.1. DR UniGene; Hs.488293; -. DR PDB; 1DNQ; Model; -; A=25-336. DR PDB; 1DNR; Model; -; A=337-645. DR PDB; 1IVO; X-ray; 3.30 A; A/B=25-646. DR PDB; 1M14; X-ray; 2.60 A; A=695-1022. DR PDB; 1M17; X-ray; 2.60 A; A=695-1022. DR PDB; 1MOX; X-ray; 2.50 A; A/B=25-525. DR PDB; 1NQL; X-ray; 2.80 A; A=25-642. DR PDB; 1XKK; X-ray; 2.40 A; A=695-1022. DR PDB; 1YY9; X-ray; 2.60 A; A=25-642. DR PDB; 1Z9I; NMR; -; A=669-721. DR PDB; 2EB2; X-ray; 2.50 A; A=695-1022. DR PDB; 2EB3; X-ray; 2.84 A; A=695-1022. DR PDB; 2EXP; Model; -; A=311-326. DR PDB; 2EXQ; Model; -; A=27-536. DR PDB; 2GS2; X-ray; 2.80 A; A=696-1022. DR PDB; 2GS6; X-ray; 2.60 A; A=696-1022. DR PDB; 2GS7; X-ray; 2.60 A; A/B=696-1022. DR PDB; 2ITN; X-ray; 2.47 A; A=696-1019. DR PDB; 2ITO; X-ray; 3.25 A; A=696-1022. DR PDB; 2ITP; X-ray; 2.74 A; A=696-1022. DR PDB; 2ITQ; X-ray; 2.68 A; A=696-1022. DR PDB; 2ITT; X-ray; 2.73 A; A=696-1022. DR PDB; 2ITU; X-ray; 2.80 A; A=696-1022. DR PDB; 2ITV; X-ray; 2.47 A; A=696-1022. DR PDB; 2ITW; X-ray; 2.88 A; A=696-1022. DR PDB; 2ITX; X-ray; 2.98 A; A=696-1022. DR PDB; 2ITY; X-ray; 3.42 A; A=696-1022. DR PDB; 2ITZ; X-ray; 2.72 A; A=696-1022. DR PDB; 2J5E; X-ray; 3.10 A; A=696-1022. DR PDB; 2J5F; X-ray; 3.00 A; A=696-1022. DR PDB; 2J6M; X-ray; 3.10 A; A=696-1022. DR PDB; 2JIT; X-ray; 3.10 A; A/B=696-1022. DR PDB; 2JIU; X-ray; 3.05 A; A/B=695-1022. DR PDB; 2JIV; X-ray; 3.50 A; A/B=695-1022. DR PDB; 2KS1; NMR; -; B=634-677. DR PDB; 2RF9; X-ray; 3.50 A; A/B=696-1022. DR PDB; 2RFD; X-ray; 3.60 A; A/B=702-1022. DR PDB; 2RFE; X-ray; 2.90 A; A/B/C/D=702-1022. DR PDB; 2RGP; X-ray; 2.00 A; A=702-1016. DR PDB; 3B2U; X-ray; 2.58 A; A/B/E/I/M/P/S/V=335-538. DR PDB; 3B2V; X-ray; 3.30 A; A=25-642. DR PDB; 3BEL; X-ray; 2.30 A; A=702-1016. DR PDB; 3BUO; X-ray; 2.60 A; A/C=1063-1075. DR PDB; 3C09; X-ray; 3.20 A; A/D=335-538. DR PDB; 3G5V; X-ray; 2.00 A; C=311-326. DR PDB; 3G5Y; X-ray; 1.59 A; E=311-326. DR PDB; 3GOP; X-ray; 2.80 A; A=669-1022. DR PDB; 3GT8; X-ray; 2.96 A; A/B/C/D=696-1022. DR PDB; 3IKA; X-ray; 2.90 A; A/B=694-1022. DR PDB; 3LZB; X-ray; 2.70 A; A/B/C/D/E/F/G/H=696-983. DR PDB; 3NJP; X-ray; 3.30 A; A/B=25-638. DR PDB; 3OB2; X-ray; 2.10 A; A=1063-1074. DR PDB; 3OP0; X-ray; 2.52 A; C/D=1066-1076. DR PDB; 3P0Y; X-ray; 1.80 A; A=334-538. DR PDB; 3PFV; X-ray; 2.27 A; C/D=1066-1076. DR PDB; 3POZ; X-ray; 1.50 A; A=696-1022. DR PDB; 3QWQ; X-ray; 2.75 A; A=1-642. DR PDBsum; 1DNQ; -. DR PDBsum; 1DNR; -. DR PDBsum; 1IVO; -. DR PDBsum; 1M14; -. DR PDBsum; 1M17; -. DR PDBsum; 1MOX; -. DR PDBsum; 1NQL; -. DR PDBsum; 1XKK; -. DR PDBsum; 1YY9; -. DR PDBsum; 1Z9I; -. DR PDBsum; 2EB2; -. DR PDBsum; 2EB3; -. DR PDBsum; 2EXP; -. DR PDBsum; 2EXQ; -. DR PDBsum; 2GS2; -. DR PDBsum; 2GS6; -. DR PDBsum; 2GS7; -. DR PDBsum; 2ITN; -. DR PDBsum; 2ITO; -. DR PDBsum; 2ITP; -. DR PDBsum; 