Activation of genes required for mating
► FIGURE 14-24 Kinase cascade that transmits signals downstream from mating factor receptors in S. cerevisiae.
The receptors for yeast a and a mating factors are coupled to the same trimeric G protein. Ligand binding leads to activation and dissociation of the G protein (see Figure 13-10). In the yeast mating pathway, the dissociated Gp7 activates a protein kinase cascade analogous to the cascade downstream of Ras that leads to activation of MAR kinase (see Figure 14-21). The final component, Fus3, is functionally equivalent to MAR kinase (MARK) in higher eukaryotes. Association of several kinases with the Ste5 scaffold contributes to specificity of the signaling pathway by preventing phosphorylation of other substrates. [See A. Whitmarsh and R. Davis, 1998, Trends Biochem. Sci. 23:481, and H. Dohlman and J. Thorner, 2001, Ann. Rev. Biochem. 70:703.]
Ras. The components of this cascade were uncovered mainly through analyses of mutants that possess functional a and a receptors and G proteins but are sterile (Ste), or defective in mating responses. The physical interactions between the components were assessed through immunoprecipitation experiments with extracts of yeast cells and other types of studies. Based on these studies, scientists have proposed the kinase cascade depicted in Figure 14-24. Gpy, which is tethered to the membrane via the y subunit, binds to and activates Ste20, a protein kinase that in turn phosphorylates and activates Ste11, a serine/threonine kinase analogous to Raf and other mammalian MEKK proteins. Activated Ste11 then phosphorylates Ste7, a dual-specificity MEK that then phosphorylates and activates Fus3, a serine/threonine kinase equivalent to MAP kinase. After translocation to the nucleus, Fus3 promotes expression of target genes by phosphorylating and thus activating nuclear transcription factors (e.g., Ste12) that control expression of proteins involved in mating-specific cellular responses. The other component of the yeast mating cascade, Ste5, interacts with Gpy as well as Ste11, Ste7, and Fus3. Ste5 has no obvious catalytic function and acts as a scaffold for assembling other components in the cascade.
Scaffold Proteins Isolate Multiple MAP Kinase Pathways in Eukaryotic Cells
In addition to the MAP kinases discussed above, both yeasts and higher eukaryotic cells contain other members of the MAP kinase superfamily. These include mammalian Jun N-terminal kinases (JNKs) and p38 kinases, which become activated by various types of stresses, and six yeast kinases described below. Collectively referred to as MAP kinases, all these proteins are serine/threonine kinases that are activated in the cytosol in response to specific extracellular signals and then translocate to the nucleus. Activation of all known MAP kinases requires phosphorylation of both a tyrosine and a threonine residue in the lip region (see Figure 14-22). Similarly, all eukaryotic cells contain several members of the dual-specificity MEK kinase superfamily that phosphorylate different members of the MAP kinase superfamily. Thus in all eukaryotic cells, binding of a wide variety of extracellular signaling molecules triggers highly conserved kinase cascades culminating in activation of a particular MAP kinase. The different MAP kinases mediate specific cellular responses, including morphogenesis, cell death, and stress responses.
Current genetic and biochemical studies in the mouse and Drosophila are aimed at determining which MAP kinases are required for mediating the response to which signals in higher eukaryotes. This 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, starvation, high osmolarity, hypotonic shock, and carbon/nitrogen deprivation. Each of these MAP kinases mediates very specific cellular responses (Figure 14-25).
In both yeasts and higher eukaryotic cells, different MAP kinase cascades share some common components. For instance, Ste11 functions in the yeast signaling pathways that regulate mating, filamentous growth, and osmoregulation. Nevertheless, each pathway activates its own MAP kinase: Fus3 in the mating pathway, Kss1 in the filamentation pathway, and Hog1 in the osmoregulation pathway. Similarly, in mammalian cells, common upstream signal-transducing proteins participate in activating multiple JNK kinases.
Once the sharing of components among different MAP kinase pathways was recognized, researchers wondered how the specificity of the cellular responses to particular signals could be 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.
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