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)

Therapeutic concentrations of digitalis drugs inhibit the proliferation of breast cancer cells by inducing the interaction of Na+/K+-ATPase with Src/EGFR, activation of ERK1/2, and the resulting upregulation of cell cycle inhibitor p21Cip1. Quantitative comparison of ouabain dose-response curves for growth arrest and pump inhibition shows that ratio of Ki (pump)/Ki (proliferation) = 7.2. Such large gains in sensitivity are characteristic of several signal transducing pathways of other receptors. Making the reasonable assumption that Na+/K+-ATPase is the only receptor for ouabain, the large amplification factor clearly shows that occupation of a small fraction of pumping Na+/K+-ATPase by digitalis drugs, or endogenous digitalis-like factors, is sufficient to cause near complete inhibition of cell growth. The likely causes of large amplification factor in the signaling function of Na+/K+-ATPase include (a) interactions among the protomers of Na+/K+-ATPase in the membrane; and (b) induced clustering of Na+/K+-ATPase oligomers with neighboring proteins. The upstream location of both mechanisms suggests that similar amplifications also occur in other cell types with different digitalis downstream effects; e.g., stimulation of proliferation or hypertrophy.
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PMID:On the importance and mechanism of amplification of digitalis signal through Na+/K+-ATPase. 1753 33

The cardiac glycoside ouabain initiates a cascade of signaling events through Na+,K+-ATPase, leading to an increase in cell growth and proliferation in different cell types. We explored the effects of ouabain on glucose metabolism in skeletal muscle and clarified the mechanisms of ouabain signal transduction. In rat soleus muscle 200 microM ouabain decreased basal glucose uptake without effect on insulin-stimulated glucose uptake. Ouabain increased glycogen synthesis additively to insulin and this effect was abolished in the presence of a MEK1/2 inhibitor (PD98059) or a c-Src inhibitor (PP2). Ouabain exposure reduced glucose oxidation, and this effect was reversed in the presence of PP2. Incubation with ouabain did not affect intramuscular ATP and its metabolites; however acetyl-CoA carboxylase phosphorylation was reduced, with no effect on AMPK phosphorylation. Insulin-stimulated Akt phosphorylation was not affected by ouabain. Ouabain reduced basal and insulin-stimulated phosphorylation of PKC alpha/beta and delta isoforms, whereas phosphorylation of PKCzeta was unchanged. Ouabain exposure increased interaction of 1- and 2-subunits of Na-pump with c-Src, as assessed by co-immunoprecipitation with c-Src. Phosphorylation of ERK1/2, GSK 3 / and p90rsk activity was increased in response to ouabain, and these effects were prevented in the presence of PD98059 and PP2. In conclusion, the cardiac glycoside ouabain stimulates glycogen synthesis additively to insulin in rat skeletal muscle. This effect is mediated by activation of c-Src-, ERK1/2- p90rsk- and GSK3-dependent signaling pathway.
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PMID:Metabolic and signaling events mediated by cardiotonic steroid ouabain in rat skeletal muscle. 1753 36

Our previous studies on cardiac myocytes showed that positive inotropic concentrations of the digitalis drug ouabain activated signaling pathways linked to Na(+)-K(+)-ATPase through Src and epidermal growth factor receptor (EGFR) and led to myocyte hypertrophy. In view of the known involvement of phosphatidylinositol 3-kinase (PI3K)-Akt pathways in cardiac hypertrophy, the aim of the present study was to determine whether these pathways are also linked to cardiac Na(+)-K(+)-ATPase and, if so, to assess their role in ouabain-induced myocyte growth. In a dose- and time-dependent manner, ouabain activated Akt and phosphorylation of its substrates mammalian target of rapamycin and glycogen synthase kinase in neonatal rat cardiac myocytes. Akt activation by ouabain was sensitive to PI3K inhibitors and was also noted in adult myocytes and isolated hearts. Ouabain caused a transient increase of phosphatidylinositol 3,4,5-trisphosphate content of neonatal myocytes, activated class IA, but not class IB, PI3K, and increased coimmunoprecipitation of the alpha-subunit of Na(+)-K(+)-ATPase with the p85 subunit of class IA PI3K. Ouabain-induced activation of ERK1/2 was prevented by Src, EGFR, and MEK inhibitors, but not by PI3K inhibitors. Activation of Akt by ouabain, however, was sensitive to inhibitors of PI3K and Src, but not to inhibitors of EGFR and MEK. Similarly, ouabain-induced myocyte hypertrophy was prevented by PI3K and Src inhibitors, but not by an EGFR inhibitor. These findings 1) establish the linkage of the class IA PI3K-Akt pathway to Na(+)-K(+)-ATPase and the essential role of this linkage to ouabain-induced myocyte hypertrophy and 2) suggest cross talk between these PI3K-Akt pathways and the signaling cascades previously identified to be associated with cardiac Na(+)-K(+)-ATPase.
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PMID:Association of PI3K-Akt signaling pathway with digitalis-induced hypertrophy of cardiac myocytes. 1772 97

