EC:2.7.11.13 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parathyroid hormone (PTH) can stimulate bone resorption by increasing the activity and the number of osteoclasts in bone tissue by several mechanisms. Recently, osteoblast-derived membrane-type matrix metalloproteinase-1 (MT1-MMP) has been implied to play an important role in the process of bone resorption by degrading bone matrix. In the present study, we observed the effects of PTH (1-34) on MT1-MMP production, and the role of the protein kinase A (PKA) and protein kinase C (PKC) pathways in the regulation of MT1-MMP in cultures of human osteoblast-like MG-63 cells. By Northern blot and Western immunoblot analysis, we found, unexpectedly, that PTH (1-34) inhibited MT1-MMP mRNA and protein expression in a dose- and time-dependent manner in MG-63 cells. The PKA antagonist H-89 blunted PTH (1-34)-mediated decreases in MT1-MMP protein synthesis. Forskolin, a PKA agonist, decreased MT1-MMP expression, which was similar to the action of PTH on MT1-MMP expression, in MG-63 cells. Staurosporine, a PKC inhibitor, also blocked the inhibition by PTH. We suggest that both the PKA and PKC pathways are involved in MT1-MMP downregulation by PTH. Furthermore, we found that PTH (1-34) induced the expression of receptor activator of nuclear factor (NF)-KappaB ligand (RANKL) mRNA in a dose- and time-dependent manner in MG-63 cells, and this effect of PTH on RANKL mRNA expression was nearly parallel to the effects of MT1-MMP downregulation, implying a correlation between MT1-MMP and RANKL expression. Our findings suggest that the decreased MT1-MMP expression induced by PTH may be involved in RANKL signaling in osteoblasts, and may play a role in the activation of bone resorption.
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PMID:Parathyroid hormone inhibits the expression of membrane-type matrix metalloproteinase-1 (MT1-MMP) in osteoblast-like MG-63 cells. 1469 82

Parathyroid hormone (PTH) inhibits Na(+),K(+)-ATPase activity through protein kinase C- (PKC) and extracellular signal-regulated kinase- (ERK) dependent pathways and increases serine phosphorylation of the alpha(1)-subunit. To determine whether specific serine phosphorylation sites within the Na(+),K(+)-ATPase alpha(1)-subunit are involved in the Na(+),K(+)-ATPase responses to PTH, we examined the effect of PTH in opossum kidney cells stably transfected with wild type rat Na(+),K(+)-ATPase alpha(1)-subunit (WT), serine 11 to alanine mutant alpha(1)-subunit (S11A), or serine 18 to alanine mutant alpha(1)-subunit (S18A). PTH increased phosphorylation and endocytosis of the Na(+),K(+)-ATPase alpha(1)-subunit into clathrin-coated vesicles in cells transfected with WT and S18A rat Na(+),K(+)-ATPase alpha(1)-subunits. PTH did not increase the level of phosphorylation or stimulate translocation of Na(+),K(+)-ATPase alpha(1)-subunits into clathrin-coated vesicles in cells transfected with the S11A mutant. PTH inhibited ouabain-sensitive (86)Rb uptake and Na(+),K(+)-ATPase activity (ouabain-sensitive ATP hydrolysis) in WT- and S18A-transfected opossum kidney cells but not in S11A-transfected cells. Pretreatment of the cells with the PKC inhibitors and ERK inhibitor blocked PTH inhibition of (86)Rb uptake, Na(+),K(+)-ATPase activity, alpha(1)-subunit phosphorylation, and endocytosis in WT and S18A cells. Consistent with the notion that ERK phosphorylates Na(+),K(+)-ATPase alpha(1)-subunit, ERK was shown to be capable of causing phosphorylation of Na(+),K(+)-ATPase alpha(1)-subunit immunoprecipitated from WT and S18A but not from S11A-transfected cells. These results suggest that PTH regulates Na(+),K(+)-ATPase by PKC and ERK-dependent alpha(1)-subunit phosphorylation and that the phosphorylation requires the expression of a serine at the 11 position of the Na(+),K(+)-ATPase alpha(1)-subunit.
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PMID:Clathrin-mediated endocytosis of Na+,K+-ATPase in response to parathyroid hormone requires ERK-dependent phosphorylation of Ser-11 within the alpha1-subunit. 1497 17

