Affinage

EGFR

Epidermal growth factor receptor · UniProt P00533

Round 2 corrected
Length
1210 aa
Mass
134.3 kDa
Annotated
2026-04-28
130 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EGFR is a transmembrane receptor tyrosine kinase that, upon binding EGF-family ligands, undergoes homo- or heterodimerization—preferentially with ErbB2—through defined extracellular and transmembrane domain interfaces, triggering asymmetric kinase domain activation and trans-autophosphorylation of cytoplasmic tail tyrosines that recruit adaptors including GRB2, Shc, STAT5, and PI3K to activate RAS/MAPK, PI3K/Akt, and STAT signaling cascades (PMID:6328312, PMID:1322798, PMID:9130710, PMID:16729043). Receptor activity is regulated at multiple levels: DHHC20-mediated palmitoylation of C-terminal tail cysteines pins the tail to the membrane and suppresses activation; cytohesin-dependent conformational rearrangements of the intracellular domain promote activation; and endocytic trafficking—governed by Cbl-mediated ubiquitination, deubiquitination by UBPY and USP22, FBXL2-directed proteasomal degradation counteracted by Grp94, and accessory proteins ARAP1 and MUC1—determines signal duration and receptor fate (PMID:27153536, PMID:20946980, PMID:8649804, PMID:17121848, PMID:34635651, PMID:18939958). In the unliganded state, EGFR assembles into autoinhibited head-to-head oligomeric chains at the plasma membrane that are disrupted by ligand binding to form signaling-competent stalk-to-stalk dimers with asymmetric kinase configurations (PMID:30337523). Oncogenic kinase domain mutations (exon-19 deletions, L858R) constitutively enhance kinase activity and selectively drive Akt/STAT survival signaling, while secondary mutations (T790M, C797S) confer resistance to successive generations of tyrosine kinase inhibitors (PMID:15118073, PMID:15284455, PMID:15728811, PMID:25939061).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1984 High

    Determination of the complete EGFR primary structure established its domain architecture—an extracellular ligand-binding domain, a single transmembrane helix, and a cytoplasmic tyrosine kinase domain—and its relationship to the v-erb-B oncogene, providing the molecular framework for all subsequent mechanistic work.

    Evidence cDNA cloning and sequencing from human A431 cells

    PMID:6328312

    Open questions at the time
    • No information on ligand-induced conformational change
    • Kinase activation mechanism unknown
    • Dimerization not yet described
  2. 1992 High

    Identification of GRB2 as an SH2-domain adaptor that links phosphorylated EGFR to Ras answered how receptor tyrosine phosphorylation is coupled to downstream mitogenic signaling.

    Evidence Co-immunoprecipitation of GRB2 with EGFR plus microinjection/DNA synthesis assays in quiescent fibroblasts

    PMID:1322798

    Open questions at the time
    • Full spectrum of EGFR phosphotyrosine-binding partners unknown
    • Quantitative stoichiometry of GRB2-EGFR interaction not determined
  3. 1997 High

    Systematic analysis of ErbB heterodimerization hierarchies revealed ErbB2 as the preferred partner for all family members, explaining how lateral signal diversification occurs and why ErbB2-containing heterodimers generate the most potent signals.

    Evidence Intracellular antibody-mediated receptor knockdown with co-IP across multiple ligand-receptor combinations

    PMID:9130710 PMID:9710588

    Open questions at the time
    • Structural basis of heterodimerization preference not resolved
    • Quantitative contribution of each heterodimer to downstream pathway output unclear
  4. 2000 High

    Real-time FRET-FLIM imaging demonstrated that EGFR phosphorylation propagates laterally across the entire plasma membrane from a focal point of ligand contact, revealing a signal amplification mechanism beyond simple receptor-ligand stoichiometry.

