Molecular balance between the regulatory and catalytic subunits of phosphoinositide 3-kinase regulates cell signaling and survival
Molecular balance between the regulatory and catalytic subunits of phosphoinositide 3-kinase regulates cell signaling and survival
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DOI：
10.1128/mcb.22.3.965-977.2002
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发表时间：
2002-02-01
影响因子：
5.3
通讯作者：
Kahn, CR
中科院分区：
文献类型：
--
作者：
Ueki, K;Fruman, DA;Kahn, CR
Ia类磷脂酰肌醇(PI)3-激酶是生长因子信号转导的核心成分，由p110催化亚基和调节亚基组成，其中最常见的亚基家族来源于p85pha基因(Pik3r1)。调节亚基和催化亚基之间的关键分子平衡决定了PI3-激酶通路的最佳信号传导途径。在野生型细胞中，p85亚基比p110更丰富，导致p85单体和p85-p110二聚体之间的竞争，从而导致无效的信号转导。杂合性干扰Pik3r1导致Akt活性增加，胰岛素样生长因子1(IGF-1)通过上调磷脂酰肌醇(3，4，5)-三磷酸的产生而减少细胞凋亡。另一方面，p85pha的完全缺失会导致细胞凋亡显著增加，这是由于PI 3-激酶依赖的信号转导减少所致。因此，p85α的降低代表了一种新的治疗靶点，可以增强IGF-1/胰岛素信号转导，延长细胞存活，并保护细胞免受凋亡的影响。
Class Ia phosphoinositide (PI) 3-kinase is a central component in growth factor signaling and is comprised of a p110 catalytic subunit and a regulatory subunit, the most common family of which is derived from the p85alpha gene (Pik3r1). Optimal signaling through the PI 3-kinase pathway depends on a critical molecular balance between the regulatory and catalytic subunits. In wild-type cells, the p85 subunit is more abundant than p110, leading to competition between the p85 monomer and the p85-p110 dimer and ineffective signaling. Heterozygous disruption of Pik3r1 results in increased Akt activity and decreased apoptosis by insulin-like growth factor 1 (IGF-1) through up-regulated phosphatidylinositol (3,4,5)-triphosphate production. Complete depletion of p85alpha, on the other hand, results in significantly increased apoptosis due to reduced PI 3-kinase-dependent signaling. Thus, a reduction in p85alpha represents a novel therapeutic target for enhancing IGF-1/insulin signaling, prolongation of cell survival, and protection against apoptosis.