Affinage

EGF

Pro-epidermal growth factor · UniProt P01133

Round 2 corrected
Length
1207 aa
Mass
134.0 kDa
Annotated
2026-04-28
130 papers in source corpus 54 papers cited in narrative 54 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EGF is a mitogenic polypeptide derived by proteolytic processing from a 1,207-amino-acid transmembrane precursor; it binds EGFR extracellular domains I and III, releasing an autoinhibited tethered conformation and exposing a domain II β-hairpin dimerization arm that drives receptor-mediated dimerization and asymmetric kinase activation via intermolecular transphosphorylation (PMID:12297050, PMID:12620237, PMID:2164634). Receptor C-tail phosphotyrosines recruit SH2-domain adaptors (PLCγ, PI3K p85, Shc/Grb2, Gab1, SHP2) to activate Ras/MAPK, PI3K/Akt, and PLCγ/Ca²⁺ cascades, with signal duration—controlled by ligand identity, dimer stability, and receptor trafficking through clathrin-mediated endocytosis (via Cbl–CIN85–endophilin and Tom1L1) and recycling (via CAML)—determining whether EGF elicits proliferative or differentiative outcomes (PMID:2472218, PMID:1372091, PMID:10648629, PMID:7953555, PMID:11894095, PMID:19798056, PMID:28988771). Membrane lipid environment (GM3 ganglioside inhibits the allosteric kinase transition) and scaffold proteins (IQGAP1) modulate activation thresholds, while nuclear-translocated EGFR cooperates with STAT3 to drive iNOS transcription and EGF-activated Rsk-2 phosphorylates histone H3 to remodel chromatin (PMID:21571640, PMID:21349850, PMID:15950906, PMID:10436156). EGF is stored in platelets and released during coagulation, and its precursor is expressed as a cell-surface transmembrane protein whose biology is co-opted by GPCR transactivation pathways involving metalloproteinase-mediated shedding of HB-EGF (PMID:6603475, PMID:11786904, PMID:9020193).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1980 High

    Establishing that EGF acts across the membrane resolved the fundamental topology question—EGF binds extracellularly while its receptor's kinase phosphorylates substrates cytoplasmically, defining EGFR as a transmembrane signaling conduit.

    Evidence Controlled proteolysis of intact vs. permeabilized cells with ³²P-ATP labeling

    PMID:6264233

    Open questions at the time
    • Mechanism of transmembrane signal transduction unknown
    • Identity of kinase substrates unresolved
  2. 1983 High

    Discovery that platelets store both mature EGF and a high-molecular-weight precursor form revealed a physiological reservoir for circulating EGF and implied regulated proteolytic processing of the precursor.

    Evidence Immunoaffinity chromatography and radioimmunoassay of platelet-rich vs. platelet-poor plasma fractions

    PMID:6603475

    Open questions at the time
    • Protease responsible for precursor cleavage in vivo not identified
    • Physiological significance of platelet-derived EGF release in wound healing not directly tested
  3. 1986 High

    Sequencing the full 1,207-residue EGF precursor and demonstrating its endosomal trafficking with EGFR established the biosynthetic origin and the post-binding itinerary of the ligand–receptor complex.

    Evidence cDNA sequencing with COS-7 expression (precursor structure); immunoelectron microscopy with HRP-EGF (endosomal co-localization)

    PMID:2868013 PMID:3491360

    Open questions at the time
    • Proteolytic mechanism releasing 53-aa mature EGF from the precursor not identified
    • Signals controlling endosome-to-lysosome sorting not defined
  4. 1987 High

    Demonstrating that EGFR overexpression confers EGF-dependent transformation and that EGF activates phosphoinositide hydrolysis linked the ligand to both oncogenic potential and second-messenger generation.

    Evidence NIH 3T3 focus formation and soft-agar assays with EGFR overexpression; radiolabeled inositol phosphate measurement in multiple cell lines

    PMID:3030297 PMID:3500791

    Open questions at the time
    • Downstream effectors of IP3/DAG pathway not mapped
    • Whether transformation requires specific signaling branches unknown
  5. 1989 High

    Identification of PLCγ as a direct EGFR substrate and mapping of a C-terminal internalization domain dissected the receptor's signaling outputs from its trafficking functions.

    Evidence Co-immunoprecipitation of PLCγ with EGFR plus tyrphostin blockade; C-terminal deletion mutant series separating internalization from transcription/transformation

    PMID:2472218 PMID:2790960

    Open questions at the time
    • Full repertoire of EGFR C-tail phosphosites and their adaptor assignments incomplete
    • Relationship between internalization and signal termination untested
  6. 1990 High

    Proving that EGFR autophosphorylation occurs by intermolecular transphosphorylation established the dimerization-dependent activation paradigm and explained how kinase-dead receptors act as dominant negatives.

    Evidence Co-expression of kinase-negative K721A and C-terminally truncated active EGFR in living cells

    PMID:2164634

    Open questions at the time
    • Structural basis for asymmetric kinase activation not yet resolved
    • Stoichiometry of higher-order oligomers unknown
  7. 1992 High

    Mapping PI3K p85 SH2-domain association with autophosphorylated EGFR and discovering a direct EGFR–F-actin interaction expanded the receptor's signaling repertoire to lipid kinase and cytoskeletal regulation.

    Evidence GST-SH2 pulldowns with phosphotyrosine competition (PI3K); purified EGFR–F-actin co-sedimentation with peptide competition and antibody blocking

    PMID:1372091 PMID:1383230

    Open questions at the time
    • Functional significance of EGFR–actin binding in vivo not demonstrated
    • Specific EGFR phosphotyrosine residues docking p85 not mapped
  8. 1997 High

    Identification of Src-dependent EGFR transactivation by GPCR Gβγ subunits revealed that EGFR integrates signals from heterologous receptor systems, functioning as a signaling hub beyond its canonical ligand inputs.

    Evidence Dominant-negative Src and Csk overexpression, autophosphorylation-specific antibodies, GST-Src-SH2 pulldown in COS-7 cells

    PMID:9020193

    Open questions at the time
    • Identity of metalloproteinase and shed ligand mediating transactivation not yet defined
    • Tissue specificity of transactivation pathway unknown
  9. 1999 High

    Systematic ligand-binding analysis across ErbB dimer combinations and discovery that EGF-stimulated Rsk-2 phosphorylates histone H3 defined both the combinatorial receptor logic and a direct chromatin-level output of EGF signaling.

    Evidence Soluble receptor–ligand binding with all ErbB combinations; Coffin-Lowry patient fibroblasts and RSK-2 knockout ES cells with EGF-stimulated H3 phosphorylation

    PMID:10214951 PMID:10436156

    Open questions at the time
    • Genomic loci targeted by H3 phosphorylation downstream of EGF not identified
    • Whether partial agonist ligands also induce H3 phosphorylation untested
  10. 2002 High

    Crystal structures of unliganded (tethered) and EGF-bound (extended/dimerized) EGFR ectodomain resolved the autoinhibition-to-activation conformational switch at atomic resolution, answering how ligand binding triggers dimerization.

