Cdk5 phosphorylates Cdh1 and modulates cyclin B1 stability in excitotoxicity

Maestre, Carolina; Delgado‐Esteban, María; Sánchez, José Carlos Gómez; Bolaños, Juan P.; Almeida, Ángeles

doi:10.1038/emboj.2008.195

Cited by 118 publications

(179 citation statements)

References 46 publications

Supporting

Mentioning

155

Contrasting

Unclassified

Order By: Relevance

“…The modestly shifted band of Cdh1 in the cytosol (Fig. S5E) likely reflects a hyperphosphorylatedinactive-form of Cdh1 (27). Furthermore, APC3 immunoprecipitation in the nuclear and cytosolic neuronal fractions, followed by immunoblotting against Rock1 and Rock2, revealed that the interaction between APC3 and Rock2 only occurred in the nucleus; however, no interaction between APC3 and Rock1 occurred either in the nucleus or the cytosol (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Importantly, we have previously described that glutamate receptor overactivation, a hallmark of neurodegenerative diseases, promotes Cdk5-induced Cdh1 phosphorylation (9,27) and inactivation, which may explain the accumulation of Rock2 that has been found in these disorders (43). Therefore, pharmacological inhibition of aberrantly accumulated Rock2 with fasudil treatment may be a suitable therapeutic strategy against these neurological diseases.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

APC/C ^Cdh1 -Rock2 pathway controls dendritic integrity and memory

Bobo-Jiménez

Delgado‐Esteban

Angibaud

et al. 2017

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

Self Cite

View full text Add to dashboard Cite

Disruption of neuronal morphology contributes to the pathology of neurodegenerative disorders such as Alzheimer's disease (AD). However, the underlying molecular mechanisms are unknown. Here, we show that postnatal deletion of Cdh1, a cofactor of the anaphasepromoting complex/cyclosome (APC/C) ubiquitin ligase in neurons [Cdh1 conditional knockout (cKO)], disrupts dendrite arborization and causes dendritic spine and synapse loss in the cortex and hippocampus, concomitant with memory impairment and neurodegeneration, in adult mice. We found that the dendrite destabilizer Rho protein kinase 2 (Rock2), which accumulates in the brain of AD patients, is an APC/C Cdh1 substrate in vivo and that Rock2 protein and activity increased in the cortex and hippocampus of Cdh1 cKO mice. In these animals, inhibition of Rock activity, using the clinically approved drug fasudil, prevented dendritic network disorganization, memory loss, and neurodegeneration. Thus, APC/C Cdh1 -mediated degradation of Rock2 maintains the dendritic network, memory formation, and neuronal survival, suggesting that pharmacological inhibition of aberrantly accumulated Rock2 may be a suitable therapeutic strategy against neurodegeneration.APC/C Cdh1 | Rock | dendrite | memory | neurodegeneration

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

APC/C ^Cdh1 -Rock2 pathway controls dendritic integrity and memory

Bobo-Jiménez

Delgado‐Esteban

Angibaud

et al. 2017

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…In addition to the changes in the activity of the proteasome, excessive NMDAR stimulation in cultured cortical neurons was also shown to induce hyperphosphorylation of the Anaphase-Promoting complex/cyclosome (APC/C) Cdh1 activator protein, which leads to a cytosolic accumulation of this E3 ligase responsible for the control of cell cycle progression (Peters, 2002;Maestre et al, 2008). The effect of excitotoxic stimulation is mediated by calpain cleavage of cyclin-dependent kinase-5 (Cdk5), with formation of a p25 product that induces the hyperphosphorylation of Cdh1 (Maestre et al, 2008). In this case, the downregulation of the E3 ligase in the nucleus allows the accumulation of cyclin B1 in this compartment, thus inducing apoptotic cell death by abnormal entry in S-phase (Almeida et al, 2005;Maestre et al, 2008).…”

Section: Ups In Glutamate-induced Excitotoxicitymentioning

confidence: 99%

“…The effect of excitotoxic stimulation is mediated by calpain cleavage of cyclin-dependent kinase-5 (Cdk5), with formation of a p25 product that induces the hyperphosphorylation of Cdh1 (Maestre et al, 2008). In this case, the downregulation of the E3 ligase in the nucleus allows the accumulation of cyclin B1 in this compartment, thus inducing apoptotic cell death by abnormal entry in S-phase (Almeida et al, 2005;Maestre et al, 2008). Excitotoxic stimulation with glutamate also downregulated total DUB activity in cultured hippocampal neurons although no effect was observed on the activity of Uch-L1, showing that not all deubiquitinating enzymes are affected (Caldeira et al, 2013).…”

Section: Ups In Glutamate-induced Excitotoxicitymentioning

confidence: 99%

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Caldeira

Salazar

Curcio

et al. 2014

Progress in Neurobiology

117

View full text Add to dashboard Cite

A B S T R A C TThe ubiquitin-proteasome system (UPS) is a catalytic machinery that targets numerous cellular proteins for degradation, thus being essential to control a wide range of basic cellular processes and cell survival. Degradation of intracellular proteins via the UPS is a tightly regulated process initiated by tagging a target protein with a specific ubiquitin chain. Neurons are particularly vulnerable to any change in protein composition, and therefore the UPS is a key regulator of neuronal physiology. Alterations in UPS activity may induce pathological responses, ultimately leading to neuronal cell death. Brain ischemia triggers a complex series of biochemical and molecular mechanisms, such as an inflammatory response, an exacerbated production of misfolded and oxidized proteins, due to oxidative stress, and the breakdown of cellular integrity mainly mediated by excitotoxic glutamatergic signaling. Brain ischemia also damages protein degradation pathways which, together with the overproduction of damaged proteins and consequent upregulation of ubiquitin-conjugated proteins, contribute to the accumulation of ubiquitincontaining proteinaceous deposits. Despite recent advances, the factors leading to deposition of such aggregates after cerebral ischemic injury remain poorly understood. This review discusses the current knowledge on the role of the UPS in brain function and the molecular mechanisms contributing to UPS dysfunction in brain ischemia with consequent accumulation of ubiquitin-containing proteins. Chemical inhibitors of the proteasome and small molecule inhibitors of deubiquitinating enzymes, which promote the degradation of proteins by the proteasome, were both shown to provide neuroprotection in brain ischemia, and this apparent contradiction is also discussed in this review. ß