An excess of free intracellular calcium can reduce the efficiency of insulin-mediated glucose transport by blocking the dephosphorylation of GLUT-4. Classical isoforms of protein kinase C (PKC) can interfere with insulin signalling via serine phosphorylation of IRS-1 and the insulin receptor. Parathyroid hormone (PTH), by activating phospholipase C-beta in adipocytes, can promote a sustained increase in intracellular free calcium in these cells, while also activating classical PKCs. This may rationalize the fact that insulin resistance is a typical feature of hyperparathyroidism, as well as epidemiological evidence that regular ingestion of dairy products or of ethanol--which down-regulates PTH secretion--reduces risk for insulin resistance syndrome and diabetes. Alpha-1 adrenergic receptors of adipocytes--like PTH receptors--also activate phospholipase C-beta, and thus have an effect analogous to PTH on intracellular free calcium and PKC activity in adipocytes. This suggests that, via activation of alpha-1 adrenergic receptors, increased sympathetic activity in adipose tissue may promote insulin resistance syndrome. In fact, measures which provoke increased sympathetic output--such as diuretic use and severe salt restriction--are known to compromise insulin sensitivity, whereas alpha-1 antagonist drugs, as well as drugs that act centrally to suppress sympathetic activity, typically have a favorable effect on insulin function. When insulin resistance syndrome is associated with elevated sympathetic activity--for example, in hypertensives who are obese or on diuretic therapy--measures which down-regulate sympathetic activity, or, more specifically, alpha-1 adrenergic activity, may be warranted. These include centrally acting imidazoline analogs (moxonidine, rilmenidine) and alpha-1 antagonists (doxazosin, prazosin). Taurine and high-dose pyridoxine may represent practical nutritional strategies for moderating elevated sympathetic activity, and exercise training and low-insulin-response diets may be useful in this regard as well.
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PMID:Elevated sympathetic activity may promote insulin resistance syndrome by activating alpha-1 adrenergic receptors on adipocytes. 1508 16

In mammals, neonatal positive calcium balance is required for adequate growth. Parathyroid hormone (PTH) plays a central role in this process mainly through its action on the distal nephron. We studied the effect of PTH on cytosolic calcium in distal segments from neonatal rat kidney. PTH elicited a concentration-dependent increase in cytosolic calcium in neonatal distal nephron (EC(50)=0.5 nM) but not in proximal tubules. At similar PTH concentrations the response was higher in the neonatal than in the adult tubules. The response was associated with protein kinase C (PKC), since phorbol myristate acetate (100 nM) increased [Ca(2+)]i, and staurosporin, an inhibitor of PKC, decreased (10 nM) or suppressed (100 nM) the PTH effect. cAMP analogues did not change [Ca(2+)]i. The response was diminished in low external calcium (0.1 mM) and absent at zero calcium, indicating dependency on external calcium. Resting calcium decreased from 80+/-10.8 to 28.6+/-2.6 nM at zero [Ca(2+)]e. PTH and nifedipine increased cytosolic calcium in an additive fashion. We show for the first time that PTH increased cytosolic calcium in the distal nephron of neonatal kidney, in a concentration-dependent pattern and in association with PKC activation. Higher sensitivity of the neonatal tubule might facilitate absorption of this cation during the neonatal period, when growth requires a positive balance of calcium.
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PMID:Parathyroid hormone increases cytosolic calcium in neonatal nephron through protein kinase C pathway. 1530 Apr 74

