scholarly journals Persistent Activation of Mitogen-Activated Protein Kinases p42 and p44 and ets-2 Phosphorylation in Response to Colony-Stimulating Factor 1/c-fms Signaling

1998 ◽  
Vol 18 (9) ◽  
pp. 5148-5156 ◽  
Author(s):  
Lindsay F. Fowles ◽  
Michele L. Martin ◽  
Lori Nelsen ◽  
Katryn J. Stacey ◽  
Douglas Redd ◽  
...  
Keyword(s):  
Map Kinase ◽  
Map Kinases ◽  
Kinase Inhibitor ◽  
Cell Types ◽  
Early Response ◽  
Colony Stimulating Factor ◽  
Conditional Expression ◽  
Mitogen Activated Protein ◽  
Upa Mrna ◽  
Stimulating Factor

ABSTRACT An antibody that specifically recognized phosphothreonine 72 in ets-2 was used to determine the phosphorylation status of endogenous ets-2 in response to colony-stimulating factor 1 (CSF-1)/c-fms signaling. Phosphorylation of ets-2 was detected in primary macrophages, cells that normally express c-fms, and in fibroblasts engineered to express human c-fms. In the former cells,ets-2 was a CSF-1 immediate-early response gene, and phosphorylated ets-2 was detected after 2 to 4 h, coincident with expression of ets-2 protein. In fibroblasts, ets-2 was constitutively expressed and rapidly became phosphorylated in response to CSF-1. In both cell systems, ets-2 phosphorylation was persistent, with maximal phosphorylation detected 8 to 24 h after CSF-1 stimulation, and was correlated with activation of the CSF-1 target urokinase plasminogen activator (uPA) gene. Kinase assays that used recombinant ets-2 protein as a substrate demonstrated that mitogen-activated protein (MAP) kinases p42 and p44 were constitutively activated in both cell types in response to CSF-1. Immune depletion experiments and the use of the MAP kinase kinase inhibitor PD98059 indicate that these two MAP kinases are the major ets-2 kinases activated in response to CSF-1/c-fms signaling. In the macrophage cell line RAW264, conditional expression of raf kinase induced ets-2 expression and phosphorylation, as well as uPA mRNA expression. Transient assays mapped ets/AP-1 response elements as critical for basal and CSF-1-stimulated uPA reporter gene activity. These results indicate that persistent activation of the raf/MAP kinase pathway by CSF-1 is necessary for both ets-2 expression and posttranslational activation in macrophages.

Hypertonicity activates MAP kinases and inhibits HCO 3 − absorption via distinct pathways in thick ascending limb

1998 ◽  
Vol 275 (4) ◽  
pp. F478-F486 ◽  
Author(s):  
Bruns A. Watts ◽  
John F. Di Mari ◽  
Roger J. Davis ◽  
David W. Good
Keyword(s):  
Map Kinase ◽  
Map Kinases ◽  
Kinase Inhibitor ◽  
Early Response ◽  
P38 Map Kinase ◽  
Renal Tubules ◽  
Thick Ascending Limb ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Erk Activity

Mitogen-activated protein (MAP) kinases are activated by osmotic stress in a variety of cells, but their function and regulation in renal tubules is poorly understood. The present study was designed to examine the osmotic regulation of MAP kinases in the medullary thick ascending limb (MTAL) of the rat and to determine their possible role in the hyperosmotic inhibition of[Formula: see text] absorption in this segment. Tissues from the inner stripe of the outer medulla and microdissected MTALs were incubated at 37°C in control (290 mosmol/kgH2O) or hyperosmotic (300 mM added mannitol) solution for 15 min. Activities of extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38 MAP kinase were then measured using immune complex assays. Hyperosmolality increased p38 MAP kinase activity (2.3-fold) and ERK activity (2.0-fold) but had no effect on JNK activity (1.1-fold). Exposure to hyperosmolality for various times showed that the activation of p38 MAP kinase was rapid (≤5 min) and was sustained for up to 60 min, whereas the activation of ERK was transient (ERK activity peaked at 15 min, then declined to basal levels at 30 min). Pretreatment with the MAP kinase kinase inhibitor PD98059 (15 μM) blocked the hyperosmotic activation of p38 MAP kinase and ERK but did not prevent hyperosmotic inhibition of[Formula: see text] absorption. These results show that hyperosmolality differentially activates p38 MAP kinase and ERK in the MTAL. In contrast, we found no evidence for involvement of JNK in the early response to hyperosmotic stress. Eliminating the activation of p38 MAP kinase and ERK does not prevent hyperosmotic inhibition of [Formula: see text]absorption, suggesting that hyperosmolality inhibits apical membrane Na+/H+exchange (NHE3) activity via a signaling pathway distinct from these MAP kinase pathways.

