Affinage

EGFR

Epidermal growth factor receptor · UniProt P00533

Length
1210 aa
Mass
134.3 kDa
Annotated
2026-06-09
100 papers in source corpus 20 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EGFR (ErbB1) is a ligand-activated receptor tyrosine kinase whose signaling output, trafficking, and physiological fate are shaped by its dimerization state, conformational regulators, and the route by which it is internalized and degraded (PMID:9710588, PMID:20946980). Ligand binding determines both partner choice and downstream wiring: EGF-activated ErbB1 binds Grb2 and internalizes rapidly with biphasic PI3-K association, whereas heterodimerization with ErbB-4 yields a Grb2-incompetent receptor with delayed internalization and distinct phosphopeptide patterns (PMID:9710588), and high-affinity ligands can drive ErbB-2/ErbB-3 surrogate signaling in the absence of ErbB1 (PMID:9546426). Receptor activation is facilitated by cytoplasmic cytohesins, which promote conformational rearrangement of the intracellular domains of dimerized receptors to enable autophosphorylation (PMID:20946980), while signaling-competent dimers of two ligand-bound receptors are long-lived and stabilized by co-confinement and cortical actin (PMID:22020299). Activated EGFR is uniquely routed toward accelerated clathrin-mediated internalization and lysosomal degradation rather than recycling, so much of its signaling occurs from endosomes (PMID:12648467); this fate is tuned by trafficking and degradation machinery including ARAP1 at Rab5 endosomes (PMID:18939958), the deubiquitinases UBPY/USP8 and USP22 (PMID:17121848, PMID:29981430), the FBXL2–Grp94 axis controlling proteasomal stability (PMID:34635651), and the stabilizing kinase DYRK1A (PMID:23635774). Additional input comes from NEU3-mediated desialylation, which enhances EGFR phosphorylation without changing its expression (PMID:25922362), and from transactivation by Wnt and other stimuli through metalloprotease-dependent shedding of soluble ligands (PMID:12612606). EGFR activity drives proliferation, survival, motility, and invasion across multiple tissue and tumor contexts, including KRAS-driven lung tumor initiation (PMID:29925636), androgen-dependent prostate cancer growth (PMID:12746839), and metastatic cell motility (PMID:19458057); in EGFR-amplified glioblastoma, constitutive signaling promotes invasion via TAB1-TAK1-NF-κB-EMP1 whereas ligand-activated EGFR suppresses invasion via BIN3-DOCK7 (PMID:35915159). EGFR also supports normal physiology, including astrocyte-mediated control of LHRH secretion (PMID:15591145) and adult cardiac function (PMID:18599591).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1998 High

    Established that EGFR signaling identity is dimerization-partner-dependent rather than fixed, explaining how the same receptor produces divergent outputs.

    Evidence Co-IP, phosphopeptide mapping, and internalization assays in NIH 3T3 cells with defined receptor combinations; plus chimeric-ligand mapping of ErbB-2/ErbB-3 surrogate activation

    PMID:9546426 PMID:9710588

    Open questions at the time
    • Structural basis of dimer-specific phosphosite selection not resolved
    • Physiological ligand concentrations for surrogate ErbB-2/ErbB-3 activation unclear
  2. 2003 Medium

    Defined EGFR as uniquely ligand-routed to lysosomal degradation, reframing endosomes as a principal signaling compartment.

    Evidence Trafficking and internalization-rate assays, cytoplasmic-domain mutant analysis, and Grb2-binding studies (review synthesizing experimental data)

    PMID:12648467

    Open questions at the time
    • Quantitative contribution of endosomal vs surface signaling not partitioned
    • Review-level synthesis rather than single primary dataset
  3. 2003 Medium

    Showed EGFR can be transactivated by Wnt through metalloprotease-dependent ligand shedding, linking it to non-canonical upstream inputs.

    Evidence Conditioned-medium transfer, ErbB1-blocking antibody, and MMP inhibitors with MAPK/cyclin D1 readouts in HC11 mammary cells

    PMID:12612606

    Open questions at the time
    • Identity of the shed ligand(s) not pinned down
    • Generality beyond mammary epithelial cells untested
  4. 2004 Medium

    Demonstrated EGFR kinase activity is required for hormone-driven cancer cell proliferation and survival, establishing cross-talk with androgen signaling.

    Evidence ErbB1 kinase inhibitors (CGP59326, PKI166), proliferation/apoptosis assays, and receptor-level Westerns in LNCaP prostate cancer cells

    PMID:12746839

    Open questions at the time
    • Mechanism by which androgens raise surface ErbB1 unknown
    • Direct vs indirect coupling to androgen receptor not resolved
  5. 2004 Medium

    Established a physiological neuroendocrine role for glial EGFR in controlling LHRH secretion and reproduction.

