PTHrP stimulated by the calcium-sensing receptor requires MAP kinase activation

2003 ◽  
Vol 284 (2) ◽  
pp. E435-E442 ◽  
Author(s):  
R. John MacLeod ◽  
Naibedya Chattopadhyay ◽  
Edward M. Brown
Keyword(s):  
Map Kinase ◽  
Map Kinases ◽  
Kinase Inhibitor ◽  
Hormone Secretion ◽  
P38 Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Humoral Hypercalcemia Of Malignancy ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Hek Cells

Increases in extracellular calcium concentration ([Ca2+]o) stimulate from normal and malignant cells secretion of parathroid hormone-related protein (PTHrP), a major mediator of humoral hypercalcemia of malignancy. Because the calcium-sensing receptor (CaR) is a determinant of calcium-regulated hormone secretion, we examined whether HEK cells stably transfected with human CaR secreted PTHrP in response to CaR stimulation. Increases in [Ca2+]o or neomycin and Gd3+ all substantially increased PTHrP secretion in CaR-HEK cells but had no effect on nontransfected cells. CaR activation likewise increased PTHrP transcripts. PD-098059 and U-0126, inhibitors of the mitogen-activated protein kinase kinase MEK1/2, abolished CaR-stimulated secretion but had no effect on basal secretion. An inhibitor of p38 MAP kinase, SB-203580, also attenuated CaR-stimulated secretion. Western analysis revealed that CaR activation caused a robust increase in MEK1/2 and p38 MAP kinase phosphorylation. A Src family kinase inhibitor, PP2, blocked both basal and CaR-stimulated secretion. We conclude that CaR specifically mediates the effect of increasing [Ca2+]o on PTHrP synthesis and secretion and that activated MEK1/2 and p38 MAP kinases are determinants of the CaR's stimulation of PTHrP secretion.

Coupling of M2 muscarinic receptors to ERK MAP kinases and caldesmon phosphorylation in colonic smooth muscle

2000 ◽  
Vol 278 (3) ◽  
pp. G429-G437 ◽  
Author(s):  
Amy K. Cook ◽  
Michael Carty ◽  
Cherie A. Singer ◽  
Ilia A. Yamboliev ◽  
William T. Gerthoffer
Keyword(s):  
Smooth Muscle ◽  
Map Kinase ◽  
Muscarinic Receptors ◽  
Map Kinases ◽  
Kinase Inhibitor ◽  
Receptor Activation ◽  
Inhibitory Effect ◽  
Subsequent Treatment ◽  
P38 Map Kinase

Coupling of M2 and M3 muscarinic receptors to activation of mitogen-activated protein (MAP) kinases and phosphorylation of caldesmon was studied in canine colonic smooth muscle strips in which M3 receptors were selectively inactivated by N, N-dimethyl-4-piperidinyl diphenylacetate (4-DAMP) mustard (40 nM). ACh elicited activation of extracellular signal-regulated kinase (ERK) 1, ERK2, and p38 MAP kinases in control muscles and increased phosphorylation of caldesmon (Ser789), a putative downstream target of MAP kinases. Alkylation of M3 receptors with 4-DAMP had only a modest inhibitory effect on ERK activation, p38 MAP kinase activation, and caldesmon phosphorylation. Subsequent treatment with 1 μM AF-DX 116 completely prevented activation of ERK and p38 MAP kinase and prevented caldesmon phosphorylation. Caldesmon phosphorylation was blocked by the MAP kinase/ERK kinase inhibitor PD-98509 but not by the p38 MAP kinase inhibitor SB-203580. These results indicate that colonic smooth muscle M2 receptors are coupled to ERK and p38 MAP kinases. Activation of ERK, but not p38 MAP kinases, results in phosphorylation of caldesmon in vivo, which is a novel function for M2receptor activation in smooth muscle.

scholarly journals Separating myoblast differentiation from muscle cell fusion using IGF-I and the p38 MAP kinase inhibitor SB202190

2015 ◽  
Vol 309 (7) ◽  
pp. C491-C500 ◽  
Author(s):  
Samantha Gardner ◽  
Sean M. Gross ◽  
Larry L. David ◽  
John E. Klimek ◽  
Peter Rotwein
Keyword(s):  
Growth Factor ◽  
Map Kinase ◽  
Cell Fusion ◽  
Muscle Cell ◽  
Map Kinases ◽  
Kinase Inhibitor ◽  
P38 Map Kinase ◽  
Myoblast Differentiation ◽  
Igf I ◽  
Muscle Biology

