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)

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

Parathyroid hormone (PTH), an anabolic agent for bone metabolism, has profound effects on gene expression in the osteoblast. Recently, we identified that amphiregulin (AR), an EGF-like ligand, is an immediate early gene for PTH treatment and has an important role in bone metabolism. In the present report, by using different PTH peptide fragments, protein kinase activators, and inhibitors, we have demonstrated that PTH regulates amphiregulin in a cAMP-protein kinase A (PKA)-dependent manner both in vitro and in vivo. We found that the phosphorylation of cAMP-response element (CRE)-binding protein (CREB) preceded AR transcription after PTH treatment. Moreover, luciferase reporter assays revealed that the binding of phosphorylated CREB to a conserved CRE site in the AR promoter plays an important role in basal, PTH-induced, and prostaglandin E2 (PGE2)-induced AR expression in osteoblastic cells. In summary, our data suggest that PTH-induced AR mRNA expression is mediated primarily through cAMP-PKA-CREB signaling.
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PMID:Stimulation of amphiregulin expression in osteoblastic cells by parathyroid hormone requires the protein kinase A and cAMP response element-binding protein signaling pathway. 1608 55

Parathyroid hormone (PTH) regulates calcium homeostasis via the type I PTH/PTH-related peptide (PTH/PTHrP) receptor (PTH1R). The purpose of the present study was to identify the contributions of distinct signaling mechanisms to PTH-stimulated activation of the mitogen-activated protein kinases (MAPK) ERK1/2. In Human embryonic kidney 293 (HEK293) cells transiently transfected with hPTH1R, PTH stimulated a robust increase in ERK activity. The time course of ERK1/2 activation was biphasic with an early peak at 10 min and a later sustained ERK1/2 activation persisting for greater than 60 min. Pretreatment of HEK293 cells with the PKA inhibitor H89 or the PKC inhibitor GF109203X, individually or in combination reduced the early component of PTH-stimulated ERK activity. However, these inhibitors of second messenger dependent kinases had little effect on the later phase of PTH-stimulated ERK1/2 phosphorylation. This later phase of ERK1/2 activation at 30-60 min was blocked by depletion of cellular beta-arrestin 2 and beta-arrestin 1 by small interfering RNA. Furthermore, stimulation of hPTH1R with PTH analogues, [Trp1]PTHrp-(1-36) and [d-Trp12,Tyr34]PTH-(7-34), selectively activated G(s)/PKA-mediated ERK1/2 activation or G protein-independent/beta-arrestin-dependent ERK1/2 activation, respectively. It is concluded that PTH stimulates ERK1/2 through several distinct signal transduction pathways: an early G protein-dependent pathway meditated by PKA and PKC and a late pathway independent of G proteins mediated through beta-arrestins. These findings imply the existence of distinct active conformations of the hPTH1R responsible for the two pathways, which can be stimulated by unique ligands. Such ligands may have distinct and valuable therapeutic properties.
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PMID:Distinct beta-arrestin- and G protein-dependent pathways for parathyroid hormone receptor-stimulated ERK1/2 activation. 1649 67

Parathyroid hormone (PTH) potently activates cAMP-protein kinase A (PKA)-driven molecular cascades in osteoblasts. The NR4A/NGFI-B orphan nuclear receptor (NR) Nurr1 is a PTH-induced, cAMP-responsive primary response gene (PRG) that transactivates osteocalcin (Ocn) expression through a putative NGFI-B response element (NBRE) in the proximal promoter. As a true orphan NR, Nurr1's expression level and coactivator recruitment regulate its transactivation capacity. We postulated that Nurr1's induction through cAMP-PKA signaling might favor a coactivator that is likewise cAMP-dependent. A possible candidate is the cAMP-inducible coactivator PPARgamma coactivator-1alpha (PGC-1alpha). We hypothesize that PGC-1alpha is a PTH-induced PRG that synergizes with Nurr1 to induce target gene transcription in osteoblasts. We show that 10 nM PTH for 2 h maximally induced PGC-1alpha mRNA in primary mouse osteoblasts (MOBs) and calvariae. Selective signaling agonists and antagonists demonstrated that PTH induced PGC-1alpha mRNA primarily through the cAMP-PKA pathway. Protein synthesis inhibition sustained PTH-induced PGC-1alpha expression. PGC-1alpha enhanced Nurr1-induced transactivation of a consensus 3xNBRE-luciferase construct and the rat (-1050)Ocn promoter-luciferase construct from 3.7- to 9.6- and 10.1-fold, respectively. This synergy required Nurr1-DNA binding, since a mutation of the Ocn promoter NBRE abolished both Nurr1- and Nurr1-PGC-1alpha-induced transactivation. Using GST pull-down assays, PGC-1alpha directly interacted with in vitro-generated and nuclear Nurr1. We conclude that PGC-1alpha is a PTH-induced, cAMP-dependent PRG that directly synergizes with Nurr1 to transactivate target genes in osteoblasts. Taken together with published data, our findings suggest that Nurr1 and PGC-1alpha may be pivotal mediators of cAMP-induced osteoblast gene expression and osteoblast function.
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PMID:PGC-1alpha is induced by parathyroid hormone and coactivates Nurr1-mediated promoter activity in osteoblasts. 1676 61