Parathyroid hormone (PTH) exerts potent and diverse effects in bone and cartilage through activation of type 1 PTH receptors (PTH1R) capable of coupling to protein kinase A (PKA) and PKC. We have used macroarrays to identify zinc finger protein butyrate response factor-1 (BRF1) as a novel PTH regulated gene in clonal and normal osteoblasts of human and rodent origin. We further demonstrate that in human osteoblast-like OHS cells, biologically active hPTH(1-84) and hPTH(1-34) stimulate BRF1 mRNA expression in a dose- and time-dependent manner, while the amino-terminally truncated hPTH(3-84) which does not activate PTH1R has no effect. Moreover, using specific stimulators or inhibitors of PKA and PKC activity, the PTH-elicited BRF1 mRNA expression is mediated through the PKA signaling pathway. In mouse calvarial osteoblasts, BRF1 mRNA levels are upregulated by PTH(1-84) and reduced in response to bone morphogenetic protein 2 (BMP-2). Hence, our data showing that BRF1 is expressed in osteoblastic cells and regulated by PTH and BMP-2, suggest an important role for BRF1 in osteoblasts within the molecular network of PTH-dependent bone remodeling.
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PMID:Butyrate response factor 1 is regulated by parathyroid hormone and bone morphogenetic protein-2 in osteoblastic cells. 1546 5

1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) treatment of osteoblastic cells was shown previously to attenuate Parathyroid hormone (PTH) response by inhibiting adenylyl cyclase (AC) activity. In this study, we have investigated the mechanism by which 1,25(OH)(2)D(3) inhibits AC in rat osteoblastic UMR 106-01 cells. 1,25(OH)(2)D(3) treatment inhibited both PTH and forskolin-stimulated AC activity by 25%-50% within 12 min in a concentration-dependent manner suggesting a direct inhibition of the AC enzyme. Treatment with 25(OH)D(3) had no effect on basal or stimulated AC activity. We determined the profile of AC subtypes expressed in UMR cells and found AC VI to be the dominant subtype accounting for 50% of AC mRNA. Since AC VI can be inhibited by protein kinase C (PKC) phosphorylation, we examined 1,25(OH)(2)D(3) activation of various PKC isoforms. 1,25(OH)(2)D(3) increased the membrane translocation of PKC-betaI, -delta, and -zeta with a concomitant increase in PKC activity. The translocation of PKC-betaI and -delta was blocked by the PLC inhibitor U73122 whereas that of PKC-zeta was abolished by the PI-3 kinase inhibitor wortmannin. The attenuation of cAMP production by 1,25(OH)(2)D(3) was antagonized by the PKC inhibitors Go6850, calphostin C, and wortmannin, but not by a calmodulin kinase II (CaMKII) inhibitor. Treatment with 1,25(OH)(2)D(3) for 20 min increased AC VI phosphorylation by 10.8-fold and this was blocked partially by Go6850 and partially by wortmannin but was unaffected by CaMKII inhibitor. These results demonstrate that 1,25(OH)(2)D(3) activation of PKC isoforms leads to phosphorylation of AC VI and inhibition of PTH-activation of this pathway in osteoblasts.
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PMID:1,25-dihydroxyvitamin D(3) stimulated protein kinase C phosphorylation of type VI adenylyl cyclase inhibits parathyroid hormone signal transduction in rat osteoblastic UMR 106-01 cells. 1559 41