2ITQ; -. DR PDBsum; 2ITT; -. DR PDBsum; 2ITU; -. DR PDBsum; 2ITV; -. DR PDBsum; 2ITW; -. DR PDBsum; 2ITX; -. DR PDBsum; 2ITY; -. DR PDBsum; 2ITZ; -. DR PDBsum; 2J5E; -. DR PDBsum; 2J5F; -. DR PDBsum; 2J6M; -. DR PDBsum; 2JIT; -. DR PDBsum; 2JIU; -. DR PDBsum; 2JIV; -. DR PDBsum; 2KS1; -. DR PDBsum; 2RF9; -. DR PDBsum; 2RFD; -. DR PDBsum; 2RFE; -. DR PDBsum; 2RGP; -. DR PDBsum; 3B2U; -. DR PDBsum; 3B2V; -. DR PDBsum; 3BEL; -. DR PDBsum; 3BUO; -. DR PDBsum; 3C09; -. DR PDBsum; 3G5V; -. DR PDBsum; 3G5Y; -. DR PDBsum; 3GOP; -. DR PDBsum; 3GT8; -. DR PDBsum; 3IKA; -. DR PDBsum; 3LZB; -. DR PDBsum; 3NJP; -. DR PDBsum; 3OB2; -. DR PDBsum; 3OP0; -. DR PDBsum; 3P0Y; -. DR PDBsum; 3PFV; -. DR PDBsum; 3POZ; -. DR PDBsum; 3QWQ; -. DR ProteinModelPortal; P00533; -. DR SMR; P00533; 26-1003. DR DisProt; DP00309; -. DR DIP; DIP-405N; -. DR DIP; DIP-5764N; -. DR IntAct; P00533; 204. DR MINT; MINT-206389; -. DR STRING; P00533; -. DR GlycoSuiteDB; P00533; -. DR PhosphoSite; P00533; -. DR DMDM; 2811086; -. DR SWISS-2DPAGE; P00533; -. DR PeptideAtlas; P00533; -. DR PRIDE; P00533; -. DR DNASU; 1956; -. DR Ensembl; ENST00000275493; ENSP00000275493; ENSG00000146648. DR GeneID; 1956; -. DR KEGG; hsa:1956; -. DR UCSC; uc003tqi.1; human. DR UCSC; uc003tqj.1; human. DR UCSC; uc003tqk.1; human. DR CTD; 1956; -. DR GeneCards; GC07P055054; -. DR H-InvDB; HIX0025338; -. DR HGNC; HGNC:3236; EGFR. DR HPA; CAB000035; -. DR HPA; HPA001200; -. DR HPA; HPA018530; -. DR MIM; 131550; gene. DR MIM; 211980; phenotype. DR neXtProt; NX_P00533; -. DR Orphanet; 360; Glioblastoma. DR PharmGKB; PA7360; -. DR eggNOG; COG0515; -. DR GeneTree; ENSGT00600000084253; -. DR HOVERGEN; HBG000490; -. DR InParanoid; P00533; -. DR KO; K04361; -. DR OMA; MRRRHIV; -. DR PhylomeDB; P00533; -. DR BRENDA; 2.7.10.1; 2681. DR Pathway_Interaction_DB; a6b1_a6b4_integrin_pathway; a6b1 and a6b4 Integrin signaling. DR Pathway_Interaction_DB; arf6cyclingpathway; Arf6 signaling events. DR Pathway_Interaction_DB; endothelinpathway; Endothelins. DR Pathway_Interaction_DB; lysophospholipid_pathway; LPA receptor mediated events. DR Pathway_Interaction_DB; telomerasepathway; Regulation of Telomerase. DR Pathway_Interaction_DB; ptp1bpathway; Signaling events mediated by PTP1B. DR Pathway_Interaction_DB; syndecan_3_pathway; Syndecan-3-mediated signaling events. DR Pathway_Interaction_DB; txa2pathway; Thromboxane A2 receptor signaling. DR Reactome; REACT_111045; Developmental Biology. DR Reactome; REACT_111102; Signal Transduction. DR Reactome; REACT_116125; Disease. DR DrugBank; DB00002; Cetuximab. DR DrugBank; DB00530; Erlotinib. DR DrugBank; DB00317; Gefitinib. DR DrugBank; DB01259; Lapatinib. DR DrugBank; DB00281; Lidocaine. DR DrugBank; DB01269; Panitumumab. DR DrugBank; DB00072; Trastuzumab. DR NextBio; 7931; -. DR PMAP-CutDB; P00533; -. DR ArrayExpress; P00533; -. DR Bgee; P00533; -. DR Genevestigator; P00533; -. DR GermOnline; ENSG00000146648; Homo sapiens. DR GO; GO:0016323; C:basolateral plasma membrane; IDA:BHF-UCL. