Sphingosine 1-phosphate signaling through its receptor S1P5 promotes chromosome segregation and mitotic progression
Sphingosine 1-phosphate signaling through its receptor S1P5 promotes chromosome segregation and mitotic progression
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DOI：
10.1126/scisignal.aah4007
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发表时间：
2017-03-28
影响因子：
7.3
通讯作者：
Hatzoglou, Anastassia
中科院分区：
文献类型：
--
作者：
Andrieu, Guillaume;Ledoux, Adeline;Hatzoglou, Anastassia
鞘氨醇激酶 1 (SphK1) 促进细胞增殖和存活，其丰度在肿瘤中通常会增加。 SphK1 产生信号脂质 1-磷酸鞘氨醇 (S1P)，该信号激活下游 5 个 G 蛋白偶联受体 (S1P(1-5)) 的信号级联，以调节血管和免疫系统功能并促进增殖。我们发现了 SphK1-S1P 通路的一个新功能，特别是在有丝分裂的控制中。 HeLa 细胞中 SphK1 的缺失导致中期停滞，而其过度表达或激活则加速有丝分裂。增加 S1P 丰度会促进有丝分裂进展，超越纺锤体组装检查点 (SAC)，并导致染色体分离缺陷。 S1P 通过转运蛋白 SPNS2 分泌，并通过结合并激活细胞外侧的 S1P(5) 刺激有丝分裂，然后激活细胞内磷脂酰肌醇 3-激酶 (PI3K)-AKT 途径。 S1P(5) 的敲低可防止 S1P 诱导的纺锤体缺陷表型。 RNA 干扰分析表明，有丝分裂激酶 Polo 样激酶 1 (PLK1) 是 HeLa 细胞中 S1P-S1P(5) 信号诱导有丝分裂的重要效应器。我们的研究结果确定了促进有丝分裂进展的细胞外信号和下游途径，并可能表明抑制癌细胞增殖的潜在治疗靶点。
Sphingosine kinase 1 (SphK1) promotes cell proliferation and survival, and its abundance is often increased in tumors. SphK1 produces the signaling lipid sphingosine 1-phosphate (S1P), which activates signaling cascades downstream five G protein-coupled receptors (S1P(1-5)) to modulate vascular and immune system function and promote proliferation. We identified a new function of the SphK1-S1P pathway specifically in the control of mitosis. SphK1 depletion in HeLa cells caused prometaphase arrest, whereas its overexpression or activation accelerated mitosis. Increasing the abundance of S1P promoted mitotic progression, overrode the spindle assembly checkpoint (SAC), and led to chromosome segregation defects. S1P was secreted through the transporter SPNS2 and stimulated mitosis by binding to and activating S1P(5) on the extracellular side, which then activated the intracellular phosphatidylinositol 3-kinase (PI3K)-AKT pathway. Knockdown of S1P(5) prevented the S1P-induced spindle defect phenotype. RNA interference assays revealed that the mitotic kinase Polo-like kinase 1 (PLK1) was an important effector of S1P-S1P(5) signaling-induced mitosis in HeLa cells. Our findings identify an extracellular signal and the downstream pathway that promotes mitotic progression and may indicate potential therapeutic targets to inhibit the proliferation of cancer cells.