    Evidence X-ray crystallography at 2.8 Å (unliganded) and 3.3 Å (2:2 EGF–EGFR complex) with mutagenesis validation

    PMID:12297050 PMID:12620237

    Open questions at the time
    • Full-length receptor structure in membrane context unavailable
    • Dynamics of tethered-to-extended transition unresolved
  11. 2002 High

    Multiple discoveries in 2002 defined how EGFR trafficking is controlled: Cbl–CIN85–endophilin complexes drive clathrin-mediated internalization separable from Cbl's ubiquitin ligase activity; SHP2 sustains Ras signaling by dephosphorylating RasGAP-binding sites; and GPCR-triggered metalloproteinase shedding of HB-EGF (by ADAM12) transactivates EGFR in cardiac and gastric contexts.

    Evidence Co-IP/siRNA/dominant-negative dissection of CIN85–endophilin; EGFR Y992F mutant with RasGAP translocation assay; dominant-negative ADAM12 in cardiomyocytes and metalloproteinase inhibitor profiling in gastric cells

    PMID:11786904 PMID:11894095 PMID:12099696 PMID:14560030

    Open questions at the time
    • Whether CIN85 pathway is universal or cell-type-specific not resolved
    • Full substrate spectrum of SHP2 at the receptor unknown
  12. 2005 High

    Discovery that nuclear EGFR cooperates with STAT3 to activate iNOS transcription, and structural determination of how cetuximab locks EGFR in the tethered conformation, established both a non-canonical transcriptional role and the structural basis for therapeutic antibody blockade.

    Evidence ChIP + co-IP + reporter assays for nuclear EGFR–STAT3 on iNOS promoter; 2.8 Å crystal structure of cetuximab Fab–sEGFR complex

    PMID:15837620 PMID:15950906

    Open questions at the time
    • Genome-wide target genes of nuclear EGFR–STAT3 undefined
    • How EGFR is imported into the nucleus mechanistically unclear
  13. 2006 High

    Characterization of NSCLC-associated EGFR mutations (L858R, exon 19 deletions) revealed they disrupt activation-loop autoinhibition to produce constitutive, ligand-independent kinase activity, and explained the hypersensitivity of these mutants to gefitinib.

    Evidence Crystal structures of L858R and G719S kinase domains with inhibitors; Ba/F3 EGF-independent mitogenesis; in vitro kinase assays showing 50-fold increased catalysis for L858R

    PMID:16953218 PMID:17349580

    Open questions at the time
    • Resistance mutations (e.g. T790M) not structurally addressed in these studies
    • Whether all activating mutants share the same autoinhibition-disruption mechanism untested
  14. 2009 High

    Tom1L1 was identified as a clathrin-engaging adaptor linking EGF-activated EGFR–Grb2–Shc complexes to the endocytic machinery, adding a required component to the receptor internalization pathway.

    Evidence RNAi knockdown of Tom1L1 inhibiting EGFR endocytosis, reciprocal co-IP, clathrin-binding domain mapping

    PMID:19798056

    Open questions at the time
    • Whether Tom1L1 is specific to EGFR or shared with other RTKs not tested
    • Structural basis of Tom1L1–clathrin interaction unresolved
  15. 2011 High

    Reconstitution of EGFR in proteoliposomes demonstrated that GM3 ganglioside inhibits the allosteric transition to the active kinase dimer through membrane-proximal lysine interactions, establishing membrane lipid composition as a direct regulator of receptor activation.

    Evidence Purified EGFR in defined-lipid proteoliposomes, autophosphorylation assay, K642G mutagenesis

    PMID:21571640

    Open questions at the time
    • Physiological regulation of local GM3 concentration at the cell surface not addressed
    • Other lipid species potentially modulating EGFR not tested
  16. 2017 High

    Structural and single-molecule analyses showed that different EGFR ligands (EGF vs. EREG/EPGN) stabilize distinct dimer conformations of varying stability, directly determining signaling kinetics and cell-fate outcomes, thus establishing a 'biased agonism' paradigm for receptor tyrosine kinases.

    Evidence X-ray crystallography of ectodomain with multiple ligands, single-molecule dimer lifetime imaging, phosphorylation dynamics and phenotypic assays in breast cancer cells

    PMID:28988771

    Open questions at the time
    • How dimer stability is decoded by intracellular signaling machinery not defined
    • Whether biased agonism extends to all seven EGFR ligands untested
  17. 2019 Medium

    Nuclear EGFR was shown to hydrolyze nuclear PI(4,5)P₂ via PLCδ4 to generate InsP₃ that triggers nucleoplasmic reticulum Ca²⁺ release, linking nuclear EGFR to cell-cycle progression through cyclin A/B1 regulation.

    Evidence siRNA knockdown of PLCδ4/PLCγ1, FRET-based InsP₃ biosensor, EGFR nuclear translocation inhibition, cyclin expression analysis

    PMID:31537645

    Open questions at the time
    • Mechanism of EGFR nuclear import still unclear
    • Whether nuclear Ca²⁺ signaling occurs in non-transformed cells not shown
    • Single study; independent replication in other cell systems needed

Open questions

Synthesis pass · forward-looking unresolved questions
  • A complete structural model of full-length EGFR in its native membrane environment, integrating extracellular conformational switching with transmembrane helix dynamics, juxtamembrane regulation, and asymmetric kinase activation, remains unavailable; the precise mechanisms of EGFR nuclear import and the genome-wide transcriptional program of nuclear EGFR are unresolved.
  • No full-length membrane-embedded EGFR structure
  • Nuclear EGFR import mechanism unknown
  • Genome-wide nuclear EGFR target genes not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 6 GO:0060089 molecular transducer activity 3 GO:0008289 lipid binding 1
Localization
GO:0005576 extracellular region 2 GO:0005886 plasma membrane 2 GO:0031410 cytoplasmic vesicle 2 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 12 R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-1643685 Disease 3 R-HSA-1640170 Cell Cycle 2 R-HSA-109582 Hemostasis 1 R-HSA-4839726 Chromatin organization 1
Partners
EGFRERBB2GAB1GRB2IQGAP1PIK3R1PLCG1SHC1

