The hormonally regulated Ca2+-dependent enzyme, cytosolic phospholipase A2 (cPLA2) is activated by a range of inflammatory stimuli. Tumour necrosis factor-α (TNF) is one of the first known stimuli for cPLA2 but it is not known whether both TNF receptor subtypes are involved in activating the lipase. In the present study, we show for the first time that both type I 55 kDa TNFR (TNFR1) and type II 75 kDa TNFR (TNFR2) stimulate cPLA2 enzyme, but with distinct signalling mechanisms. TNFR1 activates mitogen-activated protein kinase (MAPK) and p38MAPK. TNFR1 then phosphorylates and activates cPLA2 in a MAPK-dependent fashion. Furthermore, TNFR1 causes the translocation and caspase-dependent proteolysis of cPLA2 as part of its activation profile. TNFR2, on the other hand, does not cause the phosphorylation of cPLA2 as it does not activate MAPK or p38MAPK, but instead activates cPLA2 by causing its translocation to plasma membrane and perinuclear subcellular regions. TNFR2 activation causes a delayed, slight increase in [Ca2+]i of <50 nM that may contribute towards the translocation and activation of cPLA2. Therefore both TNF receptor subtypes play a role in cPLA2 activation, but by means of separate signal-transduction pathways.
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September 2003
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Research Article|
September 01 2003
Distinct regulation of cytosolic phospholipase A2 phosphorylation, translocation, proteolysis and activation by tumour necrosis factor-receptor subtypes
Orla J. JUPP;
Orla J. JUPP
∗Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, U.K.
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Peter VANDENABEELE;
Peter VANDENABEELE
†Molecular Signalling and Cell Death Unit, Department for Molecular Biomedical Research, VIB, University of Gent, Ledeganckstraat 35, B-9000 Gent, Belgium
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David J. MacEWAN
David J. MacEWAN
1
∗Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, U.K.
1To whom correspondence should be addressed (e-mail david.macewan@abdn.ac.uk).
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Publisher: Portland Press Ltd
Received:
May 13 2003
Revision Received:
May 29 2003
Accepted:
June 04 2003
Accepted Manuscript online:
June 04 2003
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2003
2003
Biochem J (2003) 374 (2): 453–461.
Article history
Received:
May 13 2003
Revision Received:
May 29 2003
Accepted:
June 04 2003
Accepted Manuscript online:
June 04 2003
Citation
Orla J. JUPP, Peter VANDENABEELE, David J. MacEWAN; Distinct regulation of cytosolic phospholipase A2 phosphorylation, translocation, proteolysis and activation by tumour necrosis factor-receptor subtypes. Biochem J 1 September 2003; 374 (2): 453–461. doi: https://doi.org/10.1042/bj20030705
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