Activation of latent cyclin‐dependent kinase 5 (Cdk5)–p35 complexes by membrane dissociation

Zhu, Ying-Shan; Saito, Taro; Asada, Akiko; Maékawa, Shohei; Hisanaga, Shin‐ichi

doi:10.1111/j.1471-4159.2005.03301.x

Cited by 29 publications

(38 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cdk5-p35 activity peaks during early postnatal days of rat brain development (24,44), and Cdk5-p35 activity in the fetal brain is greater than that in the adult brain extract. 4 These developmental differences in Cdk5-p35 activity appear, at least in part, to depend on the interaction of the protein kinase complex with membranes (45). On the other hand, the increased phosphorylation of p35 observed in cultured neurons and COS-7 cells in the presence of a phosphatase inhibitor suggests that Thr 138 is actively dephosphorylated by PP1 or PP2A under basal conditions, raising the modulation of these enzymes as possible mechanisms for regulating the susceptibility of p35 to calpain cleavage.…”

mentioning

confidence: 99%

Suppression of Calpain-dependent Cleavage of the CDK5 Activator p35 to p25 by Site-specific Phosphorylation

Kamei

Saito

Ozawa

et al. 2007

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Cdk5 is a proline-directed Ser/Thr protein kinase predominantly expressed in postmitotic neurons together with its activator, p35. N-terminal truncation of p35 to p25 by calpain results in deregulation of Cdk5 and contributes to neuronal cell death associated with several neurodegenerative diseases. Previously we reported that p35 occurred as a phosphoprotein, phospho-p35 levels changed with neuronal maturation, and that phosphorylation of p35 affected its vulnerability to calpain cleavage. Here, we identify the p35 residues 138 predominantly defines the susceptibility of p35 to calpain-dependent cleavage and that dephosphorylation of this site is a critical determinant of Cdk5-p25-induced cell death associated with neurodegeneration. Cyclin-dependent kinase 5 (Cdk5)2 is a unique member of the Cdk family. Its activity in postmitotic neurons is completely dependent upon association with one of two neuronal specific activators, p35 or p39. Cdk5/p35 is involved in a panoply of processes critical to central nervous system function both during development and throughout maturity including neuronal migration during corticogenesis, neurite outgrowth, regulation of the synaptic vesicle cycle, neurotransmitter release, and postsynaptic neurotransmitter receptor regulation and signaling (1-3). The mechanisms by which Cdk5 activity is normally regulated remains to be fully delineated. Furthermore, because aberrant Cdk5 activity has been implicated in the etiology of neurodegenerative diseases (4, 5), identifying the biochemical mechanisms contributing to deregulation of Cdk5 is of substantial biomedical relevance.Deregulation of Cdk5 results from removal of the first 98 amino acids of p35 by the Ca 2ϩ -dependent cysteine protease, calpain, leaving Cdk5 associated with the N-terminal truncated form p25. Cleavage of p35 to p25 changes the subcellular distribution of active Cdk5 from membranes to the cytosolic fraction (6, 7), thereby altering substrate specificity. p25 accumulates in neurons undergoing various types of cell death (6 -9). Expression of Cdk5/p25 in cultured cells results in increased phospho-Tau levels in comparison to cells expressing Cdk5/ p35 (6). Furthermore, exogenous overexpression of p25 in transgenic mice results in a neurodegenerative phenotype including the formation of paired helical filaments, Tau aggregation, and neuronal loss similar to that observed in Alzheimer disease (10, 11).Cdk5/p25 has also been implicated in ischemia-induced neuronal loss in the hippocampus via increased phosphorylation of the NR2A subunit of the N-methyl-D-aspartic acid receptor (12). In addition, several recent reports indicate that Cdk5-p25 mediates cell death via translocation to the nucleus (13-15). p25 generation increases nuclear Cdk5 activity in cultured neurons, facilitating phosphorylation and inhibition of the pro-survival transcription factor MEF2 (13,15,16). Aberrant Cdk5 activity may also contribute to neuronal cell death via phosphorylation of other survival factors such as the tumor suppressor protein p53 ...

show abstract

mentioning

confidence: 99%

Suppression of Calpain-dependent Cleavage of the CDK5 Activator p35 to p25 by Site-specific Phosphorylation

