scholarly journals Identification of Mitogen-activated Protein (MAP) Kinase-activated Protein Kinase-3, a Novel Substrate of CSBP p38 MAP Kinase

1996 ◽  
Vol 271 (14) ◽  
pp. 8488-8492 ◽  
Author(s):  
Megan M. McLaughlin ◽  
Sanjay Kumar ◽  
Peter C. McDonnell ◽  
Stephanie Van Horn ◽  
John C. Lee ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Map Kinase ◽  
P38 Map Kinase ◽  
Protein Map ◽  
Mitogen Activated Protein

Incretins Enhance PGF2α-Induced Synthesis of IL-6 and Osteoprotegerin in Osteoblasts

2022 ◽  
Vol 54 (01) ◽  
pp. 42-49
Author(s):  
Tomoyuki Hioki ◽  
Gen Kuroyanagi ◽  
Kazuhiko Fujita ◽  
Go Sakai ◽  
Tetsu Kawabata ◽  
...  
Keyword(s):  
Map Kinase ◽  
Prostaglandin F2α ◽  
P38 Map Kinase ◽  
Β Cells ◽  
Kinase C ◽  
Protein Map ◽  
Mitogen Activated Protein ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

AbstractIncretins including glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), which are secreted from the small intestine after oral food ingestion, are currently well-known to stimulate insulin secretion from pancreatic β-cells and used for the treatment of type 2 diabetes mellitus. We have previously reported that prostaglandin F2α (PGF2α) stimulates the synthesis of interleukin-6 (IL-6) and osteoprotegerin in osteoblast-like MC3T3-E1 cells, and that IL-6 and osteoprotegerin release are mediated through the p44/p42 mitogen-activated protein (MAP) kinase, p38 MAP kinase or stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) pathways. In the present study, we investigated the effects of incretins including GLP-1 and GIP, on the PGF2α-induced synthesis of IL-6 and osteoprotegerin and examined the detailed mechanism in osteoblast-like MC3T3-E1 cells. We found that GIP and GLP-1 significantly stimulated the PGF2α-induced synthesis of IL-6 in osteoblast-like MC3T3-E1 cells. In addition, GIP and GLP-1 significantly enhanced the PGF2α-induced mRNA expression levels of IL-6. On the other hand, GIP and GLP-1 markedly stimulated the PGF2α-induced synthesis of osteoprotegerin. However, the phosphorylation of p44/p42 MAP kinase, p38 MAP kinase, or JNK induced by PGF2α was not affected by GIP or GLP-1. Therefore, these results strongly suggest that incretins enhance the PGF2α-induced synthesis of IL-6 and osteoprotegerin in osteoblast-like MC3T3-E1 cells. However, these syntheses are not mediated through p44/p42 MAP kinase, p38 MAP kinase, or JNK pathways.

scholarly journals Role of MLK3 in the Regulation of Mitogen-Activated Protein Kinase Signaling Cascades

2005 ◽  
Vol 25 (9) ◽  
pp. 3670-3681 ◽  
Author(s):  
Deborah Brancho ◽  
Juan-Jose Ventura ◽  
Anja Jaeschke ◽  
Beth Doran ◽  
Richard A. Flavell ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Map Kinase ◽  
Selective Reduction ◽  
P38 Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Signaling Cascades ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Jnk Activation ◽  
Protein Kinase Signaling

ABSTRACT Mixed-lineage protein kinase 3 (MLK3) is a member of the mitogen-activated protein (MAP) kinase kinase kinase group that has been implicated in multiple signaling cascades, including the NF-κB pathway and the extracellular signal-regulated kinase, c-Jun NH2-terminal kinase (JNK), and p38 MAP kinase pathways. Here, we examined the effect of targeted disruption of the murine Mlk3 gene. Mlk3 −/− mice were found to be viable and healthy. Primary embryonic fibroblasts prepared from these mice exhibited no major signaling defects. However, we did find that MLK3 deficiency caused a selective reduction in tumor necrosis factor (TNF)-stimulated JNK activation. Together, these data demonstrate that MLK3 contributes to the TNF signaling pathway that activates JNK.

scholarly journals p38 mitogen-activated protein (MAP) kinase but not p44/p42 MAP kinase is involved in prostaglandin E1-induced vascular endothelial growth factor synthesis in osteoblasts