    Evidence Genetic double-mutant mouse epistasis (Waved-2 plus astrocyte dominant-negative erbB-4), PGE2 production and LHRH-release assays

    PMID:15591145

    Open questions at the time
    • Molecular link from astrocyte EGFR to PGE2 output incomplete
    • Relative contributions of erbB-1 vs erbB-4 not separated
  6. 2006 Medium

    Revealed that the deubiquitinase UBPY/USP8 paradoxically promotes EGFR degradation, refining the ubiquitin-control logic of receptor turnover.

    Evidence Co-IP, three dominant-negative UBPY constructs, and ubiquitination assays in NIH3T3/HEK293 cells

    PMID:17121848

    Open questions at the time
    • Direct DUB substrate (receptor vs ESCRT machinery) not distinguished
    • Single-lab dominant-negative approach
  7. 2008 Medium

    Characterized EGFR ectodomain shedding and exosomal secretion as kinase-dependent routes for receptor export, expanding EGFR fate beyond degradation.

    Evidence Exosome isolation, GM6001 and AG1478 inhibitor treatments, Western blotting of conditioned-medium fractions

    PMID:17910038

    Open questions at the time
    • Functional role of secreted/shed species not established
    • Responsible sheddase not identified
  8. 2008 Medium

    Identified ARAP1 as an endosomal trafficking regulator that slows EGFR progression to early endosomes and degradation, tuning ERK/JNK output.

    Evidence siRNA knockdown, co-localization microscopy with Rab5/EEA1, and ERK/JNK phosphorylation assays

    PMID:18939958

    Open questions at the time
    • GAP activity requirement for ARAP1 function not tested
    • Reciprocal validation of EGFR-dependent ARAP1 recruitment limited
  9. 2008 Medium

    Showed adult cardiac function depends on cardiomyocyte EGFR signaling, defining a homeostatic role in the heart.

    Evidence Inducible cardiomyocyte-specific dominant-negative ErbB-1, echocardiography, histology, and receptor-phosphorylation Westerns in mice

    PMID:18599591

    Open questions at the time
    • Downstream effector pathway from cardiac EGFR not defined
    • Rescue by adenylyl cyclase activator mechanism unexplained
  10. 2009 Medium

    Separated EGFR and ERBB2 contributions to metastasis, assigning EGFR to motility/invasion and ERBB2 to intravasation.

    Evidence In vivo intravital imaging in mouse mammary tumors with selective inhibitors (gefitinib, AG825)

    PMID:19458057

    Open questions at the time
    • Molecular effectors driving the invasion step not identified
    • Single-lab in vivo imaging system
  11. 2010 High

    Identified cytohesins as cytoplasmic conformational activators of EGFR, providing a mechanism for kinase-domain activation downstream of dimerization.

    Evidence Cell-free reconstitution of cytohesin-dependent autophosphorylation, anisotropy microscopy of EGFR conformation, and in vivo proliferation assays

    PMID:20946980

    Open questions at the time
    • Structural detail of cytohesin-induced rearrangement not resolved
    • Specificity across ErbB family members not fully mapped
  12. 2011 High

    Quantified how ligand binding and cortical actin stabilize signaling-competent EGFR dimers independently of kinase activity, linking membrane dynamics to activation.

    Evidence Two-color quantum-dot single-particle tracking with hidden Markov modeling, kinase inhibition, and actin disruption in living cells

    PMID:22020299

    Open questions at the time
    • Identity of the actin-coupling factor not determined
    • Relation of dimer lifetime to downstream signal strength not quantified
  13. 2013 Medium

    Established DYRK1A as a positive regulator of EGFR stability driving glioblastoma stem-cell self-renewal.

    Evidence DYRK1A pharmacological inhibition, EGFR degradation assays, and in vivo tumor burden in primary GBM lines and neural progenitors

    PMID:23635774

    Open questions at the time
    • Whether DYRK1A acts directly on EGFR or via trafficking machinery unknown
    • Phosphosite mediating stabilization not identified
  14. 2013 Medium

    Linked direct ErbB1-integrin-β1 heteroassociation to Akt-driven radioresistance in glioblastoma.

    Evidence Acceptor-photobleaching FRET on clinical sections and glioma lines, ectopic ErbB1 expression, and PI3K-inhibitor rescue

    PMID:23595626

    Open questions at the time
    • Structural interface of the heterocomplex undefined
    • Causality between heteroassociation and Akt activation correlative
  15. 2015 Medium

    Showed EGFR sialylation state modulates activation, with NEU3 desialylation enhancing phosphorylation without altering receptor levels.

