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, Hiroyuki; Saito, Taro; Sato, Ko; Furusawa, Kotaro; Hosokawa, T.; Tsutsumi, Koji; Asada, Akiko; Kamada, Shinji; Ohshima, Toshio; Hisanaga, Shin Ichi

doi:10.1074/jbc.m113.501148

Cited by 35 publications

(26 citation statements)

References 41 publications

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“…Some studies show that phosphorylation at Tyr15 heightens Cdk5 activity [6]. On the contrary, a recent data demonstrates that phosphorylation of Cdk5 at Tyr-15 does not contribute to the activation of Cdk5 [7]. More recently, Snitrosylation of Cdk5 (SNO-Cdk5) at specific cysteine residues also emerges as a novel regulatory mechanism for Cdk5 activity [8].…”

Section: Physiological Properties Of Cdk5 In Cns Biochemical Propertimentioning

confidence: 98%

The Role of Cdk5 in Alzheimer’s Disease

et al. 2015

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Alzheimer's disease (AD) is known as the most fatal chronic neurodegenerative disease in adults along with progressive loss of memory and other cognitive function disorders. Cyclin-dependent kinase 5 (Cdk5), a unique member of the cyclin-dependent kinases (Cdks), is reported to intimately associate with the process of the pathogenesis of AD. Cdk5 is of vital importance in the development of CNS and neuron movements such as neuronal migration and differentiation, synaptic functions, and memory consolidation. However, when neurons suffer from pathological stimuli, Cdk5 activity becomes hyperactive and causes aberrant hyperphosphorylation of various substrates of Cdk5 like amyloid precursor protein (APP), tau and neurofilament, resulting in neurodegenerative diseases like AD. Deregulation of Cdk5 contributes to an array of pathological events in AD, ranging from formation of senile plaques and neurofibrillary tangles, synaptic damage, mitochondrial dysfunction to cell cycle reactivation as well as neuronal cell apoptosis. More importantly, an inhibition of Cdk5 activity with inhibitors such as RNA inference (RNAi) could protect from memory decline and neuronal cell loss through suppressing β-amyloid (Aβ)-induced neurotoxicity and tauopathies. This review will briefly describe the above-mentioned possible roles of Cdk5 in the physiological and pathological mechanisms of AD, further discussing recent advances and challenges in Cdk5 as a therapeutic target.

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Section: Physiological Properties Of Cdk5 In Cns Biochemical Propertimentioning

confidence: 98%

The Role of Cdk5 in Alzheimer’s Disease

et al. 2015

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“…Likewise, phosphorylation of Cdk5 at Y15 by the kinases Abl, Ephrin receptor A (Eph A) or Fyn does not inhibit its activity as has been observed for other Cdks. Instead, phosphorylation of Cdk5 at Y15 has been shown to either increase or has no effect on its activity [10–12]. …”

Section: Introductionmentioning

confidence: 99%

A Tale of the Good and Bad: Remodeling of the Microtubule Network in the Brain by Cdk5

Shah

Lahiri

2016

Mol Neurobiol

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Cdk5, a cyclin dependent kinase family member, is a global orchestrator of neuronal cytoskeletal dynamics. During embryogenesis, Cdk5 is indispensable for brain development. In adults, it is essential for numerous neuronal processes, including higher cognitive functions such as learning and memory formation, drug addiction, pain signaling and long term behavior changes through long term potentiation and long term depression, all of which rely on rapid alterations in the cytoskeleton. Cdk5 activity becomes deregulated in various brain disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, attention-deficit hyperactivity disorder, epilepsy, schizophrenia and ischemic stroke; these all result in profound remodeling of the neuronal cytoskeleton. This Commentary specifically focuses on the pleiotropic contribution of Cdk5 in regulating neuronal microtubule remodeling. Because the vast majority of the physiological substrates of Cdk5 are associated with the neuronal cytoskeleton, our emphasis is on the Cdk5 substrates, such as CRMP2, stathmin, drebrin, dixdc1, axin, GKAP, kinesin-5, tau and PSD-95, that have allowed to unravel the molecular mechanisms through which Cdk5 exerts its divergent roles in regulating neuronal microtubule dynamics, both in healthy and disease states.

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“…Though Tyr-15 phosphorylation of CDK5 has been shown to increase kinase activity, a recent report casts doubt on the role of Tyr-15 phosphorylation in the regulation of CDK5 activity (34). We therefore also examined the effect of CDK5 inhibition on heat sensitivity using the CDK5 inhibitor roscovitine.…”

Section: Discussionmentioning

confidence: 99%

Heat Shock Inhibition of CDK5 Increases NOXA Levels through miR-23a Repression

Morey

Roufayel

Johnston

et al. 2015

Journal of Biological Chemistry

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Background: HSP70 inhibits heat-induced apoptosis by preventing NOXA accumulation. Results: Inhibition of CDK5 in heat-shocked cells reduces levels of miR-23a leading to increased NOXA abundance, which is prevented by HSP70. Conclusion: CDK5 regulates miR-23a expression and affects NOXA abundance. Significance: The prosurvival function of HSP70 can be attributed to its ability to prevent the stress-induced inhibition of CDK5.

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

Cited by 35 publications

References 41 publications

The Role of Cdk5 in Alzheimer’s Disease

The Role of Cdk5 in Alzheimer’s Disease

A Tale of the Good and Bad: Remodeling of the Microtubule Network in the Brain by Cdk5

Heat Shock Inhibition of CDK5 Increases NOXA Levels through miR-23a Repression

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