Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The recruitment of signal transduction molecules to the membrane is crucial for the efficient coupling of extracellular signals and contractile response. The trafficking is dynamic. We have investigated a possible cross talk between agonist-induced association of translocated RhoA and translocated protein kinase C-alpha (PKC-alpha) and a role for heat shock protein 27 (HSP27) in mediating this interaction. Immunoprecipitation with HSP27 monoclonal antibody followed by immunoblotting with either RhoA antibody or PKC-alpha antibody indicated that acetylcholine induced associations of HSP27-RhoA and HSP27-PKC-alpha in the membrane fraction but not in the cytosolic fraction. Immunoprecipitation with anti-RhoA monoclonal antibody followed by immunoblotting with PKC-alpha antibody indicated that acetylcholine induced a significant complexing of RhoA-PKC-alpha in the membrane fraction but not in the cytosolic fraction. In summary, the data indicate that agonist-induced contraction is associated with 1) association of translocated RhoA with HSP27 on the membrane, 2) association of translocated PKC-alpha with HSP27 on the membrane, and 3) association of PKC-alpha with RhoA on the membrane. The data suggest an important role for HSP27 in modulating a multiprotein complex that includes translocated RhoA and PKC-alpha.
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PMID:HSP27 modulates agonist-induced association of translocated RhoA and PKC-alpha in muscle cells of the colon. 1174 41

The angiotensin type 1 receptor (AT(1)) exerts a variety of its signaling and cellular actions through its effects on protein phosphorylation. Phosphoproteomic analysis of angiotensin (Ang) II-stimulated aortic smooth muscle cells revealed that heat shock protein 27 (HSP27) represents a major protein phosphorylation target of the AT(1) signaling pathway. Stimulation of cells with Ang II resulted in 1.7-fold (P<0.05) and 5.5-fold (P<0.001) increases in HSP27 phosphoisoforms at pI 5.7 and pI 5.4, respectively. This was accompanied by a 54% (P<0.01) decrease in the nonphosphorylated HSP27 isoform, located at pI 6.4. Treatment of samples with alkaline phosphatase reversed this redistribution of HSP27 phosphoisoforms. Ang II-stimulated HSP27 phosphorylation was completely blocked by pretreatment of cells with the AT(1) antagonist CV11974. Phosphoamino acid analysis demonstrated that Ang II-induced phosphorylation of both HSP27 phosphoisoforms occurred exclusively on serine. Protein kinase C inhibition completely blocked phorbol ester-induced HSP27 phosphorylation but did not impair Ang II-stimulated phosphorylation of HSP27, suggesting that AT(1) increased HSP27 phosphorylation by a protein kinase C-independent pathway. Intrajugular infusion of Ang II in rats increased HSP27 in aorta by 1.7-fold (P<0.02), and this response was inhibited by CV11974. These results suggest that Ang II-induced HSP27 phosphorylation is a physiologically relevant AT(1) signaling event. Because serine phosphorylation of HSP27 blocks its ability to cap F-actin, Ang II/AT(1)-induced HSP27 phosphorylation may play a key role in actin filament remodeling required for smooth muscle cell migration and contraction.
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PMID:Angiotensin AT(1) receptor stimulates heat shock protein 27 phosphorylation in vitro and in vivo. 1175

