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)

Na(+)-K(+)-Cl(-) cotransporter (NKCC) activity in quiescent skeletal muscle is modest. However, ex vivo stimulation of muscle for as little as 18 contractions (1 min, 0.3 Hz) dramatically increased the activity of the cotransporter, measured as the bumetanide-sensitive (86)Rb influx, in both soleus and plantaris muscles. This activation of cotransporter activity remained relatively constant for up to 10-Hz stimulation for 1 min, falling off at higher frequencies (30-Hz stimulation for 1 min). Similarly, stimulation of skeletal muscle with adrenergic receptor agonists phenylephrine, isoproterenol, or epinephrine produced a dramatic stimulation of NKCC activity. It did not appear that stimulation of NKCC activity was a reflection of increased Na(+)-K(+)-ATPase activity because insulin treatment did not stimulate NKCC activity, despite insulin's well-known stimulation of Na(+)-K(+)-ATPase activity. Stimulation of NKCC activity could be blocked by pretreatment with inhibitors of mitogen-activated protein kinase (MAPK) kinase 1/2 (MEK1/2) activity, indicating that activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) MAPKs may be required. These data indicate a regulated NKCC activity in skeletal muscle that may provide a significant pathway for potassium transport into skeletal muscle fibers.
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PMID:Insulin-independent, MAPK-dependent stimulation of NKCC activity in skeletal muscle. 1144 61

Extracellular signal-regulated protein kinases (ERKs) are important in many cellular functions. We and others have previously reported that prolonged exposure of gastric parietal cells to epidermal growth factor (EGF) enhanced gastric acid secretion stimulated by secretagogues via ERKs. In this study, we examined whether ERKs regulated H(+),K(+)-ATPase alpha-subunit gene expression using a gastric cancer cell line, AGS. EGF induced ERK activity time- and dose-dependently with a maximal effect observed at 10 min and 10 nM, respectively. The MEK inhibitors, U0126 and PD-98059, dose-dependently inhibited the ERK activity stimulated by EGF. To test H(+),K(+)-ATPase alpha-subunit gene expression, we transfected AGS cells with a plasmid containing a canine H(+),K(+)-ATPase alpha-subunit gene promoter fused to a luciferase reporter gene. EGF induced luciferase activity in transfected cells; this effect was inhibited by the MEK inhibitors, suggesting that EGF-induced gene expression involved the ERK pathway. When AGS cells were transfected with the reporter plasmids in conjunction with an expression vector encoding constitutively active MEK1, luciferase activity was strongly enhanced; this effect was attenuated by the MEK inhibitors or by an additional cotransfection of dominant negative MEK1. Taken together, our results led us to conclude that the ERK pathway may mediate H(+),K(+)-ATPase alpha-subunit gene expression, contributing to gastric acid secretion in parietal cells.
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PMID:Extracellular signal-regulated protein kinases mediate H(+),K(+)-ATPase alpha-subunit gene expression. 1181 3

Epidermal growth factor (EGF) induces tumorigenic transformation of mouse epidermal cells (JB6 P(+)). We cloned a full-length EGF-responsive cDNA in JB6P(+) cells; EGF up-regulated mRNA expression of this gene 5- to 6-fold. The deduced amino acid sequence of this cDNA exhibited 84 and 96% homology with human and rat Lon homology ATP-dependent protease, respectively, and all conserved domains of Lon, such as ATPase/protease domains, are present in the mouse gene, indicating that this gene is mouse Lon. EGF increased the transcriptional rate without affecting the mRNA stability of m-Lon. The level of m-Lon in irreversibly transformed mouse epidermal cells (JB7) was 3.4-fold higher than that in parental JB6 P(+) cells. Similarly, human mammary epithelial cells overexpressing the proto-oncogene ErbB2 expressed significantly higher levels of Lon than normal mammary epithelial cells. EGF failed to regulate Lon expression in ERK-deficient JB6 P(-) cells or cells that expressed the dominant-negative p85 P13-K regulatory unit. Furthermore, selective chemical blockers for MEK1 and P13-K (PD98059 and LY294002) inhibited EGF-mediated induction. Mitochondria-localized Lon protease plays a critical role in the regulation of mitochondrial gene expression and genome integrity. Disruption of mitochondrial homeostasis is a general characteristic of tumorigenic transformation. Thus, the role of Lon in tumor promotion warrants further study.
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PMID:Epidermal growth factor up-regulates the transcription of mouse lon homology ATP-dependent protease through extracellular signal-regulated protein kinase- and phosphatidylinositol-3-kinase-dependent pathways. 1237 43

