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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ascites sarcoma 180 (S180A) is a transplantable tumor that induces hypercalcemia in tumor-bearing mice and stimulates bone resorption in cultured neonatal mouse calvaria without parathyroid hormone (PTH)-like activity. The serum-free conditioned media of S180A cell cultures (S180A-CM) stimulated [3H]thymidine incorporation (178.3% of the control) and inhibited alkaline phosphatase activity (39.0% of the control) in the osteoblastic osteosarcoma cell line UMR 106-01, contrary to PTH. To investigate signal transduction by S180A-CM, we determined the levels of intracellular free calcium ([Ca2+]i), inositol 1,4,5-triphosphate (IP3), 1,2-diacylglycerol (DAG), phosphatidylcholine (PC) and protein kinase (PK) C activity in UMR 106-01 cells. PTH and PTH-related protein (PTHrP), both potent bone-resorbing factors (BRFs), caused an increase in [Ca2+]i and stimulated IP3 production, whereas S180A-CM had little or no effect on these parameters. On the other hand, S180A-CM stimulated DAG production, accompanied by PC breakdown, and the translocation of PKC activity from the cytosol to the membrane fraction. Sphingosine, a specific PKC inhibitor, inhibited bone-resorbing activity (BRA) in S180A-CM more effectively than PTH or PTHrP-stimulated resorption. H-7, an inhibitor of both cAMP-dependent PKA and PKC, completely inhibited BRA in S180A-CM. These results suggest that BRFs of S180A-CM stimulate osteoblastic cell proliferation and bone resorption via two signal transduction pathways, which are different from those of PTH: 1) activation of PKC by DAG resulting from PC hydrolysis and 2) activation of PKA subsequent to prostaglandin E2 production by bone.
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PMID:Humoral factors of ascites sarcoma 180 stimulate osteoblastic UMR 106-01 cell proliferation and bone resorption via signal transduction pathways, which are clearly different from those of parathyroid hormone. 891 16

In a previous study, we demonstrated that parathyroid hormone (PTH) inhibits mitogen-activated protein (MAP) kinase activation in osteosarcoma cells via a protein kinase A-dependent pathway. Here, we show that PTH can induce a transient activation of MAP kinase as well. This was observed in both Chinese hamster ovary R15 cells stably expressing high levels of rat PTH/PTH-related peptide receptor and parietal yolk sac carcinoma cells expressing the receptor endogenously. PTH was a strong activator of adenylate cyclase and phospholipase C in Chinese hamster ovary R15 cells. PTH-induced MAP kinase activation did not depend on activation of Gi, phorbol ester-sensitive protein kinase C, elevated intracellular calcium levels, or release of Gbetagamma subunits. It could, however, be mimicked by addition of forskolin or 8-bromo-cAMP to these cells. Prolonged treatment with forskolin caused sustained protein kinase A activity, whereas MAP kinase activity returned to basal levels. Subsequent treatment with PTH or 8-bromo-cAMP did not result in MAP kinase activation, whereas phorbol ester- or insulin-induced MAP kinase activation was unaffected. Finally, expression of a dominant negative form of Ras (RasAsn-17), which completely blocked insulin-induced MAP kinase activation, did not affect activation by PTH or cAMP. In conclusion, PTH regulates MAP kinase activity in a cell type-specific fashion. The activation of MAP kinase by PTH is mediated by cAMP and independent of Ras.
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PMID:Parathyroid hormone activates mitogen-activated protein kinase via a cAMP-mediated pathway independent of Ras. 901 86

