Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclin-dependent kinase 5 (Cdk5) was originally isolated through its structural homology to human Cdc2, a key regulator of cell-cycle progression. In tissue samples from adult mice, Cdk5 protein is found at the highest level in brain, at an intermediate level in testis, and at low or undetectable levels in all other tissues, but brain is the only tissue that shows Cdk5 histone H1 kinase activity. No equivalent kinase activity has been found in tissue culture cell lines despite high levels of Cdk5. This raised the possibility that a Cdk5 regulatory subunit was responsible for the activation of Cdk5 in brain. Here we describe the cloning and characterization of a regulatory subunit for Cdk5 known as p35. p35 displays a neuronal cell-specific pattern of expression, it associates physically with Cdk5 in vivo and activates the Cdk5 kinase. p35 differs from the mammalian cyclins and thus represents a new type of regulatory subunit for cyclin-dependent kinase activity.
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PMID:p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. 809 Feb 21

A synthetic peptide corresponding in sequence to residues 6-20 of p34cdc2, cdc2(6-20), and a substitution analogue, cdc2(6-20)F15K19 , which contains Thr-14 as the only phosphorylation target were used as substrates to identify a novel protein kinase in bovine thymus cytosol. The kinase catalyzed the phosphorylation of Thr-14 in both peptides and was purified extensively on the basis of its peptide phosphorylation activity. Upon SDS-polyacrylamide gel electrophoresis analyses, the purified samples consistently displayed a prominent 43-kDa protein band which could undergo in gel autophosphorylation, thus suggesting that this band represented the kinase protein. The suggestion was supported further by the observation that both cdc2(6-20) peptide phosphorylation and the autophosphorylation reaction of the 43-kDa protein were inhibited by millimolar concentrations of cAMP. The kinase was found to inactivate Cdc2/cyclin B, Cdk2/cyclin A, and neuronal Cdc2-like kinase (Nclk), a heterodimer of Cdk5 and neuronal Cdk5 activator (Nck5a), under phosphorylation conditions. The phosphorylation of Nclk by the purified thymus kinase occurred on Cdk5. The monomeric form of Cdk5 was also phosphorylated by the kinase. Phosphoamino acid and phosphopeptide analysis of the phosphorylated Nclk revealed that Thr-14 of Cdk5 was the sole site of protein phosphorylation. The results suggest that this thymus kinase is a novel Cdk inhibitory protein kinase, distinct from the recently cloned dual functional and membrane-associated Cdc2 inhibitory kinase, Myt1 (Mueller, P. R., Coleman, T. R., Kumagai, A., and Durphy, W. G. (1995) Science 270, 86-90).
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PMID:Demonstration of cyclin-dependent kinase inhibitory serine/threonine kinase in bovine thymus. 862

Cyclin-dependent kinase 5 (CDK5) is the 34 kDa catalytic subunit of a recently characterized neuronal cdc2-like protein kinase which appears to be involved in regulation of the neurocytoskeleton. Using the rat postdecapitative model, the effect of brain ischemia on histone H1 and tau protein CDK5 phosphorylating activity was examined. Histone H1 kinase activity increased in both cytosolic and particulate fractions of the hippocampus and neocortex after 5 min and 15 min of ischemia, then declined to control levels. CDK5 tau protein phosphorylating activity increased after 15 min ischemia; however, no electrophoretic shifts or changes in radiodensity of the tau bands were observed autoradiographically. On Western blot analysis, the CDK5 protein band did not change after 25 min ischemia, despite the increase and subsequent decline in enzyme activity. These data demonstrate a postischemic increase in CDK5 activity, an associated increase in CDK5 tau phosphorylating activity and a decline in activity in the absence of massive proteolysis. CDK5 appears to play a role in the events associated with neuronal response to ischemic injury.
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PMID:Cyclin-dependent protein kinase 5 activity increases in rat brain following ischemia. 930 12

Cyclin-dependent kinase 5 (cdk5) is a homologue of cell division cycle 2 (cdc2)-like protein kinase. It is mainly expressed in neurons, and supposed to be involved in the dynamic change of neurocytoskeleton structure seen in the brain after ischemia. In the present study, we investigated immunoreactivity for cdk5 and its critical regulatory subunit p35 in rat brain after 90 min of middle cerebral artery (MCA) occlusion. In the control brain, immunoreactive cdk5 was present in some neurons, while p35 was evident in almost all neurons. At 1 h after blood flow restoration, both of them were remarkably increased in the MCA territory. At 3 h, both immunoreactivities were decreased in the ischemic core region, while they became stronger in neurons at the boundary zone of the MCA territory, which decreased thereafter. These results might suggest that increased cdk5 activity in the brain after ischemia caused depolymerization of neurocytoskeletons, which resulted in neuronal cell death.
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PMID:Expression of cyclin-dependent kinase 5 and its activator p35 in rat brain after middle cerebral artery occlusion. 1032

