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:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transgenesis based on organ specific gene expression has provided the basis to elucidate the functional role of proteins for the past 15 years. Using this technology, we showed that inhibition of the protein phosphatase 1, by its constitutively active inhibitor-1, significantly increases cardiac contractility and calcium handling. To uncover protein changes accompanying the chronic increases in cardiac function of these transgenic hearts, we analyzed the cardiac proteome. Interestingly, we found significant increases in the levels of 6 proteins involved in metabolism, calcium binding and scavenging of oxido-reductive stress. These proteins were identified as: hydroxyacyl CoA dehydrogenase II, alpha subunit of the mitochondrial proton ATPase, peroxiredoxin 2, a novel EF-hand containing protein-2, annexin 5, and a previously uncharacterized cDNA. Thus, long-term cardiac specific overexpression of the protein phosphatase 1 inhibitor-1 and the associated increases in cardiac contractility appear to herald changes in a rather small number of proteins, which may reflect important compensatory adaptations in a hyperdynamic heart [corrected]
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PMID:Key protein alterations associated with hyperdynamic cardiac function: insights based on proteomic analysis of the protein phosphatase 1 inhibitor-1 overexpressing hearts. 1738 7

Plant plasma membrane (PM) proteins play important roles in signal transduction during defense response to an attacking pathogen. By using an improved method of PM protein preparation and PM-bound green fluorescent protein fusion protein as a visible marker, we conducted PM proteomic analysis of the rice suspension cells expressing the disease resistance gene Xa21, to identify PM components involved in the early defense response to bacterial blight (Xanthomonas oryzae pv. oryzae). A total of 20 regulated protein spots were observed on 2-D gels of PM fractions at 12 and 24 h after pathogen inoculation, of which some were differentially regulated between the incompatible and compatible interactions mediated by Xa21, with good correlation between biological repeats. Eleven protein spots with predicted functions in plant defense were identified by MS/MS, including nine putative PM-associated proteins H+-ATPase, protein phosphatase, hypersensitive-induced response protein (OsHIR1), prohibitin (OsPHB2), zinc finger and C2 domain protein, universal stress protein (USP), and heat shock protein. OsHIR1 was modified by the microbial challenge, leading to two differentially accumulated protein spots. Transcript analysis showed that most of the genes were also regulated at transcriptional levels. Our study would provide a starting point for functionality of PM proteins in the rice defense.
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PMID:Proteomic analysis of rice plasma membrane reveals proteins involved in early defense response to bacterial blight. 1740 82

Protein phosphatase 2A (PP2A) is a multifunctional protein phosphatase with critical roles in excitable cell signaling. In the heart, PP2A function is linked with modulation of beta-adrenergic signaling and has been suggested to regulate key ion channels and transporters including Na/Ca exchanger, ryanodine receptor, inositol 1,4,5-trisphosphate receptor, and Na/K ATPase. Although many of the functional roles and molecular targets for PP2A in heart are known, little is established regarding the cellular pathways that localize specific PP2A isoform activities to subcellular sites. We report that the PP2A regulatory subunit B56alpha is an in vivo binding partner for ankyrin-B, an adapter protein required for normal subcellular localization of the Na/Ca exchanger, Na/K ATPase, and inositol 1,4,5-trisphosphate receptor. Ankyrin-B and B56alpha are colocalized and coimmunoprecipitate in primary cardiomyocytes. Using multiple strategies, we identified the structural requirements on B56alpha for ankyrin-B association as a 13 residue motif in the B56alpha COOH terminus not present in other B56 family polypeptides. Finally, we report that reduced ankyrin-B expression in primary ankyrin-B(+/-) cardiomyocytes results in disorganized distribution of B56alpha that can be rescued by exogenous expression of ankyrin-B. These new data implicate ankyrin-B as a critical targeting component for PP2A in heart and identify a new class of signaling proteins targeted by ankyrin polypeptides.
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PMID:Molecular basis for PP2A regulatory subunit B56alpha targeting in cardiomyocytes. 1744 51

Dysregulation of the proteasome has been documented in a variety of human diseases such as Alzheimer, muscle atrophy, cataracts etc. Proteolytic activity of 26 S proteasome is ATP- and ubiquitin-dependent. O-GlcNAcylation of Rpt2, one of the AAA ATPases in the 19 S regulatory cap, shuts off the proteasome through the inhibition of ATPase activity. Thus, through control of the flux of glucose into O-GlcNAc, the function of the proteasome is coupled to glucose metabolism. In the present study we found another metabolic control of the proteasome via cAMP-dependent protein kinase (PKA). Contrary to O-Glc-NAcylation, PKA activated proteasomes both in vitro and in vivo in association with the phosphorylation at Ser(120) of another AAA ATPase subunit, Rpt6. Mutation of Ser(120) to Ala blocked proteasome function. The stimulatory effect of PKA and the phosphorylation of Rpt6 were reversible by protein phosphatase 1 gamma. Thus, hormones using the PKA system can also regulate proteasomes often in concert with glucose metabolism. This finding might lead to novel strategies for the treatment of proteasome-related diseases.
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PMID:Proteasome function is regulated by cyclic AMP-dependent protein kinase through phosphorylation of Rpt6. 1756 87