Angiotensin II (Ang II) receptor subtype 1, AT1, is expressed by the rat thyroid. A relationship between thyroid function and several components of the renin-angiotensin system has also been established, but the Ang II cellular effects in thyrocytes and its transduction signalling remain undefined. The aim of the present paper was to investigate the modulation of the activity of the Na(+)-K(+)ATPase by Ang II and its intracellular transduction pathway in PC-Cl3 cells, an established epithelial cell line derived from rat thyroid. Here we have demonstrated, by RT-PCR analysis, the expression of mRNA for the Ang II AT1 receptor in PC-Cl3 cells; mRNA for the Ang II AT2 receptor was not detected. Ang II was not able to affect the intracellular Ca(2+) concentration in fura-2-loaded cells, but it stimulated the translocation from the cytosol to the plasma membrane of atypical protein kinase C-zeta (PKC-zeta) and -iota (PKC-) isoforms with subsequent phosphorylation of the extracellular signal-regulated kinases 1 and 2 (ERK1 and 2). Translocated atypical PKCs displayed temporally different activations, the activation of PKC-zeta being the fastest. PC-Cl3 cells stimulated with increasing Ang II concentrations showed dose- and time-dependent activation of the Na(+)-K(+)ATPase activity, which paralleled the PKC-zeta translocation time course. Na(+)-K(+)ATPase activity modulation was dependent on PKC activation since the PKC antagonist staurosporine abolished the stimulatory effect of Ang II. The inhibition of the ERK kinases 1 and 2 (MEK1 and 2) by PD098059 (2'-amino-3'-methoxyflavone) failed to block the effect of Ang II on the Na(+)-K(+)ATPase activity. In conclusion, our results suggest that Ang II modulates Na(+)-K(+)ATPase activity in PC-Cl3 cells through the AT1 receptor via activation of atypical PKC-zeta while the Ang II-activated PKC- appears to have other as yet unknown functions.
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PMID:Angiotensin II AT1 receptor stimulates Na+ -K+ATPase activity through a pathway involving PKC-zeta in rat thyroid cells. 1252 32

We have recently reported that the beta-adrenergic agonist isoproterenol regulates the alveolar epithelial cell Na-K-ATPase via MAPK/extracellular signal-regulated kinase and rapamycin-sensitive pathways. Here we report that isoproterenol phosphorylated the protein S6 kinase (p70S6k) in alveolar epithelial cells, which was inhibited by both rapamycin and the MEK1/2 inhibitor U-0126. In alveolar epithelial cells transfected with a p70S6k dominant negative construct, isoproterenol did not increase Na-K-ATPase total protein expression, whereas in cells transfected with a rapamycin-resistant mutant, the isoproterenol-mediated increase in Na-K-ATPase was not prevented by rapamycin. Accordingly, we provide here first evidence that isoproterenol regulates Na-K-ATPase via p70S6k in alveolar epithelial cells.
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PMID:Beta-adrenergic agonists regulate Na-K-ATPase via p70S6k. 1295 25