Cyclin-dependent kinase 5 (cdk5) is found in an active form only in neuronal cells. Activation by virtue of association with the cyclin-like neuronal proteins p35 (or its truncated form p25) and p39 is the only mechanism currently shown to regulate cdk5 catalytic activity. In addition to cyclin binding, other members of the cdk family require for maximal activation phosphorylation of a Ser/Thr residue (Thr(160) in the case of cdk-2) that is conserved in all cdks except cdk8. This site is phosphorylated by cdk-activating kinases, which, however, do not phosphorylate cdk5. To examine the possible existence of a phosphorylation-dependent regulatory mechanism in the case of cdk5, we have metabolically labeled PC12 cells with (32)P(i) and shown that the endogenous cdk5 is phosphorylated. Bacterially expressed cdk5 also can be phosphorylated by PC12 cell lysates. Phosphorylation of cdk5 by a PC12 cell lysate results in a significant increase in cdk5/p25 catalytic activity. Ser(159) in cdk5 is homologous to the regulatory Thr(160) in cdk2. A Ser(159)-to-Ala (S159A) cdk5 mutant did not show similar activation, which suggests that cdk5 is also regulated by phosphorylation at this site. Like other members of the cdk family, cdk5 catalytic activity is influenced by both p25 binding and phosphorylation. We show that the cdk5-activating kinase (cdk5AK) is distinct from the cdk-activating kinase (cyclin H/cdk7) that was reported previously to neither phosphorylate cdk5 nor affect its activity. We also show that casein kinase I, but not casein kinase II, can phosphorylate and activate cdk5 in vitro.
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PMID:Regulation of cyclin-dependent kinase 5 catalytic activity by phosphorylation. 1050 Jan 46

Cyclin-dependent kinase 5 (Cdk5), a member of the cyclin-dependent kinase family, is expressed predominately in mature neurons and is implicated in neurite extension, neuronal migration, and neuronal differentiation. Cdk5 protein expression also has been associated with apoptosis in a number of nonneuronal model systems. In normal brain, substrates for Cdk5 include neurofilament and tau proteins. Because human tumors of glial origin can express neuronal proteins, we examined whether Cdk5 and its activator protein, P35, are present in early passage human glioblastoma multiforme (GBM) cells lines and primary tumor specimens. Here we report the expression of Cdk5 and an "active" proteolytic form of P35 in human GBM cells and demonstrate kinase activity of the holoenzyme. We also show that Cdk5 kinase activity and expression of its activator protein, P35, is increased in the human GBM cell line M059J after exposure to ionizing radiation and that P35 is localized within M059J cells undergoing apoptosis. These results suggest a possible role for Cdk5 in mediating apoptosis in human GBM cells.
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PMID:Expression and localization of cyclin-dependent kinase 5 in apoptotic human glioma cells. 1129 85

Cyclin-dependent kinase 5 (cdk5), in contrast to other members of the cyclin-dependent kinase family, is not activated by cyclins but instead is activated by complexing with neuron-specific activator molecules (p35, p39, and p67). The most effective activator of cdk5 both in vitro and in vivo is p35. We have taken a kinetic approach to study the interaction between p35, its various truncated forms, and cdk5 to understand better the mechanism of its activation. The cdk5 complexes formed with the truncated forms p25 and p21 produced similar maximum active kinase, whereas the cdk5 complexed with full-length p35 and a further truncated form spanning amino acid residues from 138 to 291, with approximate molecular weight of 16 kDa (p16), produced slightly less (80%) activation than p25. P16 was the smallest fragment of p35 that produced activation equal to or greater than that of full-length p35. By examination of further truncations of p16, we found that a small number of residues, 11 and 4 at the N- and C-termini, respectively, of p16, are essential for cdk5 activation. Further truncation, removing both essential N- and C-terminal domains, produces a peptide with markedly higher affinity for cdk5 compared with the peptides that retain either of these domains. Using these inactive truncated peptides as inhibitors, we examined the kinetics of activation. From these studies we conclude that activation involves at least three cdk5-interacting domains, one located at each end of p16 and at least one located in a central domain. The cdk5 activation process is slow: The second-order rate constant for p16 is about 1.2 microM(-1) hr(-1). On the basis of kinetic data, we suggest that cdk5 exists in two conformations. The inactive kinase conformation predominates in the absence of the activator. Activation occurs in two stages: a rapid and reversible interaction of cdk5 with its activator, which involves only one or two binding domains, followed by a slow stabilization of the active conformation as interaction with all three domains is achieved.
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PMID:Cyclin-dependent kinase 5 (cdk5) activation requires interaction with three domains of p35. 1181 40

