P00533

FUNCTION: Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TGFA/TGF-alpha, amphiregulin, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF. Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS- RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules. May also activate the NF-kappa-B signaling cascade. Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling. Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin. FUNCTION: Isoform 2 may act as an antagonist of EGF action. CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. ENZYME REGULATION: Endocytosis and inhibition of the activated EGFR by phosphatases like PTPRJ and PTPRK constitute immediate regulatory mechanisms. Upon EGF-binding phosphorylates EPS15 that regulates EGFR endocytosis and activity. Moreover, inducible feedback inhibitors including LRIG1, SOCS4, SOCS5 and ERRFI1 constitute alternative regulatory mechanisms for the EGFR signaling. SUBUNIT: Binding of the ligand triggers homo- and/or heterodimerization of the receptor triggering its autophosphorylation. Heterodimer with ERBB2. Interacts with ERRFI1; inhibits dimerization of the kinase domain and autophosphorylation. Part of a complex with ERBB2 and either PIK3C2A or PIK3C2B. Interacts with GRB2; an adapter protein coupling the receptor to downstream signaling pathways. Interacts with GAB2; involved in signaling downstream of EGFR. Interacts with STAT3; mediates EGFR downstream signaling in cell proliferation. Interacts with RIPK1; involved in NF-kappa-B activation. Interacts (autophosphorylated) with CBL; involved in EGFR ubiquitination and regulation. Interacts with SOCS5; regulates EGFR degradation through TCEB1- and TCEB2-mediated ubiquitination and proteasomal degradation. Interacts with PRMT5; methylates EGFR and enhances interaction with PTPN6. Interacts (phosphorylated) with PTPN6; inhibits EGFR-dependent activation of MAPK/ERK. Interacts with COPG1; essential for regulation of EGF- dependent nuclear transport of EGFR by retrograde trafficking from the Golgi to the ER. Interacts with TNK2; this interaction is dependent on EGF stimulation and kinase activity of EGFR. Interacts with PCNA; positively regulates PCNA. Interacts with PELP1. Interacts with MUC1. Interacts with AP2M1. Interacts with FER. May interact with EPS8; mediates EPS8 phosphorylation. Interacts (via SH2 domains) with GRB2, NCK1 and NCK2. Interacts with ATX2. SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane protein. Endoplasmic reticulum membrane; Single-pass type I membrane protein. Golgi apparatus membrane; Single-pass type I membrane protein. Nucleus membrane; Single-pass type I membrane protein. Endosome. Endosome membrane. Note=In response to EGF, translocated from the cell membrane to the nucleus via Golgi and ER. Endocytosed upon activation by ligand. SUBCELLULAR LOCATION: Isoform 2: Secreted. ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=4; Name=1; Synonyms=p170; IsoId=P00533-1; Sequence=Displayed; Name=2; Synonyms=p60, Truncated, TEGFR; IsoId=P00533-2; Sequence=VSP_002887, VSP_002888; Name=3; Synonyms=p110; IsoId=P00533-3; Sequence=VSP_002889, VSP_002890; Name=4; IsoId=P00533-4; Sequence=VSP_002891, VSP_002892; TISSUE SPECIFICITY: Ubiquitously expressed. Isoform 2 is also expressed in ovarian cancers. PTM: Phosphorylation at Ser-695 is partial and occurs only if Thr- 693 is phosphorylated. Phosphorylation at Thr-678 and Thr-693 by PRKD1 inhibits EGF-induced MAPK8/JNK1 activation. Dephosphorylation by PTPRJ prevents endocytosis and stabilizes the receptor at the plasma membrane. Autophosphorylation at Tyr-1197 is stimulated by methylation at Arg-1199 and enhances interaction with PTPN6. Autophosphorylation at Tyr-1092 and/or Tyr-1110 recruits STAT3. PTM: Monoubiquitinated and polyubiquitinated upon EGF stimulation; which does not affect tyrosine kinase activity or signaling capacity but may play a role in lysosomal targeting. Polyubiquitin linkage is mainly through 'Lys-63', but linkage through 'Lys-48', 'Lys-11' and 'Lys-29' also occur. PTM: Methylated. Methylation at Arg-1199 by PRMT5 positively stimulates phosphorylation at Tyr-1197. DISEASE: Defects in EGFR are associated with lung cancer (LNCR) [MIM:211980]. LNCR is a common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein kinase family. EGF receptor subfamily. SIMILARITY: Contains 1 protein kinase domain. WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/EGFR"; WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/egfr/"; WEB RESOURCE: Name=Wikipedia; Note=EGFR entry; URL="http://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor"; GENE SYNONYMS:EGFR ERBB ERBB1 HER1. COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License., SEQUENCE 1210 AA; 134277 MW; D8A2A50B4EFB6ED2 CRC64;

