Distinct regulation of cytosolic phospholipase A2 phosphorylation, translocation, proteolysis and activation by tumour necrosis factor-receptor subtypes.
The hormonally regulated Ca(2+)-dependent enzyme, cytosolic phospholipase A(2) (cPLA(2)) is activated by a range of inflammatory stimuli. Tumour necrosis factor-alpha (TNF) is one of the first known stimuli for cPLA(2) 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 cPLA(2) enzyme, but with distinct signalling mechanisms. TNFR1 activates mitogen-activated protein kinase (MAPK) and p38MAPK. TNFR1 then phosphorylates and activates cPLA(2) in a MAPK-dependent fashion. Furthermore, TNFR1 causes the translocation and caspase-dependent proteolysis of cPLA(2) as part of its activation profile. TNFR2, on the other hand, does not cause the phosphorylation of cPLA(2) as it does not activate MAPK or p38MAPK, but instead activates cPLA(2) by causing its translocation to plasma membrane and perinuclear subcellular regions. TNFR2 activation causes a delayed, slight increase in [Ca(2+)](i) of <50 nM that may contribute towards the translocation and activation of cPLA(2). Therefore both TNF receptor subtypes play a role in cPLA(2) activation, but by means of separate signal-transduction pathways.
Jupp
Orla J
OJ
Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK.
Vandenabeele
Peter
P
MacEwan
David J
DJ
D015703:Antigens, CD / Q000502:physiology*; D016718:Arachidonic Acid / Q000378:metabolism; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D003600:Cytosol / Q000201:enzymology* / Q000648:ultrastructure; D010450:Endopeptidases / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D020935:MAP Kinase Signaling System / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology; D010741:Phospholipases A / Q000378:metabolism* / Q000502:physiology; D054467:Phospholipases A2; D010766:Phosphorylation; D020033:Protein Isoforms / Q000502:physiology; D021381:Protein Transport; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D020033:Protein Isoforms; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D016718:Arachidonic Acid; D020928:Mitogen-Activated Protein Kinases; D010741:Phospholipases A; D054467:Phospholipases A2; D010450:Endopeptidases; D002118:Calcium