Activation of the G protein-coupled receptor for parathyroid hormone (PTH)/PTH-related protein (PTHrP) produces homologous desensitization of receptor signaling. We have shown recently that the opossum PTH/PTHrP receptor stably expressed in human embryonic kidney (HEK) 293 cells is phosphorylated upon agonist binding and upon activation of serine/threonine protein kinases (PKA and PKC), an event which for some G protein-coupled receptors has been linked to desensitization. To locate the sites of phosphorylation, mutated forms of the opossum PTH/PTHrP receptor were stably expressed in HEK 293 cells, and ligand-stimulated receptor phosphorylation was evaluated. The five serine and threonine residues of the third cytoplasmic loop of the receptor were not required for receptor phosphorylation. Basal and ligand-induced phosphorylation were, however, completely abolished upon deletion of all but the 16 juxtamembrane residues of the cytoplasmic C-terminal tail of the receptor, even though this truncated receptor resembled the wild-type receptor in its level of expression based on Western blotting and radioligand binding. To identify further the phosphorylation sites, the 129 amino acid C-terminal tail of the rat PTH/PTHrP receptor was expressed in E. coli as a recombinant glutathione S-transferase fusion protein. Elimination of a single PKA consensus site in the tail (serine 491) resulted in > or = 90% loss of PKA-mediated phosphorylation, identifying this as the preferential site for PKA, with two other sites (serine 473 and/or 475) being minor sites. Phosphorylation by PKC occurred largely in the proximal portion of the tail, whereas beta-adrenergic receptor kinase 1 (beta ARK1) phosphorylated more distally in the tail. The ability of these kinases to phosphorylate the PTH/PTHrP receptor at distinct sites on the cytoplasmic tail may allow differential regulation of receptor signaling and trafficking.
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PMID:Phosphorylation of the cytoplasmic tail of the PTH/PTHrP receptor. 915 72

Previous studies have suggested that increased secretion of bone active cytokines, such as interleukin-6 (IL-6) and interleukin-11 (IL-11), from osteoblasts and stromal cells play a pivotal role in the activation of osteoclasts and the genesis of osteoporosis. Various systemic and local factors can stimulate IL-6/IL-11 production, but the intracellular mechanism for such stimulation is largely unknown. In this study, we characterized the second messenger signaling in parathyroid hormone (PTH)- and IL-1-induced production of IL-6/IL-11 and studied the possible modulating effects of estrogen. rhPTH(1-34) and rhIL-1 alpha dose-dependently stimulated IL-6 and IL-11 production from human bone marrow stromal cells (hBMSCs). Agonists for protein kinase A (PKA) (forskolin), and protein kinase C (PKC) (phorbol 12-myristate 13-acetate; PMA) also stimulated IL-6/IL-11 production. Rp-diastereoisomer of adenosine cyclic 3',5'-phosphorothioate (Rp-cAMPS) and H-8, inhibitors of PKA, significantly inhibited PTH-stimulated IL-6/IL-11 production, but did not inhibit IL-1-stimulated IL-6/IL-11 production. In contrast, staurosporine and calphostin C, inhibitors of PKC, suppressed IL-1-stimulated, but not PTH-stimulated, IL-6/ IL-11 production. Pretreatment of cells with 17 beta-estradiol (17 beta-E2) antagonized IL-1-stimulated IL-6 production. However, PTH-stimulated IL-6 production and IL-1- and PTH-stimulated IL-11 production were not affected by 17 beta-E2. Similarly, 17 beta-E2 inhibited PMA-stimulated IL-6 production, whereas neither forskolin-stimulated IL-6/ IL-11 production nor PMA-stimulated IL-11 production was affected by 17 beta-E2. These results indicate that different second messengers are involved in PTH- and IL-1-induced IL-6 and IL-11 production by hBMSCs: PTH and IL-1 stimulate IL-6/IL-11 production via a PKA-dependent and PKC-dependent pathway, respectively. Furthermore, our results suggest that regulation of cytokine production by estrogen in hBMSCs is selective; only the IL-1-induced IL-6 production, which is mediated by PKC pathway, is inhibited, but PTH-induced IL-6 production and PTH/IL-1-induced IL-11 production are not inhibited by estrogen.
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PMID:Involvement of different second messengers in parathyroid hormone- and interleukin-1-induced interleukin-6 and interleukin-11 production in human bone marrow stromal cells. 916 47