Phospholamban (PLN) regulates calcium translocation within cardiac myocytes by shifting sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) affinity for calcium. Although the monomeric form of PLN (6 kDa) is the principal inhibitory species, recent evidence suggests that the PLN pentamer (30 kDa) also is able to bind SERCA. To date, several membrane architectures of the pentamer have been proposed, with different topological orientations for the cytoplasmic domain: (i) extended from the bilayer normal by 50-60 degrees; (ii) continuous alpha-helix tilted 28 degrees relative to the bilayer normal; (iii) pinwheel geometry, with the cytoplasmic helix perpendicular to the bilayer normal and in contact with the surface of the bilayer; and (iv) bellflower structure, in which the cytoplasmic domain helix makes approximately 20 degrees angle with respect to the membrane bilayer normal. Using a variety of cell membrane mimicking systems (i.e., lipid vesicles, oriented lipid bilayers, and detergent micelles) and a combination of multidimensional solution/solid-state NMR and EPR spectroscopies, we tested the different structural models. We conclude that the pinwheel topology is the predominant conformation of pentameric PLN, with the cytoplasmic domain interacting with the membrane surface. We propose that the interaction with the bilayer precedes SERCA binding and may mediate the interactions with other proteins such as protein kinase A and protein phosphatase 1.
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PMID:Spectroscopic validation of the pentameric structure of phospholamban. 1780 9

We studied the effect of some modulators of signal transduction on the erythrocyte Na+/ K+-ATPase. Go6976 and Go6983 (protein kinase C inhibitors) showed a stimulatory effect and calyculin A (protein phosphatase inhibitor) exerted an inhibitory effect on the Na pump activity. Some of the tested modulators of cell-signaling [protein phosphatase(s), phosphodiesterase, calmodulin and some protein kinases] interfered with the lactoferrin (Lf) stimulatory effect on the sodium pump. Lf itself was able to modulate the effect of some agents upon the pump activity. Moreover, an additive effect of stimulation was found when Lf and some agents were used simultaneously. The summarized results showed that: (i) Lf upregulates the Na+/K+-ATPase in erythrocytes and facilitates the K+ influx into the erythrocytes; (ii) the effect of pump stimulation is mediated by phosphorylation processes. These results suggest a potential opportunity for using Lf alone or together with other agents as a stimulator of the erythrocyte Na+/K+-ATPase.
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PMID:Lactoferrin stimulates erythrocyte Na+/K+ -adenosine triphosphatase: effect of some modulators of membrane phosphorylation. 1827 95

The activity of vacuolar H(+)-ATPase (V-ATPase) in the apical membrane of blowfly (Calliphora vicina) salivary glands is regulated by the neurohormone serotonin (5-HT). 5-HT induces, via protein kinase A, the phosphorylation of V-ATPase subunit C and the assembly of V-ATPase holoenzymes. The protein phosphatase responsible for the dephosphorylation of subunit C and V-ATPase inactivation is not as yet known. We show here that inhibitors of protein phosphatases PP1 and PP2A (tautomycin, ocadaic acid) and PP2B (cyclosporin A, FK-506) do not prevent V-ATPase deactivation and dephosphorylation of subunit C. A decrease in the intracellular Mg(2+) level caused by loading secretory cells with EDTA-AM leads to the activation of proton pumping in the absence of 5-HT, prolongs the 5-HT-induced response in proton pumping, and inhibits the dephosphorylation of subunit C. Thus, the deactivation of V-ATPase is most probably mediated by a protein phosphatase that is insensitive to okadaic acid and that requires Mg(2+), namely, a member of the PP2C protein family. By molecular biological techniques, we demonstrate the expression of at least two PP2C protein family members in blowfly salivary glands.
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PMID:V-ATPase deactivation in blowfly salivary glands is mediated by protein phosphatase 2C. 1946 1