Parathyroid hormone (PTH) inhibits Na+-K+-ATPase activity by serine phosphorylation of the alpha1 subunit through protein kinase C (PKC)- and extracellular signal-regulated kinase (ERK)-dependent pathways. Based on previous studies we postulated that PTH regulates sodium pump activity through isoform-specific PKC-dependent activation of ERK. In the present work utilizing opossum kidney cells, a model of renal proximal tubule, PTH stimulated membrane translocation of PKCalpha by 102 +/- 16% and PKCbetaI by 41 +/- 7% but had no effect on PKCbetaII and PKCzeta. Both PKCalpha and PKCbetaI phosphorylated the Na+-K+-ATPase alpha1 subunit in vitro. PTH increased the activity of PKCalpha but not PKCbetaI. Coimmunoprecipitation assays demonstrated that treatment with PTH enhanced the association between Na+-K+-ATPase alpha1 subunit and PKCalpha, whereas the association between Na+-K+-ATPase alpha1 subunit and PKCbetaI remained unchanged. A PKCalpha inhibitory peptide blocked PTH-stimulated serine phosphorylation of the Na+-K+-ATPase alpha1 subunit and inhibition of Na+-K+-ATPase activity. Pharmacologic inhibition of MEK-1 blocked PTH-stimulated translocation of PKCalpha, whereas transfection of constitutively active MEK-1 cDNA induced translocation of PKCalpha and increased phosphorylation of the Na+-K+-ATPase alpha1 subunit. In contrast, PTH-stimulated ERK activation was not inhibited by pretreatment with the PKCalpha inhibitory peptide. Inhibition of PKCalpha expression by siRNA did not inhibit PTH-mediated ERK activation but significantly reduced PTH-mediated phosphorylation of the Na+-K+-ATPase alpha1 subunit. Pharmacologic inhibition of phosphoinositide 3-kinase blocked PTH-stimulated ERK activation, translocation of PKCalpha, and phosphorylation of the Na+-K+-ATPase alpha1 subunit. We conclude that PTH stimulates Na+-K+-ATPase phosphorylation and decreases the activity of Na+-K+-ATPase by ERK-dependent activation of PKCalpha.
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PMID:Parathyroid hormone-mediated regulation of Na+-K+-ATPase requires ERK-dependent translocation of protein kinase Calpha. 1563 80

Recent studies demonstrate low serum levels of 25-hydroxyvitamin D in patients with congestive heart failure (CHF). Although this may in part reflect reduced capacity for outdoor exercise, the possibility that poor vitamin D status increases risk for left ventricular hypertrophy (LVH), and its common sequel CHF, merits consideration. In cardiomyocytes, hormones which activate protein kinase C (PKC) -- including norepinephrine, angiotensin II, and endostatin, implicated in the pathogenesis of LVH -- induce a hypertrophic response analogous to that seen in LVH. Transgenic mice overexpressing PKC-beta2 or its upstream activator Galphaq in cardiac myofibers develop a syndrome similar to LVH. Parathyroid hormone (PTH) also activates Galphaq and PKC in cardiomyocytes, and provokes the expected hypertrophic response. Both primary and secondary hyperparathyroidism are associated with high risk for LVH. Moreover, in uncomplicated essential hypertension, left ventricular mass index has been shown to correlate very tightly with serum PTH levels, independent of blood pressure. This latter finding suggests that variations of PTH within the normal range can influence induction of LVH in at-risk subjects. If so, nutritional and lifestyle measures which modulate PTH secretion may have an impact on LVH risk. PTH secretion should be down-regulated by good vitamin D status -- achieved through supplementation or regular uv exposure -- and by vegan diets moderately low in bioavailable phosphate. Although high calcium intakes can likewise suppress PTH, they also boost renin secretion, which could have a countervailing effect on risk for LVH. Whether these nutritional measures do indeed influence LVH risk could be examined in prospective studies targeting patients at high risk, such as hypertensives.
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PMID:Nutritional modulation of parathyroid hormone secretion may influence risk for left ventricular hypertrophy. 1578 May 3