We have previously shown that ouabain and other cardiotonic steroids interact with the plasmalemmal Na/K-ATPase and cause a time and dose dependent endocytosis of the Na/K-ATPase. This endocytosis is demonstrable using fluorescence imaging as well as conventional biochemical and biophysical cell separation methods. In proximal tubule cells, this process appears to regulate the density of basolateral Na/K-ATPase expression directly as well as indirectly modulate transepithelial sodium transport. Work with genetic manipulations, as well as pharmacological agents with cell culture models, have demonstrated that the cardiotonic steroid stimulated endocytosis of the plasmalemmal Na/K-ATPase requires caveolin and clathrin as well as the activation of c-Src, transactivation of the EGFR and activation of PI3K. Interestingly c-Src, EGFR and ERK1/2 all appear to be endocytosed along with the plasmalemmal Na/K-ATPase. These observations suggest a close analogy between a subset of plasmalemmal Na/K-ATPase and signaling companions with conventional receptor tyrosine kinases. While further studies are necessary to delineate the role of this endocytosis in the generation as well as the limit of signal transduction through the Na/K-ATPase signal cascade, we propose that it has an important role in the regulation of renal sodium handling as well as other important processes.
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PMID:Regulation of sodium pump endocytosis by cardiotonic steroids: Molecular mechanisms and physiological implications. 1796 98

The nongenomic actions of thyroid hormone require a plasma membrane receptor or nuclear receptors located in cytoplasm. The plasma membrane receptor is located on integrin alphaVbeta3 at the Arg-Gly-Asp recognition site important to the binding by the integrin of extracellular matrix proteins. l-Thyroxine (T(4)) is bound with greater affinity at this site than 3,5,3'-triiodo-l-thyronine (T(3)). Mitogen-activated protein kinase (MAPK; ERK1/2) transduces the hormone signal into complex cellular/nuclear events including angiogenesis and tumor cell proliferation. Acting at the integrin receptor and without cell entry, thyroid hormone can foster ERK1/2-dependent serine phosphorylation of nuclear thyroid hormone receptor-beta1 (TRbeta1) and de-repress the latter. The integrin receptor also mediates actions of the hormone on intracellular protein trafficking and on plasma membrane ion pumps, including the sodium/protein antiporter. Tetraiodothyroacetic (tetrac) is a T(4) analog that inhibits binding of iodothyronines to the integrin receptor and is a probe for the participation of this receptor in cellular actions of the hormone. Tetrac blocks thyroid hormone effects on angiogenesis and cancer cell proliferation. Acting on a truncated form of nuclear TRalpha1 (TRDeltaalpha1) located in cytoplasm, T(4) and 3,3',5'-triiodothyronine (reverse T(3)), but not T(3), cause conversion of soluble actin to fibrous (F) actin that is important to cell motility, e.g., in cells such as glia and neurons. Normal development of the central nervous system requires such motility. TRbeta1 in cytoplasm mediates action of T(3) on expression of certain genes via phosphatidylinositol 3-kinase (PI 3-K) and the protein kinase B/Akt pathway. PI 3-K and, possibly, cytoplasmic TRbeta1 are involved in stimulation by T(3) of insertion of Na,K-ATPase in the plasma membrane and of increase in activity of this pump. Because ambient thyroid hormone levels are constant in the euthyroid intact organism, these nongenomic hormone actions are likely to be contributors to basal rate-setting of transcription of certain genes and of complex cellular events such as angiogenesis and cancer cell proliferation.
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PMID:Mechanisms of nongenomic actions of thyroid hormone. 1798 45

