Elevated inorganic phosphate stimulates Akt-ERK1/2-Mnk1 signaling in human lung cells
Elevated inorganic phosphate stimulates Akt-ERK1/2-Mnk1 signaling in human lung cells
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DOI：
10.1165/rcmb.2005-0477oc
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发表时间：
2006-11-01
影响因子：
6.4
通讯作者：
Cho, Myung-Haing
中科院分区：
文献类型：
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作者：
Chang, Seung-Hee;Yu, Kyeong Nam;Cho, Myung-Haing
无机磷酸盐 (Pi) 在多种细胞功能中发挥着关键作用。在三类钠/磷酸盐协同转运蛋白 (NPT) 中，已在哺乳动物肺中鉴定出两种类型。 Pi 作为一种新型信号分子的潜在重要性以及 NPT 的肺部表达与包括癌症在内的多种肺部疾病的不良预后相关，促使我们开始定义 Pi 调节非致瘤性人支气管上皮细胞的途径。 Pi特异性激活Thr308上的Akt磷酸化，激活的信号在Raf/MEK/ERK信号传导上传递。在这里，我们报告 Pi 通过激活 ERK 级联并通过 Akt 介导的 MEK 途径促进 Mnk1 从细胞质易位到细胞核来控制细胞生长。随后，易位的 Mnk1 增加了 eF4E-BP1 磷酸化。结果，Pi 刺激帽依赖性蛋白质翻译。这种 Akt 介导的无机磷酸盐信号传导可能为治疗和预防多种肺部疾病提供关键线索。
Inorganic phosphate (Pi) plays a critical role in diverse cellular functions. Among three classes of sodium/phosphate co-transporters (NPTs), two types have been identified in mammalian lung. The potential importance of Pi as a novel signaling molecule and pulmonary expression of NPTs with poor prognosis of diverse lung diseases including cancer have prompted us to begin to define the pathways by which Pi regulates nontumorigenic human bronchial epithelial cells. Pi activates Akt phosphorylation on Thr308 specifically, and activated signal transmits on the Raf/MEK/ERK signaling. Here, we report that Pi controls cell growth by activating ERK cascades and by facilitating the translocation of Mnk1 from cytosol into nucleus through an Akt-mediated MEK pathway. Sequentially, translocated Mnk1 increases elF4E-BP1 phosphorylation. As a result, Pi stimulates cap-dependent protein translation. Such Akt-mediated signaling of inorganic phosphate may provide critical clues for treatment as well as prevention of diverse lung diseases.