Signaling by EGFR

Stable Identifier
R-HSA-177929
DOI
10.3180/R-HSA-177929.5
Type
Pathway
Species
Homo sapiens
Synonyms
Epidermal Growth Factor Receptor (EGFR) signaling
ReviewStatus
5/5
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Signaling by EGFR
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The epidermal growth factor receptor (EGFR) is one member of the ERBB family of transmembrane glycoprotein tyrosine receptor kinases (RTK). Binding of EGFR to its ligands induces conformational change that unmasks the dimerization interface in the extracellular domain of EGFR, leading to receptor homo- or heterodimerization at the cell surface. Dimerization of the extracellular regions of EGFR triggers additional conformational change of the cytoplasmic EGFR regions, enabling the kinase domains of two EGFR molecules to achieve the catalytically active conformation. Ligand activated EGFR dimers trans-autophosphorylate on tyrosine residues in the cytoplasmic tail of the receptor. Phosphorylated tyrosines serve as binding sites for the recruitment of signal transducers and activators of intracellular substrates, which then stimulate intracellular signal transduction cascades that are involved in regulating cellular proliferation, differentiation, and survival. Recruitment of complexes containing GRB2 and SOS1 to phosphorylated EGFR dimers either directly, through phosphotyrosine residues that serve as GRB2 docking sites, or indirectly, through SHC1 recruitment, promotes GDP to GTP exchange on RAS, resulting in the activation of RAF/MAP kinase cascade. Binding of complexes of GRB2 and GAB1 to phosphorylated EGFR dimers leads to formation of the active PI3K complex, conversion of PIP2 into PIP3, and activation of AKT signaling. Phospholipase C-gamma1 (PLCG1) can also be recruited directly, through EGFR phosphotyrosine residues that serve as PLCG1 docking sites, which leads to PLCG1 phosphorylation by EGFR and activation of DAG and IP3 signaling. EGFR signaling is downregulated by the action of ubiquitin ligase CBL. CBL binds directly to the phosphorylated EGFR dimer through the phosphotyrosine Y1069 (i.e. Y1045 in the mature protein) in the C-tail of EGFR, and after CBL is phosphorylated by EGFR, it becomes active and ubiquitinates phosphorylated EGFR dimers, targeting them for degradation. Positive regulation of EGFR signaling by direct association of EGFR with accessory proteins such as AAMP and FAM83B is being investigated. For review of EGFR signaling, please refer to Carpenter 1999, Wells 1999, Schlessinger 2002, Herbst 2004, Avraham and Yarden, 2011, Bartel et al. 2016, Uribe et al. 2021, Keflee et al. 2022.
Literature References
PubMed ID Title Journal Year
21252999 Feedback regulation of EGFR signalling: decision making by early and delayed loops

Avraham, R, Yarden, Y

Nat Rev Mol Cell Biol 2011
27221039 FAM83 proteins: Fostering new interactions to drive oncogenic signaling and therapeutic resistance

Bartel, CA, Parameswaran, N, Cipriano, R, Jackson, MW

Oncotarget 2016
15142631 Review of epidermal growth factor receptor biology

Herbst, RS

Int J Radiat Oncol Biol Phys 2004
36191627 Overview of the multifaceted resistances toward EGFR-TKIs and new chemotherapeutic strategies in non-small cell lung cancer

Dzul Keflee, R, Leong, KH, Ogawa, S, Bignon, J, Chan, MC, Kong, KW

Biochem Pharmacol 2022
10404636 EGF receptor

Wells, A

Int J Biochem Cell Biol 1999
10459005 Employment of the epidermal growth factor receptor in growth factor-independent signaling pathways

Carpenter, G

J Cell Biol 1999
12297041 Ligand-induced, receptor-mediated dimerization and activation of EGF receptor

Schlessinger, J

Cell 2002
34206026 EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance

Uribe, ML, Marrocco, I, Yarden, Y

Cancers (Basel) 2021
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Event Information
Go Biological Process
epidermal growth factor receptor signaling pathway (0007173)
Orthologous Events
Signaling by EGFR (Bos taurus)
Signaling by EGFR (Caenorhabditis elegans)
Signaling by EGFR (Canis familiaris)
Signaling by EGFR (Danio rerio)
Signaling by EGFR (Drosophila melanogaster)
Signaling by EGFR (Gallus gallus)
Signaling by EGFR (Mus musculus)
Signaling by EGFR (Rattus norvegicus)
Signaling by EGFR (Sus scrofa)
Signaling by EGFR (Xenopus tropicalis)
Cross References
BioModels Database
Authored
Jassal, B  (2008-02-28)
Castagnoli, L  (2008-02-28)
Reviewed
Muthuswamy, S  (2008-02-28)
Heldin, CH  (2008-02-28)
Hill, DP  (2023-11-08)
Created
Jassal, B  (2006-04-11)
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