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0010008; C:endosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005615; C:extracellular space; NAS:UniProtKB. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW. DR GO; GO:0045121; C:membrane raft; IDA:UniProtKB. DR GO; GO:0031965; C:nuclear membrane; IEA:UniProtKB-SubCell. DR GO; GO:0070435; C:Shc-EGFR complex; ISS:BHF-UCL. DR GO; GO:0051015; F:actin filament binding; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0003690; F:double-stranded DNA binding; NAS:UniProtKB. DR GO; GO:0005006; F:epidermal growth factor-activated receptor activity; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0004710; F:MAP/ERK kinase kinase activity; NAS:UniProtKB. DR GO; GO:0046982; F:protein heterodimerization activity; IDA:UniProtKB. DR GO; GO:0019903; F:protein phosphatase binding; IPI:UniProtKB. DR GO; GO:0004716; F:receptor signaling protein tyrosine kinase activity; IEA:InterPro. DR GO; GO:0043006; P:activation of phospholipase A2 activity by calcium-mediated signaling; TAS:UniProtKB. DR GO; GO:0007202; P:activation of phospholipase C activity; TAS:UniProtKB. DR GO; GO:0007411; P:axon guidance; TAS:Reactome. DR GO; GO:0008283; P:cell proliferation; IDA:UniProtKB. DR GO; GO:0016337; P:cell-cell adhesion; IMP:UniProtKB. DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB. DR GO; GO:0042059; P:negative regulation of epidermal growth factor receptor signaling pathway; TAS:Reactome. DR GO; GO:0042177; P:negative regulation of protein catabolic process; IDA:UniProtKB. DR GO; GO:0001503; P:ossification; NAS:UniProtKB. DR GO; GO:0035413; P:positive regulation of catenin import into nucleus; IMP:BHF-UCL. DR GO; GO:0030335; P:positive regulation of cell migration; IMP:UniProtKB. DR GO; GO:0031659; P:positive regulation of cyclin-dependent protein kinase activity involved in G1/S; IDA:BHF-UCL. DR GO; GO:0045739; P:positive regulation of DNA repair; IDA:UniProtKB. DR GO; GO:0045740; P:positive regulation of DNA replication; IDA:UniProtKB. DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; IDA:UniProtKB. DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IDA:UniProtKB. DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; IDA:UniProtKB. DR GO; GO:0042327; P:positive regulation of phosphorylation; IDA:UniProtKB. DR GO; GO:0051897; P:positive regulation of protein kinase B signaling cascade; IMP:BHF-UCL. DR GO; GO:0046777; P:protein autophosphorylation; IMP:UniProtKB. DR GO; GO:0051205; P:protein insertion into membrane; TAS:UniProtKB. DR GO; GO:0050999; P:regulation