Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

cdc25C is a phosphatase, which activates the mitosis-promoting factor cyclin B1/cdc2 by dephosphorylation, and thus triggers G(2)/M transition. The activity of cdc25C itself is controlled by phosphorylation of certain amino-acid residues, which among other things determines the subcellular localization of the enzyme. Here, we describe a new phosphorylation site at threonine 236 of cdc25C, which is phosphorylated by protein kinase CK2. This phosphorylation site is located near the nuclear localization signal (amino acids 239-245). We demonstrate that cdc25C interacts with importin beta and the importin alpha/beta heterodimer but not with importin alpha. We further found that a cdc25C phosphorylation mutant where threonine 236 was replaced by aspartic acid as well as cdc25C phosphorylated by CK2 binds importin beta or the importin alpha/beta heterodimer less efficiently than wild type or the corresponding alanine mutant. Furthermore, the cdc25C(T236D) shows a retarded uptake into the nucleus in a cell import assay. Inhibition of protein kinase CK2 enzyme activity in vivo resulted in an enhanced nuclear localization of cdc25C. Thus, phosphorylation of cdc25C at threonine 236 is an important signal for the retention of cdc25C in the cytoplasm.
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PMID:Mutation of a CK2 phosphorylation site in cdc25C impairs importin alpha/beta binding and results in cytoplasmic retention. 1506 44

Cdk-activating kinase (CAK) is a trimeric complex consisting of cdk7, cyclin H, and MAT1, which activates the cell-cycle-regulating cdks through T loop phosphorylation. In addition, other substrates of the CAK complex have been identified when CAK is assembled with the TFIIH core proteins, thereby regulating transcription and nucleotide excision repair. Little is known about the regulation of the CAK complex through cyclin H. In this study we further analyzed cyclin H regulation and identified two basic clusters in the C terminus of the protein as putative nuclear localization sequences (NLSs). Fusion constructs of full-length and truncated cyclin H sequences demonstrated the functionality of the NLSs. A peptide-binding assay revealed that at least one NLS interacts with the nuclear import receptors importin alpha/beta. Phosphorylation in the vicinity of the NLSs by cyclin C/cdk8 or protein kinase CK2, however, does not influence the nuclear translocation of cyclin H.
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PMID:Cyclin H is targeted to the nucleus by C-terminal nuclear localization sequences. 1597 Nov 11

We have previously demonstrated that the cyclin-dependent kinase inhibitor (Cki) Sic1 of Saccharomyces cerevisiae is phosphorylated in vitro by the CK2 kinase on Ser(201) residue. Moreover, we have collected evidence showing that Sic1 is functionally and structurally related to mammalian Cki p27(Kip1) and binds to the mammalian Cdk2/cyclin A complex with a similar mode of inhibition. In this paper, we use SPR analysis to investigate the binding of Sic1 to the catatytic and regulatory subunits of CK2. Evidence is presented showing that phosphorylation of Sic1 at the CK2 consensus site QES(201)EDEED increases the binding of a Sic1-derived peptide to the Cdk2/cyclin A complex, a functional homologue of the yeast Cdk1/Clb5,6. Moreover, Sic1 fully phosphorylated in vitro on Ser(201) by CK2 is shown to be a stronger inhibitor of the Cdk/cyclin complexes than the unphosphorylated protein. Taken together, these data disclose the possibility that CK2 plays a role in the regulation of Sic1 activity.
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PMID:CK2 regulates in vitro the activity of the yeast cyclin-dependent kinase inhibitor Sic1. 1616 90

Both, the activity as well as the expression of protein kinase CK2 is enhanced in various cancer types and in established tumour cell lines. This phenomenon is not due to an increase in the CK2 message but rather to posttranscriptional and posttranslational mechanisms. In order to get an insight into these posttranslational modifications we analyzed CK2 in prostate cancer cell lines, which differ by their hormone-sensitivity. We found that the CK2 activity is significantly higher in hormone-refractory than in hormone-sensitive cells although the amount of the catalytic alpha- and alpha'- subunits is comparable. In contrast, we detected seemingly lower amounts of the regulatory beta-subunit in the hormone-refractory cell lines, which later turned out to be an immunologically defined subclass. This subclass is realized by a phosphate group, which is attached to serine 209. The phosphorylation occurs in vivo during mitosis and is executed by the p34(cdc2)/cyclin B kinase. As this phosphorylation enhances the CK2 activity this change might well account for the higher activity of CK2 in prostate cancer cells.
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PMID:Immunologically defined subclasses of the protein kinase CK2 beta-subunit in prostate carcinoma cell lines. 1633 37

