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Protein

Epidermal growth factor receptor

Gene

Egfr

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses (PubMed:8404850). Known ligands include EGF, TGFA/TGF-alpha, AREG, 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 (By similarity). Plays a role in enhancing learning and memory performance (PubMed:20639532).By similarity3 Publications

Catalytic activityi

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.PROSITE-ProRule annotation

Enzyme regulationi

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.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei747ATPPROSITE-ProRule annotation1
Active sitei839Proton acceptorPROSITE-ProRule annotation1
Binding sitei857ATPPROSITE-ProRule annotation1
Sitei1018Important for interaction with PIK3C2BBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi720 – 728ATPPROSITE-ProRule annotation9
Nucleotide bindingi792 – 793ATPPROSITE-ProRule annotation2

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionDevelopmental protein, Kinase, Receptor, Transferase, Tyrosine-protein kinase
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.10.1 3474
ReactomeiR-MMU-1227986 Signaling by ERBB2
R-MMU-1236394 Signaling by ERBB4
R-MMU-1250196 SHC1 events in ERBB2 signaling
R-MMU-1257604 PIP3 activates AKT signaling
R-MMU-177929 Signaling by EGFR
R-MMU-179812 GRB2 events in EGFR signaling
R-MMU-180292 GAB1 signalosome
R-MMU-180336 SHC1 events in EGFR signaling
R-MMU-182971 EGFR downregulation
R-MMU-1963642 PI3K events in ERBB2 signaling
R-MMU-212718 EGFR interacts with phospholipase C-gamma
R-MMU-2179392 EGFR Transactivation by Gastrin
R-MMU-445144 Signal transduction by L1
R-MMU-5673001 RAF/MAP kinase cascade
R-MMU-6785631 ERBB2 Regulates Cell Motility
R-MMU-6811558 PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-MMU-8847993 ERBB2 Activates PTK6 Signaling
R-MMU-8856825 Cargo recognition for clathrin-mediated endocytosis
R-MMU-8856828 Clathrin-mediated endocytosis
R-MMU-8857538 PTK6 promotes HIF1A stabilization
R-MMU-8863795 Downregulation of ERBB2 signaling
R-MMU-9013507 NOTCH3 Activation and Transmission of Signal to the Nucleus

Names & Taxonomyi

Protein namesi
Recommended name:
Epidermal growth factor receptor (EC:2.7.10.1)
Gene namesi
Name:Egfr
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 11

Organism-specific databases

MGIiMGI:95294 Egfr

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini25 – 647ExtracellularSequence analysisAdd BLAST623
Transmembranei648 – 670HelicalSequence analysisAdd BLAST23
Topological domaini671 – 1210CytoplasmicSequence analysisAdd BLAST540

Keywords - Cellular componenti

Cell membrane, Endoplasmic reticulum, Endosome, Golgi apparatus, Membrane, Nucleus

Pathology & Biotechi

Disruption phenotypei

Mice are growth retarded and die at different stages of development depending on their genetic background. Embryonic death is due to placental defects. Mice surviving until birth or later display brain, bone, heart and various epithelial development defects in several organs, including skin, lung and gastrointestinal tract.3 Publications

Chemistry databases

ChEMBLiCHEMBL3608

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 24By similarityAdd BLAST24
ChainiPRO_000001666625 – 1210Epidermal growth factor receptorAdd BLAST1186

