Lipopolysaccharide induces Jun N-terminal kinase activation in macrophages by a novel Cdc42/Rac-independent pathway involving sequential activation of protein kinase C ζ and phosphatidylcholine-dependent phospholipase C

Blood ◽  
2000 ◽  
Vol 96 (7) ◽  
pp. 2592-2598 ◽  
Author(s):  
Katarzyna J. Procyk ◽  
Maria Rita Rippo ◽  
Roberto Testi ◽  
Fred Hofmann ◽  
Peter J. Parker ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Phospholipase C ◽  
Small Gtpases ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Activation ◽  
Kinase C ◽  
Mitogen Activated Protein ◽  
Pkc Ζ ◽  
Phosphoinositide 3 Kinase

Abstract The activation of kinases of the mitogen-activated protein kinase superfamily initiated by lipopolysaccharide (LPS) plays an important role in transducing inflammatory signals. The pathway leading to the induction of stress-activated protein kinases in macrophages stimulated with LPS was investigated. The activation of Jun N-terminal kinases (JNK) by LPS is herbimycin sensitive. Using specific inhibitors, it was shown that the pathway involves the activation of phosphoinositide 3-kinase (PI 3-K). However, in contrast to previous reports, the small GTPases Cdc42 and Rac are not required downstream of PI 3-K for JNK activation. Instead, the phosphoinositides produced by PI 3-K stimulate protein kinase C (PKC) ζ activation through PDK1. In turn, activation of this atypical PKC leads to the stimulation of phosphatidylcholine phospholipase C (PC-PLC) and acidic sphingomyelinase (ASMase). It is therefore proposed that PKCζ regulates the PC-PLC/ASMase pathway, and it is hypothesized that the resultant ceramide accumulation mediates the activation of the SEK/JNK module by LPS.

Lipopolysaccharide induces Jun N-terminal kinase activation in macrophages by a novel Cdc42/Rac-independent pathway involving sequential activation of protein kinase C ζ and phosphatidylcholine-dependent phospholipase C

Blood ◽  
2000 ◽  
Vol 96 (7) ◽  
pp. 2592-2598 ◽  
Author(s):  
Katarzyna J. Procyk ◽  
Maria Rita Rippo ◽  
Roberto Testi ◽  
Fred Hofmann ◽  
Peter J. Parker ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Phospholipase C ◽  
Small Gtpases ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Activation ◽  
Kinase C ◽  
Mitogen Activated Protein ◽  
Pkc Ζ ◽  
Phosphoinositide 3 Kinase

The activation of kinases of the mitogen-activated protein kinase superfamily initiated by lipopolysaccharide (LPS) plays an important role in transducing inflammatory signals. The pathway leading to the induction of stress-activated protein kinases in macrophages stimulated with LPS was investigated. The activation of Jun N-terminal kinases (JNK) by LPS is herbimycin sensitive. Using specific inhibitors, it was shown that the pathway involves the activation of phosphoinositide 3-kinase (PI 3-K). However, in contrast to previous reports, the small GTPases Cdc42 and Rac are not required downstream of PI 3-K for JNK activation. Instead, the phosphoinositides produced by PI 3-K stimulate protein kinase C (PKC) ζ activation through PDK1. In turn, activation of this atypical PKC leads to the stimulation of phosphatidylcholine phospholipase C (PC-PLC) and acidic sphingomyelinase (ASMase). It is therefore proposed that PKCζ regulates the PC-PLC/ASMase pathway, and it is hypothesized that the resultant ceramide accumulation mediates the activation of the SEK/JNK module by LPS.

scholarly journals Diacylglycerol generated by exogenous phospholipase C activates the mitogen-activated protein kinase pathway independent of Ras- and phorbol ester-sensitive protein kinase C: dependence on protein kinase C-ζ

1997 ◽  
Vol 323 (3) ◽  
pp. 693-699 ◽  
Author(s):  
Marc C. M. van DIJK ◽  
Francisco J. G. MURIANA ◽  
Paul C. J. van der HOEVEN ◽  
John de WIDT ◽  
Dick SCHAAP ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Phospholipase C ◽  
Phorbol Ester ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Activation ◽  
Kinase C ◽  
Mitogen Activated Protein ◽  
Pkc Ζ