of nitric-oxide synthase activity; IDA:UniProtKB. DR GO; GO:0050730; P:regulation of peptidyl-tyrosine phosphorylation; IMP:UniProtKB. DR GO; GO:0006950; P:response to stress; NAS:UniProtKB. DR GO; GO:0070141; P:response to UV-A; IDA:BHF-UCL. DR InterPro; IPR000494; EGF_rcpt_L. DR InterPro; IPR006211; Furin-like_Cys-rich_dom. DR InterPro; IPR006212; Furin_repeat. DR InterPro; IPR009030; Growth_fac_rcpt. DR InterPro; IPR011009; Kinase-like_dom. DR InterPro; IPR000719; Prot_kinase_cat_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom. DR InterPro; IPR008266; Tyr_kinase_AS. DR InterPro; IPR020635; Tyr_kinase_cat_dom. DR InterPro; IPR016245; Tyr_kinase_EGF/ERB/XmrK_rcpt. DR Pfam; PF00757; Furin-like; 1. DR Pfam; PF07714; Pkinase_Tyr; 1. DR Pfam; PF01030; Recep_L_domain; 2. DR PIRSF; PIRSF000619; TyrPK_EGF-R; 1. DR PRINTS; PR00109; TYRKINASE. DR SMART; SM00261; FU; 3. DR SMART; SM00219; TyrKc; 1. DR SUPFAM; SSF57184; Grow_fac_recept; 2. DR SUPFAM; SSF56112; Kinase_like; 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ATP-binding; Cell membrane; KW Complete proteome; Developmental protein; Direct protein sequencing; KW Disease mutation; Disulfide bond; Endoplasmic reticulum; Endosome; KW Glycoprotein; Golgi apparatus; Isopeptide bond; Kinase; Membrane; KW Methylation; Nucleotide-binding; Nucleus; Phosphoprotein; KW Polymorphism; Receptor; Reference proteome; Repeat; Secreted; Signal; KW Transferase; Transmembrane; Transmembrane helix; Tumor suppressor; KW Tyrosine-protein kinase; Ubl conjugation. FT SIGNAL 1 24 FT CHAIN 25 1210 Epidermal growth factor receptor. FT /FTId=PRO_0000016665. FT TOPO_DOM 25 645 Extracellular (Potential). FT TRANSMEM 646 668 Helical; (Potential). FT TOPO_DOM 669 1210 Cytoplasmic (Potential). FT REPEAT 75 300 Approximate. FT REPEAT 390 600 Approximate. FT DOMAIN 712 979 Protein kinase. FT NP_BIND 718 726 ATP. FT NP_BIND 790 791 ATP. FT REGION 688 704 Important for dimerization, FT phosphorylation and activation. FT COMPBIAS 1025 1071 Ser-rich. FT ACT_SITE 837 837 Proton acceptor (By similarity). FT BINDING 745 745 ATP. FT BINDING 855 855 ATP. FT SITE 1016 1016 Important for interaction with PIK3C2B. FT MOD_RES 678 678 Phosphothreonine; by PKC and PKD/PRKD1. FT MOD_RES 693 693 Phosphothreonine; by PKD/PRKD1. FT MOD_RES 695 695 Phosphoserine. FT MOD_RES 725 725 Phosphothreonine. FT MOD_RES 869 869 Phosphotyrosine. FT MOD_RES 978 978 Phosphotyrosine. FT MOD_RES 991 991 Phosphoserine. FT MOD_RES 993 993 Phosphothreonine. FT MOD_RES 995 995 Phosphoserine. FT MOD_RES 998 998 Phosphotyrosine; by autocatalysis. FT MOD_RES 1016 1016 Phosphotyrosine; by autocatalysis. FT MOD_RES 1025 1025 Phosphoserine. FT MOD_RES 1026 1026 Phosphoserine. FT MOD_RES 1037 1037 Phosphoserine. FT MOD_RES 1039 1039 Phosphoserine. FT