    Evidence Co-IP, wild-type vs catalytically inactive NEU3 comparison, Western blot, and mass spectrometry of EGFR glycosylation

    PMID:25922362

    Open questions at the time
    • Specific glycosites controlling activation not mapped
    • Single-lab study without in vivo validation
  16. 2018 Medium

    Demonstrated that ERBB/EGFR activity is required to amplify RAS signaling and initiate KRAS-mutant lung tumors, defining a therapeutic dependency.

    Evidence Autochthonous KRASG12D mouse lung-tumor model with multi-ERBB and MEK inhibitor treatment plus in vitro proliferation

    PMID:29925636

    Open questions at the time
    • Relative contribution of EGFR vs other ERBB members not isolated
    • Source of activating ligand in the tumor microenvironment unclear
  17. 2018 Medium

    Identified USP22 as a late-endosomal deubiquitinase that promotes EGFR recycling and sustains downstream signaling, driving TKI resistance.

    Evidence USP22 knockdown/overexpression, ubiquitination, degradation/recycling, and downstream signaling (STAT3, AKT/mTOR, MEK/ERK) assays with in vivo resistance models

    PMID:29981430

    Open questions at the time
    • Direct USP22-EGFR contact vs indirect action not distinguished
    • How USP22 is recruited to late endosomes unknown
  18. 2021 High

    Defined the FBXL2-Grp94 axis as a proteasomal control point for EGFR (including TKI-resistant mutants) stability in NSCLC.

    Evidence Reciprocal Co-IP, proteasome-inhibitor assays, FBXL2 and Grp94 perturbation, and in vivo NSCLC growth assays

    PMID:34635651

    Open questions at the time
    • Degron recognized by FBXL2 on EGFR not mapped
    • How Grp94 sterically blocks FBXL2 binding structurally undefined
  19. 2022 High

    Resolved how ligand status switches EGFR between opposing invasion programs in EGFR-amplified glioblastoma.

    Evidence Orthotopic mouse GBM models, pathway-specific knockdowns, invasion assays, BIN3/DOCK7 analysis, and TCGA correlation

    PMID:35915159

    Open questions at the time
    • Trigger determining constitutive vs ligand-activated state in tumors unclear
    • Generality beyond EGFR-amplified GBM untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the dimer-, conformation-, glycosylation-, and trafficking-level control layers are integrated to set a single quantitative signaling output in a given cell remains unresolved.
  • No unified model relating dimer lifetime, endosomal location, and ubiquitin/DUB balance to output magnitude
  • Structural basis for partner- and ligand-specific phosphosite selection unresolved
  • Direct vs indirect substrate relationships for most regulators (DYRK1A, USP22, ARAP1) undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0016740 transferase activity 2 GO:0060089 molecular transducer activity 2 GO:0001618 virus receptor activity 1 GO:0140657 ATP-dependent activity 1
Localization
GO:0005768 endosome 3 GO:0005886 plasma membrane 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-1266738 Developmental Biology 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
ARAP1FBXL2GRB2HSP90B1ITGB1NEU3USP22USP8

