LOSS-OF-FUNCTION OF THE PROTEIN KINASE C δ (PKC- δ) CAUSES MENDELIAN SUSCEPTIBILITY TO MYCOBACTERIAL DISEASES WITH RESPIRATORY BURST DEFECT

Stimulation of human neutrophils by the receptor agonist N-formylmethionyl-leucyl-phenylalanine (fMLP) results in a respiratory burst, catalysed by an NADPH oxidase. Concomitantly, phospholipase D (PLD) is activated. To investigate the role of protein kinase C (PKC) in these neutrophil responses, we have compared the effects of staurosporine and a structural analogue of staurosporine (cgp41251), that reflects a higher selectivity towards PKC [Meyer, Regenass, Fabbro, Alteri, Rösel, Müller, Caravatti and Matter (1989) Int. J. Cancer 43, 851-856]. Both staurosporine and cgp41251 dose-dependently inhibited the production of superoxide induced by phorbol 12-myristate 13-acetate (PMA). Both compounds also caused inhibition of the fMLP-induced respiratory burst, but with a lower efficacy during the initiation phase of this response. This latter observation cannot be taken as evidence against PKC involvement in the activation of the respiratory burst, because pretreatment of neutrophils with ionomycin before PMA stimulation also results in a lower efficacy of inhibition. Activation of PLD by fMLP was enhanced in the presence of staurosporine, but not in the presence of cgp41251. Enhancement of PLD activation was also observed in the presence of H-89, an inhibitor of cyclic-AMP-dependent protein kinase (PKA). Both staurosporine and H-89 reversed the dibutyryl-cyclic-AMP-induced inhibition of PLD activation, whereas cgp41251 was without effect. These results indicate that the potentiating effect of staurosporine on PLD activation induced by fMLP does not reflect a feedback inhibition by PKC activation, but instead a feedback inhibition by PKC activation. Taken together, our results indicate that in human neutrophils: (i) PKC activity is not essential for fMLP-induced activation of PLD; (ii) PKC activity does play an essential role in the activation of the respiratory burst by fMLP, other than mediating or modulating PLD activation; (iii) there exists a negative-feedback mechanism on fMLP-induced PLD activation by concomitant activation of PKA.

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Comparison of the roles of calmodulin and protein kinase C in activation of the human neutrophil respiratory burst

Biochemical and Biophysical Research Communications ◽

10.1016/0006-291x(87)90450-5 ◽

1987 ◽

Vol 142 (1) ◽

pp. 53-62 ◽

Cited By ~ 17

Author(s):

Clifford D. Wright ◽

Michael D. Hoffman

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Respiratory Burst ◽

Human Neutrophil ◽

Kinase C ◽

Neutrophil Respiratory Burst

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Conventional protein kinase C in the brain: 40 years later

Neuronal Signaling ◽

10.1042/ns20160005 ◽

2017 ◽

Vol 1 (2) ◽

Cited By ~ 15

Author(s):

Julia A. Callender ◽

Alexandra C. Newton

Keyword(s):

Cell Death ◽

Protein Kinase C ◽

Protein Kinase ◽

Loss Of Function ◽

Membrane Phospholipids ◽

Kinase C ◽

Pkc Isozymes ◽

Hydrolysis Of ◽

The Brain

Protein kinase C (PKC) is a family of enzymes whose members transduce a large variety of cellular signals instigated by the receptor-mediated hydrolysis of membrane phospholipids. While PKC has been widely implicated in the pathology of diseases affecting all areas of physiology including cancer, diabetes, and heart disease—it was discovered, and initially characterized, in the brain. PKC plays a key role in controlling the balance between cell survival and cell death. Its loss of function is generally associated with cancer, whereas its enhanced activity is associated with neurodegeneration. This review presents an overview of signaling by diacylglycerol (DG)-dependent PKC isozymes in the brain, and focuses on the role of the Ca2+-sensitive conventional PKC isozymes in neurodegeneration.