MOD_RES 1041 1041 Phosphothreonine. FT MOD_RES 1042 1042 Phosphoserine. FT MOD_RES 1045 1045 Phosphoserine. FT MOD_RES 1064 1064 Phosphoserine. FT MOD_RES 1069 1069 Phosphotyrosine. FT MOD_RES 1070 1070 Phosphoserine. FT MOD_RES 1071 1071 Phosphoserine. FT MOD_RES 1081 1081 Phosphoserine. FT MOD_RES 1092 1092 Phosphotyrosine; by autocatalysis. FT MOD_RES 1110 1110 Phosphotyrosine; by autocatalysis. FT MOD_RES 1138 1138 Phosphotyrosine. FT MOD_RES 1166 1166 Phosphoserine. FT MOD_RES 1172 1172 Phosphotyrosine; by autocatalysis. FT MOD_RES 1197 1197 Phosphotyrosine; by autocatalysis. FT MOD_RES 1199 1199 Omega-N-methylated arginine. FT CARBOHYD 56 56 N-linked (GlcNAc...) (complex); atypical; FT partial. FT /FTId=CAR_000227. FT CARBOHYD 73 73 N-linked (GlcNAc...). FT CARBOHYD 128 128 N-linked (GlcNAc...). FT CARBOHYD 175 175 N-linked (GlcNAc...). FT CARBOHYD 196 196 N-linked (GlcNAc...). FT CARBOHYD 352 352 N-linked (GlcNAc...). FT CARBOHYD 361 361 N-linked (GlcNAc...). FT CARBOHYD 413 413 N-linked (GlcNAc...). FT CARBOHYD 444 444 N-linked (GlcNAc...). FT CARBOHYD 528 528 N-linked (GlcNAc...). FT CARBOHYD 568 568 N-linked (GlcNAc...); partial. FT CARBOHYD 603 603 N-linked (GlcNAc...); partial. FT DISULFID 31 58 FT DISULFID 157 187 FT DISULFID 190 199 FT DISULFID 194 207 FT DISULFID 215 223 FT DISULFID 219 231 FT DISULFID 232 240 FT DISULFID 236 248 FT DISULFID 251 260 FT DISULFID 264 291 FT DISULFID 295 307 FT DISULFID 311 326 FT DISULFID 329 333 FT DISULFID 337 362 FT DISULFID 470 499 FT DISULFID 506 515 FT DISULFID 510 523 FT DISULFID 526 535 FT DISULFID 539 555 FT DISULFID 558 571 FT DISULFID 562 579 FT DISULFID 582 591 FT DISULFID 595 617 FT DISULFID 620 628 FT DISULFID 624 636 FT CROSSLNK 716 716 Glycyl lysine isopeptide (Lys-Gly) FT (interchain with G-Cter in ubiquitin). FT CROSSLNK 737 737 Glycyl lysine isopeptide (Lys-Gly) FT (interchain with G-Cter in ubiquitin). FT CROSSLNK 754 754 Glycyl lysine isopeptide (Lys-Gly) FT (interchain with G-Cter in ubiquitin). FT CROSSLNK 867 867 Glycyl lysine isopeptide (Lys-Gly) FT (interchain with G-Cter in ubiquitin). FT CROSSLNK 929 929 Glycyl lysine isopeptide (Lys-Gly) FT (interchain with G-Cter in ubiquitin). FT CROSSLNK 970 970 Glycyl lysine isopeptide (Lys-Gly) FT (interchain with G-Cter in ubiquitin). FT VAR_SEQ 404 405 FL -> LS (in isoform 2). FT /FTId=VSP_002887. FT VAR_SEQ 406 1210 Missing (in isoform 2). FT /FTId=VSP_002888. FT VAR_SEQ 628 705 CTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFM FT RRRHIVRKRTLRRLLQERELVEPLTPSGEAPNQALLR -> FT PGNESLKAMLFCLFKLSSCNQSNDGSVSHQSGSPAAQESCL FT GWIPSLLPSEFQLGWGGCSHLHAWPSASVIITASSCH (in FT isoform 3). FT /FTId=VSP_002889. FT VAR_SEQ 628 628 C -> S (in isoform 4). FT /FTId=VSP_002891. FT VAR_SEQ 629 1210 Missing (in isoform 4). FT /FTId=VSP_002892. FT