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 ErbB1 (EGFR) acquires distinct signaling properties depending on its dimerization partner: EGF-activated ErbB-1 interacts with Grb2 and undergoes rapid internalization with biphasic PI3-K association, whereas NDF-activated ErbB-1 (via ErbB-4 heterodimerization) cannot interact with Grb2 and shows delayed internalization with monophasic PI3-K association. Tryptic phosphopeptide mapping confirmed that receptor phosphorylation patterns are dependent on the dimerization partner. Co-immunoprecipitation, phosphopeptide mapping, internalization assays in NIH 3T3 cells expressing defined receptor combinations Molecular and cellular biology High 9710588
1998 At high concentrations, EGF and betacellulin can activate the ErbB-2/ErbB-3 heterodimer as a surrogate receptor in the absence of ErbB-1; the middle portion of EGF (loop B) was identified as the structural determinant enabling activation of the ErbB-2/ErbB-3 complex. Cell growth/differentiation assays with site-specific antibody blockade, EGF/TGFα chimera analysis in cells expressing defined receptor combinations Oncogene High 9546426
2003 EGFR (ErbB1) trafficking is uniquely ligand-regulated among ErbB family members: upon EGF binding, EGFR undergoes accelerated internalization and enhanced lysosomal targeting (rather than recycling), mediated by cytoplasmic domain motifs exposed by activation-induced conformational changes and Grb2 binding. Most EGFR signaling consequently occurs within endosomes. Receptor trafficking assays, receptor internalization rate measurements, domain mutant analysis, Grb2-binding studies Experimental cell research Medium 12648467
2006 UBPY (Usp8) constitutively co-precipitates with EGFR in a bivalent manner and is a substrate for Src-family tyrosine kinases activated by ligand-induced EGFR activation. Dominant-negative UBPY mutants demonstrate that UBPY-mediated deubiquitination promotes (rather than inhibits) EGFR degradation, and affects both constitutive and ligand-induced EGFR ubiquitination, expression levels, and MAPK signaling. Co-immunoprecipitation, dominant-negative UBPY mutant overexpression, ubiquitination assays in NIH3T3 and HEK293 cells The Journal of biological chemistry Medium 17121848
2008 EGFR (ErbB1) can undergo metalloprotease-dependent ectodomain shedding to generate soluble N-terminal ectodomains (which retain ligand-binding ability) and membrane-associated C-terminal remnant fragments; full-length transmembrane ErbB1 is also secreted in exosomes. Ligand-stimulated ErbB1 secretion into exosomes requires ErbB1 kinase activity, as it is blocked by the kinase inhibitor AG1478. Exosome isolation, metalloprotease inhibitor treatments (GM6001), kinase inhibitor (AG1478) treatment, Western blotting of conditioned medium fractions Journal of cellular biochemistry Medium 17910038
2008 ARAP1 (an Arf GAP/Rho GAP domain protein) regulates EGFR endocytic trafficking: after EGF treatment, ARAP1 transiently associates with Rab5-positive punctate structures containing EGFR prior to EEA1-positive early endosomes; ARAP1 recruitment requires active Rab5 and a signal from EGFR. siRNA knockdown of ARAP1 accelerated EGFR association with EEA1 endosomes and EGFR degradation, and diminished ERK and JNK phosphorylation. siRNA knockdown, fluorescence microscopy, co-localization with endosomal markers, ERK/JNK phosphorylation assays Traffic (Copenhagen, Denmark) Medium 18939958
2010 Cytohesin family proteins are cytoplasmic activators of ErbB receptors including EGFR: cytohesin inhibition decreased EGFR autophosphorylation and downstream signaling, while cytohesin overexpression stimulated receptor activation. Cell-free reconstitution of cytohesin-dependent EGFR autophosphorylation and anisotropy microscopy monitoring of EGFR conformation indicated cytohesins facilitate conformational rearrangements in intracellular domains of dimerized receptors. Cell-free reconstitution assay, anisotropy microscopy (EGFR conformation monitoring), cytohesin overexpression/inhibition, in vitro and in vivo proliferation assays Cell High 20946980
2011 ErbB1 (EGFR) dimerization is promoted by transient co-confinement of receptors and stabilized by ligand binding: two-color quantum-dot tracking revealed that dimers of two ligand-bound receptors are long-lived (>4-fold slower dimer off-rate than unliganded dimers) and dimer off-rate is independent of kinase activity. Blockade of kinase activity or disruption of actin networks results in faster diffusion of receptor dimers, implicating cortical cytoskeleton in reduced mobility of signaling-competent dimers. Two-color quantum-dot single-particle tracking, hidden Markov model analysis of dimer kinetics, kinase inhibitors, actin network disruption in living cells Nature structural & molecular biology High 22020299
2013 DYRK1A kinase regulates EGFR stability in glioblastoma: DYRK1A inhibition promoted EGFR degradation in primary GBM cell lines and neural progenitor cells, reducing self-renewal capacity. This establishes DYRK1A as a positive regulator of surface EGFR levels, and DYRK1A-dependent EGFR stabilization as a key oncogenic mechanism in a subset of GBMs. DYRK1A pharmacological inhibition, EGFR degradation assays, primary GBM cell lines, in vivo tumor burden assays The Journal of clinical investigation Medium 23635774
2018 EGFR (ERBB1) activity is required for KRAS-driven lung tumor initiation and progression: multiple ERBB RTKs are expressed and active from the earliest stages of KRASG12D-driven lung tumor development, and multi-ERBB inhibition suppresses formation of these tumors. ERBB activity amplifies signaling through the core RAS pathway, supporting proliferation of KRAS-mutant tumor cells. Autochthonous mouse lung tumor model (KRASG12D), multi-ERBB inhibitor treatment, MEK inhibitor combination, in vitro proliferation assays Science translational medicine Medium 29925636