The role of diacylglycerol (DG) formation from phosphatidylcholine in mitogenic signal transduction is poorly understood. We have generated this lipid at the plasma membrane by treating Rat-1 fibroblasts with bacterial phosphatidylcholine-specific phospholipase C (PC-PLC). This treatment leads to activation of mitogen-activated protein kinase (MAPK). However, unlike platelet-derived growth factor (PDGF) or epidermal growth factor (EGF), PC-PLC fails to activate Ras and to induce DNA synthesis, and activates MAPK only transiently (< 45 min). Down-regulation of protein kinase C (PKC) -α, -Δ and -ε isotypes has little or no effect on MAPK activation by either PC-PLC or growth factors. However, Ro 31-8220, a highly selective inhibitor of all PKC isotypes, including atypical PKC-ζ but not Raf-1, blocks MAPK activation by PDGF and PC-PLC, but not that by EGF, suggesting that atypical PKC mediates the PDGF and PC-PLC signal. In line with this, PKC-ζ is activated by PC-PLC and PDGF, but not by EGF, as shown by a kinase assay in vitro, using biotinylated ε-peptide as a substrate. Furthermore, dominant-negative PKC-ζ inhibits, while (wild-type) PKC-ζ overexpression enhances MAPK activation by PDGF and PC-PLC. The results suggest that DG generated by PC-PLC can activate the MAPK pathway independent of Ras and phorbol-ester-sensitive PKC but, instead, via PKC-ζ.

scholarly journals Platelet-derived growth factor activation of mitogen-activated protein kinase depends on the sequential activation of phosphatidylcholine-specific phospholipase C, protein kinase C-ζ and Raf-1

1997 ◽  
Vol 325 (2) ◽  
pp. 303-307 ◽  
Author(s):  
Marc C. M. VAN DIJK ◽  
Henk HILKMANN ◽  
Wim J. VAN BLITTERSWIJK
Keyword(s):  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Phospholipase C ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Platelet Derived Growth Factor ◽  
Kinase C ◽  
Mitogen Activated Protein ◽  
Pkc Ζ

The mechanism of Raf-1 activation by platelet-derived growth factor (PDGF) is poorly defined. We previously reported that, in Rat-1 fibroblasts, PDGF activates a phosphatidylcholine-specific phospholipase C (PC-PLC) and that the product, diacylglycerol, somehow activates protein kinase C-ζ (PKC-ζ). Both PC-PLC and PKC-ζ activities were required for PDGF activation of mitogen-activated protein kinase (MAPK). Now we report that MAPK activation by exogenous PC-PLC depends on Raf-1 activation. PKC-ζ co-immunoprecipitates with, phoshorylates and activates Raf-1, suggesting that in the PDGF- and PC-PLC-activated MAPK pathway, PKC-ζ operates in a signalling complex as a direct activator of Raf-1.

Protein kinase C activation by acidic proteins including 14-3-3

2000 ◽  
Vol 347 (3) ◽  
pp. 781-785 ◽  
Author(s):  
Paulus C. J. VAN DER HOEVEN ◽  
José C. M. VAN DER WAL ◽  
Paula RUURS ◽  
Wim J. VAN BLITTERSWIJK
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Assay ◽  
Kinase C ◽  
Mitogen Activated Protein ◽  
Dose Dependent Fashion ◽  
Acidic Proteins ◽  
Pkc Ζ

14-3-3 proteins may function as adapter or scaffold proteins in signal transduction pathways. We reported previously that several 14-3-3 isotypes bind to protein kinase C (PKC)-ζ and facilitate coupling of PKC-ζ to Raf-1 [van der Hoeven, van der Wal, Ruurs, van Dijk and van Blitterswijk (2000) Biochem. J. 345, 297-306], an event that boosts the mitogen-activated protein kinase (ERK) pathway in Rat-1 fibroblasts. The present work investigated whether bound 14-3-3 would affect PKC-ζ activity. Using recombinant 14-3-3 proteins and purified PKC-ζ in a convenient, newly developed in vitro kinase assay, we found that 14-3-3 proteins stimulated PKC-ζ activity in a dose-dependent fashion up to approx. 2.5-fold. Activation of PKC-ζ by 14-3-3 isotypes was unrelated to their mutual affinity, estimated by co-immunoprecipitation from COS cell lysates. Accordingly, PKC-ζ with a defective (point-mutated) 14-3-3-binding site, showed the same 14-3-3-stimulated activity as wild-type PKC-ζ. As 14-13-3 proteins are acidic, we tested several other acidic proteins, which turned out to stimulate PKC-ζ activity in a similar fashion, whereas neutral or basic proteins did not. These effects were not restricted to the atypical PKC-ζ, but were also found for classical PKC. Together, the results suggest that the stimulation of PKC activity by 14-3-3 proteins is non-specific and solely due to the acidic nature of these proteins, quite similar to that known for acidic lipids.

scholarly journals Ras-dependent and -independent pathways target the mitogen-activated protein kinase network in macrophages.

