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Titolo:
Tumour necrosis factor-alpha activation of protein kinase B in WEHI-164 cells is accompanied by increased phosphorylation of Ser(473), but not Thr(308)
Autore:
OToole, A; Moule, SK; Lockyer, PJ; Halestrap, AP;
Indirizzi:
Univ Bristol, Sch Med Sci, Dept Biochem, Bristol BS8 1TD, Avon, England Univ Bristol Bristol Avon England BS8 1TD Bristol BS8 1TD, Avon, England
Titolo Testata:
BIOCHEMICAL JOURNAL
, volume: 359, anno: 2001,
parte:, 1
pagine: 119 - 127
SICI:
0264-6021(20011001)359:<119:TNFAOP>2.0.ZU;2-5
Fonte:
ISI
Lingua:
ENG
Soggetto:
NF-KAPPA-B; GLYCOGEN-SYNTHASE KINASE-3; SIGNALING PATHWAY; INSULIN; PROLIFERATION; MECHANISMS; 3-KINASE; AKT;
Keywords:
ADP-ribosylation factor nucleotide-binding site; opener; cell survival; insulin-like growth factor 1; phosphoinositide-dependent kinase; phosphoinositide 3-kinase;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
32
Recensione:
Indirizzi per estratti:
Indirizzo: Halestrap, AP Univ Bristol, Sch Med Sci, Dept Biochem, Bristol BS8 1TD, Avon, England Univ Bristol Bristol Avon England BS8 1TD TD, Avon, England
Citazione:
A. O'Toole et al., "Tumour necrosis factor-alpha activation of protein kinase B in WEHI-164 cells is accompanied by increased phosphorylation of Ser(473), but not Thr(308)", BIOCHEM J, 359, 2001, pp. 119-127

Abstract

Tumour necrosis factor-alpha (TNF-alpha) may activate both cell survival and cell death pathways. In the murine fibrosarcoma cell line WEHI-164, physiological concentrations (1ng/ml) of TNF-alpha induced wortmannin-sensitivecell ruffling characteristic of the phosphoinositide 3-kinase (PI3-kinase)activation associated with cell survival. Wortmannin also enhanced cell death induced by TNF-alpha in the presence of actinomycin D, confirming that TNF-alpha activates a transcription-independent survival pathway requiring PI3-kinase activity. Both TNF-alpha and insulin-like growth factor 1 (IGF-1) caused a 6-10-fold wortmannin-sensitive increase in protein kinase B (PKB) activity within 5 min. For IGF-1, this was associated with an increase inphosphorylation of both Thr(308) and Ser(473) whereas for TNF-alpha only phosphorylation of Ser(473) was increased. even in the presence of okadaic acid to inhibit protein phosphatases 1 and 2A. TNF-alpha did not decrease the phosphorylation of Thr(308) induced by IGF-1, implying that TNF-alpha neither inhibits phosphoinositide-dependent kinase 1 (PDK1) nor activates an opposing phosphatase. In WEHI cellsoverexpressing a form of PKB. IGF-1 increased phosphorylation of Ser(473) on PKB, but not its kinase activity, whereas TNF-alpha failed to induce Ser(473) phosphorylation or kinase activationof either overexpressed T308A or wild-type PKB (where T308A is the mutant bearing the substitution Thr(308)-->A). IGF-1 caused translocation of green-fluorescent-protein-tagged ADP-ribosylation factor nucleotide-binding siteopener (ARNO) to the plasma membrane of WEHI cells, but this was not detected with TNF-alpha. We conclude that, at physiological concentrations, TNF-alpha activates endogenous PKB by stimulating PDK2 (increase in Ser(473) phosphorylation) in a PI3-kinase-dependent (wortmannin-sensitive) manner, without causing detectable stimulation of PDK1 (no increase in Thr(308) phosphorylation) or ARNO translocation. Possible explanations of these observations are discussed.

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Documento generato il 23/09/20 alle ore 12:00:37