Minichromosome maintenance 2-7 proteins play a pivotal role in replication of the genome in eukaryotic organisms. Upon entry into S-phase several subunits of the MCM hexameric complex are phosphorylated. It is thought that phosphorylation activates the intrinsic MCM DNA helicase activity, thus allowing formation of active replication forks. Cdc7, Cdk2, and ataxia telangiectasia and Rad3-related kinases regulate S-phase entry and S-phase progression and are known to phosphorylate the Mcm2 subunit. In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the N terminus of Mcm2 by Cdc7, Cdk2, Cdk1, and CK2. We found that Cdc7 phosphorylates Mcm2 in at least three different sites, one of which corresponds to a site also reported to be phosphorylated by ataxia telangiectasia and Rad3-related. Three serine/proline sites were identified for Cdk2 and Cdk1, and a unique site was phosphorylated by CK2. We raised specific anti-phosphopeptide antibodies and found that all the sites identified in vitro are also phosphorylated in cells. Importantly, although all the Cdc7-dependent Mcm2 phosphosites fluctuate during the cell cycle with kinetics similar to Cdc7 kinase activity and Cdc7 protein levels, phosphorylation of Mcm2 in the putative cyclin-dependent kinase (Cdk) consensus sites is constant during the cell cycle. Furthermore, our analysis indicates that the majority of the Mcm2 isoforms phosphorylated by Cdc7 are not stably associated with chromatin. This study forms the basis for understanding how MCM functions are regulated by multiple kinases within the cell cycle and in response to external perturbations.
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PMID:Identification of Mcm2 phosphorylation sites by S-phase-regulating kinases. 1644 60

The tumor suppressor p53 is an important cellular protein, which controls cell cycle progression. Phosphorylation is one of the mechanisms by which p53 is regulated. Here we report the interaction of p53 with another key regulator, cdk9, which together with cyclin T1 forms the positive transcription elongation complex, p-TEFb. This complex cooperates with the HIV-1 Tat protein to cause the phosphorylation of the carboxyl terminal domain (CTD) of RNA polymerase II and this facilitates the elongation of HIV-1 transcription. We demonstrate that cdk9 phosphorylates p53 on serine 392 through their direct physical interaction. Results from protein-protein interaction assays revealed that cdk9 interacts with the C-terminal domain (aa 361-393) of p53, while p53 interacts with the N-terminal domain of cdk9. Transfection and protein binding assays (EMSA and ChIP) demonstrated the ability of p53 to bind and activate the cdk9 promoter. Interestingly, cdk9 phosphorylates serine 392 of p53, which could be also phosphorylated by casein kinase II. Kinase assays demonstrated that cdk9 phosphorylates p53 independently of CKII. These studies demonstrate the existence of a feedback-loop between p53 and cdk9, pinpointing a novel mechanism by which p53 regulates the basal transcriptional machinery.
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PMID:Cdk9 phosphorylates p53 on serine 392 independently of CKII. 1674 55

Meta-predictors make predictions by organizing and processing the predictions produced by several other predictors in a defined problem domain. A proficient meta-predictor not only offers better predicting performance than the individual predictors from which it is constructed, but it also relieves experimentally researchers from making difficult judgments when faced with conflicting results made by multiple prediction programs. As increasing numbers of predicting programs are being developed in a large number of fields of life sciences, there is an urgent need for effective meta-prediction strategies to be investigated. We compiled four unbiased phosphorylation site datasets, each for one of the four major serine/threonine (S/T) protein kinase families-CDK, CK2, PKA and PKC. Using these datasets, we examined several meta-predicting strategies with 15 phosphorylation site predictors from six predicting programs: GPS, KinasePhos, NetPhosK, PPSP, PredPhospho and Scansite. Meta-predictors constructed with a generalized weighted voting meta-predicting strategy with parameters determined by restricted grid search possess the best performance, exceeding that of all individual predictors in predicting phosphorylation sites of all four kinase families. Our results demonstrate a useful decision-making tool for analysing the predictions of the various S/T phosphorylation site predictors. An implementation of these meta-predictors is available on the web at: http://MetaPred.umn.edu/MetaPredPS/.
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PMID:Meta-prediction of phosphorylation sites with weighted voting and restricted grid search parameter selection. 1823 18

