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Vol. 63, Issue 4, 886-895, April 2003
: A Novel Pathway Involving Sequential Activation of
Neutral Sphingomyelinase, Phosphatidylinositol-3' kinase, and Akt
Vita-Salute University-DIBIT H San Raffaele Institute, Milano,
Italy (R.B., C.P., E.C.); Department of Pharmaco-Biology, University of
Calabria, Rende, Italy (C.P., E.C.); Department of Pharmaco-Biology,
University of Catanzaro "Magna Graecia", Italy (S.B., N.B.); The
Wolfson Institute for Biomedical Research, University College London,
London, United Kingdom (S.M.); Consiglio Nazionale delle Ricerche,
Institute of Neuroscience, Cellular and Molecular Pharmacology, Milano,
Italy (N.B., E.C.)
Activation of endothelial nitric-oxide synthase (eNOS) has been shown
to occur through various pathways involving increases in the cytosolic
Ca2+ concentration, activation of the
phosphatidylinositol-3' kinase/Akt pathway, as well as regulation by
other kinases and by protein-protein interactions. We have recently
reported that eNOS, expressed in an inducible HeLa Tet-off cell line,
is activated by tumor necrosis factor-
(TNF-) in a previously
undescribed pathway that involves the lipid messenger ceramide. We have
now characterized this pathway. We report here that eNOS activation in
response to TNF- correlated with phosphorylation of Akt at Ser 473 and of eNOS itself at Ser 1179. Akt and eNOS phosphorylation, as well
as eNOS activation, were blocked by inhibitors of both
phosphatidylinositol-3' kinase and neutral sphingomyelinase. In
contrast, although acid sphingomyelinase was also stimulated by
TNF-, its inhibition was without effect. The activation of neutral
sphingomyelinase triggered by TNF- was insensitive to
phosphatidylinositol-3' kinase inhibitors. Taken together, these
results indicate that eNOS activation by TNF- occurs through
sequential activation of neutral sphingomyelinase and of the
phosphatidylinositol-3' kinase/Akt pathway. The time course of eNOS
activation induced through this pathway was markedly different from
that triggered by ATP and epidermal growth factor, which activate eNOS
through an increase in intracellular Ca2+ concentration and
through a sphingomyelinase-independent stimulation of the
phosphatidylinositol-3' kinase/Akt pathway, respectively. The novel
pathway of activation of eNOS described here may have broad biological
relevance because neutral sphingomyelinase is activated not only by
TNF- but also by a variety of other physiological and pathological stimuli.
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