2021 FBXL2 (an F-box protein) targets EGFR and EGFR TKI-resistant mutants for proteasome-mediated degradation. Grp94 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, proteasome inhibitor assays, FBXL2 knockdown/overexpression, Grp94 inhibition, in vitro and in vivo NSCLC growth assays Nature communications High 34635651
2018 USP22 deubiquitinates EGFR localized on late endosomes, prevents ubiquitination-mediated EGFR degradation, and enhances EGFR recycling after EGF stimulation, thereby sustaining activation of EGFR downstream signaling pathways (STAT3, AKT/mTOR, MEK/ERK) and promoting resistance to EGFR-TKIs. USP22 knockdown/overexpression, ubiquitination assays, EGFR degradation and recycling assays, downstream signaling analysis, in vitro and in vivo resistance assays Cancer letters Medium 29981430
2015 The plasma membrane sialidase NEU3 co-immunoprecipitates with EGFR and, when catalytically active, enhances EGFR activation (phosphorylation) without affecting EGFR mRNA or protein expression levels. Active NEU3 desialylates immunoprecipitated EGFR, as confirmed by Western blot and mass spectrometry, suggesting EGFR sialylation status modulates its activation. Co-immunoprecipitation, overexpression of wild-type vs. catalytically inactive NEU3 mutant, Western blot, mass spectrometry of EGFR glycosylation Glycobiology Medium 25922362
2003 Wnt1 and Wnt5a transactivate ErbB1 (EGFR) in HC11 mammary epithelial cells via metalloprotease-mediated release of soluble ErbB1 ligands downstream of Frizzled receptor activation. ErbB1 transactivation by Wnt was required for MAPK activation and cyclin D1 upregulation in Wnt-expressing cells. Conditioned medium transfer assays, ErbB1-blocking antibody, MMP inhibitors, MAPK and cyclin D1 measurements in HC11 cells EMBO reports Medium 12612606
2004 ErbB-1 (EGFR) kinase activity is essential for androgen-induced proliferation and survival of LNCaP prostate cancer cells: androgens increase ErbB1 surface levels while decreasing ErbB2 levels, and ErbB1 kinase inhibitors (CGP59326, PKI166) completely block androgen-induced proliferation and prevent androgen-mediated rescue from PI3K inhibitor-induced apoptosis. ErbB1 tyrosine kinase inhibitors (CGP59326, PKI166), LNCaP cell proliferation and apoptosis assays, Western blotting of receptor levels The Prostate Medium 12746839
2009 ERBB1 (EGFR) inhibition specifically blocks tumor cell motility and invasion in vivo, while ERBB2 inhibition specifically blocks intravasation, distinguishing the contributions of each receptor to distinct steps of metastasis. ERBB1 inhibition (gefitinib) rapidly (within 3 h) inhibits invasion but not intravasation, whereas ERBB2 inhibition blocks intravasation. In vivo mouse mammary tumor models, intravital imaging of tumor cell motility and intravasation, selective small-molecule inhibitors (gefitinib for ERBB1, AG825 for ERBB2) Clinical cancer research Medium 19458057
2022 Constitutive (ligand-independent) EGFR signaling promotes glioblastoma invasion via a TAB1-TAK1-NF-κB-EMP1 pathway, while ligand-activated EGFR suppresses invasion by upregulating BIN3, which inhibits a DOCK7-regulated Rho GTPase pathway. Ligand binding thus shifts EGFR from an invasion-promoting to an invasion-suppressing role in EGFR-amplified GBM. Orthotopic mouse GBM models, pathway-specific knockdowns, in vitro invasion assays, BIN3/DOCK7 pathway analysis, TCGA data correlation Nature cell biology High 35915159
2004 Glial erbB-1 and erbB-4 receptors work in a coordinated fashion to control LHRH secretion and reproductive function: double-mutant mice (Waved-2 erbB-1 point mutation plus dominant-negative erbB-4 in astrocytes) show further delayed puberty and diminished reproductive capacity compared to single mutants. Mutant astrocytes fail to produce prostaglandin E2 in response to TGFα, and conditioned medium from mutant astrocytes fails to stimulate LHRH release. Genetic epistasis (double-mutant mouse crosses), astrocyte prostaglandin E2 production assays, LHRH release assay from GT1-7 cells, LH response to ovariectomy Endocrinology Medium 15591145
2008 Cardiac ErbB-1 (EGFR) signaling is required for adult cardiac function: cardiomyocyte-specific expression of dominant-negative ErbB-1 mutant blocked endogenous ErbB-1 phosphorylation and ErbB-2 transphosphorylation, leading to cardiac hypertrophy, dilation, and dysfunction (decreased fractional shortening). Cardiac function was normalized by adenylyl cyclase activator treatment and reversed upon cessation of mutant expression. Ecdysone-inducible cardiomyocyte-specific dominant-negative ErbB-1 mutant expression, echocardiography, histology, Western blotting of receptor phosphorylation American journal of physiology. Heart and circulatory physiology Medium 18599591
2013 ErbB1-integrin-β1 physical heteroassociation (measured by FRET) in glioblastoma correlates with radioresistance: ectopic ErbB1 expression upregulated integrin-β1 and increased ErbB1-integrin-β1 heteroassociation, boosting Akt phosphorylation in response to EGF. Radioresistance could be reverted by PI3K inhibition, establishing ErbB1-integrin-β1 interaction as a driver of Akt-mediated radioresistance. Acceptor photobleaching FRET on clinical frozen sections and in vitro glioma cell lines, ErbB1 ectopic expression, PI3K inhibitor rescue, Akt phosphorylation assays Neuro-oncology Medium 23595626