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Protein Kinase C Quality Control by Phosphatase PHLPP1 Unveils Loss-of-Function Mechanism in Cancer

Molecular Cell ◽

10.1016/j.molcel.2019.02.018 ◽

2019 ◽

Vol 74 (2) ◽

pp. 378-392.e5 ◽

Cited By ~ 7

Author(s):

Timothy R. Baffi ◽

An-Angela N. Van ◽

Wei Zhao ◽

Gordon B. Mills ◽

Alexandra C. Newton

Keyword(s):

Quality Control ◽

Protein Kinase C ◽

Protein Kinase ◽

Loss Of Function ◽

Function Mechanism ◽

Kinase C

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Mechanism of inhibition by cyclic AMP of protein kinase C-triggered respiratory burst in Ehrlich ascites tumour cells

Cellular Signalling ◽

10.1016/0898-6568(92)90046-b ◽

1992 ◽

Vol 4 (6) ◽

pp. 651-663 ◽

Cited By ~ 8

Author(s):

Bharathi P. Salimath ◽

G. Savitha

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Cyclic Amp ◽

Respiratory Burst ◽

Kinase C ◽

Mechanism Of Inhibition ◽

Ehrlich Ascites ◽

Ehrlich Ascites Tumour ◽

Ascites Tumour Cells ◽

Ehrlich Ascites Tumour Cells

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Early signalling events implicated in leukotriene B4-induced activation of the NADPH oxidase in eosinophils: role of Ca2+, protein kinase C and phospholipases C and D

Biochemical Journal ◽

10.1042/bj3100795 ◽

1995 ◽

Vol 310 (3) ◽

pp. 795-806 ◽

Cited By ~ 32

Author(s):

R S Perkins ◽

M A Lindsay ◽

P J Barnes ◽

M A Giembycz

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Nadph Oxidase ◽

Respiratory Burst ◽

Leukotriene B4 ◽

Human Neutrophils ◽

H2o2 Production ◽

Intact Cells ◽

Kinase C ◽

H2o2 Generation

The early signalling events that may ultimately contribute to the assembly and subsequent activation of the NADPH oxidase in guinea-pig peritoneal eosinophils were investigated in response to leukotriene B4 (LTB4). LTB4 promoted a rapid, transient and receptor-mediated increase in the rate of H2O2 generation that was potentiated by R 59 022, a diradylglycerol (DRG) kinase inhibitor, implicating protein kinase C (PKC) in the genesis of this response. This conclusion was supported by the finding that the PKC inhibitor, Ro 31-8220, attenuated (by about 30%) the peak rate of LTB4-induced H2O2 generation under conditions where the same response evoked by 4 beta-phorbol 12,13-dibutyrate (PDBu) was inhibited by more than 90%. Paradoxically, Ro 31-8220 doubled the amount of H2O2 produced by LTB4 which may relate to the ability of PKC to inhibit cell signalling through phospholipase C (PLC). Indeed, Ro 31-8220 significantly enhanced LTB4-induced Ins(1,4,5)P3 accumulation and the duration of the Ca2+ transient in eosinophils. Experiments designed to assess the relative importance of DRG-mobilizing phospholipases in LTB4-induced oxidase activation indicated that phospholipase D (PLD) did not play a major role. Thus, although H2O2 generation was abolished by butan-1-ol, this was apparently unrelated to the inhibition of PLD, as LTB4 failed to stimulate the formation of Ptd[3H]BuOH in [3H]butan-1-ol-treated eosinophils. Rather, the inhibition was probably due to the ability of butan-1-ol to increase the eosinophil cyclic AMP content. In contrast, Ca(2+)- and PLC-driven mechanisms were implicated in H2O2 generation, as LTB4 elevated the Ins(1,4,5)P3 content and intracellular free Ca2+ concentration in intact cells, and cochelation of extracellular and intracellular Ca2+ significantly attenuated LTB4-induced H2O2 generation. Pretreatment of eosinophils with wortmannin did not affect LTB4-induced H2O2 production at concentrations at which it abolished the respiratory burst evoked by formylmethionyl-leucylphenylalanine in human neutrophils. Collectively, these data suggest that LTB4 activates the NADPH oxidase in eosinophils by PLD- and PtdIns 3-kinase-independent mechanisms that involve Ca2+, PLC and PKC. Furthermore, the activation of additional pathways that do not require Ca2+ is also suggested by the finding that LTB4 evoked a significant respiratory burst in Ca(2+)-depleted cells.

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