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)

Nek2, a mammalian protein kinase of unknown function, is closely related to the mitotic regulator NIMA of Aspergillus nidulans. Here we show by both immunofluorescence microscopy and biochemical fractionation that human Nek2 localizes to the centrosome. Centrosome association occurs throughout the cell cycle, including all stages of mitosis, and is independent of microtubules. Overexpression of active Nek2 induces a striking splitting of centrosomes, whereas prolonged expression of either active or inactive Nek2 leads to dispersal of centrosomal material and loss of a focused microtubule-nucleating activity. Surprisingly, this does not prevent entry into mitosis, as judged by the accumulation of mitotically arrested cells induced by co-expression of a non-destructible B-type cyclin. These results bear on the dynamic function of centrosomes at the onset of mitosis. Moreover, they indicate that one function of mammalian Nek2 relates to the centrosome cycle and thus provide a new perspective on the role of NIMA-related kinases.
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PMID:A centrosomal function for the human Nek2 protein kinase, a member of the NIMA family of cell cycle regulators. 943 Jun 39

PRK1 (PKN) is a serine/threonine kinase that has been shown to be activated by RhoA (Amano, M., Mukai, H., Ono, Y., Chihara, K., Matsui, T., Hamajima, Y., Okawa, K., Iwamatsu, A., and Kaibuchi, K. (1996) Science 271, 648-650). Detailed analysis of the PRK1 region involved in RhoA binding has revealed that two homologous sequences within the HR1 domain (HR1a and HR1b) both bind to RhoA; the third repeat within this domain, HR1cPRK1, does not bind RhoA. The related HR1 motif is also found to confer RhoA binding activity to the only other fully cloned member of this kinase family, PRK2. Furthermore, the predictive value of this motif is established for an HR1a sequence derived from a Caenorhabditis elegans open reading frame encoding a protein kinase of unknown function. Interestingly, the HR1aPRK1 and HR1bPRK1 subdomains are shown to display a distinctive nucleotide dependence for RhoA binding. HRIaPRK1 is entirely GTP-dependent, while HR1bPRK1 binds both GTP- and GDP-bound forms of RhoA. This distinction indicates that there are two sites of contact between RhoA and PRK1, one contact through a region that is conformationally dependent upon the nucleotide-bound state of RhoA and one that is not. Analysis of binding to Rho/Rac chimera provides evidence for a HR1aPRK1 but not HR1bPRK1 interaction in the central third of Rho. Additionally, it is observed that the V14RhoA mutant binds HR1a but does not bind HR1b. This distinct binding behavior corroborates the conclusion that there are independent contacts on RhoA for the HR1aPRK1 and HR1bPRK1 motifs.
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PMID:Multiple interactions of PRK1 with RhoA. Functional assignment of the Hr1 repeat motif. 944 75

The complete sequences of four TBE1 transposons from Oxytricha fallax and O. trifallax are presented and analyzed. Although two TBE1s are 98% identical to each other at the nucleotide level, the remaining two TBE1s are only 90% identical both to each other and to the other two. This large evolutionary divergence allows us to identify conserved TBE1 features. TBE1 transposons are 4.1 kbp long and are flanked by 3 bp target-site repeats. The elements consist of 78 bp inverted terminal repeats, of which the 17 terminal base pairs are Oxytricha telomere repeats; a central conserved section of 550 bp that includes a set of nested direct and inverted sequence repeats; and 3 open reading frames conserved for encoded amino acid sequence. The three open reading frames encode a 22 kDa basic protein of unknown function, a 42 kDa 'D,D35E' transposase, and a 57 kDa chimeric C2H2 zinc finger/protein kinase. The protein kinase domain of the 57 kDa protein is unusual, lacking a conserved ATP-binding motif.
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PMID:Conserved features of TBE1 transposons in ciliated protozoa. 946

T1alpha is a protein of unknown function that is expressed at the plasma membrane in epithelia involved in fluid transport, including type I alveolar epithelial cells, choroid plexus, and ciliary epithelium. The purpose of this study was to test the hypothesis that T1alpha functions as a water channel or a regulator of aquaporin-type water channels that are coexpressed with T1alpha. Two complementary DNAs (cDNAs) (hT1alpha-1 and hT1alpha-2) encoding human isoforms of T1alpha were cloned by homology to the rat T1alpha coding sequence. The cDNAs encoded 164 (hT1alpha-1) and 162 (hT1alpha-2) amino acid proteins with high homology to rat T1alpha in a putative membrane-spanning domain. hT1alpha-1 transcripts of 2. 6 and 1.4 kb were detected in human lung, heart, and skeletal muscle, and a single hT1alpha-2 transcript of 1.2 kb was detected in human lung. Rat and mouse T1alpha were isolated by reverse transcription-polymerase chain reaction and confirmed by DNA sequence analysis. Expression of mouse, rat, and human T1alpha isoforms in Xenopus oocytes did not increase osmotic water permeability (Pf) above that in water-injected oocytes, nor was there an effect of protein kinase A or C activation; Pf was increased > 10-fold in positive control oocytes expressing aquaporin (AQP)1 or AQP5. Coexpression of AQP1 or AQP5 with excess T1alpha gave Pf not different from that in oocytes expressing AQP1 or AQP5 alone. Oocyte plasma membrane localization of epitope-tagged T1alpha protein was confirmed and quantified by immunoprecipitation of microdissected plasma membranes. Quantitative densitometry indicated that the single-channel water permeability of T1alpha is under 2 x 10(-16) cm3/s, suggesting that T1alpha is not involved in the high transalveolar water permeability in intact lung. The cloning of hT1alpha isoforms may permit the development of an assay of type I cell antigen in airspace fluid as a marker of human lung injury.
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PMID:Evidence against a role of mouse, rat, and two cloned human t1alpha isoforms as a water channel or a regulator of aquaporin-type water channels. 965 Nov 90

