Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucose, the most abundant monosaccharide in nature, is the principal carbon and energy source for nearly all cells. The first, and rate-limiting, step of glucose metabolism is its transport across the plasma membrane. In cells of many organisms glucose ensures its own efficient metabolism by serving as an environmental stimulus that regulates the quantity, types, and activity of glucose transporters, both at the transcriptional and posttranslational levels. This is most apparent in the baker's yeast Saccharomyces cerevisiae, which has 20 genes encoding known or likely glucose transporters, each of which is known or likely to have a different affinity for glucose. The expression and function of most of these HXT genes is regulated by different levels of glucose. This review focuses on the mechanisms S. cerevisiae and a few other fungal species utilize for sensing the level of glucose and transmitting this information to the nucleus to alter HXT gene expression. One mechanism represses transcription of some HXT genes when glucose levels are high and works through the Mig1 transcriptional repressor, whose function is regulated by the Snf1-Snf4 protein kinase and Reg1-Glc7 protein phosphatase. Another pathway induces HXT expression in response to glucose and employs the Rgt1 transcriptional repressor, a ubiquitin ligase protein complex (SCF(Grr1)) that regulates Rgt1 function, and two glucose sensors in the membrane (Snf3 and Rgt2) that bind glucose and generate the intracellular signal to which Rgt1 responds. These two regulatory pathways collaborate with other, less well-understood, pathways to ensure that yeast cells express the glucose transporters best suited for the amount of glucose available.
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PMID:Function and regulation of yeast hexose transporters. 1047 8

Eukaryotic cells respond to DNA damage and stalled replication forks by activating protein kinase-mediated signaling pathways that promote cell cycle arrest and DNA repair. A central target of the cell cycle arrest program is the Cdc25A protein phosphatase. Cdc25A is required for S-phase entry and dephosphorylates tyrosine-15 phosphorylated Cdk1 (Cdc2) and Cdk2, positive regulators of cell division. Cdc25A is unstable during S-phase and is degraded through the ubiquitin-proteasome pathway, but its turnover is enhanced in response to DNA damage. Although basal and DNA-damage-induced turnover depends on the ATM-Chk2 and ATR-Chk1 pathways, how these kinases engage the ubiquitin ligase machinery is unknown. Here, we demonstrate a requirement for SCFbeta-TRCP in Cdc25A turnover during an unperturbed cell cycle and in response to DNA damage. Depletion of beta-TRCP stabilizes Cdc25A, leading to hyperactive Cdk2 activity. SCFbeta-TRCP promotes Chk1-dependent Cdc25A ubiquitination in vitro, and this involves serine 76, a known Chk1 phosphorylation site. However, recognition of Cdc25A by beta-TRCP occurs via a noncanonical phosphodegron in Cdc25A containing phosphoserine 79 and phosphoserine 82, sites that are not targeted by Chk1. These data indicate that Cdc25A turnover is more complex than previously appreciated and suggest roles for an additional kinase(s) in Chk1-dependent Cdc25A turnover.
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PMID:SCFbeta-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase. 1468 Dec 6

Calcineurin, which binds to the Z-disc in cardiomyocytes via alpha-actinin, promotes cardiac hypertrophy in response to numerous pathologic stimuli. However, the endogenous mechanisms regulating calcineurin activity in cardiac muscle are not well understood. We demonstrate that a muscle-specific F-box protein called atrogin-1, or muscle atrophy F-box, directly interacts with calcineurin A and alpha-actinin-2 at the Z-disc of cardiomyocytes. Atrogin-1 associates with Skp1, Cul1, and Roc1 to assemble an SCF(atrogin-1) complex with ubiquitin ligase activity. Expression of atrogin-1 decreases levels of calcineurin A and promotes its ubiquitination. Moreover, atrogin-1 attenuates agonist-induced calcineurin activity and represses calcineurin-dependent transactivation and NFATc4 translocation. Conversely, downregulation of atrogin-1 using adenoviral small interfering RNA (siRNA) expression enhances agonist-induced calcineurin activity and cardiomyocyte hypertrophy. Consistent with these cellular observations, overexpression of atrogin-1 in hearts of transgenic mice reduces calcineurin protein levels and blunts cardiac hypertrophy after banding of the thoracic aorta. These studies indicate that the SCF(atrogin-1) ubiquitin ligase complex interacts with and represses calcineurin by targeting calcineurin for ubiquitin-mediated proteolysis, leading to inhibition of cardiac hypertrophy in response to pathologic stimuli.
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PMID:Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex. 1548 53