We investigated the effect of prostaglandin E2 (PGE2) on the induction of heat shock protein 27 (HSP27) and HSP70, and the mechanism behind the induction in osteoblast-like MC3T3-E1 cells. PGE2 time-dependently increased the level of HSP27 without affecting the level of HSP70. PGE2 stimulated the accumulation of HSP27 dose-dependently in the range between 10 nM and 10 microM. PGE2 stimulated the increase in the level of the mRNA for HSP27. Staurosporine and calphostin C, inhibitors of protein kinase C (PKC), suppressed the PGE2-induced HSP27 accumulation. The effect of PGE2 on HSP27 accumulation was reduced in the PKC down-regulated cells. BAPTA/AM, a chelator of intracellular Ca2+, or TMB-8, an inhibitor of intracellular Ca2+ mobilization, reduced the accumulation of HSP27 induced by PGE2. Dibutyryl cAMP had little effect on the basal level of HSP27. PGE2 induced the phosphorylation of both p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase. PD98059 and U-0126, inhibitors of the upstream kinase of p44/p42 MAP kinase, reduced the accumulation of HSP27 induced by PGE2. SB203580, a specific inhibitor of p38 MAP kinase, suppressed the HSP27 accumulation induced by PGE2. U-73122, an inhibitor of phospholipase C, and calphostin C reduced the PGE2-induced phosphorylation of both p44/p42 MAP kinase and p38 MAP kinase. These results indicate that PGE2 stimulates the induction of HSP27 through PKC-dependent activations of both p44/p42 MAP kinase and p38 MAP kinase in osteoblasts.
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PMID:Mechanism of prostaglandin E2-stimulated heat shock protein 27 induction in osteoblast-like MC3T3-E1 cells. 1183 45

We have investigated the role of heat shock protein 27 (HSP27) phosphorylation and the association of HSP27 with contractile proteins actin, myosin, and tropomyosin. Smooth muscle cells were labeled with [(32)P]orthophosphate. C2-ceramide (0.1 microM), an activator of protein kinase C (PKC), induced a sustained increase in HSP27 phosphorylation that was inhibited by calphostin C. C2-ceramide-induced (0.1 microM) sustained colonic smooth muscle cell contraction was accompanied by significant increases in the association of HSP27 with tropomyosin and in the association of HSP27 with actin. The significant increases occurred at 30 s after stimulation and were sustained at 4 min. Contraction was also associated with strong colocalization of HSP27 with tropomyosin and with actin as observed after immunofluorescent labeling of tropomyosin, actin, and HSP27 followed by confocal microscopy. Transfection of smooth muscle cells with HSP27 phosphorylation mutants indicated that phosphorylation of HSP27 could affect myosin association with actin. In conclusion 1) HSP27 phosphorylation appears to be necessary for reorganization of HSP27 inside the cell and seems to be directly correlated with the PKC signal transduction pathway, and 2) agonist-induced phosphorylation of HSP27 modulates actin-myosin interaction through thin-filament regulation of tropomyosin.
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PMID:HSP27 phosphorylation and interaction with actin-myosin in smooth muscle contraction. 1196 Jul 85

The object of this theme is to offer new perspectives on the effect of aging on signal-transduction pathways associated with agonist-induced contraction of smooth muscle cells from the colon. Smooth muscle cells from old rats (32 mo old) exhibit limited cell length distribution and diminished contractility. The observed reduced contractile response may be due to the effect of aging on signal-transduction pathways, especially an inhibition of the tyrosine kinase-Src kinase pathway, a reduced activation of the PKC pathway, and a reduced association of contractile proteins [heat shock protein 27 (HSP27)-tropomyosin, HSP27-actin, actin-myosin]. Levels of HSP27 phosphorylation are also reduced compared with adult rats.
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PMID:Aging and neural control of the GI tract: V. Aging and gastrointestinal smooth muscle: from signal transduction to contractile proteins. 1248 30