The yeast CTDK-I complex has been implicated in phosphorylation of the carboxy-terminal domain of the RNA polymerase II and in transcription control. It is composed of three polypeptides: Ctk1p and Ctk2p, a cyclin-dependent kinase and a C-type cyclin subunit, respectively; and Ctk3p, a third subunit of unknown function. Cyclins are regulatory proteins whose expression is tightly controlled at the protein level. In this study, we examined the regulation of Ctk2p expression in vivo. Surprisingly, unlike what has been described for cell cycle cyclins, steady-state levels of Ctk2p are composed of two relatively abundant forms, one of them phosphorylated. We show that this phosphorylated form is extremely unstable (half-life, 5 min) and that rapid proteolysis of Ctk2p exhibits growth-related regulation. Furthermore, our data establish that similar to the case for other naturally short-lived proteins, Ctk2p degradation is mediated by the ubiquitin-proteasome pathway. This is the first demonstration that a C-type cyclin is phosphorylated and targeted to the proteasome. Strikingly, neither phosphorylation nor destruction of Ctk2p requires its associated kinase Ctk1p, a feature fundamentally different from that which has been observed for cell cycle cyclins.
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PMID:The yeast C-type cyclin Ctk2p is phosphorylated and rapidly degraded by the ubiquitin-proteasome pathway. 1008 18

In this paper we present the finding that lovastatin arrests cells by inhibiting the proteasome, which results in the accumulation of p21 and p27, leading to G1 arrest. Lovastatin is an inhibitor of hydroxymethyl glutaryl (HMG)-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. Previously, we reported that lovastatin can be used to arrest cultured cells in the G1 phase of the cell cycle, resulting in the stabilization of the cyclin-dependent kinase inhibitors (CKIs) p21 and p27. In this report we show that this stabilization of p21 and p27 may be the result of a previously unknown function of the pro-drug, beta-lactone ring form of lovastatin to inhibit the proteasome degradation of these CKIs. The lovastatin mixture used in this study is 80% open-ring form and 20% pro-drug, beta-lactone form. We show that while the lovastatin open-ring form and pravastatin (a lovastatin analogue, 100% open ring) inhibit the HMG-CoA reductase enzyme, lovastatin pro-drug inhibits the proteasome but does not inhibit HMG-CoA reductase. In addition, many of the properties of proteasome inhibition by the pro-drug are the same as the specific proteasome inhibitor lactacystin. Lastly, mevalonate (used to rescue cells from lovastatin arrest) unexpectedly abrogates the lactacystin and lovastatin pro-drug inhibition of the proteasome. Mevalonate increases the activity of the proteasome, which results in degradation of the CKIs, allowing lovastatin- and lactacystin-arrested cells to resume cell division. The lovastatin-mediated inhibition of the proteasome suggests a unique mechanism for the chemopreventative effects of this agent seen in human cancer.
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PMID:Lovastatin-mediated G1 arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase. 1039 1

Sequence analysis of cosmid clones was instrumental to identify three genes in the region flanking the Fugu rubripes NF1 gene in the 3' direction: the AKAP84 gene (A-kinase anchor protein 84), the WSB1 gene (WD-40-repeat protein with a SOCS box) and the BAW gene of yet unknown function located between the AKAP84 and the WSB1 genes. The human homologues of these genes are not located in the immediate vicinity of the NF1 gene at 17q11.2. Although synteny of the NF1, AKAP84, BAW and WSB1 genes is conserved between Fugu and human, the gene order is not conserved, and more than a simple inversion would have been necessary to explain the difference in gene order. The mammalian homologue of the Fugu BAW gene or protein has not yet been characterized. As deduced from the respective cDNAs, the Fugu AKAP84, WSB1 and BAW proteins vary concerning the overall degree of similarity to their mammalian counterparts. Whereas the overall similarity of AKAP84 between Fugu and mouse is low, three regions of known functional importance show considerable conservation. These are the N-terminal anchoring domain mediating the insertion of AKAP84 in the outer mitochondrial membrane, the binding site of the regulatory subunit (RI or RII) of protein kinase A, and the C-terminal domain present in the alternatively spliced isoform AKAP121 with an hnRNP K homology domain involved in RNA binding. A higher overall similarity of deduced protein sequences between Fugu and mouse was observed comparing the BAW gene products (74.1%) and the WSB1 proteins (77.2%).
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PMID:Characterization of three genes, AKAP84, BAW and WSB1, located 3' to the neurofibromatosis type 1 locus in Fugu rubripes. 1041 27