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Untangling the ErbB signalling network. Nature reviews. Molecular cell biology 5512 11252954
2005 ERBB receptors and cancer: the complexity of targeted inhibitors. Nature reviews. Cancer 2642 15864276
2009 ErbB receptors and signaling pathways in cancer. Current opinion in cell biology 762 19208461
2003 The ErbB receptors and their role in cancer progression. Experimental cell research 493 12648469
2003 The deaf and the dumb: the biology of ErbB-2 and ErbB-3. Experimental cell research 469 12648465
2007 ErbB receptors: from oncogenes to targeted cancer therapies. The Journal of clinical investigation 446 17671639
2020 Review on Epidermal Growth Factor Receptor (EGFR) Structure, Signaling Pathways, Interactions, and Recent Updates of EGFR Inhibitors. Current topics in medicinal chemistry 421 32124699
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 416 9496384
2018 Small molecule inhibitors targeting the EGFR/ErbB family of protein-tyrosine kinases in human cancers. Pharmacological research 377 30500458
2017 ErbB Receptors and Cancer. Methods in molecular biology (Clifton, N.J.) 347 28791631
2004 Signal transduction and oncogenesis by ErbB/HER receptors. International journal of radiation oncology, biology, physics 308 14967450
2006 ErbB receptors: new insights on mechanisms and biology. Trends in cell biology 292 17085050
2003 Trafficking of the ErbB receptors and its influence on signaling. Experimental cell research 289 12648467
2021 Antitumour immunity regulated by aberrant ERBB family signalling. Nature reviews. Cancer 227 33462501
2007 The neuregulin-I/ErbB signaling system in development and disease. Advances in anatomy, embryology, and cell biology 221 17432114
2005 The ErbB receptors and their ligands in cancer: an overview. Current drug targets 221 15857286
2011 ErbB1 dimerization is promoted by domain co-confinement and stabilized by ligand binding. Nature structural & molecular biology 215 22020299
2004 Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. The oncologist 212 15163842
1998 ErbB-1 and ErbB-2 acquire distinct signaling properties dependent upon their dimerization partner. Molecular and cellular biology 210 9710588
2003 ErbB-4: mechanism of action and biology. Experimental cell research 194 12648466
1993 Amplification and over-expression of the EGFR and erbB-2 genes in human esophageal adenocarcinomas. International journal of cancer 187 8098013
2003 ErbB-targeted therapeutic approaches in human cancer. Experimental cell research 181 12648471
2008 Ligand-induced ErbB receptor dimerization. Experimental cell research 173 19038249
1989 The neu (c-erbB-2) oncogene. Seminars in oncology 142 2565604
2007 Dual inhibition of ErbB1 (EGFR/HER1) and ErbB2 (HER2/neu). European journal of cancer (Oxford, England : 1990) 135 17208435
2006 UBPY-mediated epidermal growth factor receptor (EGFR) de-ubiquitination promotes EGFR degradation. The Journal of biological chemistry 120 17121848
2013 Current challenges and clinical investigations of epidermal growth factor receptor (EGFR)- and ErbB family-targeted agents in the treatment of head and neck squamous cell carcinoma (HNSCC). Cancer treatment reviews 116 24216225
2001 The ErbB receptor tyrosine family as signal integrators. Endocrine-related cancer 116 11566606
2013 Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth. The Journal of clinical investigation 111 23635774
2021 Rolling-translated EGFR variants sustain EGFR signaling and promote glioblastoma tumorigenicity. Neuro-oncology 106 33325513
2003 Wnt1 and Wnt5a induce cyclin D1 expression through ErbB1 transactivation in HC11 mammary epithelial cells. EMBO reports 102 12612606
1993 neu(c-erbB-2/HER2) and the epidermal growth factor receptor (EGFR) in breast cancer. Pathobiology : journal of immunopathology, molecular and cellular biology 97 7905269
2006 Signaling through ERBB receptors: multiple layers of diversity and control. Cellular signalling 96 16460914
2018 The ERBB network facilitates KRAS-driven lung tumorigenesis. Science translational medicine 95 29925636
2008 Generation of novel, secreted epidermal growth factor receptor (EGFR/ErbB1) isoforms via metalloprotease-dependent ectodomain shedding and exosome secretion. Journal of cellular biochemistry 95 17910038
