EGFR Signaling

The epidermal growth factor (EGF) family of receptor tyrosine kinases consists of four receptors, EGFR (erb1), HER2 (erb2), HER3 (erb3) and HER4 (erb4). Members of the EGF-R family contain a cytoplasmic tyrosine kinase domain, a single transmembrane domain, and an extracellular domain that is involved in ligand binding and receptor dimerization. Binding an extracellular ligand or as a result of environmental stimuli, such as ultraviolet light, will induce EGFR to form homo- or heterodimers with other family members which activates its intracellular tyrosine kinase domain and autophosphorylate its C-terminal tyrosine residues. This stabilizes the active receptor conformation and creates phosphotyrosine-docking sites for proteins that transduce signals within the cell. Transduction by activated EGFR leads to downstream effects on proteins such as phosphatidyl 3-kinase (PI3-K), Phospholipase C-gamma1(PLC-gamma1), Akt, Ras, Raf and mitogen-activated protein kinase (MAPK). These entities are associated with cell proliferation, motility and survival. The downstream activation of ERK and JNK signaling pathways, in turn, activate transcription factors, such as c-fos, AP-1, and Elk-1, that promote gene expression and contribute to cell proliferation. Upon binding to activated EGFR, PLC-γ1, a SH2-containing signal protein, is activated and phosphorylated at tyrosine residues. This leads to increased enzymatic hydrolysis of phosphatidylinositol-4, 5-bisphosphate (PI-4,5P2) to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol. This signal transduction cascade of activated EGFR through PLC-gamma1 has been implicated in various cellular functions including differentiation, growth, motility, endocytosis as well as association to breast and prostate cancers. A third pathway, the PI-3 kinase dependent Akt signaling cascade, has been a widely studied transduction pathway triggered by activated EGFR. The PI 3-kinases are ubiquitous, heterodimeric enzymes that play a pivotal role in the regulation of many cellular processes, including cell growth, motility, proliferation, and survival. Activated PI 3-kinase phosphorylates phosphoinositol (PI) substrates to produce PI(3)P, PI(3,4)P2, and PI(3,4,5)P3. These molecules act as second messengers and recruit the PI 3-K-dependent serine/threonine kinases (PDK1) and Akt from the cytoplasm to the plasma membrane. Dysregulated PI 3-K signaling pathway has been reported in a variety of human tumors. Due to their involvement in various forms of cancers, EGFR/PTKs and its downstream signaling cascades have become prominent targets for therapeutic intervention.

EGFR Signaling Subcategories