Methods to Study MAP Kinase Signalling in the Central Nervous System
The mitogen-activated protein kinase (MAPK) family of intracellular signal transducers includes ERK1/2, ERK5, JNK/SAPK, and p38 and has been shown to control survival, proliferation and differentiation of cells composing the central and peripheral nervous
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1. Introduction Intracellular signalling cascades like mitogen-activated protein kinases (MAPKs) and PI3K (phosphoinositide 3-kinase)/Akt (protein kinase B) play multiple roles in central nervous system (CNS) development, function and disease (1). MAPK actively mediate processes such as learning and memory, pain sensitivity, and neuronal survival (2–4). In general, it is believed that members of the ERK family of MAPKs mediate growth and survival responses, while members of the p38 and JNK families are promoters of cell death (1, 5, 6). However, recent reports have also
Rony Seger (ed.), MAP Kinase Signaling Protocols: Second Edition, Methods in Molecular Biology, vol. 661, DOI 10.1007/978-1-60761-795-2_30, © Springer Science+Business Media, LLC 2010
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suggested that ERK activation can lead to neuronal cell death in various neurodegeneration models highlighting the complex role of these proteins in the CNS (7). For each of these families several members are expressed in the developing and the mature brain, mediating a diverse repertoire of cellular functions (8). Initial in vitro experiments indentified the ERKs (ERK1 and ERK2) as key factors for neurotrophin, growth factor, and glutamate signalling (9, 10). These findings are substantiated knock-out experiments showing that mice lacking ERK2 in neural precursors exhibit profound learning deficits (11). Functional evidence on the role of the stress kinases in neuronal cell death was initially derived from cell culture experiments as well. Activation of JNK kinases in neuronal cells occurs following various stress stimuli resulting in increased apoptosis (12). These results are corroborated by the analysis of mice lacking JNK3, a member of the JNK family which is only expressed in the brain. These mice are protected from excitotoxicity and ischemia induced cell death, emphasizing the role of JNK3 in neuronal survival (13, 14). Similarly, mice in which the endogenous Jun AP1 transcription factor was replaced by a mutant Jun version, in which the JNK phosphorylation sites serines 63 and 73 were mutated to alanines, were also resistant to epileptic seizures and neuronal apoptosis induced by the excitatory amino acid kainite demonstrating that Jun is the main substrates of JNK3 during neuronal apoptosis (15). Neurodegenerative diseases can affect neuronal and glial cells in the nervous system and usually lead to cell death by apoptosis. The survival and differentiation of neurons depend on a variety of growth and neurotrophic factors which are only partly known to date. All MAPK have been shown to be involved in the survival, proliferation, and differentiation of nervous cells including neural stem cells (1, 16). The epidermal growth factor receptor (EGFR) can activate a number of downstream pathways, including MAPK and PI3K/Akt that regulate the migration, proliferation, and survival of neural stem cells (1, 17, 18). Mobilization of neural progenitor cells and stimulation of their differentiation into neurons or glial cells might offer new
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