Evidence

Reading pass · 54 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1989 EGF binding to EGFR triggers tyrosine phosphorylation of phospholipase C-II (PLCγ), which co-immunoprecipitates with the EGF receptor; this phosphorylation links EGFR tyrosine kinase activity to PIP2 hydrolysis and EGF-induced Ca2+ release. Tyrphostin kinase inhibitor blocks both PLC-II phosphorylation and its association with EGFR. Co-immunoprecipitation, phosphotyrosine immunoblotting, kinase inhibitor experiments Cell High 2472218
1980 The EGF binding site of the EGFR is on the extracellular (external) face of the plasma membrane, while the phosphate acceptor (kinase substrate) site is on the cytoplasmic face, demonstrating the transmembrane topology of the receptor and that EGF-stimulated phosphorylation requires cell permeabilization for ATP access. Controlled proteolysis of intact vs. permeabilized cells, direct linkage cross-linking, 32P-ATP labeling with lysolecithin permeabilization Journal of supramolecular structure High 6264233
1986 EGF stimulates its own receptor synthesis: EGF treatment of WB hepatic cells increased EGFR mRNA levels 3–5-fold and stimulated new receptor protein synthesis within 2 hours, providing a positive feedback mechanism that counterbalances ligand-induced receptor degradation. Biosynthetic [35S]methionine labeling with immunoprecipitation, Northern blot with EGFR cDNA probes The Journal of biological chemistry Medium 2420792
1986 EGF and its receptor localize together within endosomal compartments (peripheral branching tubular network and pericentriolar multivesicular bodies) following EGF stimulation; the EGF-receptor complex redistributes from peripheral to pericentriolar endosomes in a temperature-dependent step before entering lysosomes. Immunoelectron microscopy with HRP-EGF and anti-receptor antibody-gold on A431 cells, frozen thin sections The Journal of cell biology High 2868013
1986 The human EGF precursor is a 1,207 amino acid transmembrane protein with EGF flanked by large N- and C-terminal segments; it is expressed as a membrane protein with its N-terminus external to the cell surface, and its gene spans ~110 kb with 24 exons, suggesting exon duplication and shuffling in its evolution. cDNA sequencing, COS-7 cell transfection for expression, gene structure analysis Nucleic acids research High 3491360
1987 Overexpression of the EGFR in NIH 3T3 cells confers EGF-dependent transformation (focus formation, anchorage-independent growth) without altering basal growth, demonstrating that EGFR overexpression amplifies normal EGF signal transduction and is sufficient to drive oncogenic signaling in the presence of ligand. Eukaryotic expression vector transfection into NIH 3T3 and NR6 cells, focus formation assay, soft agar colony assay, DNA synthesis measurement Cell High 3500791
1987 EGF stimulates formation of inositol 1,4,5-trisphosphate (Ins-1,4,5-P3), Ins-1,3,4-P3, and Ins-1,3,4,5-P4, with concurrent decrease in PIP2, in A431 cells overexpressing EGFR and in five other EGFR-overexpressing cell lines, demonstrating EGF-induced activation of the phosphoinositide signaling pathway. Radiolabeled inositol phosphate measurement in multiple cell lines with EGFR overexpression Biochemical and biophysical research communications Medium 3030297
1988 EGF stabilizes EGF receptor mRNA (prolonging its half-life), as well as β-tubulin and β-actin mRNAs, revealing a novel post-transcriptional mechanism by which EGF upregulates receptor expression distinct from the transcriptional mechanism of phorbol ester (PMA). mRNA decay assay with actinomycin D, Northern blot analysis Nucleic acids research Medium 3260374
1989 A specific 18-amino-acid highly negatively charged C-terminal domain of the EGFR (beyond the kinase domain) is required for EGF-dependent receptor internalization via a high-affinity saturable pathway and for ligand-stimulated cytosolic calcium increases, but kinase-active internalization-defective receptors can still signal gene transcription, morphological transformation, and growth. C-terminal deletion and truncation mutants expressed in cells, internalization assays, calcium measurement, transformation assays Cell High 2790960
1990 EGF receptor autophosphorylation in living cells occurs by intermolecular cross-phosphorylation (transphosphorylation): a kinase-negative EGFR (K721A mutant) becomes tyrosine phosphorylated by co-expressed active EGFR upon EGF stimulation; the kinase-negative mutant acts as a dominant-negative to suppress mitogenic signaling. Coexpression of kinase-negative and C-terminally truncated active EGFR mutants, EGF-stimulated phosphorylation assay in living cells Molecular and cellular biology High 2164634
1992 Purified EGFR directly co-sediments with purified F-actin, identifying EGFR as an actin-binding protein. The actin-binding domain maps to amino acids 984–996 (sequence homologous to Acanthamoeba profilin actin-binding domain); a truncated EGFR lacking this region does not co-sediment with actin. Co-sedimentation assay with purified EGFR and F-actin, synthetic peptide competition, polyclonal antibody blocking, direct actin-binding assay with HL-33 peptide The Journal of cell biology High 1383230
1992 EGF receptor internalization rate is stimulated ~50-fold at saturating EGF concentrations. High-affinity EGF binding requires the intact cytoplasmic domain; tyrosine kinase activity (Lys721) and the Thr654 region (PKC phosphorylation site) are required for the enhanced internalization of high-affinity receptors at low EGF concentrations. Kinetic binding and internalization assays with EGFR point mutants (K721A, T654A), phorbol ester treatment, blocking antibody experiments The Journal of cell biology High 1556153
1992 PI 3-kinase p85 subunit associates with activated (autophosphorylated) EGFR via its SH2 domains; either N- or C-terminal SH2 domain of p85 is sufficient for receptor binding; receptor tyrosine autophosphorylation is required for p85 binding; p85 itself is not significantly tyrosine phosphorylated by EGFR, suggesting it acts as an adaptor. Co-immunoprecipitation, GST-SH2 domain pulldown, competitive binding with phosphotyrosine, anti-phosphotyrosine blotting Molecular and cellular biology High 1372091
1993 EGF receptor recycling occurs multiple times per receptor: A431 cells consume far more EGF molecules than the number of EGFR degraded or down-regulated, with apparent Michaelis-Menten kinetics for EGF consumption; individual EGFR recycle many times, consuming up to 45 EGF molecules per receptor over 6 hours. 125I-EGF consumption assay at varying cell densities and EGF concentrations, comparison with receptor down-regulation rates The Journal of cell biology Medium 8416997
