The generation of proinflammatory eicosanoids in response to tumor necrosis
factor (TNF) involves the activation of cytosolic phospholipase A(2) (cPLA
(2)), presumably by phosphorylation through extracellular signal-regulated
kinases (ERR), Earlier results had suggested that a pathway involving the p
55 TNF receptor (TNF-R55), neutral sphingomyelinase (N-SMase), and c-Raf-l
activates ERK and cPLA(2). We have previously shown that a cytoplasmic regi
on of TNF-R55 distinct from the death domain regulates the activation of N-
SMase through binding of the adapter protein FAN. Analysis of embryonal fib
roblasts from FAN knockout mice revealed that TNF-induced activation of bot
h ERK and cPLA(2) occurs without involvement of FAN. Furthermore, we provid
e evidence that the TNF-dependent activation of ERK and cPLA(2) requires th
e intact death domain of TNF-R55. Finally, we demonstrate that in murine fi
broblasts cPLA(2) is phosphorylated in response to TNF solely by ERK, but n
ot by p38 mitogen-activated protein kinase, suggesting a signaling pathway
from TNF-R55 via the death domain to ERK and cPLA(2). (C) 2000 Academic Pre
ss.