Raf kinases in lung tumor development.

Abstract

The specific response of a cell to an extracellular signal is mediated by signaling cascades that relay the excitation of one or more receptor(s) to the co-ordinated activity of a set of effector molecules which regulate cell division and growth and prevent an intrinsic cell death program. The small G protein Ras is an essential component in the transduction of extracellular signals. Raf is a serine/threonine protein kinase and a direct downstream effector of Ras, which is activated to its GTP-bound state in response to various ligands binding to their cognate receptors. Raf kinases are located at the head of one of the best characterized signaling cascades, the Raf-MEK-ERK kinase cascade which is involved in many signaling processes (Fig. 1). In multicellular organisms, the family of Raf kinases consists of three members, ARaf, BRaf and CRaf. Although all of these Raf kinases phosphorylate MEK, they differ in the way they are activated (Hagemann and Rapp, 1999). For example, cAMP potentiates BRaf kinase activity but inhibits CRaf (Erhardt et al., 1995; Cook and McCormick, 1993; Dhillon et al., 2002). Genetic and biochemical data also indicate that isoform specific functions exist for Raf kinases which correlate with specific protein interactions (Hagemann and Rapp, 1999). Recent findings regarding interaction of Raf with lipid membrane microdomains (Hekman et al., 2002; Raabe and Rapp, 2002) and the discovery of Rab binding scaffold proteins that may be regulated by MAP kinases in their ability to activate actin comet formation for vesicle transport (Kerkhoff et al., 2001; Eden et al., 2002) have suggested to us a revised model for membrane translocation of Raf (Fig. 2). The model incorporates suggestions on the role of rafts in protein sorting (Simons and Ikonen, 1997) and anticipates a self organizing element in the maturation of signaling complexes. As pictured in Fig. 2, joint sorting of Raf, Ras and upstream signal regulators, e.g., growth factor receptors together with elements of the Ras cycle as well as effectors of Ras/Raf signaling such as MEK and ERK (perhaps