We used proximal tubule-derived opossum kidney (OK) cells to determine the dependence of albumin endocytosis on regulation by protein kinases and on the cytoskeleton. Uptake was observed only across the apical but not the basolateral membrane and exceeded uptake in collecting duct-derived Madin-Darby canine kidney cells 14-fold. Inhibition of endocytosis via clathrin-coated vesicles but not via caveolae abolished uptake. Cytochalasin D reduced uptake to < 5% of control, and inhibition of microtubule polymerization by nocodazole reduced uptake to approximately 55% of control. Activation of protein kinase A (PKA) by adenosine 3',5'-cyclic monophosphate, forskolin, or parathyroid hormone (PTH) reduced uptake to approximately 65% of control. Protein kinase C (PKC) activation did affect uptake to a similar extent as PKA activation but with a certain delay. Stimulation of PKG by guanosine 3',5'-cyclic monophosphate did not affect albumin endocytosis. The inhibitor of tyrosine kinases (TRK), genistein, induced an increase of uptake to approximately 160% of control. Reexocytosis of albumin was enhanced by PKC activation but not by PKA activation. TRK inhibition reduced the rate of reexocytosis. We conclude that albumin endocytosis in OK cells requires the integrity of the actin cytoskeleton. Microtubules facilitate endocytosis. Uptake is regulated by PKA, PKC, and TRK, yet with different time course and by different mechanisms, e.g., reexocytosis. Possibly TRK activity serves in a negative feedback loop to limit albumin endocytosis via a stimulation of reexocytosis.
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PMID:Albumin endocytosis in OK cells: dependence on actin and microtubules and regulation by protein kinases. 917 79

There have been several lines of evidence that parathyroid hormone (PTH) stimulates production of insulinlike growth factor I (IGF-I) in bone and that IGF-I stimulates osteoclast formation. Thus, the present study was performed to clarify the possible role of IGF-I in PTH-stimulated osteoclastlike cell formation and the role of PTH-responsive dual signal transduction systems (cyclic [c] AMP-dependent protein kinase [PKA] and calcium/protein kinase C [PKC]) in its mechanism. Treatment with anti-IGF-I antibody (1-10 micrograms/ml) partially but significantly blocked hPTH-(1-34)-stimulated osteoclastlike cell formation in unfractionated mouse bone cell cultures, although it did not affect osteoclastlike cell formation stimulated by 1,25-dihydroxyvitamin D3. Rp-cAMP5 (10(-4) M), a direct PKA inhibitor, as well as two types of PKC inhibitors, H-7 (10 microM) and staurosporine (3 nM), and dantrolene (10(-5) M), an inhibitor of calcium mobilization from intracellular calcium stores, all significantly blocked PTH-stimulated osteoclastlike cell formation. Anti-IGF-I antibody (3 micrograms/ml) significantly blocked osteoclastlike cell formation stimulated by 10(-4) M dbcAMP, 10(-4) M Sp-cAMPS, a direct PKA activator, and 10(-5) M forskolin in mouse bone cell cultures. Dibutyryl cAMP, forskolin, and hPTH-(1-34) significantly stimulated mRNA expression of both IGF-I and IGF-binding protein 5 (IGFBP-5) in these cultures, but neither 10(-7) M PMA, a PKC activator, nor 10(-7) M A23187 did. Moreover, anti-IGF-I antibody significantly blocked osteoclastlike cell formation stimulated by the conditioned medium from MC3T3-E1 cells pretreated with 10(-8) PTH-(1-34), which induced IGF-I and IGFBP-5 mRNA expression in these cells. In conclusion, the present study indicates that IGF-I mediates osteoclastlike cell formation stimulated by PTH and that the PKA pathway is involved in its mechanism. However, IGF-I does not seem to be the sole effector molecule to be active in this system.
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PMID:Insulin-like growth factor-I mediates osteoclast-like cell formation stimulated by parathyroid hormone. 920 25