Insulin stimulates Na(+),K(+)-ATPase activity and induces translocation of Na(+),K(+)-ATPase molecules to the plasma membrane in skeletal muscle. We determined the molecular mechanism by which insulin regulates Na(+),K(+)-ATPase in differentiated primary human skeletal muscle cells (HSMCs). Insulin action on Na(+),K(+)-ATPase was dependent on ERK1/2 in HSMCs. Sequence analysis of Na(+),K(+)-ATPase alpha-subunits revealed several potential ERK phosphorylation sites. Insulin increased ouabain-sensitive (86)Rb(+) uptake and [(3)H]ouabain binding in intact cells. Insulin also increased phosphorylation and plasma membrane content of the Na(+),K(+)-ATPase alpha(1)- and alpha(2)-subunits. Insulin-stimulated Na(+),K(+)-ATPase activation, phosphorylation, and translocation of alpha-subunits to the plasma membrane were abolished by 20 microm PD98059, which is an inhibitor of MEK1/2, an upstream kinase of ERK1/2. Furthermore, inhibitors of phosphatidylinositol 3-kinase (100 nm wortmannin) and protein kinase C (10 microm GF109203X) had similar effects. Notably, insulin-stimulated ERK1/2 phosphorylation was abolished by wortmannin and GF109203X in HSMCs. Insulin also stimulated phosphorylation of alpha(1)- and alpha(2)-subunits on Thr-Pro amino acid motifs, which form specific ERK substrates. Furthermore, recombinant ERK1 and -2 kinases were able to phosphorylate alpha-subunit of purified human Na(+),K(+)-ATPase in vitro. In conclusion, insulin stimulates Na(+),K(+)-ATPase activity and translocation to plasma membrane in HSMCs via phosphorylation of the alpha-subunits by ERK1/2 mitogen-activated protein kinase.
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PMID:ERK1/2 mediates insulin stimulation of Na(+),K(+)-ATPase by phosphorylation of the alpha-subunit in human skeletal muscle cells. 1506 82

The collecting duct of normal kidney exhibits significant activity of the MEK1/2-ERK1/2 pathway as shown in vivo by immunostaining of phosphorylated active ERK1/2 (pERK1/2). The MEK1/2-ERK1/2 pathway controls many different ion transports both in proximal and distal nephron, raising the question of whether this pathway is involved in the basal and/or hormone-dependent transepithelial sodium reabsorption in the principal cell of the cortical collecting duct (CCD), a process mediated by the apical epithelial sodium channel and the basolateral sodium pump (Na,K-ATPase). To answer this question we used ex vivo microdissected CCDs from normal mouse kidney or in vitro cultured mpkCCDcl4 principal cells. Significant basal levels of pERK1/2 were observed ex vivo and in vitro. Aldosterone and vasopressin, known to up-regulate sodium reabsorption in CCDs, did not change ERK1/2 activity either ex vivo or in vitro. Basal and aldosterone- or vasopressin-stimulated sodium transport was down-regulated by the MEK1/2 inhibitor PD98059, in parallel with a decrease in pERK1/2 in vitro. The activity of Na,K-ATPase but not that of epithelial sodium channel was inhibited by MEK1/2 inhibitors in both unstimulated and aldosterone- or vasopressin-stimulated CCDs in vitro. Cell surface biotinylation showed that intrinsic activity rather than cell surface expression of Na,K-ATPase was controlled by pERK1/2. PD98059 also significantly inhibited the activity of Na,K-ATPase ex vivo. Our data demonstrate that the ERK1/2 pathway controls Na,K-ATPase activity and transepithelial sodium transport in the principal cell and indicate that basal constitutive activity of the ERK1/2 pathway is a critical component of this control.
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PMID:ERK1/2 controls Na,K-ATPase activity and transepithelial sodium transport in the principal cell of the cortical collecting duct of the mouse kidney. 1545 67