Kamei

Saito

Ozawa

et al. 2007

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although the kinetics of cdk5 activity when in complex with p35 or p25 are the same, cdk5/p25 complexes are proposed to be responsible for neurodegenerative pathophysiology because of their longer duration of activity in neurons (13,14). Cdk5 activity is largely dependent on the availability of its activators, p35 and p39 (8,(15)(16)(17). Transcription of p35 is under the control of early growth response protein 1 (EGR-1) (18)(19)(20).…”

mentioning

confidence: 99%

Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid

Tsai

Pokrass

Klauer

et al. 2015

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

View full text Add to dashboard Cite

Dysregulation of cyclin-dependent kinase 5 (cdk5) per relative concentrations of its activators p35 and p25 is implicated in neurodegenerative diseases. P35 has a short t ½ and undergoes rapid proteasomal degradation in its membrane-bound myristoylated form. P35 is converted by calpain to p25, which, along with an extended t ½ , promotes aberrant activation of cdk5 and causes abnormal hyperphosphorylation of tau, thus leading to the formation of neurofibrillary tangles. The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum chaperone that is implicated in neuronal survival. However, the specific role of the Sig-1R in neurodegeneration is unclear. Here we found that Sig-1Rs regulate proper tau phosphorylation and axon extension by promoting p35 turnover through the receptor's interaction with myristic acid. In Sig-1R-KO neurons, a greater accumulation of p35 is seen, which results from neither elevated transcription of p35 nor disrupted calpain activity, but rather to the slower degradation of p35. In contrast, Sig-1R overexpression causes a decrease of p35. Sig-1R-KO neurons exhibit shorter axons with lower densities. Myristic acid is found here to bind Sig-1R as an agonist that causes the dissociation of Sig-1R from its cognate partner binding immunoglobulin protein. Remarkably, treatment of Sig-1R-KO neurons with exogenous myristic acid mitigates p35 accumulation, diminishes tau phosphorylation, and restores axon elongation. Our results define the involvement of Sig-1Rs in neurodegeneration and provide a mechanistic explanation that Sig-1Rs help maintain proper tau phosphorylation by potentially carrying and providing myristic acid to p35 for enhanced p35 degradation to circumvent the formation of overreactive cdk5/p25.A xons are structurally and functionally distinct protrusions of neurons that modulate neurotransmitter release and neural function. Malfunction of axonal maintenance, regeneration, and target recognition contribute to CNS disorders such as Alzheimer's disease (AD), Parkinson's disease, stroke, and spinal cord injuries (1-3). Cyclin-dependent kinase (Cdk) 5 activities within the axon play a significant role in the cytoskeletal dynamics of microtubules and actin neurofilaments (NFs), which determine axonal path and length. Specifically, cdk5 active complexes phosphorylate proteins that contribute to the stabilization or destabilization of microtubules, formation of neurofibrillary tangles, and axonal pathfinding (4-6).Cdk5 is a ubiquitously expressed enzyme; however, its activator, p35, is almost exclusively expressed in neurons (7,8). Cdk5 signaling supports neurite projection and proper neuronal migration (9-11). Dysregulation of cdk5 activity leads to hyperphosphorylation of several substrates, including NF proteins and tau, which causes the formation of neurofibrillary tangles (6, 12). Although the kinetics of cdk5 activity when in complex with p35 or p25 are the same, cdk5/p25 complexes are proposed to be responsible for neurodegenerative pathophysiology because of their longer duration o...

show abstract

“…One major reason for the lack of data on p39 may be the difficulty in handling the p39-Cdk5 complex. We previously showed that p39-Cdk5 is a labile complex that dissociates and is inactivated in the presence of nonionic detergents, which is in contrast to p35-Cdk5 that is stable and activated under the same conditions (24,28). In this study, we used computer simulation to identify differences in p35-Cdk5 and p39-Cdk5 at the molecular level that could explain the apparent and different stability.…”

Section: Discussionmentioning

confidence: 99%

Structural Basis for the Different Stability and Activity between the Cdk5 Complexes with p35 and p39 Activators

Saito

Yano

Kawai

et al. 2013

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: Cdk5 activated by p39 has not been characterized, likely because of its instability. Results: Hydrogen bond interaction was reduced between p39 and Cdk5 and experimentally confirmed with amino acid substitution mutants of p35 and p39. Conclusion: Instability of p39-Cdk5 is caused by decreased hydrogen bond interaction. Significance: Structural basis of the instability of p39-Cdk5 was unveiled.

show abstract

Activation of latent cyclin‐dependent kinase 5 (Cdk5)–p35 complexes by membrane dissociation

Cited by 29 publications

References 56 publications

Suppression of Calpain-dependent Cleavage of the CDK5 Activator p35 to p25 by Site-specific Phosphorylation

Suppression of Calpain-dependent Cleavage of the CDK5 Activator p35 to p25 by Site-specific Phosphorylation

Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid

Structural Basis for the Different Stability and Activity between the Cdk5 Complexes with p35 and p39 Activators

Contact Info

Product

Resources

About