Calcineurin is a Ca(2+)/calmodulin-dependent protein phosphatase that induces myocardial growth in response to several physiological and pathological stimuli. Calcineurin inhibition, induced either via cyclosporine or genetically, can decrease myocardial hypertrophy secondary to pressure overload without affecting left ventricular (LV) systolic function. Since hypertrophy can also affect LV diastolic function, the goal of this study was to examine the effects of chronic pressure overload (2 wk aortic banding) in transgenic (Tg) mice overexpressing Zaki-4beta (TgZ), a specific endogenous inhibitor of calcineurin, on LV diastolic function. As expected, in the TgZ mice with calcineurin inhibitor overexpression, aortic banding reduced the degree of LV hypertrophy, as assessed by LV weight-to-body weight ratio (3.5 + or - 0.1) compared with that in non-Tg mice (4.6 + or - 0.2). LV systolic function remained compensated in both groups with pressure overload. However, the LV end-diastolic stress-to-LV end-diastolic dimension ratio, an index of diastolic stiffness and LV pressure half-time and isovolumic relaxation time, two indexes of isovolumic relaxation, increased significantly more in TgZ mice with aortic banding. Protein levels of phosphorylated phospholamban (PS16), sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a, phosphorylated ryanodine receptor, and the Na(+)/Ca(2+) exchanger were also reduced significantly (P < 0.05) in the banded TgZ mice. As expected, genetic calcineurin inhibition inhibited the development of LV hypertrophy with chronic pressure overload but also induced LV diastolic dysfunction, as reflected by both impaired isovolumic relaxation and increased myocardial stiffness. Thus genetic calcineurin inhibition reveals a new mechanism regulating LV diastolic function.
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PMID:Genetic inhibition of calcineurin induces diastolic dysfunction in mice with chronic pressure overload. 1971 30

L-type Ca(2+) channel activity was assayed in L6 cells as the rate of nifedipine-sensitive Ba(2+) influx in a depolarizing medium. In the absence of extracellular Ca(2+), activation of protein kinase C (PKC) with phorbol-12-myristate-13-acetate (PMA) or thymeleatoxin (TMX) inhibited Ba(2+) influx by 38%. Thapsigargin (Tg), a selective inhibitor of the Ca(2+)-ATPase in the sarcoplasmic reticulum, evoked a rise in the cytosolic Ca(2+) concentration ([Ca(2+)](i)) in a Ca(2+)-free medium from 30 to approximately 80 nM. This [Ca(2+)](i) increase declined slowly, giving rise to a modest elevation of [Ca(2+)](i) that persisted for >5 min. The inhibitory effects of PMA and TMX on channel activity were abolished when tested in Tg-treated cells in a Ca(2+)-free medium. However, when the Ca(2+) ionophore, ionomycin, was applied with Tg, PMA and TMX retained their inhibitory effect on L-type Ca(2+) channel activity, suggesting that a lower amplitude and prolonged release of Ca(2+) stores is necessary for abrogating PKC-mediated inhibition of LCC. Cyclosporin A (5 microM) and ascomycin (5 microM), inhibitors of the Ca(2+)/calmodulin-dependent protein phosphatase, calcineurin, fully restored the inhibitory effect of PMA and TMX on channel activity. Addition of 1mM CaCl(2) to the Tg-treated cells increased [Ca(2+)](i) to approximately 165 nM and also restored the inhibitory effects of PMA and TMX. These results indicate that a small, relatively prolonged [Ca(2+)](i) increase elicited by passive depletion of internal Ca(2+) stores led to activation of calcineurin, giving rise to an increase in protein phosphatase activity that counteracted the inhibitory effects of PKC on channel activity. A larger increase in [Ca(2+)](i) via store-dependent Ca(2+) entry enhanced the activity of PKC sufficiently to overcome the protein phosphatase activity of calcineurin. This study is the first to demonstrate that the regulation of L-type Ca(2+) channels in a myocyte model involves a balance between the differential Ca(2+) sensitivities and opposing actions of PKC and calcineurin.
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PMID:Calcineurin activation by slow calcium release from intracellular stores suppresses protein kinase C regulation of L-type calcium channels in L6 cells. 1975 95

We previously reported up-regulation of T-LAK cell-originated protein kinase (TOPK), a novel mitotic kinase, in the great majority of breast cancers. Here we report its critical roles in mitosis, especially in cytokinesis. We found that protein phosphatase 1 alpha (PP1alpha) inactivation by cyclin-dependent kinase 1 (CDK1)/cyclin B1 caused enhancement of autophosphorylation of TOPK and resulted in its activation at an early stage of mitosis. Then TOPK interacted with and phosphorylated p97, a member of the AAA+ family of ATPase proteins, through an interaction with p47 protein as an adaptor protein. Interestingly, knockdown of TOPK or p97 in breast cancer cells caused the mitotic failures in the abscission process. This mitotic failure could be rescued by additional exogenous introduction of wild-type TOPK protein, but not by that of its kinase-dead form. Our findings suggest that TOPK is indispensable for cancer cell cytokinesis throughout phosphorylation on p97.
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PMID:Critical roles of T-LAK cell-originated protein kinase in cytokinesis. 1990 Jan 92


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