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi31 ↔ 58By similarity
Glycosylationi128N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi157 ↔ 187By similarity
Glycosylationi175N-linked (GlcNAc...) asparagine1 Publication1
Disulfide bondi190 ↔ 199By similarity
Disulfide bondi194 ↔ 207By similarity
Glycosylationi196N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi215 ↔ 223By similarity
Disulfide bondi219 ↔ 231By similarity
Modified residuei229PhosphoserineBy similarity1
Disulfide bondi232 ↔ 240By similarity
Disulfide bondi236 ↔ 248By similarity
Disulfide bondi251 ↔ 260By similarity
Disulfide bondi264 ↔ 291By similarity
Disulfide bondi295 ↔ 307By similarity
Disulfide bondi311 ↔ 326By similarity
Disulfide bondi329 ↔ 333By similarity
Disulfide bondi337 ↔ 362By similarity
Glycosylationi352N-linked (GlcNAc...) asparagine1 Publication1
Glycosylationi413N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi444N-linked (GlcNAc...) asparagine1 Publication1
Disulfide bondi470 ↔ 499By similarity
Disulfide bondi506 ↔ 515By similarity
Disulfide bondi510 ↔ 523By similarity
Disulfide bondi526 ↔ 535By similarity
Glycosylationi528N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi539 ↔ 555By similarity
Disulfide bondi558 ↔ 571By similarity
Disulfide bondi562 ↔ 579By similarity
Glycosylationi568N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi582 ↔ 591By similarity
Disulfide bondi595 ↔ 617By similarity
Glycosylationi603N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi620 ↔ 628By similarity
Glycosylationi623N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi624 ↔ 636By similarity
Modified residuei680Phosphothreonine; by PKC and PKD/PRKD1By similarity1
Modified residuei695Phosphothreonine; by PKD/PRKD1By similarity1
Modified residuei697PhosphoserineBy similarity1
Cross-linki718Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki739Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki756Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki869Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki931Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki972Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei993PhosphoserineBy similarity1
Modified residuei997PhosphoserineBy similarity1
Modified residuei1000Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei1018Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei1028PhosphoserineBy similarity1
Modified residuei1041PhosphoserineBy similarity1
Modified residuei1043PhosphothreonineBy similarity1
Modified residuei1044PhosphoserineBy similarity1
Lipidationi1051S-palmitoyl cysteineBy similarity1
Modified residuei1069PhosphotyrosineBy similarity1
Modified residuei1070PhosphoserineBy similarity1
Modified residuei1071PhosphoserineBy similarity1
Modified residuei1092Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei1110Phosphotyrosine; by autocatalysisBy similarity1
Lipidationi1146S-palmitoyl cysteineBy similarity1
Modified residuei1166PhosphoserineBy similarity1
Modified residuei1172Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei1197PhosphotyrosineCombined sources1
Modified residuei1199Omega-N-methylarginine; alternateBy similarity1
Modified residuei1199Omega-N-methylated arginine; alternateBy similarity1

Post-translational modificationi

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 occurs. Deubiquitinated by OTUD7B, preventing degradation (By similarity). Ubiquitinated by RNF115 and RNF126.By similarity1 Publication
Phosphorylated on Tyr residues in response to EGF. Phosphorylation at Ser-697 is partial and occurs only if Thr-695 is phosphorylated. Phosphorylation at Thr-680 and Thr-695 by PRKD1 inhibits EGF-induced MAPK8/JNK1 activation. Dephosphorylation by PTPRJ prevents endocytosis and stabilizes the receptor at the plasma membrane. Autophosphorylation at Tyr-1199 is stimulated by methylation at Arg-1199 and enhances interaction with PTPN6. Autophosphorylation at Tyr-1092 and/or Tyr-1110 recruits STAT3. Dephosphorylated by PTPN1 and PTPN2.By similarity
Palmitoylated on Cys residues by ZDHHC20. Palmitoylation inhibits internalization after ligand binding, and increases the persistence of tyrosine-phosphorylated EGFR at the cell membrane. Palmitoylation increases the amplitude and duration of EGFR signaling.By similarity
Methylated. Methylation at Arg-1199 by PRMT5 stimulates phosphorylation at Tyr-1197.By similarity

Keywords - PTMi

Disulfide bond, Glycoprotein, Isopeptide bond, Lipoprotein, Methylation, Palmitate, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ01279
PeptideAtlasiQ01279
PRIDEiQ01279

PTM databases

iPTMnetiQ01279
PhosphoSitePlusiQ01279
SwissPalmiQ01279

Expressioni

Gene expression databases

BgeeiENSMUSG00000020122
CleanExiMM_EGFR
ExpressionAtlasiQ01279 baseline and differential
GenevisibleiQ01279 MM