The p38 MAP kinases play critical roles in skeletal muscle biology, but the specific processes regulated by these kinases remain poorly defined. Here we find that activity of p38α/β is important not only in early phases of myoblast differentiation, but also in later stages of myocyte fusion and myofibrillogenesis. By treatment of C2 myoblasts with the promyogenic growth factor insulin-like growth factor (IGF)-I, the early block in differentiation imposed by the p38 chemical inhibitor SB202190 could be overcome. Yet, under these conditions, IGF-I could not prevent the later impairment of muscle cell fusion, as marked by the nearly complete absence of multinucleated myofibers. Removal of SB202190 from the medium of differentiating myoblasts reversed the fusion block, as multinucleated myofibers were detected several hours later and reached ∼90% of the culture within 30 h. Analysis by quantitative mass spectroscopy of proteins that changed in abundance following removal of the inhibitor revealed a cohort of upregulated muscle-enriched molecules that may be important for both myofibrillogenesis and fusion. We have thus developed a model system that allows separation of myoblast differentiation from muscle cell fusion and should be useful in identifying specific steps regulated by p38 MAP kinase-mediated signaling in myogenesis.

Regulation of a Ca2+-activated K+ channel by calcium-sensing receptor involves p38 MAP kinase

2004 ◽  
Vol 75 (4) ◽  
pp. 491-498 ◽  
Author(s):  
Chian Ping Ye ◽  
Shozo Yano ◽  
Jacob Tfelt-Hansen ◽  
R. John MacLeod ◽  
Xianghui Ren ◽  
...  
Keyword(s):  
Map Kinase ◽  
P38 Map Kinase ◽  
K Channel ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

Spontaneous shift in transcriptional profile of explanted glomeruli via activation of the MAP kinase family

2000 ◽  
Vol 279 (5) ◽  
pp. F954-F959 ◽  
Author(s):  
Yoshihisa Ishikawa ◽  
Tsuneo Konta ◽  
Masanori Kitamura
Keyword(s):  
Gene Expression ◽  
Map Kinase ◽  
Map Kinases ◽  
Kinase Inhibitor ◽  
Ex Vivo ◽  
P38 Map Kinase ◽  
Transcriptional Profile ◽  
Activator Protein 1 ◽  
Monocyte Chemoattractant Protein 1 ◽  
Mitogen Activated Protein

To understand how isolation and explantation of glomeruli affect the function of resident cells, the present study investigated the transcriptional profile of explanted normal glomeruli. We found that ex vivo incubation of glomeruli spontaneously expressed monocyte chemoattractant protein-1 (MCP-1) and stromelysin, the genes regulated by activator protein-1 (AP-1). The expression was suppressed by heparin and quercetin, the drugs with anti-AP-1 activities. The gene expression was preceded by 1) induction of AP-1 components c- fos and c- jun and 2) phosphorylation of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein (MAP) kinase, and c-Jun NH2-terminal kinase (JNK), the upstream inducers/activators of AP-1. Suppression of ERK by PD098059 abrogated induction of c- fos and c- jun, and the p38 MAP kinase inhibitor SB203580 attenuated c- fos expression. Furthermore, treatment with either PD098059, SB203580, or the JNK-AP-1 inhibitor curcumin diminished the expression of MCP-1 and stromelysin. The transcriptional profile of glomerular cells thus alters dramatically after explantation of glomeruli. It is, at least in part, due to activation of multiple MAP kinases that lead to induction of AP-1-dependent gene expression.

scholarly journals Negative Feedback Regulation of MKK6 mRNA Stability by p38α Mitogen-Activated Protein Kinase

2003 ◽  
Vol 23 (1) ◽  
pp. 370-381 ◽  
Author(s):  
Concetta Ambrosino ◽  
Gaetane Mace ◽  
Stefanie Galban ◽  
Cornelius Fritsch ◽  
Kristina Vintersten ◽  
...  
Keyword(s):  
Map Kinase ◽  
Map Kinases ◽  
P38 Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Hek293 Cells ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Negative Feedback Regulation ◽  
Mitogen Activated Protein ◽  
The Stability

ABSTRACT p38 mitogen-activated protein (MAP) kinases play an important role in the regulation of cellular responses to all kinds of stresses. The most abundant and broadly expressed p38 MAP kinase is p38α, which can also control the proliferation, differentiation, and survival of several cell types. Here we show that the absence of p38α correlates with the up-regulation of one of its upstream activators, the MAP kinase kinase MKK6, in p38α−/− knockout mice and in cultured cells derived from them. In contrast, the expression levels of the p38 activators MKK3 and MKK4 are not affected in p38α-deficient cells. The increase in MKK6 protein concentration correlates with increased amounts of MKK6 mRNA in the p38α−/− cells. Pharmacological inhibition of p38α also up-regulates MKK6 mRNA levels in HEK293 cells. Conversely, reintroduction of p38α into p38α−/− cells reduces the levels of MKK6 protein and mRNA to the normal levels found in wild-type cells. Moreover, we show that the MKK6 mRNA is more stable in p38α−/− cells and that the 3′untranslated region of this mRNA can differentially regulate the stability of the lacZ reporter gene in a p38α-dependent manner. Our data indicate that p38α can negatively regulate the stability of the MKK6 mRNA and thus control the steady-state concentration of one of its upstream activators.