Parathyroid hormone (PTH) inhibits sodium-dependent phosphate (Na(+)-Pi) transport in the renal proximal tubule and opossum kidney (OK) cells by mechanisms involving protein kinases (PK) A and C, and 20-hydroxyeicosatetraneoic acid (20-HETE). The magnitude of the effect of PKA and PKC on Na(+)-Pi transport in OK cells varies in different studies, suggesting that OK cell subclones are functionally heterogeneous despite their morphological similarity. We studied the effect of PTH and PK effectors in two separate sets of OK cells at two different time periods. Each group of cells were derived from the same stock, at passages 75-85. In one group of OK cells 20-HETE (10(-7 )M) induced a 24% decrease in Na-(32)Pi transport. Addition of PTH (10(-7) M) inhibited Pi transport by 44%. Addition of TPA (10(-8) M) resulted in a 32% decrease in Na-(32)Pi transport. Exposure of cells to the PKC inhibitor staurosporine (10(-7) M) induced a significant increase in Na-(32)Pi transport. Simultaneous addition of 20-HETE and staurosporine restored baseline Pi transport. Finally, Br-cAMP (10(-7) M) inhibited Na-(32)Pi transport by 32%. In another group of OK cells we reexamined the affect of these substances on Na-(32)Pi transport. 20-HETE (10(-7) M) induced a significant increase (30%) in Na-(32)Pi transport. PTH (10(-7) M) had no effect on Na-(32)Pi transport (P = 0.05). TPA (10(-8) M) induced a 42% increase in Na-(32)Pi transport (P < 0.01). Staurosporine (10(-7) M) induced a slight decrease in Na-(32)Pi transport (P < 0.05). Simultaneous addition of 20-HETE and staurosporine restored Na-(32)Pi transport to baseline levels. Finally, Br-cAMP (10(-7) M) inhibited Na-(32)Pi transport by 23%. We conclude that different groups OK cells have markedly different responses to regulators of Na-Pi cotransport.
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PMID:Parathormone sensitivity and responses to protein kinases in subclones of opossum kidney cells. 1583 20

Parathyroid hormone (PTH) has significant anabolic and catabolic effects on bone. We hypothesize that PTH-induced primary response genes are important determinants of osteoblast function. PTH induces osteoblastic gene expression through PTHR1, a heptahelical receptor that triggers cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA), protein kinase C (PKC), and calcium signaling. By using representational difference analysis we found that receptor activity modifying protein-3 (RAMP3) is a PTH-induced primary response gene in osteoblastic cells. RAMP3 is a coactivator that directs calcitonin receptor (CTR) and CTR-like receptor (CRLR) glycosylation, trafficking, and ligand-binding specificity. Our purpose was to characterize PTH-induced RAMP3 messenger ribonucleic acid (mRNA) levels in primary mouse osteoblasts (MOBs) and to determine which signaling pathway mediates this effect. 10 nM PTH maximally induced RAMP3 mRNA levels in MOBs at 4 hours. Protein synthesis inhibition with 3 microg/mL cycloheximide did not affect PTH-induced RAMP3 mRNA levels. Selective activation of cAMP-PKA signaling with, 10 microM forskolin (FSK) and PKC signaling with 1 microM phorbol 12-myristate 13-acetate (PMA) significantly increased RAMP3 mRNA levels, whereas 1 microM ionomycin (a calcium ionophore) had no effect. Pretreatment with 30 microM H89, a PKA inhibitor, significantly blocked PTH- and FSK-induced RAMP3 mRNA levels. Pretreatment with 1 microM PMA, which depletes PKC, had no effect on PTH- and FSK-induced RAMP3 mRNA levels but blocked PMA-induced RAMP3 mRNA levels. 100 nM PTH (3-34), which activates PKC and calcium but not PKA, had no effect on RAMP3 mRNA levels. These findings indicate that RAMP3 is a PTH-induced primary response gene in primary MOBs and that PTH regulates RAMP3 gene expression primarily through the cAMP-PKA pathway.
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PMID:Parathyroid hormone induces receptor activity modifying protein-3 (RAMP3) expression primarily via 3',5'-cyclic adenosine monophosphate signaling in osteoblasts. 1607 64

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