EGFR_HUMAN

urn:biopax:ModificationFeature:EGFR_HUMAN_1, urn:biopax:ModificationFeature:EGFR_HUMAN_10, urn:biopax:ModificationFeature:EGFR_HUMAN_11, urn:biopax:ModificationFeature:EGFR_HUMAN_12, urn:biopax:ModificationFeature:EGFR_HUMAN_13, urn:biopax:ModificationFeature:EGFR_HUMAN_14, urn:biopax:ModificationFeature:EGFR_HUMAN_15, urn:biopax:ModificationFeature:EGFR_HUMAN_16, urn:biopax:ModificationFeature:EGFR_HUMAN_17, urn:biopax:ModificationFeature:EGFR_HUMAN_18, urn:biopax:ModificationFeature:EGFR_HUMAN_19, urn:biopax:ModificationFeature:EGFR_HUMAN_2, urn:biopax:ModificationFeature:EGFR_HUMAN_20, urn:biopax:ModificationFeature:EGFR_HUMAN_21, urn:biopax:ModificationFeature:EGFR_HUMAN_22, urn:biopax:ModificationFeature:EGFR_HUMAN_23, urn:biopax:ModificationFeature:EGFR_HUMAN_24, urn:biopax:ModificationFeature:EGFR_HUMAN_25, urn:biopax:ModificationFeature:EGFR_HUMAN_26, urn:biopax:ModificationFeature:EGFR_HUMAN_27, urn:biopax:ModificationFeature:EGFR_HUMAN_28, urn:biopax:ModificationFeature:EGFR_HUMAN_29, urn:biopax:ModificationFeature:EGFR_HUMAN_3, urn:biopax:ModificationFeature:EGFR_HUMAN_30, urn:biopax:ModificationFeature:EGFR_HUMAN_31, urn:biopax:ModificationFeature:EGFR_HUMAN_4, urn:biopax:ModificationFeature:EGFR_HUMAN_5, urn:biopax:ModificationFeature:EGFR_HUMAN_6, urn:biopax:ModificationFeature:EGFR_HUMAN_7, urn:biopax:ModificationFeature:EGFR_HUMAN_8, urn:biopax:ModificationFeature:EGFR_HUMAN_9

MRPSGTAGAALLALLAALCPASRALEEKKVCQGTSNKLTQLGTFEDHFLSLQRMFNNCEVVLGNLEITYVQRNYDLSFLKTIQEVAGYVLIALNTVERIPLENLQIIRGNMYYENSYALAVLSNYDANKTGLKELPMRNLQEILHGAVRFSNNPALCNVESIQWRDIVSSDFLSNMSMDFQNHLGSCQKCDPSCPNGSCWGAGEENCQKLTKIICAQQCSGRCRGKSPSDCCHNQCAAGCTGPRESDCLVCRKFRDEATCKDTCPPLMLYNPTTYQMDVNPEGKYSFGATCVKKCPRNYVVTDHGSCVRACGADSYEMEEDGVRKCKKCEGPCRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFMRRRHIVRKRTLRRLLQERELVEPLTPSGEAPNQALLRILKETEFKKIKVLGSGAFGTVYKGLWIPEGEKVKIPVAIKELREATSPKANKEILDEAYVMASVDNPHVCRLLGICLTSTVQLITQLMPFGCLLDYVREHKDNIGSQYLLNWCVQIAKGMNYLEDRRLVHRDLAARNVLVKTPQHVKITDFGLAKLLGAEEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSYGVTVWELMTFGSKPYDGIPASEISSILEKGERLPQPPICTIDVYMIMVKCWMIDADSRPKFRELIIEFSKMARDPQRYLVIQGDERMHLPSPTDSNFYRALMDEEDMDDVVDADEYLIPQQGFFSSPSTSRTPLLSSLSATSNNSTVACIDRNGLQSCPIKEDSFLQRYSSDPTGALTEDSIDDTFLPVPEYINQSVPKRPAGSVQNPVYHNQPLNPAPSRDPHYQDPHSTAVGNPEYLNTVQPTCVNSTFDSPAHWAQKGSHQISLDNPDYQQDFFPKEAKPNGIFKGSTAENAEYLRVAPQSSEFIGA