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Titolo:
Ceramide dissociates 3 '-phosphoinositide production from pleckstrin homology domain translocation
Autore:
Stratford, S; DeWald, DB; Summers, SA;
Indirizzi:
Colorado State Univ, Dept Biochem & Mol Biol, Ft Collins, CO 80523 USA Colorado State Univ Ft Collins CO USA 80523 iol, Ft Collins, CO 80523 USA Utah State Univ, Dept Biol, Logan, UT 84322 USA Utah State Univ Logan UT USA 84322 e Univ, Dept Biol, Logan, UT 84322 USA
Titolo Testata:
BIOCHEMICAL JOURNAL
, volume: 354, anno: 2001,
parte:, 2
pagine: 359 - 368
SICI:
0264-6021(20010301)354:<359:CD3'PF>2.0.ZU;2-5
Fonte:
ISI
Lingua:
ENG
Soggetto:
PROTEIN-KINASE-B; GUANINE-NUCLEOTIDE EXCHANGE; NERVE-GROWTH-FACTOR; CELL-CYCLE ARREST; PHOSPHATIDYLINOSITOL 3,4,5-TRISPHOSPHATE; GLUCOSYLCERAMIDE SYNTHASE; QUANTIFYING CERAMIDE; GLUT4 TRANSLOCATION; DIGLYCERIDE KINASE; GLUCOSE-TRANSPORT;
Keywords:
Akt; GLUT4 translocation; phosphoinositide 3-kinase; protein kinase B; sphingolipids;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
53
Recensione:
Indirizzi per estratti:
Indirizzo: Summers, SA Colorado State Univ, Dept Biochem & Mol Biol, Ft Collins, CO 80523 USA Colorado State Univ Ft Collins CO USA 80523 ins, CO 80523 USA
Citazione:
S. Stratford et al., "Ceramide dissociates 3 '-phosphoinositide production from pleckstrin homology domain translocation", BIOCHEM J, 354, 2001, pp. 359-368

Abstract

Numerous hormones, cytokines and transforming oncogenes activate phosphoinositide 3-kinase (PI-3K), a lipid kinase that initiates signal transductioncascades regulating cellular proliferation, survival, protein synthesis and glucose metabolism. PI-3K catalyses the production of the 3'-phosphoinositides PtdIns(3,4)P-2 and PtdIns(3,4,5)P-3, which recruit downstream effector enzymes to the membrane via their pleckstrin homology (PH) domains. Recent studies have indicated that another signalling lipid, the sphingolipid ceramide, inhibits several PI-3K-dependent events, including insulin-stimulated glucose uptake and growth-factor-stimulated cell survival. Here we show that ceramide analogues specifically prevent the recruitment of the PtdIns(3,4,5)P-3-binding proteins Akt/protein kinase B (PKB) or the general receptor for phosphoinositides-1 (GRP1), Specifically, the short-chain ceramide derivative C2-ceramide inhibited the platelet-derived growth factor (PDGF)-stimulated translocation of full-length Akt/PKB, as well as truncated proteins encoding only the PH domains of Akt/PKB or GRP1. C2-ceramide did not alter the membrane localization of the PH domain for phospholipase C delta, which preferentially binds PtdIns(4,5)P-2, nor did it affect the PDGF-stimulated production of Ptdins(3,4)P-2 or PtdIns(3,4,5)P-3. Interestingly, a glucosylceramide synthase inhibitor, 1-phenyl-2-decanoylamino-3-morpholinopropan-1-ol (PDMP), shown previously to increase intracellular ceramide concentrations without affecting PI-3K [Rani, Abe, Chang, Rosenzweig, Saltiel, Radin and Shayman (1995) J. Biol. Chem. 270, 2859-2867], recapitulated the inhibitory effects of Ca-ceramide on PDGF-stimulated Akt/PKB phosphorylation. These studies indicate that ceramide prevents the translocation of certain PtdIns(3,4,5)P-3-binding proteins, despite the presence of a full complementof PtdIns(3,4)P-2 or PtdIns(3,4,5)P-3. Furthermore, these findings suggesta mechanism by which stimuli that induce ceramide synthesis could negate the fundamental signalling pathways initiated by PI-3K.

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Documento generato il 10/07/20 alle ore 09:13:16