Cellular differentiation and programmed cell death are tightly controlled to maintain tissue homeostasis and proper organ function. In a screen for apoptosis specific gene products, we isolated an immediate early apoptosis response gene from myelomonocytic stem cells that appears to play a key regulatory role in a number of cell types and may be of particular importance in cells of the central nervous system. The gene's 28 kDa protein product interacts with the C-terminal ectodomain of the Na+/K+-ATPase (NKA) beta 1 subunit and was therefore named NKIP (NKA Interacting Protein). NKIP is coexpressed with NKA, localizes to lysosomes and the endoplasmic reticulum and is predominantly expressed in excitable tissues including polarized epithelia and the central nervous system. NKIP has been characterized as an endogenous suppressor of the NKA as reduction of NKIP in PC12 cells significantly increases NKA activity. In pluripotent NT2 progenitor cells, NKIP induced rapidly K+-level-dependent cell death. NKIP overexpression induced growth factor-independent neurite outgrowth, which was associated with MEK-independent phosphorylation of the transcription factor ERK1/2. Thus, we have identified NKIP as an important novel protein that interacts to the NKA complex, influencing cellular ion balance, induction of apoptosis and neuronal differentiation.
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PMID:Characterization of NKIP: a novel, Na+/K+-ATPase interacting protein mediates neural differentiation and apoptosis. 1809 56

We have previously implicated reactive oxygen species oxygen (ROS) as a critical signal transducer in the upregulation of Na,K-ATPase by low K+ in MDCK cells, but how ROS mediate this process has not been well defined. We reported here that both of hydrogen peroxide (H2O2) and superoxide anion (O2*(-)) were rapidly produced at the early stage of low K+-treated MDCK cells. Further analysis revealed that NADP/NADPH oxidase-derived H2O2 was specifically involved in low K+-induced Na,K-ATPase alpha1 gene transcription as well as alpha1 and beta1 subunits expressions. Exogenous H2O2 even mimicked the stimulatory effect of low K+ on Na,K-ATPase alpha1 gene transcription. Low K+ triggered a H2O2-dependent ERK1/2 phosphorylation in MDCK cells, nonetheless, this ERK1/2 activation did not finally lead to the upregulation of Na,K-ATPase. Similar to previous findings that Na,K-ATPase beta1 gene transcription was mediated by Sp1, Na,K-ATPase alpha1 gene transcription in low K+-treated MDCK cells was also closely relevant to Sp1 participation, as confirmed by siRNA as well as PCR mutagenesis technologies. Furthermore, Sp1 activation was dependent on H2O2 generation triggered by low K+. Taken together, the data described in this study outlines an essential role of H2O2 and Sp1 in mediating the upregulation of Na,K-ATPase in MDCK cells by low external K+.
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PMID:Requirement of hydrogen peroxide and Sp1 in the stimulation of Na,K-ATPase by low potassium in MDCK epithelial cells. 1815 51

Thyroid hormone (T3) increases Na-K-ATPase activity in rat adult alveolar type II cells via a PI3K-dependent pathway. In these cells, dopamine and beta-adrenergic agonists can stimulate Na-K-ATPase activity through either PI3K or MAPK pathways. We assessed the role of the MAPK pathway in the stimulation of Na-K-ATPase by T3. In the adult rat alveolar type II-like cell line MP48, T3 enhanced MAPK/ERK1/2 activity in a dose-dependent manner. Increased ERK1/2 phosphorylation was observed within 5 min, peaked at 20 min, and then decreased. Two MEK1/2 inhibitors, U0126 and PD-98059, each abolished the T3-induced increase in the quantity of Na-K-ATPase alpha(1)-subunit plasma membrane protein and Na-K-ATPase activity. T3 also increased the phosphorylation of MAPK/p38; however, SB-203580, a specific inhibitor of MAPK/p38 activity, did not prevent the T3-induced Na-K-ATPase activity. SP-600125, a specific inhibitor of the MAPK/JNK pathway, also did not block the T3-induced Na-K-ATPase activity. Phorbol 12-myristate 13-acetate (PMA) significantly increased ERK1/2 phosphorylation and Na-K-ATPase activity. The PMA-induced Na-K-ATPase activity was inhibited by U0126. These data indicate that activation of MAPK-ERK1/2 was required for the T3-induced increase in Na-K-ATPase activity in addition to the requirement for the PI3K pathway.
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PMID:T3 increases Na-K-ATPase activity via a MAPK/ERK1/2-dependent pathway in rat adult alveolar epithelial cells. 1822 61