Insulin-like growth factor-I (IGF-I) is a key factor in bone remodeling. In osteoblasts, IGF-I synthesis is enhanced by parathyroid hormone and prostaglandin E2 (PGE2) through cAMP-activated protein kinase. In rats, estrogen loss after ovariectomy leads to a rise in serum IGF-I and an increase in bone remodeling, both of which are reversed by estrogen treatment. To examine estrogen-dependent regulation of IGF-I expression at the molecular level, primary fetal rat osteoblasts were co-transfected with the estrogen receptor (hER, to ensure active ER expression), and luciferase reporter plasmids controlled by promoter 1 of the rat IGF-I gene (IGF-I P1), used exclusively in these cells. As reported, 1 microM PGE2 increased IGF-I P1 activity by 5-fold. 17beta-Estradiol alone had no effect, but dose-dependently suppressed the stimulatory effect of PGE2 by up to 90% (ED50 approximately 0.1 nM). This occurred within 3 h, persisted for at least 16 h, required ER, and appeared specific, since 17alpha-estradiol was 100-300-fold less effective. By contrast, 17beta-estradiol stimulated estrogen response element (ERE)-dependent reporter expression by up to 10-fold. 17beta-Estradiol also suppressed an IGF-I P1 construct retaining only minimal promoter sequence required for cAMP-dependent gene activation, but did not affect the 60-fold increase in cAMP induced by PGE2. There is no consensus ERE in rat IGF-I P1, suggesting novel downstream interactions in the cAMP pathway that normally enhances IGF-I expression in skeletal cells. To explore this, nuclear extract from osteoblasts expressing hER were examined by electrophoretic mobility shift assay using the atypical cAMP response element in IGF-I P1. Estrogen alone did not cause DNA-protein binding, while PGE2 induced a characteristic gel shift complex. Co-treatment with both hormones caused a gel shift greatly diminished in intensity, consistent with their combined effects on IGF-I promoter activity. Nonetheless, hER did not bind IGF-I cAMP response element or any adjacent sequences. These results provide new molecular evidence that estrogen may temper the biological effects of hormones acting through cAMP to regulate skeletal IGF-I expression and activity.
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PMID:17beta-estradiol potently suppresses cAMP-induced insulin-like growth factor-I gene activation in primary rat osteoblast cultures. 921 47

We examined the effects of prolonged exposure to parathyroid hormone (PTH) and the protein kinase C (PKC) activator mezerein (MEZ) on cyclic adenosine monophosphate (cAMP) production, PKC activity, and Na(+)-dependent phosphate (Na/Pi) transport in an opossum kidney cell line (OK/E). A 5 minute exposure to PTH stimulated, while a 6 h incubation reduced, cAMP production, Na/Pi transport was maximally inhibited under desensitizing conditions and was not affected by reintroduction of the hormone. MEZ pretreatment (6 h) enhanced PTH-, cholera toxin (CTX)-, and forskolin (FSK)-stimulated cAMP production, suggesting enhanced Gs alpha coupling and increased adenylyl cyclase activity. However, PKA- and PKC-dependent regulation of Na/Pi were blocked in MEZ-treated cells. The PTH-induced decrease in cAMP production was associated with a reduction in membrane-associated PKC activity while MEZ-induced increases in cAMP production were accompanied by decreases in membrane and cytosolic PKC activity. Enhanced cAMP production was not accompanied by significant changes in PTH/PTH related peptide (PTHrP) receptor affinity or number, nor was the loss of Na/Pi transport regulation associated with changes in PKA activity. The results indicate that down-regulation of PKC by PTH or MEZ differentially modulates cAMP production and regulation of Na/Pi transport. The distinct effects of PTH and MEZ on PKC activity suggest that agonist-specific activation and/or down-regulation of PKC isozyme(s) may be involved in the observed changes in cAMP production and Na/Pi transport.
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PMID:Down-regulation of protein kinase C by parathyroid hormone and mezerein differentially modulates cAMP production and phosphate transport in opossum kidney cells. 925 52