    Evidence Quantitative FRET-FLIM of ErbB1-GFP with EGF-coated bead stimulation in live cells

    PMID:11090353

    Open questions at the time
    • Molecular mechanism of lateral propagation (diffusion vs. kinase relay) unresolved
    • Relevance in tissues with lower receptor density not established
  5. 2004 High

    Discovery that somatic EGFR kinase domain mutations (exon-19 deletions, L858R) confer constitutive kinase activity and gefitinib sensitivity in NSCLC established the paradigm of oncogene addiction and selective pathway activation (Akt/STAT but not ERK), transforming lung cancer therapeutics.

    Evidence Tumor sequencing, in vitro kinase assays of mutant EGFR, siRNA knockdown with pathway-specific readouts and apoptosis assays

    PMID:15118073 PMID:15284455 PMID:15329413

    Open questions at the time
    • Structural explanation for selective Akt/STAT vs. ERK activation not provided
    • Heterogeneity of mutation-specific kinase activity incompletely characterized
  6. 2005 High

    Identification of the T790M gatekeeper mutation as the basis for acquired resistance to first-generation EGFR inhibitors defined the structural constraint (steric occlusion of the drug-binding pocket while preserving ATP binding) that guided development of next-generation inhibitors.

    Evidence Sequencing of resistant tumor biopsies, structural modeling, biochemical inhibition assays

    PMID:15728811

    Open questions at the time
    • Additional resistance mechanisms (e.g. MET amplification, later identified) not captured
    • Kinetic parameters of T790M-EGFR for ATP vs. inhibitor not fully determined
  7. 2006 High

    Unbiased phosphotyrosine interactome mapping of all four ErbB receptors resolved the full complement of direct adaptor-docking sites, identifying STAT5 as a direct EGFR interactor and revealing receptor-specific adaptor recruitment codes that explain signaling diversity among family members.

    Evidence SILAC-based quantitative proteomics with synthetic phosphopeptides corresponding to all cytoplasmic tyrosines

    PMID:16729043

    Open questions at the time
    • In vivo validation of all identified interactions not performed
    • Dynamics of adaptor competition at individual phosphosites uncharacterized
  8. 2006 Medium

    Characterization of EGFR ubiquitination-trafficking regulation—Cbl-mediated ubiquitination driving lysosomal degradation, counteracted by deubiquitinases UBPY and USP22 that promote recycling, and MUC1-mediated protection from ubiquitination—established endocytic trafficking as a central node controlling signal duration and receptor fate.

    Evidence Co-IP, ubiquitination assays, dominant-negative constructs, RNAi, receptor degradation/recycling kinetics across multiple studies

    PMID:16983337 PMID:17121848 PMID:18939958 PMID:29981430 PMID:8649804

    Open questions at the time
    • Relative quantitative contributions of UBPY vs. USP22 to total EGFR deubiquitination unknown
    • Spatial regulation of ubiquitination at different endosomal compartments incompletely mapped
  9. 2010 High

    NMR determination of the ErbB1/ErbB2 transmembrane heterodimer structure in lipid bicelles revealed the GG4-like and glycine-zipper motifs mediating the highest-affinity heterodimer interface, providing the first atomic-resolution view of how transmembrane helix interactions specify dimerization partner preference.

    Evidence Solution NMR in lipid bicelles

    PMID:20471394

    Open questions at the time
    • Structure of full-length active dimer spanning extracellular, TM, and intracellular domains not available
    • Homodimer TM interface not comparably resolved at atomic detail
  10. 2010 High

    Discovery that cytohesins are required for EGFR autophosphorylation—facilitating conformational rearrangements within intracellular domains of dimerized receptors—identified a new positive regulatory step between dimerization and kinase activation.

    Evidence Cell-free reconstitution plus FRET anisotropy microscopy in live cells with pharmacological cytohesin inhibition

    PMID:20946980

    Open questions at the time
    • Structural basis of cytohesin–EGFR intracellular domain interaction unresolved
    • Whether cytohesins act catalytically or stoichiometrically unclear
  11. 2015 High

    Identification of the C797S mutation as the mechanism of resistance to third-generation covalent EGFR inhibitors (osimertinib) completed the resistance mutation cascade (L858R → T790M → C797S), delineating the structural constraints that limit successive generations of targeted therapy.

