Cell signaling associated with Na(+)/K(+)-ATPase: activation of phosphatidylinositide 3-kinase IA/Akt by ouabain is independent of Src.
Cell signaling associated with Na(+)/K(+)-ATPase: activation of phosphatidylinositide 3-kinase IA/Akt by ouabain is independent of Src.
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DOI：
10.1021/bi4011804
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发表时间：
2013-12-17
期刊：
影响因子：
2.9
通讯作者：
Liu, Lijun
中科院分区：
文献类型：
--
作者：
Wu, Jian;Akkuratov, Evgeny E.;Bai, Yan;Gaskill, Cassie Miller;Askari, Amir;Liu, Lijun
将完整细胞暴露于 Na+/K+-ATP 酶的选择性抑制剂（例如哇巴因）会激活多种与生长相关的细胞信号传导途径。有人提出，这些途径的初始事件是哇巴因与质膜的 Na+/K+-ATP 酶预先存在的 Src 复合物结合。这项工作的目的是评估 Src 在哇巴因诱导的磷脂酰肌醇 3-激酶 1A (PI3K1A) 激活中的作用及其下游后果。当缺乏 Src 的成纤维细胞（SYF 细胞）和对照（Src++ 细胞）暴露于哇巴因、PI3K1A、Akt 时，两种细胞系的增殖生长均受到类似的刺激。 Src 抑制剂 PP2 不能阻止哇巴因诱导的 Akt 激活。相反，在SYF细胞中ERK1/2不被哇巴因激活，但在Src++细胞中被刺激； PP2 阻止了这一点。在分离的成年小鼠心肌细胞中，哇巴因诱导肥大生长，PP2 也不能阻止哇巴因诱导的 Akt 激活和由此产生的肥大。在 SYF 细胞、Src++ 细胞和成体心肌细胞中，哇巴因诱导的 Na+/K+-ATPase α 亚基与 PI3K1A p85 亚基的免疫共沉淀水平增加。结合之前的研究结果，本文提出的结果表明（a）如果存在 Src 和 Na+/K+-ATPase 的预先形成的复合物，则与哇巴因通过 Na+/K+-ATPase 诱导的 PI3K1A/Akt 通路激活无关；（b）Na+/K+-ATPase 与 PI3K1A 的连接更有可能但尚未确定的机制是哇巴因诱导的富含脯氨酸的相互作用。 Na+/K+-ATPase α 亚基的结构域与 PI3K1A p85 亚基的 SH3 结构域。
Exposure of intact cells to selective inhibitors of Na+/K+-ATPase such as ouabain activates several growth-related cell signaling pathways. It has been suggested that the initial event of these pathways is the binding of ouabain to a preexisting complex of Src with Na+/K+-ATPase of the plasma membrane. The aim of this work was to evaluate the role of Src in the ouabain-induced activation of phosphatidylinositide 3-kinase 1A (PI3K1A) and its downstream consequences. When fibroblasts devoid of Src (SYF cells) and controls (Src++ cells) were exposed to ouabain, PI3K1A, Akt, and proliferative growth were similarly stimulated in both cell lines. Ouabain-induced activation of Akt was not prevented by the Src inhibitor PP2. In contrast, ERK1/2 were not activated by ouabain in SYF cells but were stimulated in Src++ cells; this was prevented by PP2. In isolated adult mouse cardiac myocytes, where ouabain induces hypertrophic growth, PP2 also did not prevent ouabain-induced activation of Akt and the resulting hypertrophy. Ouabain-induced increases in the levels of co-immunoprecipitation of the α-subunit of Na+/K+-ATPase with the p85 subunit of PI3K1A were noted in SYF cells, Src++ cells, and adult cardiac myocytes. In conjunction with previous findings, the results presented here indicate that (a) if there is a preformed complex of Src and Na+/K+-ATPase, it is irrelevant to ouabain-induced activation of the PI3K1A/Akt pathway through Na+/K+-ATPase and (b) a more likely, but not established, mechanism of linkage of Na+/K+-ATPase to PI3K1A is the ouabain-induced interaction of a proline-rich domain of the α-subunit of Na+/K+-ATPase with the SH3 domain of the p85 subunit of PI3K1A.
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