VAR_SEQ 706 1210 Missing (in isoform 3). FT /FTId=VSP_002890. FT VARIANT 30 297 Missing (variant EGFR vIII; found in a FT lung cancer sample; somatic mutation; FT induces lung cancer when exogenously FT expressed). FT /FTId=VAR_066493. FT VARIANT 98 98 R -> Q (in dbSNP:rs17289589). FT /FTId=VAR_019293. FT VARIANT 266 266 P -> R (in dbSNP:rs17336639). FT /FTId=VAR_019294. FT VARIANT 521 521 R -> K (in dbSNP:rs2227983). FT /FTId=VAR_019295. FT VARIANT 674 674 V -> I (slightly increased FT autophosphorylation; dbSNP:rs17337079). FT /FTId=VAR_019296. FT VARIANT 709 709 E -> A (found in a lung cancer sample). FT /FTId=VAR_026084. FT VARIANT 709 709 E -> K (found in a lung cancer sample). FT /FTId=VAR_026085. FT VARIANT 719 719 G -> A (found in a lung cancer sample). FT /FTId=VAR_026086. FT VARIANT 719 719 G -> C (found in a lung cancer sample; FT dbSNP:rs28929495). FT /FTId=VAR_026087. FT VARIANT 719 719 G -> D (found in a lung cancer sample). FT /FTId=VAR_026088. FT VARIANT 719 719 G -> S (found in a lung cancer sample; FT somatic mutation; strongly increased FT kinase activity). FT /FTId=VAR_019297. FT VARIANT 724 724 G -> S (found in a lung cancer sample). FT /FTId=VAR_026089. FT VARIANT 734 734 E -> K (found in a lung cancer sample). FT /FTId=VAR_026090. FT VARIANT 746 750 Missing (found in a lung cancer sample). FT /FTId=VAR_026092. FT VARIANT 746 746 Missing (found in a lung cancer sample). FT /FTId=VAR_026091. FT VARIANT 747 749 Missing (found in a lung cancer sample). FT /FTId=VAR_026094. FT VARIANT 747 747 L -> F (found in a lung cancer sample). FT /FTId=VAR_026093. FT VARIANT 748 748 R -> P (found in a lung cancer sample). FT /FTId=VAR_026095. FT VARIANT 752 759 Missing (found in a lung cancer sample). FT /FTId=VAR_026096. FT VARIANT 787 787 Q -> R (found in a lung cancer sample). FT /FTId=VAR_026097. FT VARIANT 790 790 T -> M (found in a lung cancer sample; FT increased kinase activity). FT /FTId=VAR_026098. FT VARIANT 833 833 L -> V (found in a lung cancer sample). FT /FTId=VAR_026099. FT VARIANT 834 834 V -> L (found in a lung cancer sample). FT /FTId=VAR_026100. FT VARIANT 858 858 L -> M (found in a lung cancer sample). FT /FTId=VAR_026101. FT VARIANT 858 858 L -> R (found in a lung cancer sample; FT somatic mutation; constitutively FT activated enzyme with strongly increased FT kinase activity). FT /FTId=VAR_019298. FT VARIANT 861 861 L -> Q (found in a lung cancer sample). FT /FTId=VAR_026102. FT VARIANT 873 873 G -> E (found in a lung cancer sample). FT /FTId=VAR_026103. FT VARIANT 962 962 R -> G (in dbSNP:rs17337451). FT /FTId=VAR_019299. FT VARIANT 988 988 H -> P (in dbSNP:rs17290699). FT /FTId=VAR_019300. FT VARIANT 1034 1034 L -> R (in dbSNP:rs34352568). FT /FTId=VAR_042095. FT VARIANT 1210 1210 A -> V (in