Figure 15–50 The organization of two MAP kinase modules by scaffold proteins in budding yeast. Budding yeast have at least six three-component MAP kinase modules involved in a variety of biological processes, including the two responses illustrated here—a mating response and the response to high osmolarity. (A) The mating response is triggered when a mating factor secreted by a yeast of opposite mating type binds to a GPCR. This activates a G protein, the βγ complex of which indirectly activates the MAPKKK (kinase A), which then relays the response onward. Once activated, the MAP kinase (kinase C) phosphorylates and thereby activates several proteins that mediate the mating response, in which the yeast cell stops dividing and prepares for fusion. The three kinases in this module are bound to scaffold protein 1. (B) In a second response, a yeast cell exposed to a high-osmolarity environment is induced to synthesize glycerol to increase its internal osmolarity. This response is mediated by an osmolarity-sensing receptor protein and a different MAP kinase module bound to a second scaffold protein. (Note that the kinase domain of scaffold 2 provides the MAPKK activity of this module.) Although both pathways use the same MAPKKK (kinase A, green), there is no cross-talk between them because the kinases in each module are bound to different scaffold proteins, and the osmosensor is bound to the same scaffold protein as the particular kinase it activates.
Rho Family GTPases Functionally Couple Cell-Surface Receptors to the Cytoskeleton
Besides the Ras proteins, the other class of Ras superfamily GTPases that relays signals from cell-surface receptors is the large Rho family (see Table 15–5). Rho family monomeric GTPases regulate both the actin and microtubule cytoskeletons, controlling cell shape, polarity, motility, and adhesion (discussed in Chapter 16); they also regulate cell-cycle progression, gene transcription, and membrane transport. They play a key part in the guidance of cell migration and nerve axon outgrowth, mediating cytoskeletal responses to the activation of a special class of guidance receptors. We focus on this aspect of Rho family function here.
The three best-characterized family members are Rho itself, Rac, and Cdc42, each of which affects multiple downstream target proteins. In the same way as for Ras, GEFs activate and GAPs inactivate the Rho family GTPases; there are more than 80 Rho-GEFs and more than 70 Rho-GAPs in humans. Some of the GEFs and GAPs are specific for one particular family member, whereas others are less specific. Unlike Ras, which is membrane-associated even when inactive (with GDP bound), inactive Rho family GTPases are often bound to guanine nucleotide dissociation inhibitors (GDIs) in the cytosol, which prevent the GTPases from interacting with their Rho-GEFs at the plasma membrane.