p27(Kip1) (p27) blocks cell proliferation through the inhibition of cyclin-dependent kinase-2 (Cdk2). Despite its robust expression in the heart, little is known about both the function and regulation of p27 in this and other nonproliferative tissues, in which the expression of its main target, cyclin E-Cdk2, is known to be very low. Here we show that angiotensin II, a major cardiac growth factor, induces the proteasomal degradation of p27 through protein kinase CK2-alpha'-dependent phosphorylation. Conversely, unphosphorylated p27 potently inhibits CK2-alpha'. Thus, the p27-CK2-alpha' interaction is regulated by hypertrophic signaling events and represents a regulatory feedback loop in differentiated cardiomyocytes analogous to, but distinct from, the feedback loop arising from the interaction of p27 with Cdk2 that controls cell proliferation. Our data show that extracellular growth factor signaling regulates p27 stability in postmitotic cells, and that inactivation of p27 by CK2-alpha' is crucial for agonist- and stress-induced cardiac hypertrophic growth.
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PMID:Protein kinase CK2 links extracellular growth factor signaling with the control of p27(Kip1) stability in the heart. 1832 42

Protein phosphorylation is an important step in many biological processes, such as cell cycles, membrane transport, apoptosis, etc. In order to obtain more useful information about protein phosphorylation, it is necessary to develop a robust, stable, and accurate approach to predict phosphorylation sites. Although there exist a number of approaches to predict phosphorylation sites, such as those based on neural network and the support vector machine, they only use a single classifier. In general, the prediction results obtained by these approaches are not very stable and robust. In this paper, we design a new classifier ensemble approach called Bagging-AdaBoost ensemble (BAE) for the prediction of eukaryotic protein phosphorylation sites, which incorporates the bagging technique and the AdaBoost technique into the classifier framework to improve the accuracy, stability, and robustness of the final result. To our knowledge, this is the first time in which a combined bagging and boosting ensemble approach is applied to predict phosphorylation sites. Our prediction system based on BAE focuses on six kinase families: CDK, CK2, MAPK, PKA, PKC, and SRC. BAE achieves good performance in these six families, and the accuracies of the prediction system for these families are 0.8634, 0.8721, 0.8542 , 0.8537, 0.8052, and 0.7432, respectively.
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PMID:Identifying protein-kinase-specific phosphorylation sites based on the Bagging-AdaBoost ensemble approach. 2021 87

S phase is characterized by the replication of DNA and assembly of chromatin. This requires the synthesis of large amounts of histone proteins to package the newly replicated DNA. Histone mRNAs are the only mRNAs that do not have polyA tails, ending instead in a conserved stemloop sequence. The stemloop binding protein (SLBP) that binds the 3' end of histone mRNA is cell cycle regulated and SLBP is required in all steps of histone mRNA metabolism. Activation of cyclin E/cdk2 prior to entry into S-phase is critical for initiation of DNA replication and histone mRNA accumulation. At the end of S phase SLBP is rapidly degraded as a result of phosphorylation of SLBP by cyclin A/cdk1 and CK2 effectively shutting off histone mRNA biosynthesis. E2F1, which is required for expression of many S-phase genes, is regulated in parallel with SLBP and its degradation also requires a cyclin binding site, suggesting that it may also be regulated by the same pathway. It is likely that activation of cyclin A/cdk1 helps inhibit both DNA replication and histone mRNA accumulation, marking the end of S phase and entry into G(2)-phase.
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PMID:Coordinate regulation of histone mRNA metabolism and DNA replication: cyclin A/cdk1 is involved in inactivation of histone mRNA metabolism and DNA replication at the end of S phase. 2093 61


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