Interactioni

Subunit structurei

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, CBLB and CBLC; involved in EGFR ubiquitination and regulation. Interacts with SOCS5; regulates EGFR degradation through ELOC- and ELOB-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. Interacts (via SH2 domains) with GRB2, NCK1 and NCK2. Interacts with EPS8; mediates EPS8 phosphorylation. Interacts with ATX2. Interacts with GAREM1. Interacts (ubiquitinated) with ANKRD13A/B/D; the interaction is direct and may regulate EGFR internalization after EGF stimulation. Interacts with GPER1; the interaction occurs in an estrogen-dependent manner. Interacts (via C-terminal cytoplasmic kinase domain) with ZPR1 (via zinc fingers). Interacts with RNF115 and RNF126. Interacts with GPRC5A (via its transmembrane domain) (PubMed:25744720). Interacts with FAM83B; positively regulates EGFR inducing its autophosphorylation in absence of stimulation by EGF (By similarity). Interacts with LAPTM4B; positively correlates with EGFR activation (By similarity). Interacts with STX19 (PubMed:16420529).By similarity4 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

Protein-protein interaction databases

BioGridi199402, 26 interactors
CORUMiQ01279
DIPiDIP-5763N
IntActiQ01279, 17 interactors
MINTiQ01279
STRINGi10090.ENSMUSP00000020329

Chemistry databases

BindingDBiQ01279

Structurei

3D structure databases

ProteinModelPortaliQ01279
SMRiQ01279
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Repeati75 – 300ApproximateAdd BLAST226
Repeati390 – 600ApproximateAdd BLAST211
Domaini714 – 981Protein kinasePROSITE-ProRule annotationAdd BLAST268

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni690 – 706Important for dimerization, phosphorylation and activationBy similarityAdd BLAST17

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family. EGF receptor subfamily.PROSITE-ProRule annotation

Keywords - Domaini

Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG1025 Eukaryota
ENOG410XNSR LUCA
GeneTreeiENSGT00760000118799
HOGENOMiHOG000230982
HOVERGENiHBG000490
InParanoidiQ01279
KOiK04361
OMAiMRRRHIV
OrthoDBiEOG091G00NO
PhylomeDBiQ01279
TreeFamiTF106002

Family and domain databases

Gene3Di3.80.20.20, 2 hits
InterProiView protein in InterPro
IPR006211 Furin-like_Cys-rich_dom
IPR006212 Furin_repeat
IPR032778 GF_recep_IV
IPR009030 Growth_fac_rcpt_cys_sf
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR000494 Rcpt_L-dom
IPR036941 Rcpt_L-dom_sf
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
IPR008266 Tyr_kinase_AS
IPR020635 Tyr_kinase_cat_dom
IPR016245 Tyr_kinase_EGF/ERB/XmrK_rcpt
PfamiView protein in Pfam
PF00757 Furin-like, 1 hit
PF14843 GF_recep_IV, 1 hit
PF07714 Pkinase_Tyr, 1 hit
PF01030 Recep_L_domain, 2 hits
PIRSFiPIRSF000619 TyrPK_EGF-R, 1 hit
PRINTSiPR00109 TYRKINASE
SMARTiView protein in SMART
SM00261 FU, 4 hits
SM00219 TyrKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
SSF57184 SSF57184, 2 hits
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00109 PROTEIN_KINASE_TYR, 1 hit

