Cdk5 activity in the brain – multiple paths of regulation

Journal of Cell Science, Jun 2014

Cyclin dependent kinase-5 (Cdk5), a family member of the cyclin-dependent kinases, plays a pivotal role in the central nervous system. During embryogenesis, Cdk5 is indispensable for brain development and, in the adult brain, it is essential for numerous neuronal processes, including higher cognitive functions such as learning and memory formation. However, Cdk5 activity becomes deregulated in several neurological disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease, which leads to neurotoxicity. Therefore, precise control over Cdk5 activity is essential for its physiological functions. This Commentary covers the various mechanisms of Cdk5 regulation, including several recently identified protein activators and inhibitors of Cdk5 that control its activity in normal and diseased brains. We also discuss the autoregulatory activity of Cdk5 and its regulation at the transcriptional, post-transcriptional and post-translational levels. We finally highlight physiological and pathological roles of Cdk5 in the brain. Specific modulation of these protein regulators is expected to provide alternative strategies for the development of effective therapeutic interventions that are triggered by deregulation of Cdk5.

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Cdk5 activity in the brain – multiple paths of regulation

Published by The Company of Biologists Ltd | Journal of Cell Science Cdk5 activity in the brain - multiple paths of regulation Kavita Shah () Debomoy K. Lahiri Cyclin dependent kinase-5 (Cdk5), a family member of the cyclindependent kinases, plays a pivotal role in the central nervous system. During embryogenesis, Cdk5 is indispensable for brain development and, in the adult brain, it is essential for numerous neuronal processes, including higher cognitive functions such as learning and memory formation. However, Cdk5 activity becomes deregulated in several neurological disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease, which leads to neurotoxicity. Therefore, precise control over Cdk5 activity is essential for its physiological functions. This Commentary covers the various mechanisms of Cdk5 regulation, including several recently identified protein activators and inhibitors of Cdk5 that control its activity in normal and diseased brains. We also discuss the autoregulatory activity of Cdk5 and its regulation at the transcriptional, post-transcriptional and post-translational levels. We finally highlight physiological and pathological roles of Cdk5 in the brain. Specific modulation of these protein regulators is expected to provide alternative strategies for the development of effective therapeutic interventions that are triggered by deregulation of Cdk5. Cdk5; p25; p35; b-Amyloid; Excitotoxicity; Cdk; Cyclins; Neurodegeneration; Alzheimer's disease; Synaptic plasticity; Learning and memory; Pain signalling; Neuronal migration; Axonal growth; Synaptogenesis - Introduction Cyclin-dependent kinases (Cdks) are Ser/Thr protein kinases that associate with specific cyclin subunits in order to be activated. This family currently includes 11 classic Cdks (Cdk1 Cdk11) and two new family members (Cdk12, Cdk13) (Malumbres et al., 2009). All Cdks phosphorylate Ser-Pro or Thr-Pro sites, with a preference for the basic residues Lys and Arg at proximal upstream and downstream positions. Cdks are highly expressed in proliferating cells and play indispensable roles in specific phases of cell cycle. The first human Cdk was cloned in 1987 by using functional complementation in yeast, and was termed cell division cycle 2 (Cdc2; now officially known as Cdk1) because of its high homology with fission yeast kinase Cdc2 (Lee and Nurse, 1987). The second human homolog of the Cdk family to be cloned from a human cDNA library was kinase Cdk2 (Elledge and Spottswood, 1991; Ninomiya-Tsuji et al., 1991; Tsai et al., 1991). The discovery of human Cdk1 and Cdk2 paved the way for the identification of Cdk5 (Gene ID: 1020); and in 1992, five independent laboratories reported Cdk5 as a new member of the Cdk family, although each study gave it a different name, i.e. tau kinase II (Ishiguro, et al., 1992), neuronal Cdc2 like kinase (nclk) (Hellmich et al., 1992), brain proline-directed kinase (Lew et al., 1992), PSSALRE (Meyerson et al., 1992) and Cdk5 (Xiong et al., 1992). Cdk5, although highly homologous to its relatives, is a unique Cdk family member (Dhavan and Tsai, 2001). Cdk5 is ubiquitously expressed, but its functions are vital in postmitotic neurons, where other Cdks are not expressed or active. In contrast to other Cdks, Cdk5 does not participate in cell cycle progression in proliferating cells, but can aberrantly activate various components of cell cycle when it is deregulated in postmitotic neurons, leading to cell death (Chang et al., 2012). For its activation Cdk5 also requires its specific binding partners CDK5R1 and CDK5R2 (hereafter referred to as p35 and p39, respectively) (Tsai et al., 1994; Tang et al., 1995). Furthermore, unlike other family members, Cdk5 is not regulated by the cyclin-dependent kinase inhibitors CDKN1A and CDKN1B (hereafter referred to as p21Cip1 and p27Kip1, respectively) that, thus, have crucial roles in the regulation of Cdks. Accumulating evidence has revealed a plethora of Cdk5 functions in neuronal and non-neuronal cells. During embryogenesis, Cdk5 is indispensable for normal brain development (Ohshima et al., 1996), whereas in adult brains it regulates neuronal survival, synaptic plasticity, learning and memory formation, pain signaling, drug addiction and long-term behavioral changes (Bibb et al., 2001; Fischer et al., 2002; Pareek et al., 2006). Cdk5 is known to be deregulated in several neurodegenerative diseases, including Alzheimers disease (AD), Parkinsons disease (PD) and Huntingtons disease (HD), which causes neurotoxicity. Consequently, although the deregulation of other Cdks commonly occurs in many types of cancer, Cdk5 is emerging as a potential clinical target to treat multiple neurodegenerative diseases (Cheung and Ip, 2012). Thus, Cdk5 is unique among the Cdks in that it employs its own activation strategies, and has widely diverse functions in neuronal and nonneuronal tissues with different clinical implications (Hisanaga and Endo, 2 (...truncated)


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Kavita Shah, Debomoy K. Lahiri. Cdk5 activity in the brain – multiple paths of regulation, Journal of Cell Science, 2014, pp. 2391-2400, 127/11, DOI: 10.1242/jcs.147553