The MAP Kinase signal transduction pathways

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Cells respond to extracellular signals by engaging a variety of intracellular signalling pathways, which trigger both immediate and long-term cell responses. The latter activate cascades that signal to the nucleus and regulate gene expression. The signalling pathways leading to activation of mitogen-activated protein kinases (MAPKs) and their downstream effects on gene regulation represent a paradigm in cellular signalling (see reviews [12, 13]). The MAPK family comprise four groups of proteins: extracellular signal-regulated kinases (ERKs) 1 and 2; ERK5; c-Jun amino-terminal kinases (JNKs) 1, 2 and 3; and p38MAPK a, b, g, and d;  where each isoform is encoded by its own gene. Much of the present understandings of the MAPKs, especially regarding ES cell signalling, arise from the study of ERK1/2, JNK and p38MAPK proteins. These protein serine/threonine kinases are regulated by phosphorylation cascades organized in specific modules comprised of two additional protein kinases activated in series and leading to activation of a specific MAP Kinase: a MAP Kinase Kinase (MAPKK), which phosphorylates a specific MAPK, and a MAP Kinase Kinase Kinase (MAPKKK), which phosphorylates a specific MAPKK (Figure 1). Besides the activities of the different components of the cascades themselves, there are two others important means to specifically regulate these signalling pathways: interfering with the scaffolding proteins or MAPK phosphatases that are specific for each pathway.

Taking advantage of the development of specific chemical inhibitors for each MAPK pathway, numerous investigations have explored their biological functions and demonstrated their involvement in a wide variety of cellular functions. These multiple functions are dependent on the pathway that is activated and on the cellular model analysed. In addition, the duration of the stimulus can also affect the cellular response. A wide panel of different stimuli are able to activate the MAPK pathways, but a good correlation has been found between the types of stimulus and the function assigned to the pathway. Schematically, ERK is preferentially activated by mitogens such as the serum or growth factors and, accordingly, this pathway is an important regulator of cell cycle and cell proliferation; whereas p38MAPK and JNK are responsive to various stress stimuli from UV to cytokines, and constitute important mediators of cellular responses to these stimuli (see for extensive reviews [14] and [12]; and more recently: [15], [16] and [17]). For example, the JNK pathway is the mediator of apoptosis induced by TNF-a.  However, this growth factor is also able to activate the NFk-B pathway, which, in turn, inhibits JNK. Therefore the cellular response will result from the combinatorial action of distinct signalling pathways.

Regarding the process of differentiation, the role of MAPKs is extremely complex and depends on multiple parameters. The complexity is due, firstly, to the biological process itself, which, in general, involves distinct, successive steps. Furthermore, each of these steps can be modulated by MAPKs leading, sometimes, to opposite effects. Probably because of this complexity, most of the tools used for these studies have found their limitations. With regard to small molecule inhibitors of protein kinases, inhibitors of a given pathway differ widely in their inhibitory potency and specificity [18]. Therefore, interfering with a given pathway with chemical inhibitors can induce different biological effects by virtue of simple non-specific effects. Alternatively, investigators have constructed cell lines from various cellular models, overexpressing dominant-negative or activated forms of the genes encoding the components of MAPK pathways. While often informative, these experiments are not totally conclusive because of the complexity of the differentiation process and the possible cross talk between the different pathways in such conditions. Finally, homozygous knockouts of several components of MAPK pathways are now available, both in vivo, in mice, and in vitro, in ES cell lines [19]. Whereas targeted gene disruption in animals may unveil important biological functions, they also have limits, especially when the knock-out is lethal during early embryogenesis. Recently, the study of ES cells bearing disrupted MAPK genes revealed that: no role could been assigned to these pathways in undifferentiated ES cells as MAPK pathways are apparently dispensable for ES cell self-renewal and cell cycle (see below). By contrast, new biological functions can be attributed to these proteins in the modulation of ES cell lineage commitment, which is the subject of the subsequent sections of this review.