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q01279-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MRPSGTARTT LLVLLTALCA AGGALEEKKV CQGTSNRLTQ LGTFEDHFLS
60 70 80 90 100
LQRMYNNCEV VLGNLEITYV QRNYDLSFLK TIQEVAGYVL IALNTVERIP
110 120 130 140 150
LENLQIIRGN ALYENTYALA ILSNYGTNRT GLRELPMRNL QEILIGAVRF
160 170 180 190 200
SNNPILCNMD TIQWRDIVQN VFMSNMSMDL QSHPSSCPKC DPSCPNGSCW
210 220 230 240 250
GGGEENCQKL TKIICAQQCS HRCRGRSPSD CCHNQCAAGC TGPRESDCLV
260 270 280 290 300
CQKFQDEATC KDTCPPLMLY NPTTYQMDVN PEGKYSFGAT CVKKCPRNYV
310 320 330 340 350
VTDHGSCVRA CGPDYYEVEE DGIRKCKKCD GPCRKVCNGI GIGEFKDTLS
360 370 380 390 400
INATNIKHFK YCTAISGDLH ILPVAFKGDS FTRTPPLDPR ELEILKTVKE
410 420 430 440 450
ITGFLLIQAW PDNWTDLHAF ENLEIIRGRT KQHGQFSLAV VGLNITSLGL
460 470 480 490 500
RSLKEISDGD VIISGNRNLC YANTINWKKL FGTPNQKTKI MNNRAEKDCK
510 520 530 540 550
AVNHVCNPLC SSEGCWGPEP RDCVSCQNVS RGRECVEKCN ILEGEPREFV
560 570 580 590 600
ENSECIQCHP ECLPQAMNIT CTGRGPDNCI QCAHYIDGPH CVKTCPAGIM
610 620 630 640 650
GENNTLVWKY ADANNVCHLC HANCTYGCAG PGLQGCEVWP SGPKIPSIAT
660 670 680 690 700
GIVGGLLFIV VVALGIGLFM RRRHIVRKRT LRRLLQEREL VEPLTPSGEA
710 720 730 740 750
PNQAHLRILK ETEFKKIKVL GSGAFGTVYK GLWIPEGEKV KIPVAIKELR
760 770 780 790 800
EATSPKANKE ILDEAYVMAS VDNPHVCRLL GICLTSTVQL ITQLMPYGCL
810 820 830 840 850
LDYVREHKDN IGSQYLLNWC VQIAKGMNYL EDRRLVHRDL AARNVLVKTP
860 870 880 890 900
QHVKITDFGL AKLLGAEEKE YHAEGGKVPI KWMALESILH RIYTHQSDVW
910 920 930 940 950
SYGVTVWELM TFGSKPYDGI PASDISSILE KGERLPQPPI CTIDVYMIMV
960 970 980 990 1000
KCWMIDADSR PKFRELILEF SKMARDPQRY LVIQGDERMH LPSPTDSNFY
1010 1020 1030 1040 1050
RALMDEEDME DVVDADEYLI PQQGFFNSPS TSRTPLLSSL SATSNNSTVA
1060 1070 1080 1090 1100
CINRNGSCRV KEDAFLQRYS SDPTGAVTED NIDDAFLPVP EYVNQSVPKR
1110 1120 1130 1140 1150
PAGSVQNPVY HNQPLHPAPG RDLHYQNPHS NAVGNPEYLN TAQPTCLSSG
1160 1170 1180 1190 1200
FNSPALWIQK GSHQMSLDNP DYQQDFFPKE TKPNGIFKGP TAENAEYLRV
1210
APPSSEFIGA
Length:1,210
Mass (Da):134,853
Last modified:February 1, 1996 - v1
Checksum:i690E20D46DF2D2F5
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti539C → W in CAA42219 (PubMed:2030916).Curated1
Sequence conflicti991L → F in AAA17899 (PubMed:8125255).Curated1
Sequence conflicti1116 – 1117HP → DR in CAA78249 (Ref. 6) Curated2

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X78987 mRNA Translation: CAA55587.1
U03425 mRNA Translation: AAA17899.1
X59698 mRNA Translation: CAA42219.1
L06864 mRNA Translation: AAA53029.1
Z12608 mRNA Translation: CAA78249.1
CCDSiCCDS24443.1
PIRiA53183
RefSeqiNP_997538.1, NM_207655.2
UniGeneiMm.420648
Mm.439882
Mm.8534

Genome annotation databases

EnsembliENSMUST00000020329; ENSMUSP00000020329; ENSMUSG00000020122
GeneIDi13649
KEGGimmu:13649
UCSCiuc007ibo.1 mouse

Similar proteinsi

Entry informationi

Entry nameiEGFR_MOUSE
AccessioniPrimary (citable) accession number: Q01279
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1996
Last sequence update: February 1, 1996
Last modified: July 18, 2018
This is version 208 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

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