Expression of CDK5 (PSSALRE kinase), a neural cdc2-related protein kinase, in the mature and developing mouse central and peripheral nervous systems

Ino, Hiromitsu; Ishizuka, Toshiharu; Chiba, Tetsuhiro; Tatibana, Masamiti

doi:10.1016/0006-8993(94)91197-5

Cited by 84 publications

(49 citation statements)

References 44 publications

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“…Although expression and activity of Cdk5 in the peripheral nervous system have been reported (33,34), the precise molecular functions of this kinase in DRG and TG neurons have not been fully characterized. Our studies demonstrate that Cdk5 and p35 are expressed in DRG and TG and that Cdk5 activity was increased during a peripheral inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

Cyclin-dependent kinase 5 activity regulates pain signaling

Pareek

Keller

Kesavapany

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

107

151

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Several molecules and cellular pathways have been implicated in nociceptive signaling, but their precise molecular mechanisms have not been clearly defined. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine͞threonine kinase implicated in the development and disease of the mammalian nervous system. The precise role of this kinase in sensory pathways has not been well characterized. Here we report a molecular role for Cdk5 in nociception. We identified the expression of Cdk5 and its activator p35 in nociceptive neurons, which is modulated during a peripheral inflammatory response. Increased calpain activity in sensory neurons after inflammation resulted in the cleavage of p35 to p25, which forms a more stable complex with Cdk5 and, consequently, leads to elevation of Cdk5 activity. p35 knockout mice (p35 ؊/؊ ), which exhibit significantly decreased Cdk5 activity, showed delayed responses to painful thermal stimulation compared with WT controls. In contrast, mice overexpressing p35, which exhibit elevated levels of Cdk5 activity, were more sensitive to painful thermal stimuli than were controls. In conclusion, our data demonstrate a role for Cdk5͞p35 activity in primary afferent nociceptive signaling, suggesting that Cdk5͞p35 may be a target for the development of analgesic drugs.nociception ͉ inflammation ͉ dorsal root ganglia ͉ trigeminal ganglia ͉ spinal cord P ain is a combination of sensory (discriminative) and affective (emotional) components. The sensory component of pain is defined as nociception and is required for survival and the maintenance of the integrity of the organism. However, sustained or chronic pain, particularly in humans, can result in secondary symptoms such as anxiety, depression, and a marked decrease in the quality of life (1, 2). Specific cell types and several molecules have been identified that detect and regulate nociceptive activity. Additionally, the parallel pathways that distribute nociceptive information to limbic or sensory areas of the forebrain have been elucidated, but the underlying molecular mechanisms remain unclear. So far, studies using genetically modified mice, antisense knockdowns in cells, gene expression assays (including DNA microarray-based expression profiling), and linkage mapping have identified several genes the expression levels of which are directly or indirectly affected during pain sensation and͞or that are involved in modulating pain (3). As a result, the number of proteins encoded by these genes continues to expand, and further investigation of their participation in pain pathways is required.Cyclin-dependent kinase 5 (Cdk5), a unique member of the cyclin-dependent kinases (which belong to a family of small proline-directed serine͞threonine kinases), is mainly active in postmitotic neurons because of the selective neuronal expression of its activators, p35 and p39 (4, 5). Transcriptional and translational regulation of p35 and p39 plays a key role in the maintenance of normal Cdk5 activity. We and others have previously reported critical role...

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Section: Discussionmentioning

confidence: 99%

Cyclin-dependent kinase 5 activity regulates pain signaling

Pareek

Keller

Kesavapany

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

107

151

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“…In the nervous system, cdk-5 is expressed in postmitotic neurones but not glia or mitotically active cells; cdk-5 activity in the brain increases during the latter stages of development (Hellmich et at., 1992;Tsai et al, 1993;Ino et al, 1994;Matsushita et al, 1995Matsushita et al, , 1996Ino and Chiba, 1996). Cyclin D2 is expressed at high levels in the developing brain, particularly in developing and postmitotic neuroblasts, but expression levels then fall markedly in the adult (Ross and Risken, 1994;Tamaru et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Cyclin D2 Interacts with cdk‐5 and Modulates Cellular cdk‐5/p35 Activity

Guidato

McLoughlin

Grierson

et al. 1998

Journal of Neurochemistry

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Cyclin-dependent kinase-5 (cdk-5) is a serine! threonine kinase that displays neurone-specific activity. Experimental manipulation of cdk-5 expression in neurones has shown that cdk-5 is essential for proper development of the nervous system and, in particular, for outgrowth of neurites. Such observations suggest that cdk-5 activity must be tightly controlled during development of the nervous system. To identify possible regulators of cdk-5, we used the yeast two-hybrid system to search for proteins that interact with cdk-5. In two independent yeast transformation events, cyclin D2 interacted with cdk-5. Immunoprecipitation experiments confirmed that cyclin D2 and cdk-5 interact in mammalian cells. Cyclin D2 did not activate cdk-5 as assayed using three different substrates, which was in contrast to a known cdk-5 activator, p35. However, cyclin D2 expression led to a decrease in cdk-5/p35 activity in transfected cells. As cyclin D2 and cdk-5 are known to share overlapping patterns of expression during development of the CNS, the results presented here suggest a role for cyclin D2 in modulating cdk-5 activity in postmitotic developing neurones. Key Words: Cyclin-dependent kinase-5 -p35-Cyclin D2 -Neurofilaments-Tau.

