As we have just seen, both yeasts and higher eukaryotic cells contain a Ras/MAP kinase signaling pathway that is activated by extracellular protein signals and culminates in the MAP kinase–mediated phosphorylation of transcription factors and other signaling proteins, which together trigger specific changes in cell behavior. Importantly, all eukaryotes possess multiple highly conserved MAP kinase pathways that are activated by different extracellular signals and that activate different MAP kinase proteins that phosphorylate different transcription factors; these transcription factors, in turn, trigger different changes in cell division, differentiation, or function. Mammalian MAP kinases include Jun N-terminal kinases (JNKs) and p38 kinases, which are activated by signaling pathways in response to various types of stresses and which phosphorylate various transcription factors and other types of signaling proteins that affect cell division.

Current genetic and biochemical studies in the mouse and Drosophila are aimed at determining which MAP kinases mediate which responses to which signals in higher eukaryotes. This goal has already been accomplished in large part for the simpler organism S. cerevisiae. Each of the six MAP kinases encoded in the S. cerevisiae genome has been assigned by genetic analyses to specific signaling pathways triggered by various extracellular signals, such as pheromones, high osmolarity, starvation, hypotonic shock, and carbon or nitrogen deprivation. As an example, one yeast MAP kinase cascade, known as the osmoregulatory pathway, is shown in Figure 16-27b; this pathway results in activation of the MAP kinase Hog1, which in turn phosphorylates and activates proteins that induce expression of genes essential for yeast to survive in a medium of high osmotic strength.

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A complication arises because in both yeasts and higher eukaryotic cells, different MAP kinase cascades share some common components. For instance, the MEKK Ste11 functions in three yeast signaling pathways: the mating pathway, the osmoregulatory pathway, and the filamentous growth pathway, which is induced by starvation. Nevertheless, each pathway activates a distinct MAP kinase. Similarly, in mammalian cells, common upstream signal-transducing proteins participate in activating multiple JNKs.

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Once the sharing of components among different MAP kinase pathways was recognized, researchers wondered how the specificity of the cellular responses to particular signals is achieved. Studies with yeast provided the initial evidence that pathway-specific scaffold proteins enable the signal-transducing kinases in a particular pathway to interact with one another, but not with kinases in other pathways. For example, the scaffold protein Ste5 stabilizes a large complex that includes the kinases in the mating pathway; similarly, the Pbs2 scaffold is used for the kinase cascade in the osmoregulatory pathway (see Figure 16-27). Ste11 participates in both pathways, but in each one, it is constrained within a large complex that forms in response to a specific extracellular signal, so that signaling downstream from Ste11 is restricted to the complex in which it is localized. As a result, exposure of yeast cells to mating factors induces activation of a single MAP kinase, Fus3, whereas exposure to a high osmolarity induces activation of a different MAP kinase, Hog1.

Scaffolds for MAP kinase pathways are well documented in yeast, fly, and worm cells, but their presence in mammalian cells has been difficult to demonstrate. Perhaps the best-documented scaffold protein in metazoans is Ksr (kinase suppressor of Ras). Ksr functions as a molecular scaffold by binding several signaling components of the MAP kinase cascade, including both MEK and MAP kinase; and thus can enhance MAP kinase activation by regulating the efficiency of these interactions. In Drosophila, loss of the Ksr homolog blocks signaling by a constitutively active Ras protein, suggesting a positive role for Ksr in the Ras/MAP kinase pathway in fly cells. In nematodes, Ksr is required for Ras-mediated signaling during several developmental pathways. The signal specificity of different MAP kinases in mammalian cells may arise from their association with Ksr proteins or other scaffold-like proteins, but much additional research is needed to test this possibility.