1995 ◽  
Vol 15 (1) ◽  
pp. 466-475 ◽  
Author(s):  
D Büscher ◽  
R A Hipskind ◽  
S Krautwald ◽  
T Reimann ◽  
M Baccarini
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Phospholipase C ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Activation ◽  
Alternative Pathways ◽  
Kinase C ◽  
Mitogen Activated Protein ◽  
Extracellular Stimuli

Mitogen-activated protein kinases (MAPKs) are activated upon a variety of extracellular stimuli in different cells. In macrophages, colony-stimulating factor 1 (CSF-1) stimulates proliferation, while bacterial lipopolysaccharide (LPS) inhibits cell growth and causes differentiation and activation. Both CSF-1 and LPS rapidly activate the MAPK network and induce the phosphorylation of two distinct ternary complex factors (TCFs), TCF/Elk and TCF/SAP. CSF-1, but not LPS, stimulated the formation of p21ras. GTP complexes. Expression of a dominant negative ras mutant reduced, but did not abolish, CSF-1-mediated stimulation of MEK and MAPK. In contrast, activation of the MEK kinase Raf-1 was Ras independent. Treatment with the phosphatidylcholine-specific phospholipase C inhibitor D609 suppressed LPS-mediated, but not CSF-1-mediated, activation of Raf-1, MEK, and MAPK. Similarly, down-regulation or inhibition of protein kinase C blocked MEK and MAPK induction by LPS but not that by CSF-1. Phorbol 12-myristate 13-acetate pretreatment led to the sustained activation of the Raf-1 kinase but not that of MEK and MAPK. Thus, activated Raf-1 alone does not support MEK/MAPK activation in macrophages. Phosphorylation of TCF/Elk but not that of TCF/SAP was blocked by all treatments that interfered with MAPK activation, implying that TCF/SAP was targeted by a MAPK-independent pathway. Therefore, CSF-1 and LPS target the MAPK network by two alternative pathways, both of which induce Raf-1 activation. The mitogenic pathway depends on Ras activity, while the differentiation signal relies on protein kinase C and phosphatidylcholine-specific phospholipase C activation.

scholarly journals Protein kinase C (PKC)-δ/-ε mediate the PKC/Akt-dependent phosphorylation of extracellular signal-regulated kinases 1 and 2 in MCF-7 cells stimulated by bradykinin

2006 ◽  
Vol 188 (1) ◽  
pp. 79-89 ◽  
Author(s):  
S Greco ◽  
C Storelli ◽  
S Marsigliante
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Breast Cancer Cells ◽  
Mitogen Activated Protein Kinase ◽  
Kinase C ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
Mcf 7 ◽  
Protein Kinase Kinase

In this paper the signal transduction pathways evoked by bradykinin (BK) in MCF-7 breast cancer cells were investigated. BK activation of the B2 receptor provoked: (a) the phosphorylation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2); (b) the translocation from the cytosol to the membrane of the conventional protein kinase C-α (PKC-α) and novel PKC-δ and PKC-ε; (c) the phosphorylation of protein kinase B (PKB/ Akt); (d) the proliferation of MCF-7 cells. The BK-induced ERK1/2 phosphorylation was completely blocked by PD98059 (an inhibitor of the mitogen-activated protein kinase kinase (MAPKK or MEK)) and by LY294002 (an inhibitor of phosphoinositide 3-kinase (PI3K)), and was reduced by GF109203X (an inhibitor of both novel and conventional PKCs); Gö6976, a conventional PKCs inhibitor, did not have any effect. The BK-induced phosphorylation of PKB/Akt was blocked by LY294002 but not by PD98059. Furthermore, LY294002 inhibited the BK-provoked translocation of PKC-δ and PKC-ε suggesting that PI3K may be upstream to PKCs. Finally, the proliferative effects of BK were blocked by PD98059, GF109203X and LY294002. These observations demonstrate that BK acts as a proliferative agent in MCF-7 cells activating intracellular pathways involving novel PKC-δ/-ε, PKB/Akt and ERK1/2.

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