Nuclear Signaling of EGFR and EGFRvIII in Glioblastoma

Abstract

The pivotal role of kinases in signal transduction and cellular regulation has lent them considerable appeal as therapeutic targets across a broad spectrum of cancers. The epidermal growth factor receptor (EGFR) was the first receptor tyrosine kinase to be discovered and remains the most investigated. Most of the mechanistic principles of receptor tyrosine kinases were first established with the EGFR family as a model. EGFR is a single pass transmembrane receptor with two extracellular, cysteine-rich regions involved in ligand binding, and intervening region important for receptor dimerization, an intracellular tyrosine kinase domain, and a number of intracellular sites for autophosphorylation, phosphorylation by other kinases, and docking of signaling components. Three additional EGFR family members have been identified, human epidermal growth factor receptor (erbB or HER) 2, 3 and 4. In many cell types, including those of epithelial and mesenchymal lineages, receptors of the HER family transduce signals from the cell surface to the intracellular domain, regulating normal cell growth, lineage determination, repair and functional differentiation. A range of growth factors serves as ligands for these receptors, although none have been identified for the HER2 receptor. Ligands for HER1/EGFR include epidermal growth factor (EGF) and transforming growth factor-α (TGF-α), and heregulins serve as ligands for both HER3 and HER4. Binding of a ligand to a HER family member leads to receptor homodimerization, or heterodimerization with another HER receptor, bringing about receptor phosphorylation. Ligand binding to HER1, HER3 or HER4 induces rapid receptor dimerization, with a marked preference for HER2 as a partner(Graus-Porta et al., 1997). Moreover, HER2-containing heterodimers generate intracellular signals that are significantly more potent than signals emanating from other HER combinations. Of the receptor dimers, HER3 homodimers cannot initiate signal transduction.The differing signaling characteristics of the HER family members are thought to be due to their different ligand-binding affinities and the type of phosphorylated homoor heterodimer formed, and the resulting intracellular signaling events. Two of the key pathways involved in this cascade are the ras-raf-mitogen-activated protein kinase (MAPK) pathway, which affects DNA synthesis and cell proliferation, and the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway, which plays a role in cell metabolism and survival (Yarden and Sliwkowski, 2001; Bange et al., 2001).