EGFR signal transduction pathways. Three steps can be schematically defined in the activation of EGFR-dependent intracellular signaling. First, the binding of a receptor-specific ligand occurs in the extracellular portion of the EGFR or of one of the EGFR-related receptors (HER2, HER3, or HER4). Second, the formation of a functionally active EGFR-EGFR dimer (homodimer) or an EGFR-HER2, EGFR-HER3, or EGFR-HER4 dimer (heterodimer) causes the ATP-dependent phosphorylation of specific tyrosine residues in the EGFR intracellular domain. Third, this phosphorylation triggers a complex program of intracellular signals to the cytoplasm and then to the nucleus. The two major intracellular pathways activated by EGFR are the RAS-RAF-MEK-MAPK pathway, which controls gene transcription, cell-cycle progression from the G1 phase to the S phase, and cell proliferation, and the PI3K-Akt pathway, which activates a cascade of anti-apoptotic and prosurvival signals. bFGF, basic fibroblast growth factor, HB-EGF, heparin-binding EGF, MAPK, mitogen-activated protein kinase, PI3K, phosphatidylinositol 3,4,5-kinase, TGFa transforming growth factor alpha, and VEGF, vascular endothelial growth factor. Used with permission from: NEJM 2008 Ciardiello et al.).
Katzel et al. Journal of Hematology & Oncology 2009 2:2 doi:10.1186/1756-8722-2-2