Cholecystokinin (CCK) acting through its G protein-coupled receptor is now known to activate a variety of intracellular signaling mechanisms and thereby regulate a complex array of cellular functions in pancreatic acinar cells. The best studied mechanism is the coupling through heterotrimeric G proteins of the Gq family to activate a phospholipase C leading to an increase in inositol trisphosphate and release of intracellular Ca2+. This pathway along with protein kinase C activation in response to the increase in diacylglycerol stimulates the secretion of digestive enzymes by the process of exocytosis. CCK also activates signaling pathways in acini more related to other processes. The three mitogen activated protein kinase cascades leading to ERKs, JNKs and p38 MAPK are all activated by CCK. CCK activates the ERK cascade by PKC activation of Raf which in turn activates MEK and ERKs. JNKs are activated by a distinct mechanism which requires higher concentrations of CCK. Both ERKs and JNKs are presumed to regulate gene expression. CCK activation of p38 MAPK also plays a role in regulating the actin cytoskeleton through phosphorylation of the small heat shock protein HSP27. The PI3K-PKB-mTOR pathway is activated by CCK and plays a major role in regulating protein synthesis at the translational level. This includes both activation of p70 S6K leading to phosphorylation of ribosomal protein S6 and the phosphorylation of the binding protein for initiation factor 4E leading to formation of the mRNA cap binding complex. Other signaling pathways activated by CCK receptors include NF-kappaB and a variety of tyrosine kinases. Further work is needed to understand how CCK receptors activate most of the above pathways and to better understand the biological events regulated by these diverse signaling pathways.
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PMID:Cholecystokinin activates a variety of intracellular signal transduction mechanisms in rodent pancreatic acinar cells. 1268 72

We investigated whether tumor necrosis factor-alpha (TNF-alpha) stimulates the induction of heat shock protein 27 (HSP27) in human neutrophils and the mechanism underlying this induction. In intact neutrophils, almost no HSP27 was detected. Stimulation of neutrophils by TNF-alpha increased the levels of HSP27 in the presence, but not in the absence, of cycloheximide. Reverse transcription-polymerase chain reaction (RT-PCR) experiments showed that TNF-alpha also induced HSP27 mRNA in the presence of cycloheximide. TNF-alpha induced the phosphorylation of p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase. The HSP27 accumulation induced by TNF-alpha was significantly suppressed by 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole (SB203580) or 4-(4-fluorophenyl)-2-(4-nitrophenyl)-5-(4-pyridyl)-1H-imidazole (PD169316); both are specific inhibitors of p38 MAP kinase, but not by 2'-amino-3'-methoxyflavone (PD098059, a specific inhibitor of the upstream kinase that activates p44/p42 MAP kinase). The accumulation of HSP27 induced by TNF-alpha plus cycloheximide was also suppressed by pretreatment with a specific protein kinase C (PKC) inhibitor. Furthermore, phorbol myristate acetate (PMA), a PKC stimulant, but not dibutyryl cyclic AMP, a protein kinase A stimulant, stimulated the accumulation of HSP27. Interestingly, SB203580 did not inhibit PMA-stimulated HSP27 induction. These results strongly suggest that TNF-alpha may act as the regulator of HSP27 induction in neutrophils. p38 MAP kinase (but not p44/p42 MAP kinase) and PKC take part in TNF-alpha-stimulated HSP27 induction in human neutrophils.
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PMID:Involvement of p38 mitogen-activated protein kinase in heat shock protein 27 induction in human neutrophils. 1269 7