1994 Sustained vs. transient MAP kinase activation determines differentiation vs. proliferation outcome downstream of EGF. Overexpression of EGFR in PC12 cells converts EGF from a mitogen to a differentiation factor by sustaining p42/p44 MAP kinase activity and inducing nuclear translocation of p42 MAP kinase. EGFR overexpression and dominant-negative mutant expression in PC12 cells, MAP kinase activity measurement, nuclear translocation assay, neurite outgrowth measurement Current biology : CB High 7953555
1997 Gβγ subunits of Gi-coupled receptors mediate Src-dependent tyrosine phosphorylation of EGFR (transactivation) without receptor autophosphorylation; this involves Src family kinase recruitment to create phosphotyrosine docking sites for Shc/Grb2, forming a scaffold for Ras activation downstream of GPCRs. Dominant-negative c-Src and Csk expression, anti-phosphotyrosine immunoblotting, autophosphorylation-specific EGFR antibody, GST-Src-SH2 pulldown in COS-7 cells The Journal of biological chemistry High 9020193
1998 Oxidized LDL activates EGFR tyrosine phosphorylation in intact cells; 4-hydroxynonenal (4-HNE), a lipid peroxidation product, directly derivatizes and activates immunopurified EGFR in vitro, identifying EGFR as a sensor for oxidized lipids and establishing that chemical modification of EGFR can activate its kinase independently of ligand. Anti-phosphotyrosine immunoblotting in intact cells, in vitro kinase activation of immunopurified EGFR with oxLDL lipid extracts and 4-HNE FASEB journal Medium 9619445
1999 EGF receptor binding affinities to ErbB receptor dimers vary dramatically by combination: the ErbB2/4 heterodimer binds all EGF-domain ligands with moderate-to-high affinity, while ErbB3 shows highly restricted binding (only heregulin, neuregulin-2β, epiregulin, and the chimera biregulin); EGF binds ErbB1 but not ErbB4 alone; ErbB2 preferentially enhances ligand binding to ErbB3 or ErbB4. Soluble receptor-ligand binding assay with defined ErbB receptor combinations, competitive binding with EGF-domain proteins FEBS letters High 10214951
1999 EGFR-ErbB2 heterodimerization impairs EGF-induced EGFR endocytosis: in breast cancer cells with high ErbB2/EGFR ratios, EGF-stimulated EGFR endocytosis is greatly inhibited; microinjection of ErbB2 expression plasmid into low-ErbB2 cells inhibits EGFR endocytosis; the endocytosis deficiency maps to ErbB2's intracellular domain. Subcellular fractionation, co-immunoprecipitation, indirect immunofluorescence, microinjection of ErbB2 expression plasmid, ErbB2/EGFR chimera endocytosis assay Molecular biology of the cell High 10233167
1999 EGF crosses the blood-brain barrier rapidly (influx rate ~2 μl/g·min) via a saturable transport system distinct from the EGFR; the transport is competed by unlabeled EGF and TGF-α but not by anti-EGFR antibody or by EGFR mutation, suggesting a separate EGF transport receptor at the BBB. Intravenous injection of 125I-EGF in mice with competition experiments; mice with EGFR mutations; TCA precipitation of brain-recovered peptide Peptides Medium 10499427
2002 The EGF receptor extracellular region exists in an autoinhibited 'tethered' conformation where the dimerization arm in domain II is occluded by intramolecular interactions with domain IV; EGF binding to domains I and III promotes a large domain rearrangement exposing the dimerization interface for receptor-mediated dimerization. X-ray crystallography at 2.8 Å of unliganded sEGFR extracellular region; mutagenesis validation Molecular cell High 12620237
2002 Crystal structure of the 2:2 EGF:EGFR extracellular domain complex at 3.3 Å reveals: EGF docks between EGFR domains I and III; receptor dimerization occurs through a direct receptor-receptor interaction mediated by a protruding β-hairpin arm from domain II of each monomer; dimerization is receptor-mediated, not ligand-mediated. Validated by EGFR mutagenesis. X-ray crystallography at 3.3 Å resolution, EGFR mutagenesis to verify dimerization interface Cell High 12297050
2002 Decorin binds to EGFR at a narrow region within the L2 domain (residues His394–Ile402) that partially overlaps with but is distinct from the EGF-binding site (K465 required for EGF but not decorin binding); decorin binding antagonizes EGFR tyrosine kinase. Central LRR6 of decorin mediates EGFR interaction. Decorin/alkaline phosphatase chimera, cDNA library expression cloning, yeast two-hybrid, EGF competition assays, EGFR deletion mutants, site-directed mutagenesis The Journal of biological chemistry High 12105206
2002 Cbl recruits CIN85 (constitutively bound to endophilins) to form a complex with activated EGFR upon EGF stimulation, controlling receptor internalization via clathrin-coated vesicles. This mechanism is functionally separable from Cbl's ubiquitin ligase activity: blocking CIN85-endophilin interaction inhibits EGFR internalization and delays degradation without affecting receptor ubiquitination. Co-immunoprecipitation, dominant-negative and siRNA approaches, internalization assays, ubiquitination assays Nature High 11894095
2002 Cisplatin activates EGFR in a ligand-independent manner requiring EGFR kinase activity; this activation is mediated by c-Src kinases (blocked by Src inhibitor PP1 and dominant-negative kinase-dead receptor); EGFR activation by cisplatin represents a survival response, as EGFR inhibition enhances cisplatin-induced cell death. EGFR phosphorylation assays, kinase inhibitor (EGFR and Src), kinase-dead EGFR expression, cell death assays Oncogene Medium 12483525
2002 Laminin-5 domain III (DIII), liberated by matrix metalloproteinases during mammary gland involution, binds to EGFR and stimulates downstream MAPK signaling, MMP-2 gene expression, and cell migration. This ECM fragment functions as a cryptic EGFR ligand in tissue remodeling. Recombinant DIII binding to EGFR, downstream MAPK signaling measurement, MMP-2 expression, cell migration assay, TIMP-3 knockout mouse model The Journal of cell biology Medium 12695504
2002 H. pylori induces HB-EGF gene expression and EGFR transactivation through the 'triple membrane passing signal' (TMPS): H. pylori triggers metalloprotease cleavage of surface HB-EGF precursor, releasing soluble HB-EGF that activates EGFR; this cascade requires metalloprotease, EGFR, and MEK1 activities and enhances IL-8 production. EGFR phosphorylation assays with metalloprotease inhibitors, HB-EGF gene expression analysis, IL-8 release measurement in gastric cancer cell lines Biochemical and biophysical research communications Medium 12099696
2002 ADAM12 metalloprotease specifically sheds HB-EGF in cardiomyocytes stimulated by GPCR agonists; dominant-negative ADAM12 abrogates HB-EGF shedding and EGFR transactivation; KB-R7785 inhibitor binds ADAM12 directly; this pathway mediates cardiac hypertrophy. Identifies ADAM12 as the specific enzyme for cardiac HB-EGF shedding. ADAM12 cloning, dominant-negative expression, direct binding of KB-R7785 to ADAM12, EGFR phosphorylation, cardiac hypertrophy model in mice Nature medicine High 11786904