dbSNP:rs35918369). FT /FTId=VAR_042096. FT MUTAGEN 275 275 Y->A: Strongly reduced FT autophosphorylation and activation of FT downstream kinases; when associated with FT A-309. FT MUTAGEN 287 287 F->A: Strongly reduced FT autophosphorylation and activation of FT downstream kinases; when associated with FT A-309. FT MUTAGEN 309 309 R->S: Strongly reduced FT autophosphorylation and activation of FT downstream kinases; when associated with FT A-275. Strongly reduced FT autophosphorylation and activation of FT downstream kinases; when associated with FT A-287. FT MUTAGEN 429 429 R->E: Abolishes autophosphorylation and FT activation of downstream kinases. FT MUTAGEN 587 590 DGPH->AGPA: Decreases intramolecular FT interactions and facilitates EGF binding. FT MUTAGEN 609 609 K->A: Decreases intramolecular FT interactions and facilitates EGF binding. FT MUTAGEN 688 688 L->A: Strongly reduced phosphorylation. FT MUTAGEN 689 689 V->A: Reduced autophosphorylation. FT MUTAGEN 689 689 V->M: Constitutively activated kinase. FT MUTAGEN 690 690 E->A: Reduced phosphorylation. FT MUTAGEN 692 692 L->A,P: Strongly reduced phosphorylation. FT MUTAGEN 693 693 T->A: Increased phosphorylation. FT MUTAGEN 693 693 T->D: Strongly reduced phosphorylation. FT MUTAGEN 694 694 P->A: Strongly reduced phosphorylation. FT MUTAGEN 699 699 P->A: Reduced phosphorylation. FT MUTAGEN 700 700 N->A: Abolishes phosphorylation. FT MUTAGEN 704 704 L->A: Abolishes phosphorylation. FT MUTAGEN 705 705 R->A: Abolishes phosphorylation. FT MUTAGEN 706 706 I->A: Abolishes phosphorylation. FT MUTAGEN 745 745 K->A,M: Abolishes kinase activity. FT MUTAGEN 974 974 D->A: Strongly reduced phosphorylation. FT MUTAGEN 977 977 R->A: Reduced phosphorylation. FT MUTAGEN 1005 1006 ED->RK: Constitutively activated kinase. FT MUTAGEN 1016 1016 Y->F: 50% decrease in interaction with FT PIK3C2B. 65% decrease in interaction with FT PIK3C2B; when associated with F-1197. FT Abolishes interaction with PIK3C2B; when FT associated with F-1197 and F-1092. FT MUTAGEN 1092 1092 Y->F: No change in interaction with FT PIK3C2B. Abolishes interaction with FT PIK3C2B; when associated with F-1197 and FT F-1016. FT MUTAGEN 1110 1110 Y->F: No change in interaction with FT PIK3C2B. FT MUTAGEN 1172 1172 Y->F: No change in interaction with FT PIK3C2B. FT MUTAGEN 1197 1197 Y->F: No change in interaction with FT PIK3C2B. 65% decrease in interaction with FT PIK3C2B; when associated with F-1016. FT Abolishes interaction with PIK3C2B; when FT associated with F-1092 and F-1016. FT CONFLICT 540 540 N -> K (in Ref. 1; CAA25240). FT STRAND 40 43 FT HELIX 44 55 FT STRAND 59 63 FT STRAND 65 67 FT HELIX 77 81 FT STRAND 84 87 FT STRAND 89 93 FT HELIX 101 103 FT TURN 114 116 FT STRAND 117 122 FT STRAND 145 152 FT HELIX 159 161 FT TURN 164 