When glucose is added to Saccharomyces cerevisiae cells grown into stationary phase or on non-fermentable carbon sources a rapid loss of heat stress resistance occurs. Mutants that retain high stress resistance after addition of glucose are called 'fil', for deficient in fermentation induced loss of stress resistance. Transformation of the fil1 mutant, which harbours a point mutation in adenylate cyclase, with a yeast gene library on a single copy plasmid resulted in transformants that were again stress-sensitive. One of the genes isolated in this way was a gene of previously unknown function. We have called it SFI1, for suppressor of fil1. SFI1 is an essential gene. Combination of Sfi1 and cAMP pathway mutations indicates that Sfi1 itself is not involved in the cAMP pathway. Conditional sfi1 mutants did not show enhanced heat resistance under the restrictive condition, whereas overexpression of SFI1 rendered cells heat-sensitive. Sfi1 may be a downstream target of the protein kinase A pathway, but its precise relationship with heat resistance remains unclear. Further analysis showed that Sfi1 is required for cell cycle progression, more specifically for progression through G(2)-M transition. Cells expressing SFI1 under the control of a galactose-inducible promoter arrest after addition of glucose as doublets of undivided mother and daughter cells. These doublets contain a single nucleus and lack mitotic spindles. Sfi1 shares homology with Xenopus laevis XCAP-C, a protein required for chromosome assembly. The conserved residues between these two proteins show a strong bias for charged amino acids. Hence, Sfi1 might be required for correct mitotic spindle assembly and its precise role might be in chromosome condensation. In conclusion, we have identified an essential function in the G(2)-M transition of the cell cycle for a yeast gene of previously unknown function.
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PMID:Deletion of SFI1, a novel suppressor of partial Ras-cAMP pathway deficiency in the yeast Saccharomyces cerevisiae, causes G(2) arrest. 1045 33

In Saccharomyces cerevisiae, the Wee1 family kinase Swe1p is normally stable during G(1) and S phases but is unstable during G(2) and M phases due to ubiquitination and subsequent degradation. However, perturbations of the actin cytoskeleton lead to a stabilization and accumulation of Swe1p. This response constitutes part of a morphogenesis checkpoint that couples cell cycle progression to proper bud formation, but the basis for the regulation of Swe1p degradation by the morphogenesis checkpoint remains unknown. Previous studies have identified a protein kinase, Hsl1p, and a phylogenetically conserved protein of unknown function, Hsl7p, as putative negative regulators of Swe1p. We report here that Hsl1p and Hsl7p act in concert to target Swe1p for degradation. Both proteins are required for Swe1p degradation during the unperturbed cell cycle, and excess Hsl1p accelerates Swe1p degradation in the G(2)-M phase. Hsl1p accumulates periodically during the cell cycle and promotes the periodic phosphorylation of Hsl7p. Hsl7p can be detected in a complex with Swe1p in cell lysates, and the overexpression of Hsl7p or Hsl1p produces an effective override of the G(2) arrest imposed by the morphogenesis checkpoint. These findings suggest that Hsl1p and Hsl7p interact directly with Swe1p to promote its recognition by the ubiquitination complex, leading ultimately to its destruction.
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PMID:The morphogenesis checkpoint in Saccharomyces cerevisiae: cell cycle control of Swe1p degradation by Hsl1p and Hsl7p. 1049 Jun 30

The cDNA encoding the protein kinase pEg2 was originally cloned through a differential screening performed during the early development of Xenopus laevis. pEg2 orthologues were found in various organisms and were classified in a new family of oncogenic mitotic protein kinases named 'aurora/Ipl1-related kinases' after the Drosophila melanogaster gene aurora and the Saccharomyces cerevisiae gene Ipl1. The catalytic activity of pEg2 is necessary for the mitotic microtubule spindle formation in Xenopus laevis egg extracts. The addition of a dominant negative form of pEg2 to in vitro spindle assembly assays leads to monopolar spindles generated by a defect of centrosome separation. In Xenopus cultured cells, pEg2 was confined around the pericentriolar material once centrosomes were duplicated. The centrosome localization does not depend on the presence of microtubules. However, in vitro, the protein binds to taxol-stabilized microtubules independently of its kinase activity. During mitosis the location of the protein changes, in metaphase the kinase localizes on the microtubules at the poles of the mitotic spindle whereas it is not present on astral microtubules. This localization persists until the segregation of the chromosomes is completed. The presence of the kinase on the spindle may reveal another yet unknown function.
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PMID:The Xenopus laevis centrosome aurora/Ipl1-related kinase. 1051 6


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