2003 SHP2 acts upstream of Ras in EGFR signaling by dephosphorylating RasGAP binding sites at the plasma membrane (specifically Tyr992 of EGFR), preventing RasGAP membrane translocation and thereby extending the half-life of GTP-Ras and enhancing Ras-dependent mitogenic signaling. Dominant-negative SHP2, EGFR Y992F point mutation, RasGAP translocation assay, GTP-Ras half-life measurement Molecular and cellular biology High 14560030
2003 CAML (calcium-modulating cyclophilin ligand) directly associates with the kinase domain of EGFR in a ligand-dependent manner and is required for efficient recycling of internalized EGFR to the plasma membrane; CAML-deficient cells show impaired EGF-induced proliferation despite normal EGF-induced signaling and internalization. CAML gene disruption in mice, EGF-stimulated proliferation assay, EGFR internalization assay, direct CAML-EGFR association by co-immunoprecipitation Developmental cell Medium 12919676
2003 Gab1 associates with EGFR at pTyr1068 and pTyr1086 in the receptor C-tail; Gab1 overexpression potentiates EGF-induced MAPK and JNK activation; PI3K (via its product PtdIns(3,4,5)P3 binding to Gab1 PH domain) acts as both upstream regulator and downstream effector of Gab1, creating a positive feedback loop; PTEN lipid phosphatase blocks this loop. Co-immunoprecipitation, GST-pulldown mapping, dominant-interfering p85, Wortmannin, PH domain-PIP3 binding, PTEN expression, GFP-Gab1 translocation imaging Molecular and cellular biology High 10648629
2003 EGF-induced actin polymerization remains locally restricted at the site of EGF bead stimulation (requires Arp2/3 complex and cofilin, independent of PI3K and Rho), while EGF-induced ERK activation spreads throughout the cell, demonstrating spatially distinct signaling scales from locally stimulated EGFR. Biotin-EGF streptavidin magnetic bead local stimulation, actin polymerization assay, PI3K and Rho inhibitors, Arp2/3 and cofilin functional analysis, ERK activation imaging The Journal of cell biology Medium 12952932
2004 Acetylcholine triggers mitochondrial ROS generation in cardiomyocytes via sequential metalloproteinase-dependent shedding of HB-EGF from the proHB-EGF precursor, followed by EGFR transactivation and PI3K activation; blocking metalloproteinase, HB-EGF (with CRM-197), or EGFR abrogates ROS generation and cardioprotection in intact hearts. MitoTracker Red fluorescence, metalloproteinase inhibitor III, CRM-197 HB-EGF inhibitor, anti-HB-EGF neutralizing antibody, EGFR phosphorylation in perfused hearts, infarct size measurement Journal of molecular and cellular cardiology Medium 15010282
2005 Cetuximab inhibits EGFR by binding exclusively to domain III of the EGFR extracellular region (in its autoinhibited tethered conformation), partially occluding the EGF ligand-binding region and sterically preventing the receptor from adopting the extended conformation required for dimerization. X-ray crystallography at 2.8 Å of cetuximab Fab–sEGFR complex Cancer cell High 15837620
2005 Nuclear EGFR physically interacts with STAT3 in the nucleus, and this complex directly activates transcription of the iNOS gene; nuclear EGFR abundance positively correlates with iNOS levels in breast carcinomas; this reveals a transcription factor mode of action for nuclear EGFR requiring STAT3 as a DNA-binding co-factor. Co-immunoprecipitation of nuclear EGFR and STAT3, chromatin immunoprecipitation, reporter gene assays, IHC in breast carcinomas Cancer cell High 15950906
2005 Lung cancer EGFR mutations (L858R, G719S) activate EGFR by disrupting autoinhibitory interactions between the activation loop and αC helix in the kinase domain; L858R accelerates catalysis up to 50-fold in vitro; gefitinib binds 20-fold more tightly to L858R mutant than wild-type; crystal structures show similar inhibitor binding modes for gefitinib and AEE788 but a staurosporine rotation in G719S. Crystal structures of mutant kinases with inhibitors, in vitro kinase activity measurement, direct binding measurements by fluorescence Cancer cell High 17349580
2006 Somatic EGFR mutations found in gefitinib-sensitive NSCLC (e.g., L858R, exon 19 deletions) cause EGF-independent constitutive EGFR signaling; mutant receptors at the cell surface are fully competent to bind EGF; mutations predicted to disrupt activation loop-αC helix autoinhibitory interactions elevate ligand-independent kinase activity. Expression of EGFR mutants in null background (NR6 cells), EGF-independent Ba/F3 cell mitogenesis assay, tyrosine phosphorylation analysis, EGF binding assay Oncogene High 16953218
2007 Rabring7, a Rab7-interacting RING finger domain protein, has E3 ubiquitin ligase activity (preferentially using Ubc4/Ubc5 as E2 enzymes) and accelerates ligand-induced EGFR degradation; a catalytic mutant (C229S) inhibits cCbl-induced EGFR degradation, demonstrating Rabring7 participates in late endocytic trafficking of EGFR through its E3 ligase activity. In vitro ubiquitination assay with recombinant E1/E2/E3, RING domain mutagenesis, EGFR degradation assay with wild-type and C229S Rabring7 Biochemical and biophysical research communications Medium 17462600
2008 EGF increases TRPM6 Mg2+ channel activity and plasma membrane surface expression through a pathway involving Src family tyrosine kinases and downstream Rac1; constitutively active Rac1 mimics EGF effects; dominant-negative Rac1 abrogates EGF-stimulated TRPM6 activity; the TRPM6 alpha-kinase domain is not required. Whole-cell patch-clamp recording of TRPM6, dominant-negative and constitutively active Rac1 expression, FRAP for TRPM6 mobility, Src inhibitor experiments in HEK293 cells Journal of the American Society of Nephrology High 19073827
2008 ARAP1, a multidomain protein with Arf GAP and Rho GAP activities, localizes to endosomal compartments (including internal membranes of multivesicular bodies) and controls late steps of EGFR endocytic trafficking; ARAP1 knockdown causes EGFR accumulation in sorting/late endosomes and inhibits EGFR degradation with prolonged signaling. siRNA knockdown, ARAP1 localization by immunofluorescence/immunoelectron microscopy, EGFR trafficking and degradation assays Traffic Medium 18764928
2009 The intracellular juxtamembrane domain of EGFR is required for both negative cooperativity in EGF binding and for the positive linkage between EGF binding and receptor dimerization; autophosphorylation abolishes the positive linkage but not cooperativity; this reveals inside-out signaling where intracellular events regulate extracellular ligand binding. Equilibrium EGF binding analysis with multiple EGFR mutants (juxtamembrane deletions, autophosphorylation site mutants), quantitative binding modeling The Journal of biological chemistry Medium 19336395
2009 Tom1L1 is transiently tyrosine-phosphorylated by Src family kinases upon EGF stimulation and forms a complex with activated EGFR bridged by Grb2 and Shc; Tom1L1 contains a novel clathrin-interacting motif in its C-terminal tail that engages clathrin heavy chain; RNAi knockdown of Tom1L1 inhibits EGFR endocytosis, identifying Tom1L1 as an adaptor linking activated EGFR to clathrin endocytic machinery. RNAi knockdown, co-immunoprecipitation, tyrosine phosphorylation assay, clathrin binding domain mapping, dominant-negative mutants The EMBO journal High 19798056