167 FT TURN 173 175 FT STRAND 195 197 FT STRAND 200 202 FT TURN 203 205 FT STRAND 211 215 FT STRAND 224 229 FT STRAND 236 238 FT STRAND 241 247 FT STRAND 249 256 FT STRAND 259 263 FT STRAND 267 271 FT TURN 272 275 FT STRAND 276 279 FT STRAND 285 287 FT STRAND 290 294 FT STRAND 299 301 FT STRAND 305 309 FT STRAND 321 323 FT STRAND 330 332 FT STRAND 340 342 FT HELIX 343 345 FT HELIX 353 355 FT HELIX 357 359 FT STRAND 363 367 FT STRAND 369 371 FT HELIX 373 377 FT TURN 380 383 FT HELIX 389 397 FT STRAND 400 403 FT STRAND 405 408 FT HELIX 418 420 FT TURN 433 435 FT STRAND 436 442 FT STRAND 458 464 FT HELIX 472 474 FT HELIX 477 480 FT STRAND 492 494 FT HELIX 496 498 FT TURN 499 503 FT TURN 507 509 FT STRAND 515 519 FT STRAND 522 525 FT STRAND 540 543 FT STRAND 548 557 FT STRAND 571 575 FT STRAND 579 587 FT STRAND 590 594 FT STRAND 597 600 FT STRAND 602 611 FT STRAND 616 619 FT STRAND 629 632 FT TURN 633 635 FT STRAND 704 706 FT TURN 709 711 FT STRAND 712 720 FT STRAND 722 731 FT STRAND 740 747 FT HELIX 756 768 FT STRAND 777 791 FT HELIX 798 804 FT STRAND 806 808 FT HELIX 811 830 FT HELIX 840 842 FT STRAND 843 847 FT STRAND 850 853 FT HELIX 858 861 FT TURN 862 865 FT TURN 878 880 FT HELIX 883 888 FT HELIX 893 908 FT TURN 914 917 FT HELIX 920 922 FT HELIX 923 929 FT HELIX 941 950 FT HELIX 955 957 FT HELIX 961 973 FT HELIX 975 978 FT TURN 982 986 FT HELIX 996 1002 FT HELIX 1013 1016 SQ SEQUENCE 1210 AA; 134277 MW; D8A2A50B4EFB6ED2 CRC64; MRPSGTAGAA LLALLAALCP ASRALEEKKV CQGTSNKLTQ LGTFEDHFLS LQRMFNNCEV VLGNLEITYV QRNYDLSFLK TIQEVAGYVL IALNTVERIP LENLQIIRGN MYYENSYALA VLSNYDANKT GLKELPMRNL QEILHGAVRF SNNPALCNVE SIQWRDIVSS DFLSNMSMDF QNHLGSCQKC DPSCPNGSCW GAGEENCQKL TKIICAQQCS GRCRGKSPSD CCHNQCAAGC TGPRESDCLV CRKFRDEATC KDTCPPLMLY NPTTYQMDVN PEGKYSFGAT CVKKCPRNYV VTDHGSCVRA CGADSYEMEE DGVRKCKKCE GPCRKVCNGI GIGEFKDSLS INATNIKHFK NCTSISGDLH ILPVAFRGDS FTHTPPLDPQ ELDILKTVKE ITGFLLIQAW PENRTDLHAF ENLEIIRGRT KQHGQFSLAV VSLNITSLGL RSLKEISDGD VIISGNKNLC YANTINWKKL FGTSGQKTKI ISNRGENSCK ATGQVCHALC SPEGCWGPEP RDCVSCRNVS RGRECVDKCN LLEGEPREFV ENSECIQCHP ECLPQAMNIT CTGRGPDNCI QCAHYIDGPH CVKTCPAGVM GENNTLVWKY ADAGHVCHLC HPNCTYGCTG PGLEGCPTNG PKIPSIATGM VGALLLLLVV ALGIGLFMRR RHIVRKRTLR RLLQERELVE PLTPSGEAPN QALLRILKET EFKKIKVLGS GAFGTVYKGL WIPEGEKVKI PVAIKELREA TSPKANKEIL DEAYVMASVD NPHVCRLLGI CLTSTVQLIT QLMPFGCLLD YVREHKDNIG SQYLLNWCVQ IAKGMNYLED RRLVHRDLAA RNVLVKTPQH VKITDFGLAK LLGAEEKEYH AEGGKVPIKW MALESILHRI YTHQSDVWSY GVTVWELMTF GSKPYDGIPA SEISSILEKG ERLPQPPICT IDVYMIMVKC WMIDADSRPK FRELIIEFSK MARDPQRYLV IQGDERMHLP SPTDSNFYRA LMDEEDMDDV VDADEYLIPQ QGFFSSPSTS RTPLLSSLSA TSNNSTVACI DRNGLQSCPI KEDSFLQRYS SDPTGALTED SIDDTFLPVP EYINQSVPKR PAGSVQNPVY HNQPLNPAPS RDPHYQDPHS TAVGNPEYLN TVQPTCVNST FDSPAHWAQK GSHQISLDNP DYQQDFFPKE AKPNGIFKGS TAENAEYLRV APQSSEFIGA //