The mammalian circadian regulatory proteins PER1 and PER2 undergo a daily cycle of accumulation followed by phosphorylation and degradation. Although phosphorylation-regulated proteolysis of these inhibitors is postulated to be essential for the function of the clock, inhibition of this process has not yet been shown to alter mammalian circadian rhythm. We have developed a cell-based model of PER2 degradation. Murine PER2 (mPER2) hyperphosphorylation induced by the cell-permeable protein phosphatase inhibitor calyculin A is rapidly followed by ubiquitination and degradation by the 26S proteasome. Proteasome-mediated degradation is critically important in the circadian clock, as proteasome inhibitors cause a significant lengthening of the circadian period in Rat-1 cells. CKIepsilon (casein kinase Iepsilon) has been postulated to prime PER2 for degradation. Supporting this idea, CKIepsilon inhibition also causes a significant lengthening of circadian period in synchronized Rat-1 cells. CKIepsilon inhibition also slows the degradation of PER2 in cells. CKIepsilon-mediated phosphorylation of PER2 recruits the ubiquitin ligase adapter protein beta-TrCP to a specific site, and dominant negative beta-TrCP blocks phosphorylation-dependent degradation of mPER2. These results provide a biochemical mechanism and functional relevance for the observed phosphorylation-degradation cycle of mammalian PER2. Cell culture-based biochemical assays combined with measurement of cell-based rhythm complement genetic studies to elucidate basic mechanisms controlling the mammalian clock.
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PMID:Control of mammalian circadian rhythm by CKIepsilon-regulated proteasome-mediated PER2 degradation. 1576 83

Sister chromatid segregation is triggered at the metaphase-to-anaphase transition by the activation of the protease separase. For most of the cell cycle, separase activity is kept in check by its association with the inhibitory chaperone securin. Activation of separase occurs at anaphase onset, when securin is targeted for destruction by the anaphase-promoting complex or cyclosome E3 ubiquitin protein ligase. This results in the release of the cohesins from chromosomes, which in turn allows the segregation of sister chromatids to opposite spindle poles. Here we show that human securin (hSecurin) forms a complex with enzymatically active protein phosphatase 2A (PP2A) and that it is a substrate of the phosphatase, both in vitro and in vivo. Treatment of cells with okadaic acid, a potent inhibitor of PP2A, results in various hyperphosphorylated forms of hSecurin which are extremely unstable, due to the action of the Skp1/Cul1/F-box protein complex ubiquitin ligase. We propose that PP2A regulates hSecurin levels by counteracting its phosphorylation, which promotes its degradation. Misregulation of this process may lead to the formation of tumors, in which overproduction of hSecurin is often observed.
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PMID:Protein phosphatase 2A stabilizes human securin, whose phosphorylated forms are degraded via the SCF ubiquitin ligase. 1670 56

Lafora disease (LD), an autosomal recessive neurodegenerative disorder, is characterized by the presence of cytoplasmic polyglucosan inclusions known as Lafora bodies in several tissues including the brain. Laforin, a protein phosphatase, and malin, an ubiquitin ligase, are two of the proteins that are known to be defective in LD. Malin interacts with laforin and promotes its polyubiquitination and degradation. Here we show that malin and laforin co-localize in endoplasmic reticulum (ER) and that they form centrosomal aggregates when treated with proteasomal inhibitors in both neuronal and non-neuronal cells. Laforin/malin aggregates co-localize with gamma-tubulin and cause redistribution of alpha-tubulin. These aggregates are also immunoreactive to ubiquitin, ubiquitin-conjugating enzyme, ER chaperone and proteasome subunits, demonstrating their aggresome-like properties. Furthermore, we show that the centrosomal aggregation of laforin and malin is dependent on the functional microtubule network. Laforin and malin form aggresome when expressed together or otherwise, suggesting that the two proteins are recruited to the centrosome independent of each other. Taken together, our results suggest that the centrosomal accumulation of malin, possibly with the help of laforin, may enhance the ubiquitination of its substrates and facilitate their efficient degradation by proteasome. Defects in malin or laforin may thus lead to increased levels of misfolded and/or target proteins, which may eventually affect the physiological processes of the neuron. Thus, defects in protein degradation and clearance are likely to be the primary trigger in the physiopathology of LD.
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PMID:Lafora disease proteins malin and laforin are recruited to aggresomes in response to proteasomal impairment. 1733 85

The highly conserved RCN family of proteins regulates the serine/threonine protein phosphatase calcineurin, which is required for the expression of genes involved in Ca(2+)-dependent processes, such as the control of memory, apoptosis, T cell activation, cell cycle, Ca(2+)-homeostasis, and skeletal and cardiac muscle growth and differentiation. However, RCNs regulate calcineurin through two paradoxical actions: they act as feedback inhibitors of calcineurin, whereas their phosphorylation stimulates calcineurin. Here we show that phosphorylation of yeast RCN, Rcn1, triggers degradation through the SCF(Cdc4) ubiquitin ligase complex. Degradation of phosphorylated Rcn1 is required to mitigate inhibition of calcineurin by Rcn1 and results in activation of calcineurin activity in response to Ca(2+) as well as in reactivation of calcineurin in response to changes in Ca(2+) concentration. The SCF(Cdc4)-dependent degradation required phosphorylation of Rcn1 by Mck1, a member of the GSK3 family of protein kinases, and was promoted by Ca(2+). However, such degradation was counteracted by dephosphorylation of Rcn1, which was promoted by Ca(2+)-stimulated calcineurin. Thus, calcineurin activity is fine-tuned to Ca(2+) signals by mechanisms that have opposite functions. Our results identify the molecular mechanism of Rcn1 phosphorylation-induced stimulation of the phosphatase activity of calcineurin. The results provide insight into the mechanism involved in maintaining proper responses to Ca(2+) signals.
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PMID:The SCFCdc4 ubiquitin ligase regulates calcineurin signaling through degradation of phosphorylated Rcn1, an inhibitor of calcineurin. 1795 14

