Almost all receptor tyrosine kinases and cytokine receptors activate the Ras/MAP kinase pathway (see Figure 16-6b). The monomeric Ras protein belongs to the GTPase superfamily of intracellular switch proteins (see Figure 15-5). Activated Ras promotes the formation of a signal transduction complex, containing three sequentially acting protein kinases, at the cytosolic surface of the plasma membrane. This kinase cascade culminates in activation of certain members of the MAP kinase family, which can translocate into the nucleus and phosphorylate many different proteins. Among the target proteins for MAP kinase are transcription factors that regulate the expression of proteins with important roles in the cell cycle and in cell differentiation. Importantly, different cell-surface receptors can activate different signaling pathways that result in activation of different members of the MAP kinase family.

Because an activating mutation in an RTK, Ras, or a protein in the MAP kinase cascade is found in almost all types of human tumors, the RTK/Ras/MAP kinase pathway has been subjected to extensive study, and a great deal is known about the components of this pathway (see Chapter 24). We begin our discussion by reviewing how Ras cycles between the active and inactive state. We then describe how Ras is activated and passes a signal to the MAP kinase pathway. Finally, we examine recent studies indicating that both yeasts and cells of higher eukaryotes contain multiple MAP kinase pathways, and we consider the ways in which cells keep different MAP kinase pathways separate from one another through the use of scaffold proteins.