文章：

磷脂酰肌醇3-激酶- AKT通路在人类癌症中的作用

The phosphatidylinositol 3-Kinase–AKT pathway in human cancer

原文发布日期：2002-07-01

DOI: 10.1038/nrc839

类型: Review Article

开放获取: 否

要点：

1. The phosphatidylinositol 3-kinase (PI3K) pathway regulates various cellular processes, such as proliferation, growth, apoptosis and cytoskeletal rearrangement.
2. PI3Ks are heterodimeric lipid kinases that are composed of a regulatory and catalytic subunit that are encoded by different genes. The genes that encode the regulatory domains are also subject to differential splicing.
3. Class IA PI3Ks are activated by receptor tyrosine kinases, and deregulation of their function has been implicated in several human cancers.
4. One of the main functions of PI3K is to synthesize the second messenger PtdIns(3,4,5)P3 (PIP₃) from PtdIns(4,5)P₂ (PIP₂).
5. AKT — a serine/threonine kinase that has a wide range of substrates — is activated by recruitment to the plasma membrane through direct contact of its pleckstrin-homology (PH) domain with PIP₃, and phosphorylation at Thr308 and Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase PDK1, whereas Ser473 is phosphorylated by a molecularly unidentified kinase, often termed PDK2.
6. AKT acts downstream of PI3K to regulate many biological processes, such as proliferation, apoptosis and growth, but other signalling pathways are also known to be regulated by PI3K activity and might be involved in PI3K-mediated tumorigenesis.
7. The available clinical evidence of PI3K-pathway deregulation in various cancers and the identification of downstream kinases that are involved in mediating the effects of PI3K (AKT, mTOR, PDK1 and ILK) provide potential targets for the development of small-molecule therapies.
8. The importance of lipid–protein interaction domains (such as the PH domains of AKT and PDK1) for the activation of PI3K targets provides another potential strategy for developing targeted therapies.

要点翻译：

1. 磷脂酰肌醇3-激酶（PI3K）通路调控多种细胞过程，如增殖、生长、凋亡和细胞骨架重组。
2. PI3Ks是由调节亚基和催化亚基组成的异源二聚体脂质激酶，这些亚基由不同基因编码。编码调节结构域的基因还会经历差异性剪接。
3. IA类PI3Ks被受体酪氨酸激酶激活，其功能失调与多种人类癌症的发生密切相关。
4. PI3K的主要功能之一是将第二信使PtdIns(4,5)P2（PIP2）转化为PtdIns(3,4,5)P3（PIP3）。
5. 丝氨酸/苏氨酸激酶AKT拥有广泛作用底物，其通过pleckstrin同源（PH）结构域与PIP3直接结合并被招募至质膜，同时在Thr308和Ser473位点发生磷酸化而激活。Thr308由3-磷酸肌醇依赖性蛋白激酶PDK1磷酸化，而Ser473则由分子身份尚未明确的激酶（通常称为PDK2）磷酸化。
6. AKT在PI3K下游发挥作用，调控增殖、凋亡和生长等多种生物学过程，但已知其他信号通路也受PI3K活性调控，并可能参与PI3K介导的肿瘤发生。
7. 现有临床证据表明PI3K通路在多种癌症中存在失调，且介导PI3K效应的下游激酶（如AKT、mTOR、PDK1和ILK）的鉴定，为小分子疗法的开发提供了潜在靶点。
8. 脂质-蛋白质相互作用结构域（如AKT和PDK1的PH结构域）对PI3K靶点激活的重要性，为开发靶向治疗提供了另一种潜在策略。

英文摘要：

One signal that is overactivated in a wide range of tumour types is the production of a phospholipid, phosphatidylinositol (3,4,5) trisphosphate, by phosphatidylinositol 3-kinase (PI3K). This lipid and the protein kinase that is activated by it — AKT — trigger a cascade of responses, from cell growth and proliferation to survival and motility, that drive tumour progression. Small-molecule therapeutics that block PI3K signalling might deal a severe blow to cancer cells by blocking many aspects of the tumour-cell phenotype.

摘要翻译： 

在多种肿瘤类型中过度激活的一个信号是磷脂酰肌醇3-激酶（PI3K）生成一种磷脂——磷脂酰肌醇（3,4,5）三磷酸。这种脂质及其激活的蛋白激酶AKT会触发一连串反应，从细胞生长、增殖到存活和运动，推动肿瘤进展。阻断PI3K信号的小分子药物可通过抑制肿瘤细胞表型的多个方面，对癌细胞造成沉重打击。

原文链接：

The phosphatidylinositol 3-Kinase–AKT pathway in human cancer