Alzheimer's disease (AD) is characterized by two pathological hallmarks, namely, senile plaques and neurofibrillary tangles (NFTs). The former are mainly composed of amyloid-beta peptides (Abeta) while the latter consists mainly of filaments of hyperphosphorylated tau. Cyclin-dependent kinase 5 (cdk5) has been implicated not only in the tangle pathology, but recent data also implicate cdk5 in the generation of Abeta peptides. Since both Abeta peptides and NFTs are believed to play a role in neurodegeneration in AD, this proline-directed serine/threonine protein kinase is likely to contribute to the pathogenesis of AD. In vitro and in vivo animal data demonstrate the ability of cdk5 to induce phosphorylation and aggregation of tau, and NFT deposition and neurodegeneration. Findings from AD brain samples also show an elevated cdk5 activity and conditions that support the activation of cdk5. Evidence for the role of cdk5 in regulating Abeta production is just emerging. The mechanisms for this potentially damaging activity of cdk5 are largely unknown although amyloid precursor protein and presenilin-1 are both cdk5 substrates.
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PMID:Role of cdk5 in the pathogenesis of Alzheimer's disease. 1467 7

Cyclin-dependent kinase 5 (Cdk5) is a member of the cyclin-dependent kinase family that is involved in the regulation of the cell cycle. As their name suggests, the Cdks require association with activator proteins called cyclins for their activity. Cdk5, however, is unique to this family of proline-directed serine/threonine kinases on two accounts. Firstly, Cdk5 has not been found to function in the cell cycle and, although expressed in a number of tissues, its activity is restricted to the nervous system. Secondly, unlike the other members of the Cdk family, Cdk5 is not activated by association with a cyclin, although it can bind them. Instead, Cdk5 is activated by the activator proteins p35 and p39 that are structurally distinct from cyclins and have, for the most part, a neuronal-specific expression pattern. In the past decade of research on Cdk5, it is now established that Cdk5 activity is critical for the proper formation and function of the brain. Moreover, its role as a central kinase, phosphorylating its substrates in its 'cross-talk' control of other kinase and signal transduction pathways, has also been determined. In addition to the normal physiological role of Cdk5, the kinase has been implicated in certain neurodegenerative disorders. For example, Cdk5 associates with the proteolytic, more active p25 fragment that is derived through the cleavage of p35. In turn, the p25/Cdk5 complex aberrantly phosphorylates its substrates tau and neurofilaments, which has been implicated in the pathogenesis of these disorders. Here, we attempt to review the past decade of research on Cdk5 from our laboratory and others, on the roles of Cdk5 in nervous system function. Additionally, our research has recently uncovered a possible therapeutic avenue of research, focusing on inhibition of aberrant Cdk5 hyperactivity which may well be used to treat the symptoms of a number of neurodegenerative diseases. The elucidation of a specific inhibitor of p25/Cdk5, termed CIP, also inhibits p25/Cdk5-mediated tau phosphorylation. This may well provide us with avenues of research focusing on the inhibition of pathologically damaging p25/Cdk5 species.
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PMID:Neuronal cyclin-dependent kinase 5: role in nervous system function and its specific inhibition by the Cdk5 inhibitory peptide. 1502 57

Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine protein kinase that requires association with a regulatory protein, p35 or p39, to form an active enzyme. Munc18-1 plays an essential role in membrane fusion, and its function is regulated by phosphorylation. We report here that both p35 and p39 were expressed in insulin-secreting beta-cells, where they exhibited individual subcellular distributions and associated with membranous organelles of different densities. Overexpression of Cdk5, p35, or p39 showed that Cdk5 and p39 augmented Ca(2+)-induced insulin exocytosis. Suppression of p39 and Cdk5, but not of p35, by antisense oligonucleotides selectively inhibited insulin exocytosis. Transient transfection of primary beta-cells with Munc18-1 templates mutated in potential Cdk5 or PKC phosphorylation sites, in combination with Cdk5 and the different Cdk5 activators, suggested that Cdk5/p39-promoted Ca(2+)-dependent insulin secretion from primary beta-cells by phosphorylating Munc18-1 at a biochemical step immediately prior to vesicle fusion.
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PMID:Cyclin-dependent kinase 5 associated with p39 promotes Munc18-1 phosphorylation and Ca(2+)-dependent exocytosis. 1512 26


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