2003 ERBB receptor tyrosine kinases and cellular radiation responses. Oncogene 95 12947392
2017 Genomic alterations of ERBB receptors in cancer: clinical implications. Oncotarget 91 29371993
2013 Diarrhea associated with afatinib: an oral ErbB family blocker. Expert review of anticancer therapy 87 23506556
2002 The EGF/ErbB receptor family and apoptosis. Growth factors (Chur, Switzerland) 85 11999214
1998 The oncogenic ErbB-2/ErbB-3 heterodimer is a surrogate receptor of the epidermal growth factor and betacellulin. Oncogene 79 9546426
2006 Epidermal growth factor receptor (ErbB1) expression in prostate cancer progression: correlation with androgen independence. The Prostate 78 16741920
2008 Interaction of antibodies with ErbB receptor extracellular regions. Experimental cell research 75 18992239
2000 Evolutionary analysis of the ErbB receptor and ligand families. Journal of molecular evolution 75 10824084
2009 Resistance to EGF-R (erbB-1) and VEGF-R modulating agents. European journal of cancer (Oxford, England : 1990) 73 19124237
2006 Expression and genomic status of EGFR and ErbB-2 in alveolar and embryonal rhabdomyosarcoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 72 16729016
2010 ErbB signaling in cardiac development and disease. Seminars in cell & developmental biology 71 20933094
2014 SOX9 regulates ERBB signalling in pancreatic cancer development. Gut 70 25336113
2011 Targeting the HER/EGFR/ErbB family to prevent breast cancer. Cancer prevention research (Philadelphia, Pa.) 70 21816844
2002 HER (erbB) tyrosine kinase inhibitors in the treatment of breast cancer. Seminars in oncology 70 12138392
2013 The role of EGFR and ErbB family related proteins in the oligodendrocyte specification in germinal niches of the adult mammalian brain. Frontiers in cellular neuroscience 69 24381541
2006 Lessons from the drug discovery of lapatinib, a dual ErbB1/2 tyrosine kinase inhibitor. Current topics in medicinal chemistry 68 16719802
2007 New molecular targets for hepatocellular carcinoma: the ErbB1 signaling system. Liver international : official journal of the International Association for the Study of the Liver 67 17311611
2008 The role of protease activity in ErbB biology. Experimental cell research 63 19013149
2004 erbB-1 and erbB-4 receptors act in concert to facilitate female sexual development and mature reproductive function. Endocrinology 61 15591145
2010 Cytohesins are cytoplasmic ErbB receptor activators. Cell 59 20946980
2003 Investigation of ErbB1 and ErbB2 expression for therapeutic targeting in primary liver tumours. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 58 12846405
2006 Modeling the effects of HER/ErbB1-3 coexpression on receptor dimerization and biological response. Biophysical journal 57 16533841
2011 Expression and function of ErbB receptors and ligands in the pituitary. Endocrine-related cancer 56 21917845
2007 Differential ErbB1 signaling in squamous cell versus basal cell carcinoma of the skin. The American journal of pathology 55 17525275
2001 Anti-ErbB-2 monoclonal antibodies and ErbB-2-directed vaccines. Cancer immunology, immunotherapy : CII 55 11807621
2021 FBXL2 counteracts Grp94 to destabilize EGFR and inhibit EGFR-driven NSCLC growth. Nature communications 54 34635651
2018 USP22 promotes resistance to EGFR-TKIs by preventing ubiquitination-mediated EGFR degradation in EGFR-mutant lung adenocarcinoma. Cancer letters 52 29981430
2017 The Role of ErbB Receptors in Infection. Trends in microbiology 52 28522156
2003 c-erbB-4/HER4: friend or foe? The Journal of pathology 51 12845622
2001 Localization and modulation of ErbB receptor tyrosine kinases. Current opinion in cell biology 48 11248544
2015 NEU3 activity enhances EGFR activation without affecting EGFR expression and acts on its sialylation levels. Glycobiology 47 25922362
2003 Metalloprotease-dependent ErbB ligand shedding in mediating EGFR transactivation and vascular remodelling. Biochemical Society transactions 47 14641025
2019 Grb7, a Critical Mediator of EGFR/ErbB Signaling, in Cancer Development and as a Potential Therapeutic Target. Cells 46 31083325
2017 ERBB signaling attenuates proinflammatory activation of nonclassical monocytes. American journal of physiology. Heart and circulatory physiology 44 28235789