scholarly journals Insulin signal transduction in rat small intestine: role of MAP kinases in expression of mucosal hydrolases

2001 ◽  
Vol 280 (2) ◽  
pp. G229-G240 ◽  
Author(s):  
Soheila Marandi ◽  
Nadine De Keyser ◽  
Alain Saliez ◽  
Anne-Sophie Maernoudt ◽  
Etienne Marc Sokal ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Map Kinase ◽  
Insulin Receptor ◽  
Map Kinases ◽  
Kinase Inhibitor ◽  
Protein Kinase B ◽  
Insulin Signal Transduction ◽  
Mitogen Activated Protein ◽  
Src Homology ◽  
Mucosal Mass

The postreceptor events regulating the signal of insulin downstream in rat intestinal cells have not yet been analyzed. Our objectives were to identify the nature of receptor substrates and phosphorylated proteins involved in the signaling of insulin and to investigate the mechanism(s) by which insulin enhances intestinal hydrolases. In response to insulin, the following proteins were rapidly phosphorylated on tyrosine residues: 1) insulin receptor substrates-1 (IRS-1), -2, and -4; 2) phospholipase C-isoenzyme-γ; 3) the Ras-GTPase-activating protein (GAP) associated with Rho GAP and p62Src; 4) the insulin receptor β-subunit; 5) the p85 subunits of phosphatidylinositol 3-kinase (PI 3-kinase); 6) the Src homology 2 α-collagen protein; 7) protein kinase B; 8) mitogen-activated protein (MAP) kinase-1 and -2; and 9) growth receptor-bound protein-2. Compared with controls, insulin enhanced the intestinal activity of MAP kinase-2 and protein kinase B by two- and fivefold, respectively, but did not enhance p70/S6 ribosomal kinase. Administration of an antireceptor antibody or MAP-kinase inhibitor PD-98059 but not a PI 3-kinase inhibitor (wortmannin) to sucklings inhibited the effects of insulin on mucosal mass and enzyme expression. We conclude that normal rat enterocytes express all of the receptor substrates and mediators involved in different insulin signaling pathways and that receptor binding initiates a signal enhancing brush-border membrane hydrolase, which appears to be regulated by the cascade of MAP kinases but not by PI 3-kinase.

scholarly journals Activation of mitogen-activated protein kinase by heat shock treatment in Drosophila

1995 ◽  
Vol 312 (2) ◽  
pp. 341-349 ◽  
Author(s):  
F Chen ◽  
M Torres ◽  
R F Duncan
Keyword(s):  
Heat Shock ◽  
Map Kinase ◽  
Tyrosine Phosphorylation ◽  
Map Kinases ◽  
Early Response ◽  
Shock Treatment ◽  
Mitogen Activated Protein Kinase ◽  
Heat Shock Treatment ◽  
Kinase Activation ◽  
Mitogen Activated Protein

Heat shock treatment of Drosophila melanogaster tissue culture cells causes increased tyrosine phosphorylation of several 44 kDa proteins, which are identified as Drosophila mitogen-activated protein (MAP) kinases. Tyrosine phosphorylation occurs within 5 min, and is maintained at high levels during heat shock. It decreases to basal levels during recovery, concurrent with the repression of heat shock transcription and heat-shock-protein synthesis. The increased MAP kinase tyrosine phosphorylation is parallelled by increased MAP kinase activity. At least two MAP kinases, DmERK-A and DmERK-B, are identified whose tyrosine phosphorylation increases during heat shock. Thus MAP kinase activation is an immediate early response to heat shock, and its increased activity is maintained throughout heat shock treatment. Protracted MAP kinase activation may contribute to heat shock transcription factor phosphorylation and the numerous metabolic alterations that constitute the heat-shock response.

