Ras-MAP kinase signaling pathways and control of cell proliferation: relevance to cancer therapy

The mitogen-activated protein (MAP) kinase pathways represent several families of signal transduction cascades that mediate information provided by extracellular stimuli. MAP kinase pathways regulate a wide range of physiological responses, including cell proliferation, apoptosis, cell differentiation, and tissue development. Constitutive activation of MAP kinase proteins in experimental models has been shown to cause cell transformation and is implicated in tumorigenesis. Of clinical importance, MAP kinase pathways are regulated by Ras G-proteins, which are found to be mutated and constitutively active in approximately 30% of all human cancers. Thus, a major goal in the treatment of cancer is the development of specific compounds that target Ras and critical downstream signaling proteins responsible for uncontrolled cell growth. A variety of biochemical, molecular, and structural approaches have been used to develop drug compounds that target signaling proteins important for MAP kinase pathway activation. These compounds have been useful tools for identifying the mechanisms of MAP kinase pathway signaling and hold promise for clinical use. This review will present an overview of the major proteins involved in Ras and MAP kinase signaling pathways and their function in regulating cell cycle events and proliferation. In addition, some of the relevant compounds that have been developed to inhibit the activities of these proteins and MAP kinase signaling are discussed.