HSP25 has been shown to induce resistance to radiation and oxidative stress; however, its exact mechanisms remain unclear. In the present study, a high concentration of H2O2 was found to induce DNA fragmentation in L929 mouse fibroblast cells, and HSP25 overexpression attenuated this phenomenon. To elucidate the mechanisms of H2O2-mediated cell death, ERK1/2, p38 MAPK, and JNK1/2 phosphorylation in the cells after treatment with H2O2 were examined. ERK1/2 and JNK1/2 were activated by H2O2; ERK1/2 activation was inhibited in HSP25-overexpressed cells, while JNK1/2 was indifferent. Inhibition of ERK1/2 activation by treatment of the cells with PD98059 or dominant-negative ERK2 transfection blocked H2O2-induced cell death; similarly treated HSP25-overexpressed cells were not at all affected. Moreover, inhibition of JNK1/2 by dominant-negative JNK1 or JNK2 transfection did not affect H2O2-mediated cell death in control cells. Dominant-negative Ras or Raf transfection inhibited H2O2-mediated ERK1/2 activation and cell death in control cells. On the contrary, HSP25-overexpressed cells did not show any differences. Upstream pathways of H2O2-mediated ERK1/2 activation and cell death involved both tyrosine kinase (PDGFbeta receptor and Src) and PKCdelta, while in HSP25-overexpressed cells these kinases did not respond to H2O2 treatment. Since HSP25 overexpression reduced reactive oxygen species (ROS), increased manganese superoxide dismutase (MnSOD) gene expression, and increased enzyme activity, involvement of MnSOD in HSP25-mediated attenuation of H2O2-mediated ERK1/2 activation and cell death was examined. Blockage of MnSOD with antisense oligonucleotides prevented DNA fragmentation and returned the ERK1/2 activation to the control level. Indeed, when MnSOD was overexpressed in L929 cells, similar to in HSP25-overexpressed cells, DNA fragmentation and ERK1/2 activation were reduced. From the above results, we suggest for the first time that reduced oxidative damage by HSP25 was due to MnSOD-mediated downregulation of ERK1/2.
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PMID:HSP25 overexpression attenuates oxidative stress-induced apoptosis: roles of ERK1/2 signaling and manganese superoxide dismutase. 1497 46

Mechanical stimulation is known to modulate cell physiology in a variety of different tissues. Particularly, epithelial cells are permanently exposed to mechanical stimulation generated by externally applied forces. The present in vitro study demonstrated mechanical pressure as a trigger-factor of the p38 mitogen-activated protein kinase (MAPK) pathway in epithelial cells. Mechanical pressure applied by teflon weights (1.02g/cm(2)) led to a rapid phosphorylation of p38 peaking between 5 and 10min. Furthermore, phosphorylation of the small heat shock protein 27 (HSP27) was shown in response to mechanical pressure. Suppression of p38 function by using specific inhibitors blocked the pressure-mediated phosphorylation of HSP27. In order to identify upstream regulators of p38, a contribution of Src and protein kinase C (PKC) in pressure-signaling was investigated. We could demonstrate that inhibition of Src or PKC suppressed the pressure-induced phosphorylation of p38. These findings suggest mechanical pressure as a new type of effector stimulus for the p38 pathway with implications to (patho-) physiological conditions.
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PMID:Mechanical pressure-induced phosphorylation of p38 mitogen-activated protein kinase in epithelial cells via Src and protein kinase C. 1503 52

As for the pathogenesis of rheumatoid arthritis (RA), prostaglandins (PGs) act as important mediators of inflammation and joint destruction. Among them, PGD2 is well recognized as a potent regulator of osteoblastic functions. We previously showed that PGD2 stimulates the induction of heat shock protein 27 (HSP27) via protein kinase C (PKC)-dependent p38 mitogen-activated protein (MAP) kinase and p44/p42 MAP kinase in osteoblast-like MC3T3-E1 cells. Therefore, it is a current topic to clarify how HSP27 plays a role for regulating osteoblastic functions in the lesion of RA. On the other hand, methotrexate (MTX) is one of the most effective medicines for the treatment of RA. Here, we examined the effect of MTX on PGD2-stimulated HSP27 induction in MC3T3-E1 cells. The cells were pretreated with various doses of MTX including therapeutic dosage for RA, and then stimulated by PGD2. MTX significantly enhanced the PGD2- increased levels of HSP27 in a dose-dependent manner, although MTX alone had no effect on the levels of HSP27. In addition, MTX amplified the PGD2-increased levels of HSP27 mRNA. On the contrary, MTX had little effect on PGD2-induced formation of inositol phosphates, PKC activation and phosphorylations of MAP kinases. Our results strongly suggest that MTX enhances PGD2-stimulated HSP27 induction at a point downstream from MAP kinases in osteoblasts.
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PMID:Methotrexate enhances prostaglandin D2-stimulated heat shock protein 27 induction in osteoblasts. 1551 94


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