Introduction

The Mitogen-Activated Protein Kinase (MAPK or ERK) pathway is a central regulator of cellular proliferation and is frequently activated in human tumors. This pathway consists of the RAF, MEK (mitogen-activated protein kinase (MAPK) kinase) and ERK (extra-cellular signal-regulated kinase) kinases (see Figure 22.1). In normal cells, the RAS (K-, N-, and HRAS) small GTPase proteins activate the RAF kinases (ARAF, BRAF, and CRAF/RAF1) by regulating their cellular localization and homo- and heterodimerization (1). Recruitment of RAF to the plasma membrane by activated RAS induces an “open” conformation, which facilitates its phosphorylation and resulting kinase activation (2). Activation of RAF initiates a series of phosphorylation events, including the phosphorylation of the MEK1 and MEK2, and ERK1 and ERK2 kinases. Phosphorylated ERK in turn regulates several cellular processes such as cell-cycle progression and survival through phosphorylation of nuclear transcription factors and cytosolic proteins (3–8).

The ERK pathway operates as a negative feedback loop in which activation of the pathway is balanced by feedback regulatory elements including the dual-specificity phosphatases (DUSPs) and the Sprouty family proteins, the expression of which are ERK dependent (9,10). ERK pathway activity is also regulated by cross-talk with parallel signaling pathways such as the PI3K/AKT pathway and by scaffold proteins such as 14-3-3 that regulate RAF subcellular localization and stability (11).