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Sphingosine 1-phosphate increases glucose uptake through trans-activation of insulin receptor

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Abstract

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 S1P2 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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Acknowledgements

This research was supported by grants from the University of Florence (ex 60%) and Ente Cassa di Risparmio di Pistoia e Pescia to P.B. and by the Italian Association for Cancer Research, the Interuniversity Biotechnology Consortium, the Ente Cassa di Risparmio di Firenze, and the Tuscany Regional Project TRESOR to P.C.

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Correspondence to Paola Chiarugi.

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E. Rapizzi and M. L. Taddei contributed equally to this work.

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Rapizzi, E., Taddei, M.L., Fiaschi, T. et al. Sphingosine 1-phosphate increases glucose uptake through trans-activation of insulin receptor. Cell. Mol. Life Sci. 66, 3207–3218 (2009). https://doi.org/10.1007/s00018-009-0106-3

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