文章：

癌症中的磷酸肌苷信号：超越PI3K和PTEN

Phosphoinositide signalling in cancer: beyond PI3K and PTEN

原文发布日期：2010-05-01

DOI: 10.1038/nrc2842

类型: Review Article

开放获取: 否

要点：

1. The phosphoinositide signalling system can be viewed as a network of interconverting enzymes, phospholipid messengers and their binding proteins. Interactions between phosphoinositides and their binding proteins are key to their regulatory actions.
2. Control of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P₃) signals in cell survival, proliferation and growth is frequently dysfunctional in cancer, resulting in enhanced PtdIns(3,4,5)P₃ signalling. The phosphoinositide enzymes PI3KIα and 3-phosphatase PTEN stringently control this signalling.
3. Some important downstream targets of PtdIns(3,4,5)P₃, such as the protein kinase Akt, are also regulated by PtdIns(3,4)P₂. The phosphoinositide enzymes that generate PtdIns(3,4)P₂ from PtdIns(3,4,5)P₃, phosphoinositide 5-phosphatases, and enzymes that degrade PtdIns(3,4)P₂ to PtdIns3P, phosphoinositide 4-phosphatases, are also implicated in cancer.
4. The most abundant phosphoinositide, PtdIns(4,5)P₂, binds to proteins important for actin polymerization, formation and turnover of focal contacts and cell–cell adhesion. These proteins could be regulated by local changes in the PtdIns(4,5)P₂ levels through the action of enzymes such as PtdIns4P-5 kinases (PIPKIγ) and PLC (PLCγ) that are implicated in the regulation of cancer cell motility.
5. In addition to the local regulation of PtdIns(4,5)P₂ levels, diverse functions of PLC enzymes in cancer could be mediated by the generation of the second messengers diacylglycerol and inositol-1,4,5-trisphosphate or in some instances by their function as signalling scaffolds.
6. The most important outstanding task is to further evaluate the role and extent of involvement of different phosphoinositide enzymes in the generation and progression of human tumours.

要点翻译：

1. 磷酸肌醇信号系统可被视为一个由相互转化的酶类、磷脂信使及其结合蛋白组成的网络。磷酸肌醇与其结合蛋白之间的相互作用是其调控功能的关键。
2. 在细胞存活、增殖和生长过程中，磷脂酰肌醇-3,4,5-三磷酸（PtdIns(3,4,5)P₃）信号的控制在癌症中常出现功能紊乱，导致PtdIns(3,4,5)P₃信号增强。磷酸肌醇酶PI3KIα和3-磷酸酶PTEN对此信号通路进行严格调控。
3. PtdIns(3,4,5)P₃的某些重要下游靶点（如蛋白激酶Akt）也受PtdIns(3,4)P2调控。将PtdIns(3,4,5)P₃转化为PtdIns(3,4)P₂的磷酸肌醇5-磷酸酶，以及将PtdIns(3,4)P₂降解为PtdIns3P的磷酸肌醇4-磷酸酶，同样与癌症发生相关。
4. 含量最丰富的磷酸肌醇PtdIns(4,5)P₂可与肌动蛋白聚合、粘着斑形成与更新以及细胞间粘附相关的重要蛋白质结合。这些蛋白质可能通过PtdIns4P-5激酶（PIPKIγ）和PLC（PLCγ）等酶的作用引起的PtdIns(4,5)P₂水平局部变化而受到调控，这些酶类与癌细胞运动调控密切相关。
5. 除对PtdIns(4,5)P2水平的局部调控外，PLC酶在癌症中的多种功能还可能通过第二信使二酰甘油和1,4,5-三磷酸肌醇的生成，或在某些情况下通过其信号支架功能来实现。
6. 当前最重要的研究任务是进一步评估不同磷酸肌醇酶在人类肿瘤发生和发展过程中的作用及参与程度。

英文摘要：

There are numerous studies that suggest multiple links between the cellular phosphoinositide system and cancer. As key roles in cancer have been established for PI3K and PTEN — enzymes that regulate the levels of phosphatidylinositol-3,4,5-trisphosphate — compounds targeting this pathway are entering the clinic at a rapid pace. Several other phosphoinositide-modifying enzymes, including phosphoinositide kinases, phosphatases and phospholipase C enzymes, have been implicated in the generation and progression of tumours. Studies of these enzymes are providing new insights into the mechanisms and the extent of their involvement in cancer, highlighting new potential targets for therapeutic intervention.

摘要翻译： 

大量研究表明，细胞磷脂酰肌醇系统与癌症之间存在多重关联。由于PI3K和PTEN——这两种调控磷脂酰肌醇-3,4,5-三磷酸水平的酶——在癌症中的关键作用已被确立，针对该通路的化合物正迅速进入临床。其他多种磷脂酰肌醇修饰酶，包括磷脂酰肌醇激酶、磷酸酶和磷脂酶C，也被发现参与肿瘤的发生与进展。对这些酶的研究正不断揭示其在癌症中的作用机制及程度，为治疗干预提供新的潜在靶点。

原文链接：

Phosphoinositide signalling in cancer: beyond PI3K and PTEN