Akt phosphorylates the TR3 orphan receptor and blocks its targeting to the mitochondria
Akt phosphorylates the TR3 orphan receptor and blocks its targeting to the mitochondria
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Akt 磷酸化 TR3 孤儿受体并阻止其靶向线粒体
DOI：
10.1093/carcin/bgn197
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发表时间：
2008-11-01
期刊：
影响因子：
4.7
通讯作者：
Wu, Qiao
中科院分区：
文献类型：
--
作者：
Chen, Hang-Zi;Zhao, Bi-Xing;Wu, Qiao
啮齿动物T细胞淋巴瘤（Akt）中的急性转化逆转录病毒AKT 8磷酸化并调节参与代谢、凋亡和增殖等过程的许多细胞蛋白的功能。然而，Akt促进细胞存活和抑制细胞凋亡的确切机制仅被部分表征。TR 3是一种孤儿受体，作为一种转录因子，可以正向或负向调节基因表达。我们以前曾报道过TR 3从细胞核到线粒体的易位可以引起胃癌细胞的促凋亡作用。在我们目前的研究中，我们证明Akt通过与TR 3的N-末端的物理相互作用磷酸化胞质TR 3。当与Akt共表达时，TR 3线粒体靶向被阻断，并且该蛋白在细胞质中采用弥散表达模式。此外，Akt显示出破坏TR 3与Bcl-2的相互作用的能力，这被认为是线粒体TR 3引发细胞凋亡的关键要求。同时，胰岛素也能诱导TR 3磷酸化，并消除12-O-十四酰佛波醇-13-乙酸酯诱导的线粒体定位，这依赖于磷酸肌醇-3-OH-激酶-Akt信号通路的激活。总而言之，我们目前的数据表明Akt在抑制TR 3功能方面具有独特的作用，这些功能与转录活性无关，但与其线粒体结合的调节相关。这可能代表了Akt在胃癌细胞中发挥其抗凋亡作用的一种新的信号通路，即通过调节孤儿受体的磷酸化和再分布。
Acutely transforming retrovirus AKT8 in rodent T cell lymphoma (Akt) phosphorylates and regulates the function of many cellular proteins involved in processes such as metabolism, apoptosis and proliferation. However, the precise mechanisms by which Akt promotes cell survival and inhibits apoptosis have been characterized in part only. TR3, an orphan receptor, functions as a transcription factor that can both positively or negatively regulate gene expression. We have reported previously that the translocation of TR3 from the nucleus to the mitochondria can elicit a proapoptotic effect in gastric cancer cells. In our present study, we demonstrate that Akt phosphorylates cytoplasmic TR3 through its physical interaction with the N-terminus of TR3. When coexpressed with Akt, TR3 mitochondrial targeting was blocked and this protein adopted a diffuse expression pattern in the cytoplasm. Moreover, Akt displayed an ability to disrupt the interaction of TR3 with Bcl-2, which is thought to be a critical requirement for mitochondrial TR3 to elicit apoptosis. Consistently, insulin was also found to induce the phosphorylation of TR3 and abolish 12-O-tetradecanoylphorbol-13-acetate-induced mitochondrial localization, which was dependent upon the activation of the phophatidylinositol-3-OH-kinase-Akt signaling pathway. Taken together, our current data demonstrate a unique role for Akt in inhibiting TR3 functions that are not related to transcriptional activity but that correlate with the regulation of its mitochondrial association. This may represent a novel signal pathway by which Akt exerts its antiapoptotic effects in gastric cancer cells, i.e. by regulating the phosphorylation and redistribution of orphan receptors.