2001 ◽  
Vol 170 (3) ◽  
pp. 629-638 ◽  
Author(s):  
H Tokuda ◽  
O Kozawa ◽  
M Miwa ◽  
T Uematsu
Keyword(s):  
Map Kinase ◽  
Cholera Toxin ◽  
Prostaglandin E1 ◽  
Specific Inhibitor ◽  
P38 Map Kinase ◽  
Vascular Endothelial ◽  
Kinase Activation ◽  
Protein Map ◽  
Mitogen Activated Protein ◽  
Endothelial Growth Factor

We investigated the mechanism underlying vascular endothelial growth factor (VEGF) synthesis stimulated by prostaglandin E1 (PGE1) in osteoblast-like MC3T3-E1 cells. PGE1 induced the phosphorylation of both p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase. SB203580, a specific inhibitor of p38 MAP kinase, inhibited the PGE1-stimulated VEGF synthesis as well as PGE1-induced phosphorylation of p38 MAP kinase. PD98059, an inhibitor of the upstream kinase that activates p44/p42 MAP kinase, which reduced the PGE1-induced phosphorylation of p44/p42 MAP kinase, had little effect on the VEGF synthesis stimulated by PGE1. AH-6809, an antagonist of the subtypes of the PGE receptor, EP1 and EP2, or SC-19220, an antagonist of EP1 receptor, did not inhibit the PGE1-induced VEGF synthesis. H-89, an inhibitor of cAMP-dependent protein kinase, and SQ22536, an inhibitor of adenylate cyclase, reduced the VEGF synthesis induced by PGE1. Cholera toxin, an activator of G(s), and forskolin, an activator of adenylate cyclase, induced VEGF synthesis. SB203580 and PD169316, another specific inhibitor of p38 MAP kinase, reduced the cholera toxin-, forskolin- or 8bromo-cAMP-stimulated VEGF synthesis. However, PD98059 failed to affect the VEGF synthesis stimulated by cholera toxin, forskolin or 8-bromoadenosine-3',5'-cyclic monophosphate (8bromo-cAMP). SB203580 reduced the phosphorylation of p38 MAP kinase induced by forskolin or 8bromo-cAMP. These results strongly suggest that p44/p42 MAP kinase activation is not involved in the PGE1-stimulated VEGF synthesis in osteoblasts but that p38 MAP kinase activation is involved.

NHE3-dependent cytoplasmic alkalinization is triggered by Na+-glucose cotransport in intestinal epithelia

2001 ◽  
Vol 281 (5) ◽  
pp. C1533-C1541 ◽  
Author(s):  
Jerrold R. Turner ◽  
Eric D. Black
Keyword(s):  
Map Kinase ◽  
Kinase Inhibitors ◽  
P38 Map Kinase ◽  
Intestinal Epithelial ◽  
Cell Monolayers ◽  
Intestinal Epithelia ◽  
Protein Map ◽  
Mitogen Activated Protein ◽  
Epithelial Cell Monolayers ◽  
P38 Map Kinase Inhibitors

Cytoplasmic pH (pHi) was evaluated during Na+-glucose cotransport in Caco-2 intestinal epithelial cell monolayers. The pHi increased by 0.069 ± 0.002 within 150 s after initiation of Na+-glucose cotransport. This increase occurred in parallel with glucose uptake and required expression of the intestinal Na+-glucose cotransporter SGLT1. S-3226, a preferential inhibitor of Na+/H+ exchanger (NHE) isoform 3 (NHE3), prevented cytoplasmic alkalinization after initiation of Na+-glucose cotransport with an ED50 of 0.35 μM, consistent with inhibition of NHE3, but not NHE1 or NHE2. In contrast, HOE-694, a poor NHE3 inhibitor, failed to significantly inhibit pHi increases at <500 μM. Na+-glucose cotransport was also associated with activation of p38 mitogen-activated protein (MAP) kinase, and the p38 MAP kinase inhibitors PD-169316 and SB-202190 prevented pHi increases by 100 ± 0.1 and 86 ± 0.1%, respectively. Conversely, activation of p38 MAP kinase with anisomycin induced NHE3-dependent cytoplasmic alkalinization in the absence of Na+-glucose cotransport. These data show that NHE3-dependent cytoplasmic alkalinization occurs after initiation of SGLT1-mediated Na+-glucose cotransport and that the mechanism of this NHE3 activation requires p38 MAP kinase activity. This coordinated regulation of glucose (SGLT1) and Na+ (NHE3) absorptive processes may represent a functional activation of absorptive enterocytes by luminal nutrients.

scholarly journals Inhibition by adenylyl cyclase-cAMP system of ET-1-induced HSP27 in osteoblasts