AHA1 (activator of HSP90 ATPase) is a cochaperone of the ATP-dependent molecular chaperone, HSP90, which is involved in the maturation, stabilization/degradation, and function of oncogenic proteins. HSP90 operates in a multimeric complex driven by the binding and hydrolysis of ATP. Treatment of cells with the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) results in the degradation of client proteins via the ubiquitin-proteasome pathway. As AHA1 increases the ATPase activity of HSP90, we hypothesized that modulation of AHA1 expression could influence the activity of client proteins and/or the cellular response to 17-AAG. We show that the basal expression of AHA1 is different across a panel of human cancer cell lines, and that treatment with 17-AAG resulted in sustained AHA1 up-regulation. Increasing the expression of AHA1 did not affect the sensitivity to 17-AAG, but did increase C-RAF activity and the levels of phosphorylated MEK1/2 and ERK1/2 without affecting total levels of these proteins or of client proteins C-RAF, ERBB2, or CDK4. Conversely, small interfering RNA-selective knockdown of >80% of AHA1 expression decreased C-RAF activity and reduced the levels of MEK1/2 and ERK1/2 phosphorylation. Moreover, the AHA1 knockdown resulted in a significant (P < 0.05) increase in sensitivity to 17-AAG, due in part to a 2- to 3-fold increase in apoptosis. These results show that the reduction of AHA1 levels could decrease the phosphorylation of key signal transduction proteins, and for the first time, separate the activation and stabilization functions of HSP90. Furthermore, AHA1 knockdown could sensitize cancer cells to 17-AAG. We conclude that modulation of AHA1 might be a potential therapeutic strategy to increase sensitivity to HSP90 inhibitors.
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PMID:Silencing of HSP90 cochaperone AHA1 expression decreases client protein activation and increases cellular sensitivity to the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin. 3060 23

Intracerebroventricular (ICV) injection of ouabain, a specific Na-K ATPase inhibitor, induced behavioral changes in rats, a putative animal model for bipolar disorder. The binding of ouabain to Na-K ATPase is known to affect signaling molecules in vitro such as extracellular signal-regulated kinase1/2 (ERK1/2). Although ERK has been suggested to be related to the behavioral alterations induced by various psychotomimetics, the effect of ouabain on ERK in the brain related to behavioral changes has not been examined. After ICV injection of ouabain in rats, we investigated changes in the phosphorylation of mitogen-activated protein kinase kinase1/2 (MEK1/2), ERK1/2, and p90 ribosomal s6 kinase (p90RSK) in rat striatum, frontal cortex, and hippocampus along with changes in locomotor activity. Ouabain induced the following biphasic dose-dependent changes in locomotor activity: no change with 10(-6) M, a statistically significant decrease with 10(-5) M, no change with 10(-4) M, and a statistically significant increase with 0.5x10(-3) and 10(-3) M. The phosphorylation level of MEK1/2, ERK1/2, and p90RSK in rat striatum showed dose-dependent changes similar to those observed in locomotor activity with relatively high correlation. The phosphorylation of these molecules in rat frontal cortex and hippocampus also changed in a similar dose-dependent pattern. Taken together, ouabain induced biphasic dose-dependent changes in locomotor activity and the phosphorylation of the ERK1/2 pathway. These findings suggest a possible relationship between ouabain-induced behavioral changes and ERK activity in the brain and suggest an important role of ERK in regulating locomotor activity and mood state.
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PMID:Dose-dependent effect of intracerebroventricular injection of ouabain on the phosphorylation of the MEK1/2-ERK1/2-p90RSK pathway in the rat brain related to locomotor activity. 1859 Jul 92


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