Cardiac hypertrophy is a major cause of human morbidity and mortality. Although much is known about the pathways that promote hypertrophic responses, mechanisms that antagonize these pathways have not been as clearly defined. Atrogin-1, also known as muscle atrophy F-box, is an F-box protein that inhibits pathologic cardiac hypertrophy by participating in a ubiquitin ligase complex that triggers degradation of calcineurin, a factor involved in promotion of pathologic hypertrophy. Here we demonstrated that atrogin-1 also disrupted Akt-dependent pathways responsible for physiologic cardiac hypertrophy. Our results indicate that atrogin-1 does not affect the activity of Akt itself, but serves as a coactivator for members of the Forkhead family of transcription factors that function downstream of Akt. This coactivator function of atrogin-1 was dependent on its ubiquitin ligase activity and the deposition of polyubiquitin chains on lysine 63 of Foxo1 and Foxo3a. Transgenic mice expressing atrogin-1 in the heart displayed increased Foxo1 ubiquitylation and upregulation of known Forkhead target genes concomitant with suppression of cardiac hypertrophy, while mice lacking atrogin-1 displayed the opposite physiologic phenotype. These experiments define a role for lysine 63-linked ubiquitin chains in transcriptional coactivation and demonstrate that atrogin-1 uses this mechanism to disrupt physiologic cardiac hypertrophic signaling through its effects on Forkhead transcription factors.
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PMID:Atrogin-1 inhibits Akt-dependent cardiac hypertrophy in mice via ubiquitin-dependent coactivation of Forkhead proteins. 1796 79

Breast cancer-associated gene 1 (BRCA1) regulates the duplication and the function of centrosomes in breast cells. We have previously shown that BRCA1 ubiquitin ligase activity directly inhibits centrosome-dependent microtubule nucleation. However, there is a paradox because centrosome microtubule nucleation potential is highest during mitosis, a phase when BRCA1 is most abundant at the centrosome. In this study, we resolve this conundrum by testing whether centrosomes from cells in M phase are regulated differently by BRCA1 when compared with other phases of the cell cycle. We observed that BRCA1-dependent inhibition of centrosome microtubule nucleation was high in S phase but was significantly lower during M phase. The cell cycle-specific effects of BRCA1 on centrosome-dependent microtubule nucleation were detected in living cells and in cell-free experiments using centrosomes purified from cells at specific stages of the cell cycle. We show that Aurora-A kinase modulates the BRCA1 inhibition of centrosome function by decreasing the E3 ubiquitin ligase activity of BRCA1. In addition, dephosphorylation of BRCA1 by protein phosphatase 1 alpha enhances the E3 ubiquitin ligase activity of BRCA1. These observations reveal that the inhibition of centrosome microtubule nucleation potential by the BRCA1 E3 ubiquitin ligase is controlled by Aurora-A kinase and protein phosphatase 1 alpha-mediated phosphoregulation through the different phases of the cell cycle.
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PMID:Aurora-A kinase regulates breast cancer associated gene 1 inhibition of centrosome-dependent microtubule nucleation. 1805 43

In the budding yeast Saccharomyces cerevisiae, the protein phosphatase Cdc14 triggers exit from mitosis by promoting the inactivation of cyclin-dependent kinases (CDKs). Cdc14's activity is controlled by Cfi1/Net1, which holds and inhibits the phosphatase in the nucleolus from G1 until metaphase. During anaphase, two regulatory networks, the Cdc14 Early Anaphase Release (FEAR) network and the Mitotic Exit Network (MEN), promote the dissociation of Cdc14 from its inhibitor, allowing the phosphatase to reach its targets throughout the cell. The molecular circuits that trigger the return of Cdc14 into the nucleolus after the completion of exit from mitosis are not known. Here we show that activation of a ubiquitin ligase known as the Anaphase-Promoting Complex or Cyclosome (APC/C) bound to the specificity factor Cdh1 triggers the degradation of the Polo kinase Cdc5, a key factor in releasing Cdc14 from its inhibitor in the nucleolus.
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PMID:APC/C-Cdh1-mediated degradation of the Polo kinase Cdc5 promotes the return of Cdc14 into the nucleolus. 1817 66


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