scholarly journals Sphingosine 1-phosphate stimulates proliferation and migration of human endothelial cells possibly through the lipid receptors, Edg-1 and Edg-3

2000 ◽  
Vol 348 (1) ◽  
pp. 71-76 ◽  
Author(s):  
Takao KIMURA ◽  
Tomoko WATANABE ◽  
Koichi SATO ◽  
Junko KON ◽  
Hideaki TOMURA ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Migration ◽  
Dna Synthesis ◽  
Map Kinase ◽  
Kinase Inhibitor ◽  
P38 Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Sphingosine 1 Phosphate ◽  
And Migration ◽  
Proliferation And Migration

Sphingosine 1-phosphate (S1P) stimulates thymidine incorporation (DNA synthesis), cell growth and cell migration in human aortic endothelial cells (HAECs). The extent of the S1P-induced responses are comparable to those stimulated by vascular endothelial growth factor, one of the most potent stimulators of angiogenesis. These responses to S1P were mimicked by dihydrosphingosine 1-phosphate, an S1P receptor agonist, and inhibited by pertussis toxin (PTX), an inactivator of Gi/Go-proteins. S1P also induced activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAP kinase). The activation of these enzymes was inhibited again by PTX and also by suramin, a non-selective receptor antagonist. S1P-induced DNA synthesis and ERK activation were inhibited by PD98059, an ERK kinase inhibitor, but not by SB203580, a p38 MAP kinase inhibitor. In contrast, cell migration and p38 MAP kinase activation, in response to S1P, were inhibited by SB203580 but not by PD98059. In HAECs, high-affinity S1P binding activity and expression of Edg-1 and Edg-3 mRNA were detected. These results suggest that S1P might be a novel angiogenesis factor and that the lipid-induced proliferation and migration of endothelial cells are possibly mediated through cell-surface S1P receptors, Edg-1 and Edg-3, which are linked to signalling pathways.

scholarly journals A Conserved p38 Mitogen-Activated Protein Kinase Pathway Regulates Drosophila Immunity Gene Expression

1998 ◽  
Vol 18 (6) ◽  
pp. 3527-3539 ◽  
Author(s):  
Zhiqiang Stanley Han ◽  
Hervé Enslen ◽  
Xiaodi Hu ◽  
Xiangjun Meng ◽  
I-Huan Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Map Kinase ◽  
Map Kinases ◽  
P38 Map Kinase ◽  
Insect Immunity ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Peptide Gene ◽  
Kinase Pathway

ABSTRACT Accumulating evidence suggests that the insect and mammalian innate immune response is mediated by homologous regulatory components. Proinflammatory cytokines and bacterial lipopolysaccharide stimulate mammalian immunity by activating transcription factors such as NF-κB and AP-1. One of the responses evoked by these stimuli is the initiation of a kinase cascade that leads to the phosphorylation of p38 mitogen-activated protein (MAP) kinase on Thr and Tyr within the motif Thr-Gly-Tyr, which is located within subdomain VIII. We have investigated the possible involvement of the p38 MAP kinase pathway in the Drosophila immune response. Two genes that are highly homologous to the mammalian p38 MAP kinase were molecularly cloned and characterized. Furthermore, genes that encode two novelDrosophila MAP kinase kinases, D-MKK3 and D-MKK4, were identified. D-MKK3 is an efficient activator of bothDrosophila p38 MAP kinases, while D-MKK4 is an activator of D-JNK but not D-p38. These data establish that Drosophilaindeed possesses a conserved p38 MAP kinase signaling pathway. We have examined the role of the D-p38 MAP kinases in the regulation of insect immunity. The results revealed that one of the functions of D-p38 is to attenuate antimicrobial peptide gene expression following exposure to lipopolysaccharide.

scholarly journals Mitogen-activated protein kinase p38 modulates pacemaker ion channels differentiation in P19-derived pluripotent cells

2020 ◽  
Vol 70 (1) ◽  
Author(s):  
Mingqi Zheng ◽  
Lin Kang ◽  
Tomoko Uchino ◽  
Gang Liu ◽  
Yan Wang ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Ion Channels ◽  
Map Kinase ◽  
Kinase Inhibitor ◽  
Cardiac Pacemaker ◽  
P38 Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Pluripotent Cells ◽  
Intracellular Signals ◽  
Mitogen Activated Protein