show abstract

“…who measured the activity of immunoprecipitates of these enzymes (46), and Sakaue et al, who tested both enzymes against several FTDP-17 mutants of tau (47). Recently, Maestras et al (48) reported that CDK5/p25 is significantly more active than CDK5/p35 toward the anaphase-promoting complex factor, cdh1, suggesting that differential enzyme activity may be substrate-dependent. Alternatively, it is possible that intracellular protein-protein, proteinlipid interactions, or posttranslational modification may differentially affect catalytic specificity in vivo.…”

Section: Discussionmentioning

confidence: 99%

No difference in kinetics of tau or histone phosphorylation by CDK5/p25 versus CDK5/p35 in vitro

Peterson¹,

Ando²,

Taketa³

et al. 2010

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

View full text Add to dashboard Cite

CDK5/p35 is a cyclin-dependent kinase essential for normal neuron function. Proteolysis of the p35 subunit in vivo results in CDK5/p25 that causes neurotoxicity associated with a number of neurodegenerative diseases. Whereas the mechanism by which conversion of p35 to p25 leads to toxicity is unknown, there is common belief that CDK5/p25 is catalytically hyperactive compared to CDK5/p35. Here, we have compared the steady-state kinetic parameters of CDK5/p35 and CDK5/p25 towards both histone H1, the best known substrate for both enzymes, and the microtubule-associated protein, tau, a physiological substrate whose in vivo phosphorylation is relevant to Alzheimer's disease. We show that the kinetics of both enzymes are the same towards either substrate in vitro. Furthermore, both enzymes display virtually identical kinetics towards individual phosphorylation sites in tau monitored by NMR. We conclude that conversion of p35 to p25 does not alter the catalytic efficiency of the CDK5 catalytic subunit by using histone H1 or tau as substrates, and that neurotoxicity associated with CDK5/p25 is unlikely attributable to CDK5 hyperactivation, as measured in vitro.Alzheimer's disease | neurotoxicity | NMR | protein kinase | proteolysis C DK5/p25 was first identified as a tau kinase (1, 2) that displayed a CDK1 (formerly p34 cdc2 ) -like substrate specificity in brain (3, 4). Of particular interest, phosphorylation of normal tau by CDK5/p25 could partially recapitulate several characteristics inherent to PHF-tau associated with Alzheimer's disease (1, 2). The CDK5 catalytic subunit was homologous to other CDKs and displayed ubiquitous expression (5), but p25 was originally discovered as a unique protein expressed predominantly in neurons, and generated by proteolytic cleavage of a larger protein precursor, p35 (6-9). Whereas CDK5/p35 is associated with normal neuron development and function (10), endogenous cleavage of p35 to p25 is associated with neuronal cell death, neuropathology, and is implicated in the progression of Alzheimer's disease (11-18), Parkinson's disease (19), and ALS (20). CDK5/p25, but not CDK5/p35, is toxic when overexpressed in transformed cell lines or when generated by cleavage of endogenous p35 in neurons (11,21,22). The cellular mechanism by which cleavage causes toxicity is not known, but in theory could relate to one or more known key differences between these two enzyme forms, including differences in subcellular distribution (11, 23), stability of the protein (11, 24), and/or cellular substrate specificity (11,25).There is common belief that the catalytic activity of CDK5/p25 is significantly elevated in comparison to CDK5/p35, and therefore that p25 causes "hyperactivity" of CDK5 compared to p35, contributing to its toxicity (10). To rigorously demonstrate its hyperactivity, however, it is necessary to show that the catalytic parameters associated with steady-state phosphorylation of substrates are different between the two enzymes. Hashiguchi et al. (26) previously conducted such experiments,...

show abstract

Cdk5 phosphorylates Cdh1 and modulates cyclin B1 stability in excitotoxicity

Cited by 118 publications

References 46 publications

APC/C ^Cdh1 -Rock2 pathway controls dendritic integrity and memory

APC/C ^Cdh1 -Rock2 pathway controls dendritic integrity and memory

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

No difference in kinetics of tau or histone phosphorylation by CDK5/p25 versus CDK5/p35 in vitro

Contact Info

Product

Resources

About

Cdk5 phosphorylates Cdh1 and modulates cyclin B1 stability in excitotoxicity

Cited by 118 publications

References 46 publications

APC/C Cdh1 -Rock2 pathway controls dendritic integrity and memory

APC/C Cdh1 -Rock2 pathway controls dendritic integrity and memory

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

No difference in kinetics of tau or histone phosphorylation by CDK5/p25 versus CDK5/p35 in vitro

Contact Info

Product

Resources

About

APC/C ^Cdh1 -Rock2 pathway controls dendritic integrity and memory

APC/C ^Cdh1 -Rock2 pathway controls dendritic integrity and memory