2011 Ganglioside GM3 strongly inhibits EGFR kinase domain autophosphorylation in a membrane context; this inhibition requires membrane phase separation and is released by removing GM3's neuraminic acid headgroup or by mutating EGFR membrane-proximal lysine K642G; GM3 prevents the allosteric transition from inactive to signaling EGFR dimer. Reconstitution of EGFR in proteoliposomes of defined lipid composition, autophosphorylation assay, headgroup modification, K642G mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 21571640
2011 IQGAP1 scaffold protein directly associates with EGFR (via its IQ domain binding to EGFR kinase domain) independent of EGF stimulation; calmodulin disrupts this interaction; IQGAP1-null cells show severely attenuated EGF-stimulated EGFR autophosphorylation; IQGAP1 S1443 (phosphorylated by PKCα downstream of EGFR) modulates EGFR activation. Co-immunoprecipitation (endogenous proteins), in vitro direct association assay, mass spectrometry phosphorylation mapping, IQGAP1 null cells with reconstitution, siRNA knockdown of PKCα The Journal of biological chemistry High 21349850
2012 The EGF transcriptional response is primarily elicited by EGFR at the cell surface, not from endosomes: keeping EGFR at the cell surface (by blocking endocytosis or ubiquitination) increases EGF-induced transcript abundance, while ESCRT depletion (trapping EGFR in endosomes with enhanced kinase activity) has little effect on the transcriptional profile. ESCRT depletion (siRNA), inhibition of EGFR endocytosis and ubiquitination, transcriptome profiling, kinase activity measurement Science signaling Medium 22416276
2012 Annexin A1 interaction with S100A11 in endosomes is required for efficient lysosomal targeting of EGFR: a dominant-negative N-terminal truncation of annexin A1 (lacking both the EGFR phosphorylation site and S100A11 binding site) delays EGFR transport to LAMP1+ compartments and prolongs EGFR/MAPK signaling; S100A11 depletion produces the same trafficking defect. Dominant-negative annexin A1 mutant overexpression, S100A11 siRNA, EGFR trafficking assays, EGFR degradation and MAPK signaling measurements Biochimica et biophysica acta Medium 23246849
2012 Following EGF or ionomycin treatment, rhomboid intramembrane proteases (not γ-secretase) cleave the EGFR to produce a ~60 kDa intracellular domain (ICD) fragment present in both membrane and nuclear fractions; calpain inhibition increases detectable ICD levels; this regulated intramembrane cleavage occurs slowly over 3–24 hours. Chemical inhibitor profiling (γ-secretase vs. rhomboid inhibitors), rhomboid cDNA overexpression, calpain inhibitor, subcellular fractionation of ICD fragment in A431 cells Traffic Medium 22531034
2013 Molecular dynamics simulations of membrane-embedded EGFR show that in ligand-bound dimers, extracellular domains favor N-terminal transmembrane helix dimerization and asymmetric (active) kinase dimer formation; in ligand-free dimers, extracellular domains favor C-terminal transmembrane dimerization, juxtamembrane burial, and symmetric (inactive) kinase dimers; electrostatic membrane interactions of the intracellular module are critical for this coupling. Molecular dynamics simulations of full-length membrane-embedded EGFR Cell Low 23374350
2014 EGFR is fully activated by EGF during mitosis (all five major tyrosine residues phosphorylated equivalently to interphase); however, in mitosis EGFR selectively activates PI3K, AKT2 (not AKT1), c-Src, c-Cbl, and PLCγ1 but cannot activate ERK1/2 because Raf-1 is not fully activated (lacks pY341, retains pS259); EGFR-dependent endocytosis during M phase requires EGFR kinase activity (unlike in interphase). EGF stimulation of synchronized mitotic cells, phosphorylation assays for EGFR and multiple downstream effectors, EGFR endocytosis assay in M phase vs. interphase Cellular signalling Medium 25479591
2017 EGFR ligands EGF, epiregulin (EREG), and epigen (EPGN) stabilize different dimeric conformations of the EGFR extracellular region; EREG and EPGN act as partial agonists of EGFR dimerization (inducing less stable dimers than EGF) and elicit more sustained EGFR signaling and differentiation-associated responses in breast cancer cells, rather than the proliferative response induced by EGF. X-ray crystallography of EGFR extracellular domain with different ligands, single-molecule imaging of EGFR dimerization, phosphorylation and signaling dynamics assays Cell High 28988771
1999 EGF-stimulated phosphorylation of histone H3 requires Rsk-2 (pp90rsk family kinase); fibroblasts from Coffin-Lowry syndrome patients (RSK-2 mutations) fail to show EGF-stimulated H3 phosphorylation; RSK-2 gene disruption in ES cells abolishes EGF-stimulated H3 phosphorylation; H3 appears to be a direct or indirect Rsk-2 target, linking EGF/MAPK signaling to chromatin remodeling. Coffin-Lowry patient fibroblasts, RSK-2 gene KO in ES cells, RSK-2 cDNA rescue, EGF stimulation with H3 phosphorylation assay Science High 10436156
1983 Human EGF/beta-urogastrone in plasma is associated with blood platelets: it is present in platelet-rich plasma and platelet fraction of whole blood; platelets contain both mature EGF and a high-molecular weight precursor form (cleaved to EGF by arginine esterase or trypsin); platelet-associated EGF is released during coagulation. Immunoaffinity chromatography extraction from plasma fractions, Sephadex G-50 gel chromatography, radioimmunoassay, radioreceptor assay, enzymatic cleavage The Journal of clinical investigation High 6603475
2019 EGF triggers nuclear calcium signaling through PLCδ4 (not PLCγ1): nuclear EGFR hydrolyzes nuclear PI(4,5)P2 via PLCδ4, releasing InsP3 that activates InsP3 receptors on the nucleoplasmic reticulum to release Ca2+; nuclear Ca2+ signaling requires EGFR nuclear translocation; PLCδ4 and InsP3 modulate cell cycle progression by regulating cyclin A and B1 expression. Subcellular fractionation, siRNA knockdown of PLCδ4 and PLCγ1, FRET-based InsP3 biosensor, EGFR nuclear translocation inhibition, cyclin expression analysis The Journal of biological chemistry Medium 31537645
2020 EGF/PKB-Akt signaling promotes FOXO4 degradation via a CSN6-COP1 axis: EGF treatment elevates CSN6 and COP1 levels; CSN6 binds FOXO4 and enhances COP1 E3 ligase activity toward FOXO4; COP1 directly interacts with FOXO4 via a VP motif and accelerates ubiquitin-mediated FOXO4 degradation; this reduces FOXO4-mediated suppression of serine-glycine-one-carbon (SGOC) metabolic pathway genes. Co-immunoprecipitation (CSN6-FOXO4 and COP1-FOXO4), ubiquitination assay, COP1 E3 ligase activity assay, ChIP for FOXO4 binding to SGOC gene promoters, metabolomic analysis Advanced science Medium 33101846

