The MAP Kinase Signaling Cascades: A System of Hundreds of Components Regulates a Diverse Array of Physiological Functio
Sequential activation of kinases within the mitogen-activated protein (MAP) kinase (MAPK) cascades is a common, and evolutionary-conserved mechanism of signal transduction. Four MAPK cascades have been identified in the last 20 years and those are usually
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1. Overview In order to perform their functions and to survive, cells need to respond to a large number of extracellular stimuli and environmental changes, including mitogens, hormones, stresses, as well Rony Seger (ed.), MAP Kinase Signaling Protocols: Second Edition, Methods in Molecular Biology, vol. 661, DOI 10.1007/978-1-60761-795-2_1, © Springer Science+Business Media, LLC 2010
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Keshet and Seger
as changes in temperature, osmotic pressure, and more. The response of cells to the plethora of extracellular signals is often mediated through the activation of transcription factors, which, in turn, induce the necessary cellular processes. However, most extracellular agents cannot cross the plasma membrane in order to activate their corresponding genes. Instead, these agents use intracellular “communication lines,” which are known in fact as signaling pathways, to transmit their signals to various cytoplasmatic and nuclear targets (1). In many cases, these pathways operate through sequential phosphorylation events that are termed protein kinase cascades. This type of signaling mechanism is utilized by the mitogen-activated protein (MAP) kinase (MAPK) signaling cascades, which are evolutionary-conserved, central signal transduction pathways. Among others, these cascades respond to various extracellular factors and consequently regulate diverse cellular processes such as proliferation, differentiation, stress response, and apoptosis. The MAPK signaling cascades have been extensively studied over the past two decades and showed to operate in a large number of cells and conditions (for recent reviews see (2–8)). Transmission of signals via these cascades is usually initiated by activation of a small G protein (e.g., Ras) or by activating interaction of upstream components of the cascade with adaptor proteins. Then, the signals are further transmitted downstream the cascade by cytosolic protein kinases that are organized in three to five tiers. The kinases in each tier phosphorylate and activate the kinases located in their downstream tier to allow a rapid and regulated transmission of the signals to various targets of the cascades. Three of the tiers, MAP3K, MAPKK, MAPK, are considered as core ones (Fig. 1), while the upstream (MAP4K) or the downstream (MAP Kinase-activated kinase; MAPKAPK) tiers are not always necessary for signaling through the cascades. Kinases downstream of MAPKAPKs do exist as well, but those are not considered as part of the cascades. Importantly, each of the tiers of the different cascades is composed of several components that are usually distinct gene products, and are often translated to several alternative spliced isoforms. About 70 genes are known today to encode for close to 200 distinct components that compose the entire MAPK system. This multiplicity of components allows the extended specificity and tight regulation, which are hallmarks of these cascades. Four MAPK cascades have been fully elucidated by now, and named according to the components in their MAPK tier. These are extrace
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