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▲ FIGURE 14-25 Overview of five MAP kinase pathways in S. cerevisiae. Each pathway is triggered by a specific extracellular signal and leads to activation of a single different MAP kinase, which mediates characteristic cellular responses. Formation of pathway-specific complexes of MAP kinases and scaffold proteins prevents "cross talk" between pathways containing a common component such as the MEKK Ste11, which occurs in the mating, filamentation, and osmoregulatory pathways (see Figure 14-24). [Adapted from H. D. Madhani and G. R. Fink, 1998, Trends Genet. 14(4):152.]

For example, the scaffold protein Ste5 stabilizes a large complex that includes Ste11 and other kinases in the mating pathway (see Figure 14-24). Different Ste11-binding scaffold proteins, however, stabilize signaling complexes containing the components of the filamentation and osmoregulation pathways. In each pathway in which Ste11 participates, it is constrained within a large complex that forms in response to a specific extracellular signal, and 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 or starvation induces activation of different MAP kinases (see Figure 14-25).

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 is Ksr (kinase suppressor of Ras), which binds both MEK and MAP kinase. Loss of the Drosophila Ksr homolog blocks signaling by a constitutively active Ras protein, suggesting a positive role for Ksr in Ras-MAP kinase signaling in fly cells. Although knockout mice that lack Ksr are grossly normal, activation of MAP ki-nase by growth factors or cytokines is lower than normal in several types of cells in these animals. This finding suggests that Ksr functions as a scaffold that enhances but is not essential for Ras-MAP kinase signaling in mammalian cells. other proteins also have been found to bind to specific mammalian MAP kinases. Thus the signal specificity of different MAP kinases in animal cells may arise from their association with various scaffold-like proteins, but much additional research is needed to test this possibility.

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