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
2008 Identification of host proteins required for HIV infection through a functional genomic screen. Science (New York, N.Y.) 1165 18187620
2002 Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell 941 12297050
2005 Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. Cancer cell 887 15837620
2007 Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer cell 878 17349580
2020 A reference map of the human binary protein interactome. Nature 849 32296183
1998 Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. The EMBO journal 842 9687510
2008 Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nature genetics 817 18583979
1999 EGF receptor. The international journal of biochemistry & cell biology 814 10404636
1989 EGF induces tyrosine phosphorylation of phospholipase C-II: a potential mechanism for EGF receptor signaling. Cell 785 2472218
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1987 Overexpression of the human EGF receptor confers an EGF-dependent transformed phenotype to NIH 3T3 cells. Cell 636 3500791
2013 EGF receptor trafficking: consequences for signaling and cancer. Trends in cell biology 635 24295852
2003 EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization. Molecular cell 614 12620237
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
2002 Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy. Nature medicine 606 11786904
2002 Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors. Nature 471 11894095
1994 EGF triggers neuronal differentiation of PC12 cells that overexpress the EGF receptor. Current biology : CB 441 7953555
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway. Cancer cell 435 15950906
1983 Human plasma epidermal growth factor/beta-urogastrone is associated with blood platelets. The Journal of clinical investigation 433 6603475
1997 Gbetagamma subunits mediate Src-dependent phosphorylation of the epidermal growth factor receptor. A scaffold for G protein-coupled receptor-mediated Ras activation. The Journal of biological chemistry 428 9020193
2013 Architecture and membrane interactions of the EGF receptor. Cell 419 23374350
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
1999 Requirement of Rsk-2 for epidermal growth factor-activated phosphorylation of histone H3. Science (New York, N.Y.) 406 10436156
1989 Functional independence of the epidermal growth factor receptor from a domain required for ligand-induced internalization and calcium regulation. Cell 369 2790960
1986 Human epidermal growth factor precursor: cDNA sequence, expression in vitro and gene organization. Nucleic acids research 349 3491360
1995 Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation. Cell 346 7736574
1992 Interaction of phosphatidylinositol 3-kinase-associated p85 with epidermal growth factor and platelet-derived growth factor receptors. Molecular and cellular biology 331 1372091
1999 Binding specificities and affinities of egf domains for ErbB receptors. FEBS letters 317 10214951
1997 Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferation. The EMBO journal 309 9135143
2017 EGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling Kinetics. Cell 300 28988771
2013 Loci associated with N-glycosylation of human immunoglobulin G show pleiotropy with autoimmune diseases and haematological cancers. PLoS genetics 292 23382691
2000 A novel positive feedback loop mediated by the docking protein Gab1 and phosphatidylinositol 3-kinase in epidermal growth factor receptor signaling. Molecular and cellular biology 291 10648629
2000 The EGF receptor: a nexus for trafficking and signaling. BioEssays : news and reviews in molecular, cellular and developmental biology 290 10918300
2005 Epidermal growth factor and hypoxia-induced expression of CXC chemokine receptor 4 on non-small cell lung cancer cells is regulated by the phosphatidylinositol 3-kinase/PTEN/AKT/mammalian target of rapamycin signaling pathway and activation of hypoxia inducible factor-1alpha. The Journal of biological chemistry 277 15802268
2007 Nimrod, a putative phagocytosis receptor with EGF repeats in Drosophila plasmatocytes. Current biology : CB 267 17363253
1995 The epidermal growth factor. Cell biology international 263 7640657
1993 EGF receptor in neoplasia and metastasis. Cancer metastasis reviews 258 8281612
2003 Molecular mechanism for a role of SHP2 in epidermal growth factor receptor signaling. Molecular and cellular biology 257 14560030
2011 Regulation of human EGF receptor by lipids. Proceedings of the National Academy of Sciences of the United States of America 249 21571640
2016 EGF receptor ligands: recent advances. F1000Research 246 27635238
2003 Binding to EGF receptor of a laminin-5 EGF-like fragment liberated during MMP-dependent mammary gland involution. The Journal of cell biology 237 12695504
1992 The EGF receptor is an actin-binding protein. The Journal of cell biology 231 1383230
1998 EGF, TGF-alpha, and EGF-R in human colorectal adenocarcinoma. Acta oncologica (Stockholm, Sweden) 216 9677101
2002 Decorin binds to a narrow region of the epidermal growth factor (EGF) receptor, partially overlapping but distinct from the EGF-binding epitope. The Journal of biological chemistry 194 12105206
1986 Epidermal growth factor (EGF) stimulates EGF receptor synthesis. The Journal of biological chemistry 175 2420792
1999 Endocytosis deficiency of epidermal growth factor (EGF) receptor-ErbB2 heterodimers in response to EGF stimulation. Molecular biology of the cell 155 10233167
2005 Evolution of distinct EGF domains with specific functions. Protein science : a publication of the Protein Society 135 15772310
2008 EGF increases TRPM6 activity and surface expression. Journal of the American Society of Nephrology : JASN 133 19073827
1986 Localization of the epidermal growth factor (EGF) receptor within the endosome of EGF-stimulated epidermoid carcinoma (A431) cells. The Journal of cell biology 128 2868013
1998 Activation of EGF receptor by oxidized LDL. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 124 9619445
1990 Evidence for epidermal growth factor (EGF)-induced intermolecular autophosphorylation of the EGF receptors in living cells. Molecular and cellular biology 123 2164634
2002 Cisplatin-induced activation of the EGF receptor. Oncogene 122 12483525
1991 The EGF receptor system as a target for antitumor therapy. Cancer investigation 120 1933488
2002 Role of Grb2 in EGF-stimulated EGFR internalization. Journal of cell science 115 11956311
1994 FGF and EGF are mitogens for immortalized neural progenitors. Journal of neurobiology 109 8089657
1997 Divergence in signal transduction pathways of platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) receptors. Involvement of sphingosine 1-phosphate in PDGF but not EGF signaling. The Journal of biological chemistry 107 9099730
1987 Epidermal growth factor (EGF) stimulates inositol trisphosphate formation in cells which overexpress the EGF receptor. Biochemical and biophysical research communications 107 3030297
2002 Helicobacter pylori-stimulated EGF receptor transactivation requires metalloprotease cleavage of HB-EGF. Biochemical and biophysical research communications 106 12099696
2000 Aging fibroblasts present reduced epidermal growth factor (EGF) responsiveness due to preferential loss of EGF receptors. The Journal of biological chemistry 104 10764734
1993 Bradykinin inhibition of EGF- and PDGF-induced DNA synthesis in human fibroblasts. The American journal of physiology 95 8396328
1992 Kinetics of binding, endocytosis, and recycling of EGF receptor mutants. The Journal of cell biology 90 1556153
1999 Entry of EGF into brain is rapid and saturable. Peptides 89 10499427
2000 Drosophila bunched integrates opposing DPP and EGF signals to set the operculum boundary. Development (Cambridge, England) 81 10648233
2011 MAPK scaffold IQGAP1 binds the EGF receptor and modulates its activation. The Journal of biological chemistry 80 21349850
2006 EGF-independent activation of cell-surface EGF receptors harboring mutations found in gefitinib-sensitive lung cancer. Oncogene 72 16953218
2009 The intracellular juxtamembrane domain of the epidermal growth factor (EGF) receptor is responsible for the allosteric regulation of EGF binding. The Journal of biological chemistry 71 19336395
2012 Regulation of the EGF transcriptional response by endocytic sorting. Science signaling 70 22416276