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 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.

scholarly journals Imbalanced gp130-Dependent Signaling in Macrophages Alters Macrophage Colony-Stimulating Factor Responsiveness via Regulation of c-fms Expression

2004 ◽  
Vol 24 (4) ◽  
pp. 1453-1463 ◽  
Author(s):  
Brendan J. Jenkins ◽  
Dianne Grail ◽  
Melissa Inglese ◽  
Cathy Quilici ◽  
Steven Bozinovski ◽  
...  
Keyword(s):  
Map Kinase ◽  
Tyrosine Phosphorylation ◽  
Colony Formation ◽  
Gene Activation ◽  
Colony Stimulating Factor ◽  
Mitogen Activated Protein ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
The Individual ◽  
Stimulating Factor

ABSTRACT The mechanisms by which interleukin-6 (IL-6) family cytokines, which utilize the common receptor signaling subunit gp130, influence monocyte/macrophage development remain unclear. Here we have utilized macrophages devoid of either gp130-dependent STAT1/3 (gp130ΔSTAT/ΔSTAT) or extracellular signal-regulated kinases 1 and 2 (ERK1/2) mitogen-activated protein (MAP) kinase (gp130Y757F/Y757F) activation to assess the individual contribution of each pathway to macrophage formation. While the inhibition by IL-6 of macrophage colony-stimulating factor (M-CSF)-induced colony formation observed in gp130wt/wt mice was abolished in gp130ΔSTAT/ΔSTAT mice, inhibition of macrophage colony formation was enhanced in gp130Y757F/Y757F mice. In gp130ΔSTAT/ΔSTAT bone marrow-derived macrophages (BMMs), both IL-6- and M-CSF-induced ERK1/2 tyrosine phosphorylation was enhanced. By contrast, tyrosine phosphorylation of ERK1/2 in response to M-CSF was reduced in gp130Y757F/Y757F BMMs, and the pattern of ERK1/2 activation in gp130 mutant BMMs correlated with their opposing responsiveness to M-CSF-induced proliferation. When compared to the level of expression in gp130wt/wt BMMs, c-fms expression was elevated in gp130ΔSTAT/ΔSTAT BMMs but reduced in gp130Y757F/Y757F BMMs. Finally, an ERK1/2 inhibitor suppressed M-CSF-induced BMM proliferation, and this result corresponded to a reduction in c-fms expression. Collectively, these results provide a functional and causal correlation between gp130-dependent ERK MAP kinase signaling and c-fms gene activation, a finding that provides a potential mechanism underlying the inhibition of M-CSF-dependent macrophage development by IL-6 family cytokines in mice.

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.

scholarly journals Listeria monocytogenes, an invasive bacterium, stimulates MAP kinase upon attachment to epithelial cells.

1994 ◽  
Vol 5 (4) ◽  
pp. 455-464 ◽  
Author(s):  
P Tang ◽  
I Rosenshine ◽  
B B Finlay
Keyword(s):  
Listeria Monocytogenes ◽  
Epithelial Cells ◽  
Map Kinase ◽  
Tyrosine Phosphorylation ◽  
Map Kinases ◽  
Kinase Inhibitor ◽  
Signal Transduction Pathway ◽  
Host Cells ◽  
Kinase Activation ◽  
Mitogen Activated Protein

Protein tyrosine phosphorylation is an important regulatory mechanism for many cellular processes in eucaryotic cells. During the invasion of the gram-positive pathogen, Listeria monocytogenes, into host epithelial cells, two host proteins become tyrosine phosphorylated. We have identified these major tyrosine phosphorylated species to be two isoforms of mitogen-activated protein (MAP) kinase, the 42 and 44 kDa MAP kinases. This activation begins within 5 to 15 min of bacterial infection. The tyrosine kinase inhibitor, genistein, blocks invasion as well as the tyrosine phosphorylation of these MAP kinases. Using cytochalasin D to block bacterial internalization but not adhesion, we showed that bacterial adherence rather than uptake is required for MAP kinase activation. Internalin mutants, which are unable to adhere efficiently to host cells, do not trigger MAP kinase activation. Other invasive bacteria, including enteropathogenic Escherichia coli (EPEC), and E. coli expressing Yersinia enterocolitica invasion, were not observed to activate MAP kinase during invasion into cultured epithelial cells. These results suggest that L. monocytogenes activates MAP kinase during invasion and a MAP kinase signal transduction pathway may be involved in mediating bacterial uptake.

