2019年6月4日出版的《Cell Metabolism》杂志，报道了瑞典哥德堡大学Giovanni Solinas研究组的最新成果。他们发现了肝细胞中胰岛素驱动的PI3K/AKT信号由异常的PI3Kα和PI3Kβ活性介导，并由RAS促进。

该研究团队发现，胰岛素驱动的PI3K/AKT信号依赖异常的PI3Kα和PI3Kβ活性，而PI3Kδ和PI3Kγ在很大程度上是可有可无的。该课题组研究人员还发现，RAS活性促进胰岛素刺激的肝细胞中的Akt磷酸化，RAS促进胰岛素驱动的Akt磷酸化依赖于pi3kα。这些发现揭示了胰岛素激活Akt的详细机制，提供了对胰岛素信号传导的理解。胰岛素信号转导的改进模型预测，鉴别PI3Kα和PI3Kβ的异种选择性PI3K抑制剂应低于其高血糖阈值，以实现异种选择性。

据悉，磷脂酰肌醇-3-激酶(PI3K)活性在肿瘤中异常，PI3K抑制剂被作为肿瘤治疗药物。PI3K信号介导胰岛素在代谢中的作用，但PI3K亚型在胰岛素信号中的作用尚未明确。明确PI3K亚型在胰岛素信号转导中的作用，是了解胰岛素作用机制和开发具有最佳治疗指标的PI3K抑制剂的必要条件。

附：英文原文

Title: Insulin-Driven PI3K-AKT Signaling in the Hepatocyte Is Mediated by Redundant PI3Kα and PI3Kβ Activities and Is Promoted by RAS

Author: Angela Molinaro, Barbara Becattini, Arianna Mazzoli, Augusto Bleve, Lucia Radici, Ingela Maxvall, Victoria Rotter Sopasakis, Antonio Molinaro, Fredrik Bckhed, Giovanni Solinas

Issue&Volume: Jun 04, 2019 Volume 29Issue 6

Abstract: Phosphatidylinositol-3-kinase (PI3K) activity is aberrant in tumors, and PI3K inhibitors are investigated as cancer therapeutics. PI3K signaling mediates insulin action in metabolism, but the role of PI3K isoforms in insulin signaling remains unresolved. Defining the role of PI3K isoforms in insulin signaling is necessary for a mechanistic understanding of insulin action and to develop PI3K inhibitors with optimal therapeutic index. We show that insulin-driven PI3K-AKT signaling depends on redundant PI3Kα and PI3Kβ activities, whereas PI3Kδ and PI3Kγ are largely dispensable. We have also found that RAS activity promotes AKT phosphorylation in insulin-stimulated hepatocytes and that promotion of insulin-driven AKT phosphorylation by RAS depends on PI3Kα. These findings reveal the detailed mechanism by which insulin activates AKT, providing an improved mechanistic understanding of insulin signaling. This improved model for insulin signaling predicts that isoform-selective PI3K inhibitors discriminating between PI3Kα and PI3Kβ should be dosed below their hyperglycemic threshold to achieve isoform selectivity.

DOI: https://doi.org/10.1016/j.cmet.2019.03.010

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30138-Xh