Abstract Signal regulators during early cardiogenetic differentiation for the cellular automaticity are largely unknown. Our investigations were designed to clarify the role of transcription factors and their modulators in P19-derived cardiomyocytes to the expression of cardiac pacemaker ion channels. Transcription factors Csx/Nkx2.5 and GATA4 but not MEF2C were markedly inhibited by p38 MAP kinase inhibition in a distinct manner; expression but not phosphorylation of GATA4 was reduced by inhibition of p38 MAP kinase actions. In the presence of an ERK1/2,5 inhibitor PD98059 or a JNK MAP kinase inhibitor SP600125, P19 cells successfully differentiated into cardiomyocytes displaying spontaneous beatings with expression of three types of pacemaker ion channels. We demonstrate that acquisition of cellular automaticity and the expression of pacemaker ion channels are regulated by the transcription factors, Csx/Nkx2.5 and GATA4, through intracellular signals including p38 MAP kinase in the process of P19-derived pluripotent cells differentiation into cardiomyocytes.

scholarly journals Effect of lipopolysaccharide on mitogen-activated protein kinases and cytosolic phospholipase A2

1995 ◽  
Vol 308 (3) ◽  
pp. 815-822 ◽  
Author(s):  
S I Fouda ◽  
T F P Molski ◽  
M S E Ashour ◽  
R I Sha′afi
Keyword(s):  
Phospholipase A2 ◽  
Map Kinase ◽  
Map Kinases ◽  
Kinase Inhibitor ◽  
Cytosolic Phospholipase A2 ◽  
Mitogen Activated Protein Kinase ◽  
Human Neutrophils ◽  
Cytosolic Phospholipase ◽  
Low Concentrations ◽  
Mitogen Activated Protein

The addition of platelet-activating factor (PAF) to human neutrophils increases phosphorylation on tyrosine residues and stimulates the activity of p42erk2 mitogen-activated protein kinase (MAP kinase). This action is rapid and transient. In contrast, p42erk2, p44erk1 and the p40hera MAP kinase isoforms are all not tyrosine phosphorylated or activated in human neutrophils stimulated with low concentrations of lipopolysaccharide (LPS) in combination with serum. In spite of this, the PAF-induced tyrosine phosphorylation and activation of the p42erk2 MAP kinase are greatly potentiated in cells pretreated with LPS. More interestingly, although low concentrations of LPS do not affect MAP kinase isoforms in these cells, they cause the phosphorylation of cytosolic phospholipase A2 (cPLA2), as evidenced by a decrease in the electrophoretic mobility of the enzyme. In addition, this stimulus-induced upward shift in the mobility of the enzyme is not inhibited by the tyrosine kinase inhibitor, genistein. Furthermore, LPS increases the release of arachidonic acid in control and PAF-stimulated human neutrophils. These observations clearly show that cPLA2 can be phosphorylated and activated by kinases other than the currently known MAP kinases. It is proposed that there are MAP kinase-dependent and -independent mechanisms for the phosphorylation of cPLA2.

SAPKs regulation of ischemic preconditioning

2000 ◽  
Vol 279 (3) ◽  
pp. H901-H907 ◽  
Author(s):  
Motoaki Sato ◽  
Gerald A. Cordis ◽  
Nilanjana Maulik ◽  
Dipak K. Das
Keyword(s):  
Map Kinase ◽  
Map Kinases ◽  
Kinase Inhibitor ◽  
Signal Transduction Pathway ◽  
P38 Map Kinase ◽  
Kinase Activation ◽  
Protein Levels ◽  
Rat Hearts ◽  
Mitogen Activated Protein ◽  
Sb 203580

The role of stress-activated protein kinases (SAPKs), c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase, in preconditioning (PC) was examined with the use of isolated rat hearts subjected to four cyclic episodes of 5-min ischemia and 10-min reperfusion followed by 30-min ischemia and 2-h reperfusion (I/R). A group of hearts was preperfused with 100 μM curcumin, a c-Jun and JNK1 inhibitor, or 5 μM SB 203580, a p38 MAP kinase inhibitor. Another group of hearts was preperfused with 20 μM anisomycin, a stimulator for both JNK and p38 MAP kinases. I/R increased the protein levels of JNK1, c-Jun, and p38 MAP kinase. PC also enhanced the induction of these kinases, but subsequent I/R-mediated increase was blocked by PC. Curcumin blocked I/R- and PC-mediated increase in JNK1 and c-Jun protein levels, whereas it had no effects on p38 MAP kinase. SB 203580, on the other hand, was equally effective in reducing the p38 MAP kinase activation but exerted no effects on JNK1 and c-Jun induction. I/R-mediated increased myocardial infarction was reduced by any of the following compounds: anisomycin, curcumin, and SB 203580. The cardioprotective effects of PC were abolished by either curcumin or SB 203580. The results demonstrate that PC is mediated by a signal-transduction pathway involving both JNK1 and p38 MAP kinase. Activation of SAPKs, although transient, is obligatory for PC.

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