    Evidence Cell-free plasma DNA sequencing, droplet digital PCR, cell line expression of C797S mutant with drug sensitivity assays

    PMID:25939061

    Open questions at the time
    • Therapeutic strategies to overcome triple-mutant EGFR not yet established at time of discovery
    • Whether C797S alters intrinsic kinase activity beyond drug binding unknown
  12. 2016 High

    Discovery that DHHC20-mediated palmitoylation of EGFR C-terminal cysteines pins the tail to the membrane and suppresses receptor activation revealed a lipid-modification-based autoinhibitory mechanism, explaining how post-translational modification independent of phosphorylation gates EGFR signaling.

    Evidence Mass spectrometry identification of palmitoylation sites, site-directed mutagenesis, DHHC20 knockdown, cell migration and transformation assays

    PMID:27153536

    Open questions at the time
    • Dynamics of palmitoylation turnover relative to ligand stimulation not quantified
    • Whether other palmitoyltransferases compensate for DHHC20 loss not tested
  13. 2018 High

    Super-resolution imaging revealed that unliganded EGFR assembles into head-to-head autoinhibited polymer chains at the plasma membrane, which ligand binding or activating mutations disrupt to form signaling-competent stalk-to-stalk dimers, fundamentally revising the model of ligand-induced activation from simple monomer-to-dimer transition to polymer disassembly.

    Evidence Multiple super-resolution modalities, single-particle tracking, FRET, molecular dynamics simulations

    PMID:30337523

    Open questions at the time
    • Stoichiometry and length distribution of autoinhibited oligomers in native tissue unknown
    • How oligomer disassembly is coordinated with cytohesin-mediated activation unclear
  14. 2021 High

    Identification of the FBXL2-Grp94 axis controlling EGFR proteasomal degradation—where FBXL2 targets EGFR (including TKI-resistant mutants) for ubiquitin-proteasome degradation and Grp94 competitively blocks FBXL2 binding—revealed a proteasomal quality-control layer distinct from lysosomal degradation.

    Evidence Co-IP, ubiquitination assays, proteasome inhibition, shRNA knockdown, xenograft models

    PMID:34635651

    Open questions at the time
    • Whether FBXL2 targets EGFR co-translationally or post-surface internalization not determined
    • Interplay between FBXL2-mediated proteasomal and Cbl-mediated lysosomal degradation pathways not characterized
  15. 2022 High

    Demonstration that constitutive versus ligand-activated EGFR drive opposing phenotypes in glioblastoma (invasion via TAB1-TAK1-NF-κB vs. proliferation with invasion suppression via BIN3-DOCK7) revealed that ligand availability switches EGFR from oncogenic to tumor-suppressive behavior, resolving a longstanding paradox of EGFR function in brain tumors.

    Evidence Genetic epistasis (knockdown/overexpression of pathway intermediates), orthotopic GBM models, TCGA correlation

    PMID:35915159

    Open questions at the time
    • Whether ligand-dependent pathway switching occurs in non-GBM EGFR-driven cancers unknown
    • Mechanism by which ligand-free EGFR selectively activates TAB1-TAK1 not structurally resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple layers of EGFR regulation—oligomeric autoinhibition, palmitoylation, cytohesin-mediated activation, endocytic trafficking, and proteasomal degradation—are spatiotemporally coordinated in vivo to produce quantitatively distinct signaling outputs remains unresolved.
  • Integrated quantitative model linking oligomer state, palmitoylation, cytohesin binding, and endocytic sorting not available
  • Full-length active EGFR dimer structure spanning all domains not yet determined
  • In vivo tissue-level regulation of EGFR oligomeric state uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016740 transferase activity 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 6 GO:0005768 endosome 3 GO:0005576 extracellular region 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1643685 Disease 5 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-5357801 Programmed Cell Death 1
Partners
ARAP1CBLDHHC20ERBB2FBXL2GRB2USP22USP8
Complex memberships
EGFR homodimerEGFR-ErbB2 heterodimer