1993 Consumption of EGF by A431 cells: evidence for receptor recycling. The Journal of cell biology 69 8416997
1991 Cytotoxic properties of DAB486EGF and DAB389EGF, epidermal growth factor (EGF) receptor-targeted fusion toxins. The Journal of biological chemistry 69 1939154
1987 Stimulation by EGF of the growth of EGF receptor-hyperproducing tumor cells in athymic mice. International journal of cancer 65 2824387
1991 Epidermal growth factor (EGF) expression in the congenital polycystic mouse kidney. Kidney international 63 2002633
2003 CAML is required for efficient EGF receptor recycling. Developmental cell 61 12919676
1992 Implications of epidermal growth factor (EGF) induced egf receptor aggregation. Biophysical journal 61 1420877
1988 Retinoic acid alters EGF receptor expression during palatogenesis. Development (Cambridge, England) 61 3168791
2004 Mitochondrial ROS generation following acetylcholine-induced EGF receptor transactivation requires metalloproteinase cleavage of proHB-EGF. Journal of molecular and cellular cardiology 60 15010282
2006 EGF-induced activation of the EGF receptor does not trigger mobilization of caveolae. Traffic (Copenhagen, Denmark) 54 16984407
1998 The EGF\EGF-receptor axis modulates enterocyte apoptosis during intestinal adaptation. The Journal of surgical research 54 9698526
1991 Immunoreactivities for epidermal growth factor (EGF) and for EGF receptors in rats with gastric ulcers. Cell and tissue research 53 1934026
1999 Hedgehog activates the EGF receptor pathway during Drosophila head development. Development (Cambridge, England) 52 10331974
1998 Complexity of EGF receptor signalling revealed in Drosophila. Current opinion in genetics & development 52 9729715
1998 EGF domain swap converts a drosophila EGF receptor activator into an inhibitor. Genes & development 51 9531530
1980 Controlled proteolysis of EGF receptors: evidence for transmembrane distribution of the EGF binding and phosphate acceptor sites. Journal of supramolecular structure 51 6264233
2000 EGF receptor transactivation mediated by the proteolytic production of EGF-like agonists. Science's STKE : signal transduction knowledge environment 50 11865189
1988 A novel effect of EGF on mRNA stability. Nucleic acids research 47 3260374
1997 Epithelial induction in dermatofibroma: a role for the epidermal growth factor (EGF) receptor. The American Journal of dermatopathology 42 9056652
1997 Coupling of epidermal growth factor (EGF) with the antiproliferative activity of cAMP induces neuronal differentiation. The Journal of biological chemistry 42 9202048
2004 Srcasm modulates EGF and Src-kinase signaling in keratinocytes. The Journal of biological chemistry 41 15579470
1999 Spatial organization of EGF receptor transmodulation by PDGF. Biochemical and biophysical research communications 41 10441488
2004 Epidermal growth factor gene (EGF) polymorphism and risk of melanocytic neoplasia. The Journal of investigative dermatology 40 15373782
1994 Targeting the EGF receptor in breast cancer treatment. Breast cancer research and treatment 40 7819590
2016 Decline in Proliferation and Immature Neuron Markers in the Human Subependymal Zone during Aging: Relationship to EGF- and FGF-Related Transcripts. Frontiers in aging neuroscience 39 27932973
2010 Colocalization of mineralocorticoid and EGF receptor at the plasma membrane. Biochimica et biophysica acta 39 20211660
1998 High-affinity binding of epidermal growth factor (EGF) to EGF receptor is disrupted by overexpression of mutant dynamin (K44A). The Journal of biological chemistry 39 9642213
2001 EGF family ligand-dependent phenotypic modulation of smooth muscle cells through EGF receptor. Biochemical and biophysical research communications 38 11181057
2001 Identification of serum factor inducing ectodomain shedding of proHB-EGF and sStudies of noncleavable mutants of proHB-EGF. Biochemical and biophysical research communications 38 11350072
1991 EGF- and PDGF-stimulated phosphorylation in young and senescent WI-38 cells. Experimental cell research 37 1847336
2008 ARAP1 regulates EGF receptor trafficking and signalling. Traffic (Copenhagen, Denmark) 36 18764928
2003 Local signaling by the EGF receptor. The Journal of cell biology 36 12952932
1993 Phosphatase inhibitors, gap junctional intercellular communication and [125I]-EGF binding in hamster fibroblasts. Carcinogenesis 36 8242852
2012 Disruption of the annexin A1/S100A11 complex increases the migration and clonogenic growth by dysregulating epithelial growth factor (EGF) signaling. Biochimica et biophysica acta 35 23246849
2005 A role for ERK1/2 in EGF- and ATP-dependent regulation of amiloride-sensitive sodium absorption. American journal of physiology. Cell physiology 35 15634742
2016 EGF Functionalized Polymer-Coated Gold Nanoparticles Promote EGF Photostability and EGFR Internalization for Photothermal Therapy. PloS one 33 27788212
2014 EGF stimulates the activation of EGF receptors and the selective activation of major signaling pathways during mitosis. Cellular signalling 33 25479591
2007 Involvement of Rabring7 in EGF receptor degradation as an E3 ligase. Biochemical and biophysical research communications 33 17462600
2007 Epidermal growth factor (EGF) receptor targeted delivery of PEGylated adenovirus. Biochemical and biophysical research communications 33 18083120
2020 EGF Relays Signals to COP1 and Facilitates FOXO4 Degradation to Promote Tumorigenesis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 31 33101846
1979 Hormone-induced modification of EGF receptor proteolysis in the induction of EGF action. Journal of supramolecular structure 31 233024
2007 SNP analyses of growth factor genes EGF, TGFbeta-1, and HGF reveal haplotypic association of EGF with autism. Biochemical and biophysical research communications 30 17626784
2004 Origins of growth factors: NGF and EGF. Annals of the New York Academy of Sciences 30 15838103
2001 Attenuation of EGF signaling in senescent cells by caveolin. Annals of the New York Academy of Sciences 30 11795531
1998 Role of epidermal growth factor (EGF) in oesophageal mucosal integrity. Current medical research and opinion 30 9787980
2009 Participation of Tom1L1 in EGF-stimulated endocytosis of EGF receptor. The EMBO journal 28 19798056
1995 Human lens epithelial cells proliferate in response to exogenous EGF and have EGF and EGF receptor. Ophthalmic research 28 8927309
1984 Transport of 125I-EGF into milk and effect of sialoadenectomy on milk EGF in mice. The American journal of physiology 28 6332542
1995 A single amino acid exchange, Arg-45 to Ala, generates an epidermal growth factor (EGF) mutant with high affinity for the chicken EGF receptor. The Journal of biological chemistry 27 7673217
1996 Epidermal growth factor (EGF). Bailliere's clinical gastroenterology 26 8732299
1992 Evidence for intracellular down-regulation of the epidermal growth factor (EGF) receptor during adenovirus infection by an EGF-independent mechanism. Journal of virology 26 1727483
2008 NM23H2 inhibits EGF- and Ras-induced proliferation of NIH3T3 cells by blocking the ERK pathway. Cancer letters 25 19022560
1998 Suppression of ruffling by the EGF receptor in chemotactic cells. Experimental cell research 25 9665807
1989 Epidermal growth factor (EGF) prevents methylprednisolone-induced inhibition of wound healing. The Journal of surgical research 25 2475671
2013 Deja Vu: EGF receptors drive resistance to BRAF inhibitors. Cancer discovery 24 23658295
2012 Regulated intramembrane cleavage of the EGF receptor. Traffic (Copenhagen, Denmark) 24 22531034
2002 Modulation of trophoblast cell death by oxygen and EGF. Molecular medicine (Cambridge, Mass.) 24 12606820
2000 Evidence that Argos is an antagonistic ligand of the EGF receptor. Oncogene 24 10918615
1984 Epidermal growth factor (EGF) binding to membranes immobilized in microtiter wells and estimation of EGF-related transforming growth factor activity. Biochimica et biophysica acta 24 6322847
2010 Regulation of EGF-stimulated EGF receptor endocytosis during M phase. Traffic (Copenhagen, Denmark) 23 21059162
2019 Epidermal growth factor (EGF) triggers nuclear calcium signaling through the intranuclear phospholipase Cδ-4 (PLCδ4). The Journal of biological chemistry 22 31537645
1995 Epidermal growth factor (EGF) receptor carboxy-terminal domains are required for EGF-induced glucose transport in transgenic 3T3-L1 adipocytes. Endocrinology 22 7835273