Extracellular signals usually activate MAP kinases only transiently, and the period during which the kinase remains active influences the response. When EGF activates its receptors in a neural precursor cell line, for example, Erk MAP kinase activity peaks at 5 minutes and rapidly declines, and the cells later go on to divide. By contrast, when NGF activates its receptors on the same cells, Erk activity remains high for many hours, and the cells stop proliferating and differentiate into neurons.
Many factors influence the duration and other features of the signaling response, including positive and negative feedback loops, which can combine to
Figure 15–49 The MAP kinase module activated by Ras. The three-component module begins with a MAP kinase kinase kinase called Raf. Ras recruits Raf to the plasma membrane and helps activate it. Raf then activates the MAP kinase kinase Mek, which then activates the MAP kinase Erk. Erk in turn phosphorylates a variety of downstream proteins, including other protein kinases, as well as transcription regulators in the nucleus. The resulting changes in protein activities and gene expression cause complex changes in cell behavior.
give responses that are either graded or switchlike and either brief or long lasting. In an example illustrated earlier, in Figure 15–19, MAP kinase activates a complex positive feedback loop to produce an all-or-none, irreversible response when frog oocytes are stimulated to mature by a brief exposure to the extracellular signal molecule progesterone. In many cells, MAP kinases activate a negative feedback loop by increasing the concentration of a protein phosphatase that removes the phosphate from MAP kinase. The increase in the phosphatase results from both an increase in the transcription of the phosphatase gene and the stabilization of the enzyme against degradation. In the Ras–MAP-kinase pathway shown in Figure 15–49, Erk also phosphorylates and inactivates Raf, providing another negative feedback loop that helps shut off the MAP kinase module.
Three-component MAP kinase signaling modules operate in all eukaryotic cells, with different modules mediating different responses in the same cell. In budding yeast, for example, one such module mediates the response to mating pheromone, another the response to starvation, and yet another the response to osmotic shock. Some of these MAP kinase modules use one or more of the same kinases and yet manage to activate different effector proteins and hence different responses. As discussed earlier, one way in which cells avoid cross-talk between the different parallel signaling pathways and ensure that each response is specific is to use scaffold proteins (see Figure 15–10A). In budding yeast cells, such scaffolds bind all or some of the kinases in each MAP kinase module to form a complex and thereby help to ensure response specificity (Figure 15–50).
Mammalian cells also use this scaffold strategy to prevent cross-talk between different MAP kinase modules. At least five parallel MAP kinase modules can operate in a mammalian cell. These modules make use of at least 12 MAP kinases, 7 MAPKKs, and 7 MAPKKKs. Two of these modules (terminating in MAP kinases called JNK and p38) are activated by different kinds of cell stresses, such as ultraviolet (UV) irradiation, heat shock, and osmotic stress, as well as by inflammatory cytokines; others mainly mediate responses to signals from other cells.
Although the scaffold strategy provides precision and avoids cross-talk, it reduces the opportunities for amplification and spreading of the signal to different parts of the cell, which require at least some of the components to be diffusible. It is unclear to what extent the individual components of MAP kinase modules can dissociate from the scaffold during the activation process to permit amplification.