The aims of this study were to clarify the role of cell maturation stage on chondrocyte response to parathyroid hormone (PTH) by examining the effect of PTH(1-34) on alkaline-phosphatase-specific activity (ALPase) of chondrocyte cultures at two distinct stages of maturation, and to determine the signaling pathways used by the cells to mediate this effect. Confluent, fourth passage rat costochondral resting zone (RC) and growth zone (GC) chondrocytes were used. ALPase was measured in the cell layer, as well as in matrix vesicles (MV) and plasma membranes (PM), after the addition of 10(-7) 10(-11) mol/L bovine PTH(1-34), the active peptide, or bovine PTH(3-34), the inactive peptide, to the cultures. PTH(1-34) increased ALPase in the GC cultures at two separate times: between 5 and 180 min, with maximal stimulation at 10 min, and 36 to 48 h. In contrast, PTH(3-34) had no effect. At 10 min and 48 h, PTH(1-34) produced a dose-dependent increase in ALPase of both MV and PM isolated from GC cultures. Addition of forskolin and IBMX to increase cAMP increased ALPase in GC cultures to a level similar to that seen after addition of PTH(1-34). In contrast, the addition of PTH(1-34) to RC cells only increased ALPase between 5 and 60 min, with peak activity at 10 min. As with GC, PTH increased ALPase in both MV and PM. Moreover, the addition of PTH(3-34) or forskolin and IBMX had no effect on ALPase in RC. PTH(1-34) had no effect on GC protein kinase C (PKC) activity; however, the addition of PTH(1-34) to RC caused a dose-dependent increase in PKC activity. H8, an inhibitor of PKA, had no effect on PTH-stimulated ALPase in RC cells, but inhibited the PTH-dependent response in GC cells. In contrast, chelerythrine, an inhibitor of PKC activity, inhibited PTH-stimulated ALPase in RC cells, but had no effect on PTH-stimulated ALPase in GC cells. This study shows that the effect of PTH(1-34) on RC and GC cells is maturation dependent in terms of time course and mechanism. Whereas both cell types exhibit a rapid response to PTH, only GC cells show a long-term response. In GC, the effects of PTH are associated with changes in cAMP and may also involve at least one other pathway, whereas, in RC, the PTH effects appear to be associated with changes in PKC.
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PMID:Rapid and long-term effects of PTH(1-34) on growth plate chondrocytes are mediated through two different pathways in a cell-maturation-dependent manner. 927 90

Parathyroid hormone (PTH) functions in part by regulating osteoblast cytokine expression. We recently demonstrated that PTH induced a rapid and transient increase in interleukin-6 (IL-6) mRNA expression in rat bones in vivo. To determine the molecular basis of this effect, we analyzed the human IL-6 promoter fused (-1,179 to +9) with the chloramphenicol acetyltransferase (CAT) reporter gene in stable transfections into human osteoblast-like osteosarcoma SaOS-2 cells. We compared the effects of PTH on IL-6 expression with adenylate cyclase activator forskolin, PKC activator phorbol 12-myristate 13-acetate (PMA), calcium ionophore A23187, interleukin-1 alpha (IL-1 alpha), prostaglandin E-2 (PGE-2), RS-66271 (a parathyroid hormone-related peptide analog), and platelet-derived growth factor-BB (PDGF-BB). Analyses of cell clones showed that IL-6 promoter expression was extremely low in the unstimulated state. Exposure to PTH (0.001-100 nM) for 12 h stimulated CAT expression in a dose-dependent manner (200-500% of control). Treatment with IL-1 alpha was more potent than PTH in inducing transcription of the IL-6 promoter (900-1,000%). Activation of the cAMP-PKA pathway by treatment with forskolin induced a comparable level of induction with PTH. Together, the effects of PTH and forskolin were additive. RS-66271, previously shown to have PTH-like effects, induced a comparable level of IL-6 promoter expression. When examined together, PTH+RS-66271 effects were comparable to PTH effects alone. Exposure to PGE-2, PMA, PDGF-BB, or A23187 for 12 h did not significantly alter IL-6 promoter expression. These results demonstrate PTH, forskolin, the PTHrP analog RS-66271, and IL-1 alpha stimulate IL-6 expression by stimulating gene transcription. The response to forskolin suggests that the messenger system mediated by PKA is sufficient to induce IL-6 expression.
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PMID:Parathyroid hormone (1-34)-mediated interleukin-6 induction. 932 32


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