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
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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)