Figure 1.
EGFR signaling: EGFR is activated by ligand binding and subsequent receptor heterodimerization or homodimerization which results in auto-phosphorylation of tyrosine residues and binding of adaptor molecules like shc, gab -1 to the cytoplasmic domain. Intracellular signaling pathways include RAS/ Raf-1/ MAPK, PI3K/AKT, PLC- γ /PKC pathways which require the adaptor molecules for signaling. Src and STAT pathways are directly activated by phosphorylated receptors. Alternately, the activated receptors can undergo endocytosis followed by importin-mediated translocation to the nucleus, and co-transcriptional activation of key genes like Cox-2, iNOS, aurora kinase-A and cyclin-D1. All pathways lead to changes in gene expression and stimulation of cell proliferation, survival, invasion and metastasis. EGFR manipulation can be approached extracellularly by monoclonal antibodies through inhibiton of ligand binding and intracellularly, by tyrosine kinase inhibitor (TKI), which compete with ATP binding to receptor kinase for activation. Shc, Src homology-2 domain containing transforming protein-1; Grb2, growth factor receptor bound protein-2; Sos son of sevenless; Ras, rat sarcoma; Raf-1, rapidly accelerated fibrosarcoma; MAPK, mitogen activated protein kinase; Gab-1, Grb2 associated binding protein-1; PI3K, phosphoinositide 3 kinase; AKT, protein kinase B; Src, sarcoma gene; FAK, focal adhesion kinase; STAT, signal transducer and activator of transcription; TKI, tyrosine kinase inhibitor; PLC-γ, phospholipase C-γ; phapatidylinositol 4,5-bisphosphate (PIP2); IP3, inositol 1,3,5–triphosphate; DAG, 1,2-diacylglycerol; PKC, protein kinase C; ER, endoplasmic reticulum.