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1984 The complete 1,210-amino acid sequence of the human EGFR precursor was determined from cDNA clones, revealing a single transmembrane domain of 23 amino acids separating an extracellular EGF-binding domain from a cytoplasmic tyrosine kinase domain, with close similarity between the cytoplasmic/transmembrane domains and the v-erb-B oncogene product; the EGFR gene is amplified and rearranged in A431 cells, generating a truncated 2.8-kb mRNA encoding only the extracellular domain. cDNA cloning and sequencing, Northern blot, molecular biology Nature High 6328312
1992 GRB2, a protein containing one SH2 and two SH3 domains, links activated EGFR (and PDGFR) to Ras signaling; GRB2 associates with tyrosine-phosphorylated EGFR via its SH2 domain, and microinjection of GRB2 together with H-Ras stimulates DNA synthesis in quiescent fibroblasts, establishing GRB2 as a key adaptor coupling EGFR to the Ras/MAPK pathway. Immunoblotting/co-immunoprecipitation, microinjection, functional DNA synthesis assay Cell High 1322798
1996 c-Cbl couples specifically to ligand-activated ErbB1/EGFR but not to ErbB2, ErbB3, or ErbB4; EGF stimulation induces rapid and sustained tyrosine phosphorylation of c-Cbl in fibroblasts and epithelial cells, and in vitro experiments indicate the interaction is indirect, mediated by the constitutively Cbl-bound adaptor Grb2. Co-immunoprecipitation, Western blot, in vitro binding assays Oncogene Medium 8649804
1997 ErbB2 is the preferred heterodimerization partner for all ErbB receptors; ligand-induced ErbB receptor heterodimerization follows a strict hierarchy, with ErbB2 dominant over other partners. NDF-activated ErbB3/4 only heterodimerize with ErbB1 when ErbB2 is absent. EGF- and BTC-induced ErbB3 activation is impaired without ErbB2, demonstrating that ErbB2 mediates lateral signal transmission. ErbB1 activated by all EGF-related peptides couples to Shc, but only EGF/HB-EGF-activated ErbB1 associates with and phosphorylates Cbl. Intracellular antibody-mediated receptor down-regulation, co-immunoprecipitation, Western blot The EMBO journal High 9130710
1998 ErbB1 and ErbB2 acquire distinct signaling properties depending on their dimerization partner: EGF-activated ErbB1 interacts with Grb2, whereas NDF-activated ErbB1 (heterodimerized with ErbB4) does not; EGF-activated ErbB1 shows rapid internalization while NDF-transactivated ErbB1 shows delayed internalization; differential tryptic phosphopeptide mapping showed that receptor phosphorylation patterns depend on the dimerization partner. Co-immunoprecipitation, phosphopeptide mapping, internalization assays, pairwise receptor expression in NIH 3T3 cells Molecular and cellular biology High 9710588
2000 Ligand-independent lateral propagation of EGFR (ErbB1) phosphorylation occurs across the plasma membrane: focal stimulation of ErbB1-GFP with EGF-coated beads leads to rapid and extensive phosphorylation wave spreading over the entire cell, demonstrated by quantitative FRET-FLIM imaging. Quantitative FRET-FLIM imaging of ErbB1-GFP in live cells with focal EGF-bead stimulation Science High 11090353
2003 Ligand-activated EGFR undergoes accelerated internalization and enhanced lysosomal targeting (compared to constitutive slow recycling in unstimulated state); altered trafficking is mediated by motifs in the cytoplasmic domain exposed by activation-induced conformational changes and Grb2 binding; most EGFR signaling occurs within endosomes, unlike other ErbB family members which signal predominantly from the cell surface. Receptor trafficking assays, internalization/degradation kinetics, co-immunoprecipitation Experimental cell research Medium 12648467