2001 ◽  
Vol 281 (6) ◽  
pp. E1260-E1266 ◽  
Author(s):  
Daijiro Hatakeyama ◽  
Osamu Kozawa ◽  
Masayuki Niwa ◽  
Hiroyuki Matsuno ◽  
Kanefusa Kato ◽  
...  
Keyword(s):  
Map Kinase ◽  
Adenylyl Cyclase ◽  
Mrna Level ◽  
P38 Map Kinase ◽  
Hsp 27 ◽  
Kinase C ◽  
Protein Map ◽  
Mitogen Activated Protein ◽  
Camp System ◽  
Kinase Phosphorylation

We have previously reported that endothelin-1 (ET-1) stimulates heat shock protein (HSP) 27 induction in osteoblast-like MC3T3-E1 cells and that p38 mitogen-activated protein (MAP) kinase acts at a point downstream from protein kinase C (PKC) in HSP27 induction. In the present study, we investigated the effect of the adenylyl cyclase-cAMP system on ET-1-stimulated induction of HSP27 in MC3T3-E1 cells. Dibutyryl-cAMP (DBcAMP) dose dependently inhibited the HSP27 accumulation stimulated by ET-1. Forskolin and cholera toxin significantly suppressed the ET-1-stimulated accumulation of HSP27. However, dideoxyforskolin, a forskolin derivative that does not activate cAMP, failed to suppress the ET-1-induced HSP27 accumulation. Forskolin reduced the p38 MAP kinase phosphorylation induced by ET-1 or 12- O-tetradecanoylphorbol-13-acetate (TPA). PGE1, an extracellular agonist that activates cAMP production, reduced the ET-1-induced HSP27 accumulation. In addition, the phosphorylation of p38 MAP kinase induced by ET-1 or TPA was suppressed by PGE1. Forskolin, DBcAMP, and PGE1suppressed the ET-1-stimulated increase in the mRNA level for HSP27. These results indicate that the adenylyl cyclase-cAMP system has an inhibitory role in ET-1-stimulated HSP27 induction in osteoblasts and that the effect is exerted at the point between PKC and p38 MAP kinase in osteoblasts.

Hypoxia/aglycemia increases endothelial permeability: role of second messengers and cytoskeleton

1999 ◽  
Vol 277 (6) ◽  
pp. C1066-C1074 ◽  
Author(s):  
J. H. Park ◽  
N. Okayama ◽  
D. Gute ◽  
A. Krsmanovic ◽  
H. Battarbee ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Map Kinase ◽  
Time Course ◽  
Kinase Inhibitor ◽  
Second Messengers ◽  
Endothelial Permeability ◽  
P38 Map Kinase ◽  
Microcarrier Beads ◽  
Mitogen Activated Protein ◽  
Microvascular Endothelial

The effects of hypoxia/aglycemia on microvascular endothelial permeability were evaluated, and the second messenger systems and the cytoskeletal-junctional protein alterations in this response were also examined. Monolayers of human dermal microvascular endothelial cells on microcarrier beads were exposed to either thioglycolic acid (5 mM, an O2 chelator), glucose-free medium, or both stresses together. Permeability measurements were performed over a 90-min time course. Although neither hypoxia alone nor aglycemia alone increased endothelial permeability significantly, the combination of both increased significantly as early as 15 min. Intracellular Ca2+ measurements with fura 2-AM showed that hypoxia/aglycemia treatment increased Ca2+ influx. To determine the second messengers involved in increased permeability, monolayers were incubated for 30 min with the cytosolic Ca2+ scavenger 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester (TMB-8, 0.1 mM), a classical protein kinase C (PKC) blocker, Gö-6976 (10 nM), a cGMP-dependent protein kinase (PKG) antagonist, KT-5823 (0.5 μM), or the mitogen-activated protein (MAP) kinase inhibitor PD-98059 (20 μM). Hypoxia/aglycemia-mediated permeability changes were blocked by chelating cell Ca2+, PKC blockade, PKG blockade, and by inhibiting p38 MAP kinase-1. Finally, changes in the binding of junctional proteins to the cytoskeleton under the same conditions were assessed. The concentrations of occludin and pan-reactive cadherin binding to the cytoskeleton were significantly decreased by only both stresses together. However, these effects were also blocked by pretreatment with TMB-8, Gö-6976, KT-5823 (not in occludin), and PD-98059. These data suggest that hypoxia/aglycemia-mediated endothelial permeability may occur through PKC, PKG, MAP kinase, and Ca2+related to dissociation of cadherin-actin and occludin-actin junctional bonds.

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