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 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.

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 Protein Kinase C and Cerebral Vasospasm

2001 ◽  
Vol 21 (8) ◽  
pp. 887-906 ◽  
Author(s):  
Ismail Laher ◽  
John H. Zhang
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Cerebral Vasospasm ◽  
Protein Tyrosine Kinase ◽  
Vascular Reactivity ◽  
Receptor Activation ◽  
Mitogen Activated Protein Kinase ◽  
Kinase C ◽  
Mitogen Activated Protein

Twenty-five years after the discovery of protein kinase C (PKC), the physiologic function of PKC, and especially its role in pathologic conditions, remains a subject of great interest with 30,000 studies published on these aspects. In the cerebral circulation, PKC plays a role in the regulation of myogenic tone by sensitization of myofilaments to calcium. Protein kinase C phosphorylates various ion channels including augmenting voltage-dependent Ca2+ channels and inhibiting K+ channels, which both lead to vessel contraction. These actions of PKC amplify vascular reactivity to different agonists and may be critical in the regulation of cerebral artery tone during vasospasm. Evidence accumulated during at least the last decade suggest that activation of PKC in cerebral vasospasm results in a delayed but prolonged contraction of major arteries after subarachnoid hemorrhage. Most of the experimental results in vitro or in animal models support the view that PKC is involved in cerebral vasospasm. Implication of PKC in cerebral vasospasm helps explain increased arterial narrowing at the signal transduction level and alters current perceptions that the pathophysiology is caused by a combination of multiple receptor activation, hemoglobin toxicity, and damaged neurogenic control. Activation of protein kinase C also interacts with other signaling pathways such as myosin light chain kinase, nitric oxide, intracellular Ca2+, protein tyrosine kinase, and its substrates such as mitogen-activated protein kinase. Even though identifying PKC revolutionized the understanding of cerebral vasospasm, clinical advances are hampered by the lack of clinical trials using selective PKC inhibitors.

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.

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