Membrane Association Facilitates Degradation and Cleavage of the Cyclin-Dependent Kinase 5 Activators p35 and p39

Minegishi, Seiji; Asada, Akiko; Miyauchi, Shinya; Fuchigami, Takahiro; Saito, Taro; Hisanaga, Shin‐ichi

doi:10.1021/bi100631f

Cited by 45 publications

(52 citation statements)

References 53 publications

(119 reference statements)

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“…In the present study, we demonstrate aberrant redox regulation of Cdk5 activity by S-nitrosylation in AD models and in human brain. NOS1 and Cdk5 are both localized at the cell surface (45,46), and the close proximity of NOS1 to Cdk5 may thus make endogenous NO available for reaction to form SNO-Cdk5. We found that S-nitrosylation increases Cdk5 kinase activity, identified the cysteine residues susceptible to (patho)physiological regulation by .…”

Section: Discussionmentioning

confidence: 99%

S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by β-amyloid peptide

Nakamura

Cao

et al. 2011

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

167

182

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The activity of Cdk5 and its regulatory subunit p35 is thought to be important in both normal brain function and neurodegenerative disease pathogenesis. Increased Cdk5 activity, via proteolytic cleavage of p35 to a p25 fragment by the calcium-activated protease calpain or by phosphorylation at Cdk5(Tyr15), can contribute to neurotoxicity. Nonetheless, our knowledge of regulation of Cdk5 activity in disease states is still emerging. Here we demonstrate that Cdk5 is activated by S-nitrosylation or reaction of nitric oxide (NO)-related species with the thiol groups of cysteine residues 83 and 157, to form SNO-Cdk5. We then show that S-nitrosylation of Cdk5 contributes to amyloid-β (Aβ) peptide-induced dendritic spine loss. Furthermore, we observed significant levels of SNO-Cdk5 in postmortem Alzheimer's disease (AD) but not in normal human brains. These findings suggest that S-nitrosylation of Cdk5 is an aberrant regulatory mechanism of enzyme activity that may contribute to the pathogenesis of AD.C dk5 is a cyclin-dependent kinase that is activated by proteins p35, p25, and p39 (1-3). As a predominantly neuronalspecific kinase, Cdk5 lacks a role in cell-cycle control but has been implicated in an array of neuronal functions, including cell survival, axon guidance, neuronal migration, and regulation of synaptic spine density (4-6). Dysregulation of Cdk5 activity may play a role in the pathogenesis of stroke and several neurodegenerative disorders, including Alzheimer's disease (AD), amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease (7-11). Cdk5 is also hyperactivated in response to oxidative stress, mitochondrial dysfunction, excitotoxicity, amyloid-β (Aβ) exposure, calcium overload, and neuroinflammation, thus contributing to neuronal damage. These neurotoxic stimuli activate calpain, which cleaves the Cdk5 activator p35 (or p39) into p25 (or p29); p25 accumulation thus contributes to Cdk5 activation (12-16). These changes trigger various events associated with neurodegeneration. Although increased Cdk5 activity has been observed in AD brains compared with nondemented control brains, the mechanism remains contentious (17).Similarly, nitric oxide (NO) and related species contribute to a number of neurodegenerative diseases. The major source of NO in neurons is neuronal nitric oxide synthase (NOS1). Excitotoxic stress increases intracellular Ca 2+ , which in turn activates NOS1, thus generating NO. In general, NO can stimulate soluble guanylate cyclase to form cGMP or can S-nitrosylate critical cysteine residues to regulate the activity of multiple target proteins, in some sense akin to phosphorylation. Indeed, S-nitrosylation may explain many cGMP-independent mechanisms of NO action in neurodegenerative diseases (18). Our group has demonstrated that NO contributes to neurodegenerative disorders by redox reaction consisting of S-nitrosylation; in some cases this reaction is followed by further oxidation. Proteins affected in this manner include the gelatinase enzyme matrix metalloprotineas...

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Section: Discussionmentioning

confidence: 99%

S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by β-amyloid peptide

Nakamura

Cao

et al. 2011

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

167

182

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“…Plasmid Construction-pCMV5-mouse Cdk5, pCMV2-FLAG-mouse Cdk5, pCMV5-kinase-negative (kn) Cdk5 D144N, pCMV5-mouse p35, pcDNA3-mouse p35-myc, pcDNA3-mouse p25-myc, pCAGGS-GFP, pCAGGS-DsRed, pCMV5-FLAG-p39 activation domain (AD), and pCMV2-FLAG-Cyclin I have been described previously (21)(22)(23)(24)(25)(26)(27). pME-Fyn, constitutively active (ca) pME-Fyn Y531F, kinasenegative pME-Fyn K299M, and pcDNA-caSrc Y530F were provided by T. Tezuka and T. Yamamoto at the University of Tokyo (28).…”

Section: Methodsmentioning

confidence: 99%

“…These results suggest that the activation of Cdk5 is due to the increased p35 but not Tyr-15 phosphorylation, at least in the cell culture overexpression system. p35 is a protein with a short half-life (24,34). To ask how Fyn increases p35 protein, we measured the synthesis and degradation of p35 in the presence of MG132 proteasome inhibitor and cycloheximide protein synthesis inhibitor, respectively.…”

Section: Coexpression Of Cdk5 Activators Suppresses Tyr-15mentioning

confidence: 99%

Phosphorylation of Cyclin-dependent Kinase 5 (Cdk5) at Tyr-15 Is Inhibited by Cdk5 Activators and Does Not Contribute to the Activation of Cdk5

Kobayashi

Saito

Sato

et al. 2014

Journal of Biological Chemistry

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“…Similar to p35, p39 possesses a N-terminal myristoylation site, although p39 has a longer half-life than p35 (Minegishi et al, 2010). p39 is also cleaved by calpain to yield p10 and p29 under neurotoxic conditions (Patzke and Tsai, 2002).…”

Section: Introductionmentioning

confidence: 99%

Cdk5 activity in the brain – multiple paths of regulation

Shah

Lahiri

2014

Journal of Cell Science

167

126

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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.

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Membrane Association Facilitates Degradation and Cleavage of the Cyclin-Dependent Kinase 5 Activators p35 and p39

Cited by 45 publications

References 53 publications

S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by β-amyloid peptide

S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by β-amyloid peptide

Phosphorylation of Cyclin-dependent Kinase 5 (Cdk5) at Tyr-15 Is Inhibited by Cdk5 Activators and Does Not Contribute to the Activation of Cdk5

Cdk5 activity in the brain – multiple paths of regulation

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