2004 Somatic mutations in the EGFR tyrosine kinase domain (small in-frame deletions or amino acid substitutions around the ATP-binding pocket, e.g., exon-19 deletions and L858R) are found specifically in gefitinib-responsive NSCLC; in vitro, EGFR mutants show enhanced tyrosine kinase activity in response to EGF and increased sensitivity to gefitinib inhibition compared to wild-type EGFR. DNA sequencing of tumor specimens, in vitro kinase activity assay, cell culture transfection studies The New England journal of medicine High 15118073
2004 EGFR somatic mutations in the tyrosine kinase domain correlate with gefitinib sensitivity; an exon-19 deletion mutant showed diminished overall phosphotyrosine levels compared to wild-type, whereas an exon-21 L858R mutant was inhibited at 10-fold lower drug concentrations, demonstrating mechanistically distinct mutant behaviors. EGFR gene sequencing of tumor samples, immunoblotting of transiently transfected cell lysates, drug inhibition assays Proceedings of the National Academy of Sciences of the United States of America High 15329413
2004 Gefitinib-sensitizing EGFR kinase domain mutations selectively activate Akt and STAT signaling pathways (promoting cell survival) but do not activate ERK (proliferative signaling); NSCLC cells with mutant EGFR undergo extensive apoptosis upon siRNA knockdown of mutant EGFR or pharmacological Akt/STAT inhibition, demonstrating addiction to EGFR-driven survival signaling. siRNA knockdown, pharmacological inhibition, phospho-specific Western blot, apoptosis assays Science High 15284455
2005 A secondary EGFR T790M mutation (threonine-to-methionine at position 790, the gatekeeper residue) is acquired in gefitinib-resistant NSCLC; structural modeling and biochemical studies showed this mutation causes steric hindrance of gefitinib binding while preserving ATP binding, thus conferring drug resistance. DNA sequencing of resistant tumor biopsy, structural modeling, biochemical inhibition assays The New England journal of medicine High 15728811
2005 Unbiased phosphotyrosine interactome mapping of all four ErbB receptors revealed characteristic interaction preferences: EGFR and ErbB4 each have multiple Grb2 docking sites; ErbB3 has six PI3K-binding sites; STAT5 was identified as a direct binding partner of both EGFR and ErbB4; new recognition motifs for Shc and STAT5 were discovered. Phosphorylation kinetics of specific tyrosine residues correlated with interaction partner preference. Quantitative proteomics using SILAC pull-downs with phosphorylated/non-phosphorylated synthetic peptides corresponding to all cytosolic tyrosine residues; mass spectrometry Molecular systems biology High 16729043
2006 UBPY (Usp8) constitutively co-precipitates with EGFR in a bivalent manner and is a substrate of Src-family kinases activated after EGF-induced EGFR activation; dominant-negative UBPY mutants demonstrate that UBPY-mediated deubiquitination promotes (rather than prevents) EGFR degradation, affecting constitutive and ligand-induced EGFR ubiquitination, expression levels, and downstream MAPK signaling. Co-immunoprecipitation, dominant-negative UBPY mutant overexpression, Western blot for ubiquitination and EGFR levels, MAPK signaling assays The Journal of biological chemistry Medium 17121848
2008 Cytohesins (cytoplasmic GEF-family proteins) are required for ErbB receptor autophosphorylation and signaling; cytohesin inhibition decreased EGFR autophosphorylation, while cytohesin overexpression stimulated receptor activation; cell-free reconstitution and anisotropy FRET microscopy showed cytohesins facilitate conformational rearrangements in intracellular domains of dimerized receptors. Cell-free reconstitution of cytohesin-dependent EGFR autophosphorylation, FRET anisotropy microscopy, pharmacological cytohesin inhibition, overexpression studies Cell High 20946980
2008 ARAP1, an Arf-GAP and Rho-GAP domain protein, transiently associates with EGFR-containing early endocytic puncta (Rab5-positive but EEA1-negative) following EGF treatment; ARAP1 depletion by siRNA accelerated EGFR association with EEA1 endosomes, accelerated EGFR degradation, and produced diminished and more transient ERK and JNK phosphorylation, establishing ARAP1 as a regulator of EGFR endocytic traffic and signal attenuation. siRNA knockdown, fluorescence microscopy, co-localization with endosomal markers, Western blot for signaling and degradation kinetics Traffic Medium 18939958