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“…However, Cdk5 contains a stretch of acidic residues, 38 DDDDE 42 (12). This stretch is located within the kinase subdomain II and is highly variable among members of different kinase families (41) but identical in Cdk5 from human (42), mouse (43), rat (44), bovine (12), and Xenopus (45) and has only one conserved substitution, Asp 39 3 Glu in Drosophila (46). Experiments are underway in our laboratory to determine if this stretch is involved in tau binding.…”

Section: Fig 2 Fplc Gel Filtration Of Microtubule-associated Nclkmentioning

confidence: 99%

Interaction of Neuronal Cdc2-like Protein Kinase with Microtubule-associated Protein Tau

Sobue¹,

Agarwal-Mawal²,

Li³

et al. 2000

Journal of Biological Chemistry

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Neuronal Cdc2-like protein kinase (NCLK), a ϳ58-kDa heterodimer, was isolated from neuronal microtubules (Ishiguro, K., Takamatsu, M., Tomizawa, K., Omori, A., Takahashi, M., Arioka, M., Uchida, T. and Imahori, K. (1992) J. Biol. Chem. 267, 10897-10901). The biochemical nature of NCLK-microtubule association is not known. In this study we found that NCLK is released from microtubules upon microtubule disassembly as a 450-kDa species. The 450-kDa species is an NCLK⅐tau complex, and NCLK-bound tau is in a nonphosphorylated state. Tau phosphorylation causes NCLK⅐tau complex dissociation, and phosphorylated tau does not bind to NCLK. In vitro, the Cdk5 subunit of NCLK binds to the microtubule-binding region of tau and NCLK associates with microtubules only in the presence of tau. Our data indicate that in brain extract NCLK is complexed with tau in a tau phosphorylation-dependent manner and that tau anchors NCLK to microtubules. Recently NCLK has been suggested to be aberrantly activated and to hyperphosphorylate tau in Alzheimer's disease brain (Patrick, G. N., Zukerberg, L., Nikolic, M., de la Monte, S., Dikkes, P, and Tsai, L.-H. (1999) Nature 402, 615-622). Our findings may explain why in Alzheimer's disease NCLK specifically hyperphosphorylates tau, although this kinase has a number of protein substrates in the brain.The neuronal Cdc2-like protein kinase (NCLK) 1 (also known as tau kinase II and brain proline-directed protein kinase) is a heterodimer of cyclin-dependent kinase 5 (Cdk5) and a neuronal-specific activator p25 subunit (reviewed in Ref. 1). The p25 subunit is a proteolytic fragment of a 35-kDa protein, p35 (1, 2). Targeted disruption of the cdk5 gene in mice results in unique lesions in the central nervous system, lack of cortical laminar structure, as well as cerebellar foliate and prenatal death (3). In differentiating neurons, neurite outgrowth is inhibited by the introduction of a dominant negative Cdk5 mutant and is enhanced by Cdk5 and p35 overexpression (4). Similarly, mice lacking p35 do not show NCLK activity and display cortical lamination defects, seizures, and adult lethality (5). These observations indicate that NCLK plays an important role in brain development, neuronal differentiation, and neurite outgrowth. In neurons NCLK phosphorylates inhibitor 1 (6) and DARPP-32 (7), the two inhibitory proteins that upon phosphorylation suppress phosphoprotein phosphatase 1 activity. Munc18 (8) and synapsin (9), which respectively regulate synaptic vesicle exocytosis and neurotransmitter release, are phosphorylated by NCLK. NCLK also phosphorylates the microtubule-associated protein tau (10, 11) and neurofilaments (12,13). These data indicate that NCLK regulates neural signaling, vesicular exocytosis, neurotransmitter release, and microtubule dynamics.

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Expression of CDK5 (PSSALRE kinase), a neural cdc2-related protein kinase, in the mature and developing mouse central and peripheral nervous systems

Cited by 84 publications

References 44 publications

Cyclin-dependent kinase 5 activity regulates pain signaling

Cyclin-dependent kinase 5 activity regulates pain signaling

Cyclin D2 Interacts with cdk‐5 and Modulates Cellular cdk‐5/p35 Activity

Interaction of Neuronal Cdc2-like Protein Kinase with Microtubule-associated Protein Tau

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