Journal
CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 66, Issue 19, Pages 3207-3218Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00018-009-0106-3
Keywords
Sphingosine 1-phosphate; Insulin; Insulin receptor; Protein-tyrosine phosphatase; Reactive oxygen species; Glucose uptake
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Funding
- University of Florence (ex 60%)
- Ente Cassa di Risparmio di Pistoia e Pescia
- Italian Association
- Interuniversity Biotechnology Consortium
- Ente Cassa di Risparmio di Firenze
- Tuscany Regional Project TRESOR
- Associazione Italiana per la Ricerca sul Cancro Funding Source: Custom
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Sphingosine 1-phosphate (S1P) is a bioactive lipid that acts through a family of G-protein-coupled receptors. Herein, we report evidence of a novel redox-based cross-talk between S1P and insulin signaling pathways. In skeletal muscle cells S1P, through engagement of its S1P(2) receptor, is found to produce a transient burst of reactive oxygen species through a calcium-dependent activation of the small GTPase Rac1. S1P-induced redox-signaling is sensed by protein tyrosine phosphatase-1B, the main negative regulator of insulin receptor phosphorylation, which undergoes oxidation and enzymatic inhibition. This redox-based inhibition of the phosphatase provokes a ligand-independent trans-phosphorylation of insulin receptor and a strong increase in glucose uptake. Our results propose a new role of S1P, recognizing the lipid as an insulin-mimetic cue and pointing at reactive oxygen species as critical regulators of the cross-talk between S1P and insulin pathways. Any possible implication of S1P-directed insulin signaling in diabetes and insulin resistance remains to be established.
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