Cdk5 Modulation of Mitogen-activated Protein Kinase Signaling Regulates Neuronal Survival

Abstract

Cdk5, a cyclin-dependent kinase, is critical for neuronal development, neuronal migration, cortical lamination, and survival. Its survival role is based, in part, on "cross-talk" interactions with apoptotic and survival signaling pathways. Previously, we showed that Cdk5 phosphorylation of mitogen-activated protein kinase kinase (MEK)1 inhibits transient activation induced by nerve growth factor (NGF) in PC12 cells. To further explore the nature of this inhibition, we studied the kinetics of NGF activation of extracellular signal-regulated kinase (Erk)1/2 in cortical neurons with or without roscovitine, an inhibitor of Cdk5. NGF alone induced an Erk1/2-transient activation that peaked in 15 min and declined rapidly to baseline. Roscovitine, alone or with NGF, reached peak Erk1/2 activation in 30 min that was sustained for 48 h. Moreover, the sustained Erk1/2 activation induced apoptosis in cortical neurons. Significantly, pharmacological application of the MEK1 inhibitor PD98095 to roscovitine-treated cortical neurons prevented apoptosis. These results were also confirmed by knocking down Cdk5 activity in cortical neurons with Cdk5 small interference RNA. Apoptosis was correlated with a significant shift of phosphorylated tau and neurofilaments from axons to neuronal cell bodies. These results suggest that survival of cortical neurons is also dependent on tight Cdk5 modulation of the mitogen-activated protein kinase signaling pathway. INTRODUCTIONSignal transduction cascades translate extracellular signals into cytoplasmic and nuclear compartments that control cell proliferation, differentiation, and survival in neurons as well as other cell types. The mitogen-activated protein kinase (MAPK) signaling network comprises a cascade of sequential kinase phosphorylations to elicit specific cellular behaviors. The duration of the activation determines the cellular response in neurons or neuron progenitors such as PC12 cells (Marshall, 1995;Stork, 2002). A transient extracellular signal-regulated kinase (Erk) activation (10 -20 min) as in epidermal growth factor activation of PC12 cells (Heasley and Johnson, 1992;Traverse et al., 1992) induces cell proliferation, a sustained activation (several hours) initiates neurite outgrowth and differentiation, whereas a more chronic activation of the Erk1/2 pathway (24 h), particularly in neurons under stress, is responsible for neuronal apoptosis (Subramaniam et al., 2003(Subramaniam et al., , 2004Cheung and Slack, 2004). Specific pharmacological inhibition of mitogen-activated protein kinase kinase (MEK)1, the upstream kinase from Erk1/2, prevents apoptosis (Alessandrini et al., 1997), which suggests that neuronal survival requires a precisely timed down-regulation of the activated Erk1/2 kinase. Timing depends, in part, on down-regulation of receptors, or feedback inhibition by phosphatases (Keyse, 2000), and/or cross-talk interactions with other signaling cascades. One of these crosstalk regulatory interactions may be exclusive to neurons, which, in contrast to most cells, po...

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