Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

EGFR (P00533) - Overview - Molecular Target Synopsis

Protein


EGFR, Epidermal growth factor receptor
Enzyme Classification 2.7.10.1
UniProt P00533

Also Known as EGFR_HUMAN, EGFR, ERBB, ERBB1, HER1

Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses (PubMed:2790960, PubMed:10805725, PubMed:27153536). Known ligands include EGF, TGFA/TGF-alpha, AREG, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF (PubMed:2790960, PubMed:7679104, PubMed:8144591, PubMed:9419975, PubMed:15611079, PubMed:12297049, PubMed:27153536, PubMed:20837704). 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 (PubMed:27153536). May also activate the NF-kappa-B signaling cascade (PubMed:11116146). 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 (PubMed:11602604). Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin (PubMed:11483589). Plays a role in enhancing learning and memory performance (By similarity)., Isoform 2 may act as an antagonist of EGF action., (Microbial infection) Acts as a receptor for hepatitis C virus (HCV) in hepatocytes and facilitates its cell entry. Mediates HCV entry by promoting the formation of the CD81-CLDN1 receptor complexes that are essential for HCV entry and by enhancing membrane fusion of cells expressing HCV envelope glycoproteins. Binding of the ligand triggers homo- and/or heterodimerization of the receptor triggering its autophosphorylation. Heterodimer with ERBB2 (PubMed:10805725). Interacts with ERRFI1; inhibits dimerization of the kinase domain and autophosphorylation (PubMed:18046415). Part of a complex with ERBB2 and either PIK3C2A or PIK3C2B (PubMed:10805725). 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 (PubMed:17115032). 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 (PubMed:10026169). 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 (PubMed:23418353). Interacts with GPRC5A (via its transmembrane domain) (PubMed:25311788). Interacts with FAM83B; positively regulates EGFR inducing its autophosphorylation in absence of stimulation by EGF (PubMed:23912460). Interacts with LAPTM4B; positively correlates with EGFR activation (PubMed:28479384). Interacts with STX19 (PubMed:16420529). Interacts with CD44 (PubMed:23589287).

5ZTO
CRYSTAL STRUCTURE OF EGFR 696-1022 T790M/C797S IN COMPLEX WITH D3003
RCSB/PDB
Inspect Structure
See all 3D Structures for EGFR

Isoforms / Transcripts (Protein Coding)


Drugs


EGFR is targeted by Approved Drugs Panitumumab, Osimertinib, Lapatinib, Cetuximab, Erlotinib, Gefitinib, Afatinib, Vandetanib, Dacomitinib. (see details)
Panitumumab
Osimertinib
Lapatinib
Cetuximab
Erlotinib
Gefitinib
Afatinib
Vandetanib
Dacomitinib

Sub-cellular localization


Gene Copy Number Variation


In COSMIC - Cell Lines Project EGFR has gain in 33 cell-lines, loss in 0 cell-lines and no signal in 971 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: SN12C, OVCAR_5, NCI_H226

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: HCC827, MDA-MB-468, A-431

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: HMEC, SK-N-SH, NHLF

(see details)

RNA Interference


EGFR was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: JIMT1, ASPC1. (see details)

3D Structures


For EGFR there are:
185 structures (279 chains) solved
150 are solved in complex with at least one small molecule ligand
11 are solved with an approved drug

EGFR is solved in complex with the approved drug(s):

AQ4/ERLOTINIB (1M17_A, 4HJO_A),
FMM/LAPATINIB (1XKK_A),
IRE/GEFITINIB (2ITO_A, 2ITY_A, 2ITZ_A, 3UG2_A, 4I22_A, 4WKQ_A),
YY3/OSIMERTINIB (4ZAU_A),
0WM/AFATINIB (4G5J_A).

(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


EGFR has been screened with 11596 compounds (24683 bioactivities), 4334 compounds have bioactivities that show binding affinity of <= 500nM (7255 bioactivities). (see details)