Liao Yong, Hung Mien-Chie
Am J Transl Res. 2010 Jan 1;2(1):19-42.
The serine/threonine protein kinase B (PKB, also known as Akt) constitutes an important node in diverse signaling cascades downstream of growth factor receptor tyrosine kinases. Akt plays an essential role in cell survival, growth, migration, proliferation, polarity, and metabolism (lipid and glucose); cell cycle progression; muscle and cardiomyocyte contractility; angiogenesis; and self-renewal of stem cells. Altered Akt activity has been associated with cancer and other disease conditions, such as diabetes mellitus, neurodegenerative diseases, and muscle hypotrophy. In the past decade, the upstream signals that lead to Akt activation, the downstream substrates that exert the effects of Akt, and the secondary binding proteins that regulate Akt activation have been well documented. Recent reports from our group and others have revealed how the stability of Akt protein is regulated through phosphorylation on its Thr-Pro motifs. This literature review details findings of those reports and others relevant to the regulation of Akt activation by its upstream kinases, with a focus on mammalian target of rapamycin complexes (mTORCs) and inactivation by PHLDA3 and the protein phosphatases PP2A and pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP). Reports on ubiquitin-dependent Akt degradation, caspase-dependent cleavage, and the roles of molecular chaperone heat shock protein 90 (Hsp90) in the regulation of Akt stability are summarized. The highlight will be on the role of "turn motif" phosphorylation and an isomerase, Pin1, in the regulation of Akt stability. We also discuss issues related to the intricate mTORC2-AktmTORC1 loop and the contradictory regulation of Akt phosphorylation and stabilization of Akt by mTORC2. Finally, we offer perspective on potential future directions for investigation, particularly on translating the knowledge we learned on the regulation of Akt stability into therapeutic intervention on human cancer with Akt alteration.
丝氨酸/苏氨酸蛋白激酶B（PKB，也称为Akt）是生长因子受体酪氨酸激酶下游多种信号级联反应中的一个重要节点。Akt在细胞存活、生长、迁移、增殖、极性和代谢（脂质和葡萄糖）；细胞周期进程；肌肉和心肌细胞收缩性；血管生成；以及干细胞自我更新中发挥着至关重要的作用。Akt活性改变与癌症和其他疾病状况相关，如糖尿病、神经退行性疾病和肌肉萎缩。在过去十年中，导致Akt激活的上游信号、发挥Akt作用的下游底物以及调节Akt激活的二级结合蛋白都有了充分的记录。我们小组和其他团队最近的报告揭示了Akt蛋白的稳定性是如何通过其苏氨酸-脯氨酸基序上的磷酸化来调节的。这篇文献综述详细阐述了这些报告以及其他与Akt上游激酶调节Akt激活相关的研究结果，重点关注雷帕霉素复合物的哺乳动物靶点（mTORCs）以及PHLDA3、蛋白磷酸酶PP2A和pleckstrin同源结构域富含亮氨酸重复蛋白磷酸酶（PHLPP）对Akt的失活作用。总结了关于泛素依赖性Akt降解、半胱天冬酶依赖性切割以及分子伴侣热休克蛋白90（Hsp90）在Akt稳定性调节中的作用的报告。重点将放在“转折基序”磷酸化和异构酶Pin1在Akt稳定性调节中的作用上。我们还讨论了与复杂的mTORC2-Akt-mTORC1环以及mTORC2对Akt磷酸化和Akt稳定化的矛盾调节相关的问题。最后，我们对未来潜在的研究方向提出了展望，特别是关于将我们在Akt稳定性调节方面学到的知识转化为对Akt改变的人类癌症的治疗干预。