2008 EGFRvIII (truncated oncogenic EGFR) expressed in glioma cells stimulates formation of lipid-raft-related microvesicles containing EGFRvIII; these microvesicles are released into the extracellular milieu and transfer EGFRvIII to glioma cells lacking it, activating MAPK and Akt signaling, inducing EGFRvIII-regulated gene expression changes (VEGF, Bcl-xL, p27), and increasing anchorage-independent growth. Microvesicle isolation and characterization, receptor transfer assays, Western blot for signaling activation, anchorage-independent growth assay Nature cell biology High 18425114
2010 Spatial NMR structure of the ErbB1/ErbB2 transmembrane domain heterodimer embedded in lipid bicelles shows the two TM helices associate in a right-handed alpha-helical bundle through N-terminal double GG4-like motifs (T648G649X2G652A653 in ErbB1) and a glycine zipper motif (T652X3S656X3G660 in ErbB2); this heterodimer conformation is believed to correspond to the receptor active state and the multiple polar interactions explain the highest affinity of the ErbB1/ErbB2 heterodimer. Solution NMR in lipid bicelles Journal of molecular biology High 20471394
2011 Two-color quantum-dot single-particle tracking showed that ErbB1 dimerization is promoted by transient co-confinement of receptors in membrane domains; dimers composed of two ligand-bound receptors are long-lived (k_off >4-fold slower than unliganded dimers); kinase activity and intact actin networks are required for reduced mobility of signaling-competent ErbB1 dimers; blockade of kinase activity or actin disruption results in faster receptor dimer diffusion. Two-color quantum-dot single-particle tracking in live cells, hidden Markov model analysis, pharmacological kinase inhibition, actin disruption Nature structural & molecular biology High 22020299
2015 Acquired EGFR C797S mutation (cysteine-to-serine at position 797) mediates resistance to the third-generation irreversible inhibitor AZD9291 (osimertinib); the serine residue at position 797 is unable to form the covalent adduct with the drug that the cysteine normally forms, abolishing drug binding and conferring resistance. Cell-free plasma DNA next-generation sequencing, droplet digital PCR of serial cfDNA specimens, cell line expression of C797S mutant EGFR with drug resistance assay Nature medicine High 25939061
2016 EGFR is palmitoylated on cysteine residues within its unstructured C-terminal tail by the palmitoyltransferase DHHC20; palmitoylation 'pins' the C-terminal tail to the plasma membrane, impeding EGFR activation; mutation of the palmitoylated cysteines to alanine is sufficient to activate EGFR signaling and promote cell migration and transformation; loss of DHHC20-mediated palmitoylation increases sustained EGFR activation. Mass spectrometry identification of palmitoylated cysteines, site-directed mutagenesis, DHHC20 knockdown/inhibition, cell migration and transformation assays Molecular cell High 27153536
2018 EGFR assembles in head-to-head autoinhibited polymer chains at the plasma membrane in the absence of ligand; ligand binding or activating mutations split these autoinhibited polymers to form stalk-to-stalk dimers coupled to active asymmetric tyrosine kinase dimers; extended dimers couple to inactive symmetric kinase dimers; dysregulated (mutant/overexpressed) species maintain coexisting symmetric and asymmetric kinase dimer populations at the plasma membrane. Multiple super-resolution imaging modalities, single-particle tracking, FRET, molecular dynamics simulations Nature communications High 30337523
