PI3K signaling in cancer: beyond AKT.
PI3K signaling in cancer: beyond AKT.
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DOI：
10.1016/j.ceb.2017.02.007
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发表时间：
2017-04
影响因子：
7.5
通讯作者：
Toker A
中科院分区：
文献类型：
--
作者：
Lien EC;Dibble CC;Toker A
磷脂酰肌醇3-激酶（PI 3 K）信号通路是人类癌症中最常改变的通路之一，在驱动肿瘤发生和进展中起关键作用。尽管PI 3 K及其脂质产物磷脂酰肌醇-3，4，5-三磷酸（PIP 3）已显示激活多种下游信号传导蛋白，但绝大多数研究集中于蛋白激酶AKT作为PI 3 K信号传导的主要效应物。然而，最近的研究已经证明了其他PIP 3依赖性信号蛋白对癌症进展有重要贡献的许多背景，说明了理解PI 3 K下游的AKT非依赖性信号传导的重要性。在这里，我们强调了三个PI 3 K依赖性但AKT独立性的信号分支，最近已证明它们在促进与恶性肿瘤相关的表型方面具有重要作用。首先，PDK 1-mT 0 RC 2-SGK轴可以在存活、迁移和生长信号传导中替代AKT，并且已经成为对PI 3 K和AKT抑制剂耐药的主要机制。其次，Rac信号传导介导肌动蛋白细胞骨架的重组以调节癌细胞迁移、侵袭和代谢。最后，TEC家族激酶BTK在B细胞功能和恶性肿瘤中具有关键作用，并且代表了癌症中有效治疗靶标的最近实例。这些机制强调了如何理解PI 3 K依赖性，但AKT不依赖性，驱动癌症进展的信号传导机制将是至关重要的新的和更有效的方法来靶向PI 3 K途径在癌症中的治疗效益的发展。
The phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most frequently altered pathways in human cancer and has a critical role in driving tumor initiation and progression. Although PI3K and its lipid product phosphatidylinositol-3,4,5-trisphosphate (PIP3) have been shown to activate multiple downstream signaling proteins, the vast majority of studies have focused on the protein kinase AKT as the dominant effector of PI3K signaling. However, recent studies have demonstrated many contexts under which other PIP3-dependent signaling proteins critically contribute to cancer progression, illustrating the importance of understanding AKT-independent signaling downstream of PI3K. Here, we highlight three PI3K-dependent, but AKT-independent, signaling branches that have recently been shown to have important roles in promoting phenotypes associated with malignancy. First, the PDK1 -mTORC2-SGK axis can substitute for AKT in survival, migration, and growth signaling and has emerged as a major mechanism of resistance to PI3K and AKT inhibitors. Second, Rac signaling mediates the reorganization of the actin cytoskeleton to regulate cancer cell migration, invasion, and metabolism. Finally, the TEC family kinase BTK has a critical role in B cell function and malignancy and represents a recent example of an effective therapeutic target in cancer. These mechanisms highlight how understanding PI3K-dependent, but AKT-independent, signaling mechanisms that drive cancer progression will be crucial for the development of novel and more effective approaches for targeting the PI3K pathway for therapeutic benefit in cancer.