Parathyroid hormone-related peptide (PTHrP) is known to be a strong vasorelaxant peptide. The mechanisms by which PTHrP reduces the coronary resistance of the rat heart have not been worked out but seem to be independent of the classical PTH/PTHrP receptor-mediated, cAMP-dependent effect. In this study we hypothesized that PTHrP reduces the coronary resistance of the rat heart via endothelial cell hyperpolarization. Isolated microvascular endothelial cells from rat heart were incubated with PTHrP(1-36), and changes in the membrane potential were recorded via DiBAC fluorescence. Cells exposed to PTHrP showed a hyperpolarization of approximately 7mV. In the isolated Langendorff preparation, PTHrP-dependent vasodilatation of l-nitro-arginine-exposed hearts was abolished under depolarizing conditions (high potassium). Denudation of the endothelial cell layer significantly impaired the vasodilatory effect of PTHrP. In the presence of H89 (a cAMP/protein kinase A pathway antagonist) and indomethacin (a cyclooxygenase inhibitor), PTHrP dilated the vessels. In conclusion, PTHrP exerted a nitric oxide-independent vasodilatory effect that depends on endothelial cell hyperpolarization.
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PMID:N-terminal parathyroid hormone-related peptide hyperpolarizes endothelial cells and causes a reduction of the coronary resistance of the rat heart via endothelial hyperpolarization. 1680 82

Parathyroid hormone-related peptide (PTHrP) is known as an important local factor for chondrogenesis, promoting chondrocyte proliferation and inhibiting their differentiation into the hypertrophic phenotype. Signaling transduction through the PTH/PTHrP receptor has two possible pathways: the activation of adenylate cyclase and subsequent protein kinase A (PKA), and the activation of phospholipase C (PLC). Recent studies with mice carrying PTH/PTHrP receptor inactivated for PLC and chondrocyte-specific deletion of the G (s) gene have shown that cAMP/PKA signaling appears to stimulate chondrocyte proliferation and inhibit their differentiation, whereas PLC signaling enhanced chondrocyte differentiation and inhibited their proliferation. In a physiological state, cAMP/PKA signaling may predominate over PLC pathway. Also, Na(+)/H(+)exchanger regulatory factor 2 (NHERF2) has been reported to down-regulate adenylate cyclase activity, in a switch mechanism that results in signal transduction through the PLC pathway.
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PMID:[Histological function of PTHrP in cartilage]. 1681 85

Parathyroid hormone (PTH) stimulates ERK1/2 through both G-protein signaling and beta-arrestin2-mediated internalization. Beta-arrestin may serve as a scaffold for c-Src. However, the molecular mechanisms for ERK1/2 activation by PTH remain unclear. By using a targeted mutagenesis approach, we investigated the PTH/PTH-related protein receptor (PTH1R) structural determinants for ERK1/2 activation and transcriptional activity in HEK-293 cells. First, ERK1/2 activation was inhibited by PTH1R mutations that specifically abrogate G(q)-protein kinase C signaling without a decrease in cAMP-protein kinase A. Second, PTH1R C-terminal mutations and/or deletions that prevent interaction with beta-arrestin inhibited ERK1/2 activation. Similar results were obtained in HEK-293 cells co-expressing wild-type PTH1R and a dominant-negative beta-arrestin2. Third, the c-Src inhibitor PP2 and a kinase-dead c-SrcK295M mutant co-expressed with wild-type PTH1R both inhibited ERK1/2 activation. Furthermore, c-Src co-precipitated with both PTH1R and beta-arrestin2 in response to PTH. Deleting the PTH1R-proximal C terminus abolished these interactions. However, the need for receptor interaction with beta-arrestin to co-precipitate Src and activate ERK1/2 was obviated by expressing a constitutively active c-SrcY527A mutant, suggesting direct binding of activated Src to PTH1R. Subsequently, we identified and mutated to alanine four proline-rich motifs in the PTH1R distal C terminus, which resulted in loss of both c-Src and arrestin co-precipitation and significantly decreased ERK1/2 activation. These data delineate the multiple PTH1R structural determinants for ERK1/2 activation and newly identify a unique mechanism involving proline-rich motifs in the receptor C terminus for reciprocal scaffolding of c-Src and beta-arrestin2 with a class II G-protein-coupled receptor.
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PMID:Proline-rich motifs in the parathyroid hormone (PTH)/PTH-related protein receptor C terminus mediate scaffolding of c-Src with beta-arrestin2 for ERK1/2 activation. 1703 11