2021 F-box protein FBXL2 targets EGFR and EGFR TKI-resistant mutants for proteasome-mediated degradation; Grp94 (glucose-regulated protein 94) protects EGFR from FBXL2-mediated degradation by blocking FBXL2 binding to EGFR; the FBXL2-Grp94-EGFR axis controls EGFR protein stability in NSCLC. Co-immunoprecipitation, ubiquitination assays, proteasome inhibition, shRNA/siRNA knockdown, xenograft in vivo models Nature communications High 34635651
2022 In EGFR-amplified glioblastoma, constitutive (ligand-independent) EGFR signaling promotes invasion via a TAB1-TAK1-NF-κB-EMP1 pathway; ligand-activated EGFR surprisingly suppresses invasion by upregulating BIN3, which inhibits DOCK7-regulated Rho GTPase signaling, while promoting proliferation; thus EGFR ligand levels determine whether EGFR acts as oncogene (invasion-promoting) or tumor suppressor (proliferation-promoting, invasion-suppressing). Genetic knockdown/overexpression, pathway inhibition, orthotopic glioblastoma models, TCGA data correlation Nature cell biology High 35915159
2006 MUC1 inhibits ligand-induced ErbB1 degradation and promotes ErbB1 recycling over lysosomal degradation; MUC1 expression decreases EGF-stimulated ubiquitination of ErbB1, protecting surface ErbB1 pools from degradation while increasing its internalization and recycling. RNAi knockdown and overexpression, surface biotinylation, ubiquitination assays, receptor degradation kinetics Oncogene Medium 16983337
2011 Nucleolin simultaneously interacts in vivo with endogenous Ras and ErbB1 (EGFR) in cancer cells; the C-terminal 212 amino acids of nucleolin are sufficient for binding both ErbB1 and all Ras isoforms; activated (mutant) Ras facilitates nucleolin interaction with ErbB1 and stabilizes ErbB1 receptor levels; these three oncogenes synergistically promote anchorage-independent growth in vitro and tumor growth in vivo. Co-immunoprecipitation of endogenous proteins, deletion mapping, cell transformation assays, xenograft in vivo Cancer research Medium 21257709
2007 MET amplification is a mechanism of acquired resistance to gefitinib/erlotinib in EGFR-mutant NSCLC, occurring in ~21% of resistant tumors independently of EGFR T790M; resistant cell lines harboring MET amplification alongside EGFR mutations are insensitive to EGFR inhibitors but sensitive to MET inhibition (XL880), demonstrating MET as a bypass activator of downstream signaling. Array CGH, FISH for MET amplification, cell viability with targeted inhibitors, analysis of multiple patient cohorts Proceedings of the National Academy of Sciences of the United States of America High 18093943
2013 DYRK1A kinase controls EGFR stability in GBM cells; DYRK1A inhibition promotes EGFR degradation in primary GBM cell lines and neural progenitor cells, sharply reducing self-renewal capacity; a subset of GBMs depends on high surface EGFR levels for survival, as DYRK1A inhibition compromises their viability. DYRK1A knockdown/pharmacological inhibition, EGFR surface expression and degradation assays, neurosphere self-renewal assays, in vivo tumor burden measurement The Journal of clinical investigation Medium 23635774
2018 USP22 deubiquitinates EGFR localized on late endosomes, preventing ubiquitination-mediated EGFR degradation and enhancing EGFR recycling after EGF stimulation; USP22 silencing sensitizes EGFR-mutant lung cancer cells to EGFR-TKIs both in vitro and in vivo. Co-immunoprecipitation, ubiquitination assays, receptor trafficking/recycling assays, siRNA knockdown, xenograft models Cancer letters Medium 29981430
2020 HIF-2A promotes transcription-independent induction of EGFR (ERBB1) protein during hypoxia/ischemia through RNA-binding protein 4; myocyte-specific HIF-2A or ERBB1 knockout mice show larger myocardial infarct sizes and cannot be rescued by amphiregulin treatment, demonstrating that HIF-2A-dependent EGFR induction provides cardioprotection during ischemia-reperfusion. shRNA knockdown, conditional cardiac-specific knockout mice, infarct size measurement, immunoblotting Anesthesiology Medium 31794514

