Mitogen-activated protein kinases: specific messages from ubiquitous messengers

HJ Schaeffer, MJ Weber - Molecular and cellular biology, 1999 - Am Soc Microbiol
HJ Schaeffer, MJ Weber
Molecular and cellular biology, 1999Am Soc Microbiol
Signal transduction networks allow cells to perceive changes in the extracellular
environment and to mount an appropriate response. Mitogen-activated protein kinase
(MAPK) cascades are among the most thoroughly studied of signal transduction systems
and have been shown to participate in a diverse array of cellular programs, including cell
differentiation, cell movement, cell division, and cell death. A key question in studies of this
cascade is, how does a ubiquitously activated regulatory enzume generate a specific and …
Signal transduction networks allow cells to perceive changes in the extracellular environment and to mount an appropriate response. Mitogen-activated protein kinase (MAPK) cascades are among the most thoroughly studied of signal transduction systems and have been shown to participate in a diverse array of cellular programs, including cell differentiation, cell movement, cell division, and cell death. A key question in studies of this cascade is, how does a ubiquitously activated regulatory enzume generate a specific and biologically appropriate cellular response? In this review we describe recent findings that provide insight into ways that the regulation, structure, and localization of MAPKs and the participation of adapters and scaffolds can help determine biological outcomes. MAPK cascades are evolutionarily conserved in all eucaryotes and play a key role in the regulation of gene expression as well as cytoplasmic activities. They typically are organized in a three-kinase architecture consisting of a MAPK, a MAPK activator (MEK, MKK, or MAPK kinase), and a MEK activator (MEK kinase [MEKK] or MAPK kinase kinase). Transmission of signals is achieved by sequential phosphorylation and activation of the components specific to a respective cascade. In the yeast Saccharomyces cerevisiae, five MAPK modules have been described; they regulate mating, filamentation, high-osmolarity responses, cell wall remodeling, and sporulation (Fig. 1A)(reviewed in references 56 and 77). In mammalian systems five distinguishable MAPK modules have been identified so far (Fig. 1B). These include the extracellular signal-regulated kinase 1 and 2 (ERK1/2) cascade, which preferentially regulates cell growth and differentiation, as well as the c-Jun N-terminal kinase (JNK) and p38 MAPK cascades, which function mainly in stress responses like inffammation and apoptosis (reviewed in references 57, 74, and 103). Moreover, MAPK pathways control several developmental programs, such as morphogenesis and spatial patterning in Dictyostelium amoebae (17, 45), eye development in Drosophila melanogaster (124), vulva induction in Caenorhabditis elegans (113), and T-cell development in mammals (31). Individual MAPK modules generally can signal independently from each other, and this specificity is manifested in distinct physiologic responses. This is most obvious when studying MAPK signaling in S. cerevisiae. Here a particular extracellular event characteristically activates a specific MAPK module and initiates a unique cellular program (reviewed in references 56 and 77). For example, stimulation of cells with pheromone leads to the activation of the pheromone response pathway (STE11, STE7, and FUS3)(Fig. 2), which ultimately results in cell cycle arrest and the induction of mating-specific genes. However, related MAPKs whose modules share some components with the pheromone response pathway are not affected by pheromone stimulation but are activated only in response to the appropriate stimulus. For example, under conditions of high osmolarity Ste11 can lead to activation of Hog1 but does not induce mating-specific genes. Conversely, conditions that activate the filamentation pathway (which utilizes STE11 and STE7) induce only genes that regulate filamentous growth without triggering pheromone responses or responses to high osmolarity. These observations suggest that yeast cells have developed efficient mechanisms to generate pathway specificity and to successfully suppress cross talk, even when individual components participate in more than one signaling pathway.
In metazoan cells the problem is more complex because each cell is …
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