2006 Mechanisms of curcumin- and EGF-receptor related protein (ERRP)-dependent growth inhibition of colon cancer cells. Nutrition and cancer 44 17044774
2008 ARAP1 regulates endocytosis of EGFR. Traffic (Copenhagen, Denmark) 42 18939958
2020 Discovery of a novel EGFR ligand DPBA that degrades EGFR and suppresses EGFR-positive NSCLC growth. Signal transduction and targeted therapy 41 33033232
2008 Effector mechanisms of therapeutic antibodies against ErbB receptors. Current opinion in immunology 40 18585454
2020 EGFR activity addiction facilitates anti-ERBB based combination treatment of squamous bladder cancer. Oncogene 39 32978523
2012 Quantification of differential ErbB1 and ErbB2 cell surface expression and spatial nanoclustering through plasmon coupling. Nano letters 39 22587495
2003 ErbB1 and prostate cancer: ErbB1 activity is essential for androgen-induced proliferation and protection from the apoptotic effects of LY294002. The Prostate 39 12746839
2009 ERBB1 and ERBB2 have distinct functions in tumor cell invasion and intravasation. Clinical cancer research : an official journal of the American Association for Cancer Research 38 19458057
2010 E3 ubiquitin ligases in ErbB receptor quantity control. Seminars in cell & developmental biology 36 20868762
2011 Targeting ErbB receptors in high-grade glioma. Current pharmaceutical design 35 21827413
2019 Second-generation EGFR and ErbB tyrosine kinase inhibitors as first-line treatments for non-small cell lung cancer. OncoTargets and therapy 34 31496745
2001 Truncated ErbB2 receptor enhances ErbB1 signaling and induces reversible, ERK-independent loss of epithelial morphology. International journal of cancer 34 11668496
2022 EGFR ligand shifts the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastoma by suppressing invasion through BIN3 upregulation. Nature cell biology 33 35915159
2021 The immune microenvironment in EGFR- and ERBB2-mutated lung adenocarcinoma. ESMO open 33 34487971
2008 Cardiac ErbB-1/ErbB-2 mutant expression in young adult mice leads to cardiac dysfunction. American journal of physiology. Heart and circulatory physiology 33 18599591
1997 Roles of ErbB-3 and ErbB-4 in the physiology and pathology of the mammary gland. Journal of mammary gland biology and neoplasia 33 10882304
2006 ErbB receptors and their ligands in the breast. Expert reviews in molecular medicine 32 16984691
2009 MEK and EGFR inhibition demonstrate synergistic activity in EGFR-dependent NSCLC. Cancer biology & therapy 31 19305165
2000 Neuregulins and erbB receptor expression in adult human oligodendrocytes. Glia 31 11102970
2015 Targeting HER (ERBB) signaling in head and neck cancer: An essential update. Molecular aspects of medicine 30 26163475
2013 Molecular interactions of ErbB1 (EGFR) and integrin-β1 in astrocytoma frozen sections predict clinical outcome and correlate with Akt-mediated in vitro radioresistance. Neuro-oncology 29 23595626
2011 Protein-intrinsic and signaling network-based sources of resistance to EGFR- and ErbB family-targeted therapies in head and neck cancer. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 29 21920801
2015 ErbB polymorphisms: insights and implications for response to targeted cancer therapeutics. Frontiers in genetics 28 25699077
2014 A new class of protein cancer biomarker candidates: differentially expressed splice variants of ERBB2 (HER2/neu) and ERBB1 (EGFR) in breast cancer cell lines. Journal of proteomics 28 24802673
2020 EGFR and anti-EGFR nanobodies: review and update. Journal of drug targeting 27 33210573
2004 The role of ErbB inhibitors in trastuzumab resistance. The oncologist 27 15163843
2020 ErBb Family Proteins in Cholangiocarcinoma and Clinical Implications. Journal of clinical medicine 25 32708604
2019 Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation. eLife 25 31613219
2014 The spatiotemporal organization of ErbB receptors: insights from microscopy. Cold Spring Harbor perspectives in biology 25 24370847
2010 Targeting erbB receptors. Seminars in cell & developmental biology 25 20850557
2002 Expression of ERRP in normal and neoplastic pancreata and its relationship to clinicopathologic parameters in pancreatic adenocarcinoma. Pancreas 24 12409827

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