Rapizzi Elena, Taddei Maria Letizia, Fiaschi Tania, Donati Chiara, Bruni Paola, Chiarugi Paola
Department of Biochemical Sciences, University of Florence, Viale G.B. Morgagni 50, 50134, Florence, Italy.
Cell Mol Life Sci. 2009 Oct;66(19):3207-18. doi: 10.1007/s00018-009-0106-3. Epub 2009 Aug 7.
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.
1-磷酸鞘氨醇（S1P）是一种通过G蛋白偶联受体家族发挥作用的生物活性脂质。在此，我们报告了S1P与胰岛素信号通路之间基于氧化还原的新型相互作用的证据。在骨骼肌细胞中，S1P通过其S1P(2)受体的作用，被发现通过小GTPase Rac1的钙依赖性激活产生短暂的活性氧爆发。S1P诱导的氧化还原信号由蛋白酪氨酸磷酸酶-1B感知，蛋白酪氨酸磷酸酶-1B是胰岛素受体磷酸化的主要负调节因子，其会发生氧化和酶抑制。这种基于氧化还原的磷酸酶抑制引发了胰岛素受体的配体非依赖性反式磷酸化，并导致葡萄糖摄取大幅增加。我们的结果提出了S1P的新作用，将该脂质识别为胰岛素模拟信号，并指出活性氧是S1P与胰岛素信号通路之间相互作用的关键调节因子。S1P定向胰岛素信号在糖尿病和胰岛素抵抗中的任何可能影响仍有待确定。
