Disease relevance of Cdk5

• Deregulation of the Cdk5 enzymatic activity was found to associate with a number of neurodegenerative diseases [1].
• Hypoxia/reoxygenation alone reduced both the protein amount and activity of Cdk5, and this reduction was inhibited by pre-treatment with ASA [2].
• Recently, the toxicity of Abeta to neurons was shown to be dependent upon the activation of cyclin-dependent kinase 5 (Cdk5), thought to promote tau phosphorylation that leads to cytoskeletal disruption, morphological degeneration and apoptosis [3].
• An immunohistochemical study showed that Cdk5 was expressed in the ganglion cells and in some cells in the inner nuclear layer at an early stage [4].
• The present results suggest that IGF-1 has a significant effect on ameliorating brain injury after transient focal brain ischemia with affecting the expressions of cdk5 and its activator p35 [5].

Psychiatry related information on Cdk5

• Moreover, Cdk5 is thought to be involved in the promotion of neurodegeneration in Alzheimer's disease [6].
• Single Cdk5 IR was also examined in several brain areas implicated in alcohol drinking [7].
• It has been shown previously that chronic cocaine administration increases the expression of cyclin-dependent kinase-5 in this brain region and that this neuronal protein kinase regulates cocaine-induced locomotor activity [8].

High impact information on Cdk5

• Cdk5 activation induces hippocampal CA1 cell death by directly phosphorylating NMDA receptors [9].
• Thus, we conclude that modulation of NMDA receptors by Cdk5 is the primary intracellular event underlying the ischemic injury of CA1 pyramidal neurons [9].
• Ser1232 phosphorylation is catalyzed by cyclin-dependent kinase 5 (Cdk5) [9].
• Cdk5 is involved in neuregulin-induced AChR expression at the neuromuscular junction [10].
• Here we describe an important involvement of Cdk5/p35 in regulating the gene expression of acetylcholine receptor (AChR) at the neuromuscular synapse [10].

Chemical compound and disease context of Cdk5

• Cyclin dependent kinase 5 (Cdk5) is a proline-direct protein kinase that is most active in the CNS, and has been implicated as a contributing factor in certain neurodegenerative diseases [11].

Biological context of Cdk5

• The biological activity of Cdk5 has been ascribed to its phosphorylation of cytoplasmic substrates [12].
• Here we investigate the mechanism by which Cdk5 promotes neuronal apoptosis [12].
• Cdk5 is essential for synaptic vesicle endocytosis [13].
• Notably, Cdk5 phosphorylated serine 1144, which is adjacent to the endophilin binding site [14].
• Cdk5 and Trio modulate endocrine cell exocytosis [15].
• Cdk5 regulated axon formation of cortical neurons through phosphorylating a scaffold protein Axin in developing mouse cerebral cortex [16].

Anatomical context of Cdk5

• Together, these data suggest that control of the cortical actin cytoskeleton, long known to modulate hormone exocytosis and subsequent endocytosis, involves Cdk5-mediated activation of Trio [15].
• L6 myoblast differentiation is modulated by Cdk5 via the PI3K-AKT-p70S6K signaling pathway [17].
• Cdk5 and p35 are highly localized in the growth cone of cultured neurons, and Cdk5 activity is associated with neurite outgrowth [18].
• Retardation of axonal regeneration by Cdk5 inhibition was confirmed by reduced labeling of facial motor neurons using retrograde tracer fluorogold (FG) [18].
• Here we report evidence on the functional involvement of Cdk5 kinase in regenerating peripheral nerve fibers [18].

Associations of Cdk5 with chemical compounds

• Neurotoxic insults deregulate Cdk5 activity, which leads to neuronal apoptosis and may contribute to neurodegeneration [12].
• The complex of Cdk5 and its neuronal activator p35 is a proline-directed Ser/Thr kinase that plays an important role in various neuronal functions [1].
• Hormone secretion by pituitary cells is decreased by roscovitine, an inhibitor of cyclin-dependent kinase 5 (Cdk5) [15].
• Administration of Cdk5 inhibitors, roscovitine and olomoucine, into the crushed nerves resulted in decreases in Cdk5 kinase activity in nerves and retardation of nerve fiber regrowth [18].
• The prevention of the loss in Cdk5 activity during reoxygenation was crucial for ASA-induced protection, because co-administration of Cdk5 inhibitors at the onset ofreoxygenation abolished the protection [2].

Physical interactions of Cdk5

• Activity and regulation of p35/Cdk5 kinase complex [19].

Enzymatic interactions of Cdk5

• Endophilin-SH3 binding to the high affinity site was disrupted when dynamin-1 PRD was phosphorylated with Cdk5, indicating that this site overlaps the phosphorylation sites, but amphiphysin-SH3 binding was unaffected [20].
• Cdk5 phosphorylates CRMP-2 at serine 522, possibly facilitating phosphorylation of serine 518 and threonine 514 by glycogen synthase kinase 3beta (GSK3beta), a kinase previously implicated in Sema 3A signaling [21].
• We conclude that cdk-5 and GSK-3 phosphorylate different residues or sets of residues within NF-H sidearm in cells [22].

Regulatory relationships of Cdk5

• Cyclin-dependent kinase 5 (Cdk5) is a serine-threonine kinase that is activated by the binding of p35 or p39 regulatory protein [18].
• Exogenously expressed p67 stimulated Cdk5 kinase activity in vitro in a dose-dependent manner and when presented as an affinity matrix, selectively adsorbed Cdk5 from a cleared rat brain homogenate [23].
• A specific interaction between muskelin and the cyclin-dependent kinase 5 activator p39 promotes peripheral localization of muskelin [24].

Other interactions of Cdk5

• Both N-methyl-D-aspartate (NMDA) and non-NMDA receptors mediate glutamate-induced cleavage of the cyclin-dependent kinase 5 (cdk5) activator p35 in cultured rat hippocampal neurons [25].
• PD90859, a p44/42 MAPK inhibitor, had no effect on ASA-induced tolerance, but olomoucine and roscovitine, Cdk5 inhibitors, reduced ASA neuroprotection [2].
• We recently reported the novel function of Cdk5 in the neuregulin signaling pathway during the development of neuromuscular junction (NMJ) [26].
• Multiple proteins involved in the intricate control of neuronal migration were also altered in response to this treatment, primarily the downstream targets of c-Abl: Cdk5, p25, and the cytoskeletal elements neurofilament H and F-actin and catalase [27].
• To further understand the mechanism of cell death, we used a rat cerebellar granule cell culture system to investigate whether the calpain/cyclin-dependent kinase 5 (cdk5)/p35 cascade, an important cascade for neuronal apoptosis, is involved in the methylmercury-induced death [28].

Analytical, diagnostic and therapeutic context of Cdk5

• Elevated levels of Cdk5 protein were found in regenerating axons of facial motor neurons after nerve crush, and Cdk5 kinase activity was increased with a similar time course as increases in Cdk5 protein levels [18].
• Western blot techniques revealed that acute and repeated 'binge' cocaine decreased expression of the Cdk5 protein in the amygdala [29].
• In addition to the induction of mRNA expression, the total Cdk5 and p35-associated kinase activity in muscle increased prominently after nerve denervation [26].
• The changes in the p35 and p25 protein levels coincided with decreases in cdk5 activity and tau phosphorylation after treatment with HNE and etoposide [30].
• Co-immunoprecipitation studies revealed the association between Cdk5, p35 and ErbB receptors in muscle and cultured myotubes [10].

References