Proinsulin-connecting peptide (C-peptide) exerts physiological effects partially via stimulation of Na(+), K(+)-ATPase. We determined the molecular mechanism by which C-peptide stimulates Na(+), K(+)-ATPase in primary human renal tubular cells (HRTCs). Incubation of the cells with 5 nM human C-peptide at 37 degrees C for 10 min stimulated (86)Rb(+) uptake by 40% (p<0.01). The carboxy-terminal pentapeptide was found to elicit 57% of the activity of the intact molecule. In parallel with ouabain-sensitive (86)Rb(+) uptake, C-peptide increased alpha subunit phosphorylation and basolateral membrane (BLM) abundance of the Na(+), K(+)-ATPase alpha(1) and beta(1) subunits. The increase in BLM abundance of the Na(+), K(+)-ATPase alpha(1) and beta(1) subunits was accompanied by depletion of alpha(1) and beta(1) subunits from the endosomal compartments. C-peptide action on Na(+), K(+)-ATPase was ERK1/2-dependent in HRTCs. C-peptide-stimulated Na(+), K(+)-ATPase activation, phosphorylation of alpha(1)-subunit and translocation of alpha(1) and beta(1) subunits to the BLM were abolished by a MEK1/2 inhibitor (20 muM PD98059). C-peptide stimulation of (86)Rb(+) uptake was also abolished by preincubation of HRTCs with an inhibitor of PKC (1 muM GF109203X). C-peptide stimulated phosphorylation of human Na(+), K(+)-ATPase alpha subunit on Thr-Pro amino acid motifs, which form specific ERK substrates. In conclusion, C-peptide stimulates sodium pump activity via ERK1/2-induced phosphorylation of Thr residues on the alpha subunit of Na(+), K(+)-ATPase.
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PMID:C-peptide stimulates Na+, K+-ATPase via activation of ERK1/2 MAP kinases in human renal tubular cells. 1554 82

We studied the proton secretion mechanisms involved with pHi regulation in immortalized rat proximal tubule cells (IRPTC), a SV40-immortalized cell line derived from rat proximal tubule, and characterized the effects of serum deprivation on them. Using pHi measurements with the fluorescent probe BCECF, we demonstrated that the IRPTC express both Na+/H+ exchanger and H+-ATPase, but only NHE1 is modulated by serum deprivation. In these cells, 24 h of serum starvation increased pHi from 7.08+/-0.008 (n=34) to 7.18+/-0.018 (n=33) as well as the pH recovery rate from intracellular acidification with NH4Cl from 0.29+/-0.022 pH U/min (n=14) to 0.50+/-0.024 pH U/min (n=14), without modifying their buffering capacity. These effects were followed by several modifications in morphological features, indicating an increase in differentiation status. The altered activity of NHE1 was consistent with an increase of both transcription and translation of the antiporter, as the utilization of actinomycin D and cycloheximide significantly inhibited the upregulation of NHE1 induced by serum withdrawal. Inhibition of tyrosine phosphorylation by genistein blocked the serum deprivation-dependent activation of NHE. Moreover, the pharmacological inhibition of MEK1/2, the upstream activator of ERK1/2 by UO-126, significantly inhibited the stimulatory effect of serum starvation on Na+/H+ exchanger activity, whereas the putative p38 MAPK inhibitor SB-203580 failed to cause any effect on pHi recovery rates. Our findings indicate that during IRPTC differentiation by serum deprivation, there was a net enhancement of NHE1 activity. This upregulation of NHE by serum removal was consistent with an increase of RNA and protein synthesis of the exchanger, which depends on tyrosine kinase phosphorylation and ERK pathway activation.
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PMID:Increased NHE1 expression is associated with serum deprivation-induced differentiation in immortalized rat proximal tubule cells. 1649 13

The small guanosine triphosphatase KRAS and the protein kinases BRAF, which is a mitogen-activated protein kinase kinase kinase (MAPKKK), and mitogen-activated protein kinase kinase 1 and 2 (MAPKK1/2, also known as MKK1/2 or MEK1/2) are signaling partners in the MAPK signal transduction pathway. They are involved in many biological processes and play crucial roles during embryonic development. When inappropriately expressed, KRAS, BRAF, and MEK1/2 are also frequently implicated in tumor progression. Hence, it might reasonably have been predicted that either loss- or gain-of-function germline mutations in the genes that encode them would cause embryonic death. However, in a surprising development, two articles report that germline mutations in the KRAS, BRAF, and MEK1/2 genes are associated with cardio-facio-cutaneous (CFC) syndrome. This unexpected discovery demonstrates that mutations in KRAS, BRAF, and MEK can pass through the germline to cause specific developmental syndromes. This finding will undoubtedly stimulate further research into the function of these proteins in development and in both inherited and sporadic cancers.
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PMID:BRAF and MEK mutations make a late entrance. 1656 17


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