Critical roles of the Raf/MEK/ERK pathway in apoptosis and drug resistance

The Ras/Raf/MEK/ERK pathway plays a critical role in the transmission of signals from growth factor receptors to the nucleus to regulate gene expression. Components of this pathway (e.g., Ras and B-Raf) are frequently mutated in human cancer. Mutations at upstream receptors (e.g., epidermal growth factor receptor [EGFR] and Flt-3) and chimeric chromosomal translocations (e.g., BCR-ABL), which transmit their signals through the Ras/Raf/MEK/ERK cascade were also frequently observed in human cancer. This pathway also interacts with other signaling pathways (e.g., PI3K/PTEN/Akt) to regulate cell growth. In some cells, mutation of PTEN may contribute to suppression of Raf/MEK/ERK because of the ability of Akt to phosphorylate and inactivate Raf-1. Other regulatory components of the Raf/MEK/ERK pathway (e.g., the Raf Kinase Inhibitor Protein, RKIP) may display altered expression during metastasis, which lead to activation of the pathway. This chapter describes the roles of the Raf/MEK/ERK pathway in signal transduction, prevention of apoptosis and induction of drug resistance.