Evidence for the role of p38 MAP kinase in hypoxia-induced pulmonary vasoconstriction

2002 ◽  
Vol 283 (4) ◽  
pp. L859-L866 ◽  
Author(s):  
M. R. Karamsetty ◽  
J. R. Klinger ◽  
N. S. Hill
Keyword(s):  
Map Kinase ◽  
Map Kinases ◽  
Kinase Inhibitor ◽  
Acute Hypoxia ◽  
Pulmonary Arteries ◽  
P38 Map Kinase ◽  
Pulmonary Vasoconstriction ◽  
Protein Map ◽  
Mitogen Activated Protein

Mitogen-activated protein (MAP) kinases regulate smooth muscle cell contraction. Hypoxia contracts pulmonary arteries by mechanisms that are incompletely understood. We hypothesized that hypoxic contraction of pulmonary arteries involves activation of the MAP kinases. To test this hypothesis, we studied the effects of SB-202190, a p38 MAP kinase inhibitor, PD-98059 and UO-126, two structurally different MEKK inhibitors, and anisomycin, a stimulator of p38 MAP kinase on acute hypoxia-induced contraction in rat conduit pulmonary artery rings precontracted with phenylephrine or KCl. Hypoxia induced a transient contraction, followed by a relaxation, and then a slowly developing sustained contraction. Hypoxia also significantly increased phosphorylation of p38 MAP kinase. SB-202190 did not affect the transient phase but abrogated the sustained phase of hypoxic contraction, whereas anisomycin enhanced both phases of contraction. SB-202190 also attenuated and anisomycin enhanced the phenylephrine-induced contraction. In contrast, PD-98059 and UO-126 had minimal effects on either hypoxic or phenylephrine-induced contraction. None of the treatments modified KCl-induced contraction. We conclude that p38, but not the ERK1/ERK2 MAP kinase pathway, mediates the sustained phase of hypoxic contraction in isolated rat pulmonary arteries.

scholarly journals Proliferative but not nonproliferative responses to granulocyte colony- stimulating factor are associated with rapid activation of the p21ras/MAP kinase signalling pathway

Blood ◽  
1994 ◽  
Vol 83 (4) ◽  
pp. 949-957 ◽  
Author(s):  
A Bashey ◽  
L Healy ◽  
CJ Marshall
Keyword(s):  
Map Kinase ◽  
Cell Line ◽  
Map Kinases ◽  
Human Neutrophils ◽  
Target Cells ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Granulocytic Differentiation ◽  
Rapid Activation ◽  
Stimulating Factor

Abstract Granulocyte colony-stimulating factor (G-CSF) can elicit responses that include proliferation, granulocytic differentiation, and activation of cellular functions in target cells. The biochemical pathways responsible for transduction of these signals from the G-CSF receptor (G-CSFR) have not been defined. In this report, we show that, in murine (NFS-60) and human (OCI-AML 1) myeloid leukemia cell lines and in murine pro-B-lymphocytic cells, BAF/B03, transfected with the murine G- CSFR, proliferative responses to G-CSF are associated with rapid activation of p42 and p44 MAP kinases and p21ras. Truncation of the cytoplasmic portion of the murine G-CSFR at residue 646 but not at residue 739 abolished G-CSF-induced stimulation of cellular proliferation as well as activation of MAP kinase and p21ras in transfected BAF/B03 cells. G-CSF-induced granulocytic differentiation of the murine leukemic cell line 32DC13(G) occurred in the absence of detectable activation of p42 MAP kinase. Nonproliferative responses to G-CSF in the human promyelocytic cell line HL-60 and in human neutrophils were similarly associated with no MAP kinase activation. These results imply that differing cellular effects of G-CSF may be involve the recruitment of differing signal transduction pathways with the p21ras/MAP kinase pathway being limited to proliferative responses.

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