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. The New England journal of medicine 9300 15118073
2004 EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science (New York, N.Y.) 7948 15118125
2009 Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. The New England journal of medicine 6906 19692680
2010 Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer cell 5824 20129251
2001 Untangling the ErbB signalling network. Nature reviews. Molecular cell biology 5489 11252954
2010 Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. The New England journal of medicine 4652 20573926
2012 Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. The Lancet. Oncology 4586 22285168
2004 EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proceedings of the National Academy of Sciences of the United States of America 3572 15329413
2009 Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. The Lancet. Oncology 3483 20022809
2002 The human plasma proteome: history, character, and diagnostic prospects. Molecular & cellular proteomics : MCP 3407 12488461
2005 EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. The New England journal of medicine 3342 15728811
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
1984 Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature 2605 6328312
2013 Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clinical cancer research : an official journal of the American Association for Cancer Research 2076 23470965
2005 Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. Journal of the National Cancer Institute 2027 15741570
1995 Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. The Journal of biological chemistry 2014 7535770
2009 Screening for epidermal growth factor receptor mutations in lung cancer. The New England journal of medicine 1988 19692684
1995 Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 1763 7543024
2015 AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. The New England journal of medicine 1750 25923549
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2014 Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. The Lancet. Oncology 1691 24439929
2008 Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nature cell biology 1603 18425114
2009 Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1566 19667264
1992 The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell 1557 1322798
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2007 MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proceedings of the National Academy of Sciences of the United States of America 1417 18093943
2004 Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science (New York, N.Y.) 1364 15284455
2005 Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. Journal of the National Cancer Institute 1325 15870435
1987 Receptors for epidermal growth factor and other polypeptide mitogens. Annual review of biochemistry 1296 3039909
2015 Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. The Lancet. Oncology 1295 25589191
2015 Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nature medicine 1287 25939061
1997 ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. The EMBO journal 1270 9130710
2003 The ErbB receptors and their role in cancer progression. Experimental cell research 493 12648469
2005 Phosphotyrosine interactome of the ErbB-receptor kinase family. Molecular systems biology 419 16729043
1997 Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials. Annals of oncology : official journal of the European Society for Medical Oncology 413 9496384
2020 Review on Epidermal Growth Factor Receptor (EGFR) Structure, Signaling Pathways, Interactions, and Recent Updates of EGFR Inhibitors. Current topics in medicinal chemistry 409 32124699
2018 Small molecule inhibitors targeting the EGFR/ErbB family of protein-tyrosine kinases in human cancers. Pharmacological research 371 30500458
2017 ErbB Receptors and Cancer. Methods in molecular biology (Clifton, N.J.) 343 28791631
2002 Modulation of p53, ErbB1, ErbB2, and Raf-1 expression in lung cancer cells by depsipeptide FR901228. Journal of the National Cancer Institute 336 11929951
1999 Binding specificities and affinities of egf domains for ErbB receptors. FEBS letters 317 10214951
2004 Signal transduction and oncogenesis by ErbB/HER receptors. International journal of radiation oncology, biology, physics 304 14967450
2006 ErbB receptors: new insights on mechanisms and biology. Trends in cell biology 289 17085050
2003 Trafficking of the ErbB receptors and its influence on signaling. Experimental cell research 289 12648467
2000 Quantitative imaging of lateral ErbB1 receptor signal propagation in the plasma membrane. Science (New York, N.Y.) 278 11090353
2001 The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer. Cancer research 260 11585755
2021 Antitumour immunity regulated by aberrant ERBB family signalling. Nature reviews. Cancer 224 33462501
2007 The neuregulin-I/ErbB signaling system in development and disease. Advances in anatomy, embryology, and cell biology 221 17432114
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