Akt activation induced by lysophosphatidic acid and sphingosine-1-phosphate requires both mitogen-activated protein kinase kinase and p38 mitogen-activated protein kinase and is cell-line specific
Akt activation induced by lysophosphatidic acid and sphingosine-1-phosphate requires both mitogen-activated protein kinase kinase and p38 mitogen-activated protein kinase and is cell-line specific
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DOI：
10.1124/mol.62.3.660
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发表时间：
2002-09-01
影响因子：
3.6
通讯作者：
Xu, Y
中科院分区：
文献类型：
--
作者：
Baudhuin, LM;Cristina, KL;Xu, Y
溶血磷脂酸（LPA）和鞘氨醇-1-磷酸（S1 P）用于激活卵巢癌细胞中Akt的信号通路在这里进行了研究。我们第一次表明，使用药理学和遗传抑制剂，激酶活性和S473磷酸化的Akt诱导LPA和S1 P需要两个丝裂原活化蛋白（MAP）激酶（MEK）和p38 MAP激酶，和MEK很可能是上游的p38，在HEY卵巢癌细胞。MEK和p38的需求是细胞类型和刺激特异性的。在我们测试的12个细胞系中，11个对LPA和S1 P有反应，所有的反应细胞系都需要p38，但只有9个需要MEK。在测试的不同刺激物中，血小板衍生生长因子以MEK和p38依赖性方式刺激Akt的S473磷酸化。然而，表皮生长因子、凝血酶和内皮素-1刺激的Akt S473磷酸化需要p38而不是MEK。另一方面，在HEY细胞中，胰岛素刺激Akt S473磷酸化，而不依赖于MEK和p38。LPA/S1 P刺激的T308磷酸化需要MEK而不是p38激活。MEK和p38激活足以使HEY细胞中Akt S473磷酸化，但不能使T308磷酸化。与S1 P和PDGF相反，LPA需要Rho进行Akt S473磷酸化，并且Rho位于磷脂酰肌醇3-激酶（PI 3-K）的上游。LPA/S1 P诱导的Akt活化可能参与细胞存活，因为LPA和S1 P处理HEY卵巢癌细胞导致紫杉醇诱导的caspase-3活性以PI 3-K/ MEK/p38依赖的方式降低。
The signaling pathways that lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) use to activate Akt in ovarian cancer cells are investigated here. We show for the first time, with the use of both pharmacological and genetic inhibitors, that the kinase activity and S473 phosphorylation of Akt induced by LPA and S1P requires both mitogen-activated protein (MAP) kinase kinase (MEK) and p38 MAP kinase, and MEK is likely to be upstream of p38, in HEY ovarian cancer cells. The requirement for both MEK and p38 is cell type- and stimulus-specific. Among 12 cell lines that we tested, 11 respond to LPA and S1P and all of the responsive cell lines require p38 but only nine of them require MEK. Among different stimuli tested, platelet-derived growth factor stimulates S473 phosphorylation of Akt in a MEK- and p38-dependent manner. However, epidermal growth factor, thrombin, and endothelin-1-stimulated Akt S473 phosphorylation require p38 but not MEK. Insulin, on the other hand, stimulates Akt S473 phosphorylation independent of both MEK and p38 in HEY cells. T308 phosphorylation stimulated by LPA/S1P requires MEK but not p38 activation. MEK and p38 activation were sufficient for Akt S473 but not T308 phosphorylation in HEY cells. In contrast to S1P and PDGF, LPA requires Rho for Akt S473 phosphorylation, and Rho is upstream of phosphatidylinositol 3-kinase (PI3-K). LPA/S1P-induced Akt activation may be involved in cell survival, because LPA and S1P treatment in HEY ovarian cancer cells results in a decrease in paclitaxel-induced caspase-3 activity in a PI3-K/ MEK/p38-dependent manner.