Parathyroid hormone (PTH) is a major regulatory factor in skeletal physiology. However, the molecular mechanism underlying the effects of PTH on bones has yet to be elucidated in detail. Recently, some reports have demonstrated the crucial role of bone vasculature with regard to bone density. Angiopoietin-1 (Ang-1), along with VEGF, has been established as a primary angiogenic regulatory agent. In this study, we have attempted to characterize the effects of PTH (1-34) on Ang-1 expression and signaling molecules, employing primary-cultured human osteoblast-like cells. Quiescent osteoblasts were exposed to PTH (1-34), after which Ang-1 expression was determined at the mRNA and protein levels. Reverse transcription-polymerase chain reaction (RT-PCR) analyses indicated that Ang-1 mRNA expression increased as the result of PTH (1-34) treatment. The expression of the Ang-1 protein was also augmented as the result of treatment with PTH (1-34). An adenylyl cyclase activator, forskolin, was shown to induce Ang-1 mRNA expression, whereas the protein kinase A inhibitor, H-89, blocked the PTH (1-34)-mediated expression of Ang-1 mRNA. These findings indicate that PTH (1-34)-mediated Ang-1 expression involves adenylyl cyclase-protein kinase A dependent signaling. Our observations also show that Ang-1 may perform a crucial role in the effects of PTH (1-34) on bones, possibly involving alterations in bone vasculature.
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PMID:Parathyroid hormone (1-34) augments angiopoietin-1 expression in human osteoblast-like cells. 1703 26

In the present study, we examined the role of Parathyroid hormone (PTH) on the c-Jun N-terminal kinase (JNK) 1/2 and p38 mitogen-activated protein kinase (MAPK) members of the MAPK family as it relates to ageing by measuring hormone-induced changes in their activity in enterocytes isolated from young (3 month old) and aged (24 month old) rats. Our results show that PTH induces a transient activation of JNK 1/2, peaking at 1 min (+threefold). The hormone also stimulates JNK 1/2 tyrosine phosphorylation, in a dose-dependent fashion, this effect being maximal at 10 nM. PTH-induced JNK 1/2 phosphorylation was suppressed by its selective inhibitor SP600125. Moreover, hormone-dependent activation of JNK 1/2 was dependent on calcium, since pretreatment of cells with BAPTA-AM or EGTA blocked PTH effects. With ageing, the response to PTH was significantly reduced. JNK basal protein expression was not different in the enterocytes from young and aged rats, however, basal protein phosphorylation increased with ageing. PTH did not stimulate, within 1-10 min, the basal activity and phosphorylation of p38 MAPK in rat intestinal cells. The hormone increased enterocyte DNA synthesis; the response was dose-dependent and decreased (-40%) with ageing. In agreement with the mitogenic role of the MAPK cascades, this effect was blocked by specific inhibitors of extracellular signal-regulated protein kinase (ERK) 1/2 and JNK 1/2. The results obtained in this work expand our knowledge on the mechanism of action of PTH in duodenal cells.
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PMID:PTH regulation of c-Jun terminal kinase and p38 MAPK cascades in intestinal cells from young and aged rats. 1712 84

Parathyroid hormone (PTH), the major systemic calcium-regulating hormone, has been linked to uremic vascular changes. Considering the possible deleterious action of PTH on vascular structures, it seemed logical to evaluate the impact of PTH on the receptor of advanced glycation end products (RAGE) and interleukin 6 (IL-6) mRNA and protein expression, taking into account that such parameters might be involved in the pathogenesis of vascular calcification, atherosclerosis, and/or arteriolosclerosis. Human umbilical vein cord endothelial cells (HUVEC) were stimulated for 24 h with 10(-12)-10(-10) mol/l PTH. The mRNA expression of RAGE and IL-6 was established by reverse transcriptase/PCR techniques. RAGE protein levels were determined by Western blot and IL-6 secretion was measured by ELISA. The pathways by which PTH may have an effect on HUVEC functions were evaluated. PTH (10(-11)-10(-10)mol/l) significantly increased RAGE mRNA and protein expression. PTH also significantly increased IL-6 mRNA expression without changes at protein levels. The addition of protein kinase (PKC or PKA) inhibitors or nitric oxide (NO) synthase inhibitors significantly reduced the RAGE and IL-6 mRNA expression and the RAGE protein expression. PTH stimulates the mRNA expressions of RAGE and IL-6 and the protein expression of RAGE. These stimulatory effects are probably through PKC and PKA pathways and are also NO dependent. Such data may explain the possible impact of PTH on the atherosclerotic and arteriosclerotic progression.
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PMID:Parathyroid hormone stimulates endothelial expression of atherosclerotic parameters through protein kinase pathways. 1719 Sep 8


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