Phosphorylation of EGFR by SRC kinase Pro-EGF is cleaved to form mature EGF EGFR binds EGF ligand EGFR dimerization EGFR autophosphorylation Signaling by EGFR Authored: Jassal, B, Castagnoli, L, 2008-02-28 00:00:00 Edited: Orlic-Milacic, Marija, 2011-08-25 Epidermal Growth Factor Receptor (EGFR) signaling GENE ONTOLOGYGO:0007173 Pubmed10404636 Pubmed10459005 Pubmed12297041 Pubmed15142631 Pubmed21252999 Reactome Database ID Release 43177929 Reactome, http://www.reactome.org ReactomeREACT_9417 Reviewed: Muthuswamy, S, Heldin, CH, 2008--0-2- 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 Y1045 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. For a recent review of EGFR signaling, please refer to Avraham and Yarden, 2011. EGFR interacts with phospholipase C-gamma GRB2 events in EGFR signaling GAB1 signalosome SHC1 events in EGFR signaling EGFR downregulation PathwayStep3926 PathwayStep3906 PathwayStep3863 PathwayStep3858 PathwayStep3820 PathwayStep3819 PathwayStep3817 PathwayStep3818 PathwayStep3816 PathwayStep3842