Nuclear but Not Cytosolic Phosphoinositide 3-Kinase Beta Has an Essential Function in Cell Survival
Nuclear but Not Cytosolic Phosphoinositide 3-Kinase Beta Has an Essential Function in Cell Survival
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DOI：
10.1128/mcb.01313-10
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发表时间：
2011-05-01
影响因子：
5.3
通讯作者：
Carrera, Ana C.
中科院分区：
文献类型：
--
作者：
Kumar, Amit;Redondo-Munoz, Javier;Carrera, Ana C.
I-A类磷酸肌醇3-激酶（PI 3 Ks）是由p85调节亚基和p110催化亚基组成的异二聚体酶，其诱导3-聚磷酸肌醇的形成，所述3-聚磷酸肌醇介导细胞存活、分裂和迁移。有两种普遍存在的PI 3 K亚型p110 α和p110 β，它们在胚胎发育和细胞分裂中具有非冗余功能。然而，p110 α集中在细胞质中，而p110 β定位于细胞核并调节核过程，如DNA复制和修复。目前，决定p110 β核定位的结构特征仍然未知。我们在这里描述的协会与p85 β调节亚基控制p110 β核定位。我们在p110 β C2结构域中鉴定了一个核定位信号（NLS），它介导p110 β C2进入核，在p85 β中鉴定了一个核输出序列（内斯）。p110 β的缺失诱导细胞凋亡，与胞质C2-NLS p110 β突变体互补不能恢复细胞存活。这些研究表明，p110 β NLS和p85 β内斯调节p85 β/p110 β核定位，支持核，而不是细胞质，p110 β控制细胞存活的想法。
Class I-A phosphoinositide 3-kinases (PI3Ks) are heterodimeric enzymes composed of a p85 regulatory and a p110 catalytic subunit that induce the formation of 3-polyphosphoinositides, which mediate cell survival, division, and migration. There are two ubiquitous PI3K isoforms p110 alpha and p110 beta that have nonredundant functions in embryonic development and cell division. However, whereas p110 alpha concentrates in the cytoplasm, p110 beta localizes to the nucleus and modulates nuclear processes such as DNA replication and repair. At present, the structural features that determine p110 beta nuclear localization remain unknown. We describe here that association with the p85 beta regulatory subunit controls p110 beta nuclear localization. We identified a nuclear localization signal (NLS) in p110 beta C2 domain that mediates its nuclear entry, as well as a nuclear export sequence (NES) in p85 beta. Deletion of p110 beta induced apoptosis, and complementation with the cytoplasmic C2-NLS p110 beta mutant was unable to restore cell survival. These studies show that p110 beta NLS and p85 beta NES regulate p85 beta/p110 beta nuclear localization, supporting the idea that nuclear, but not cytoplasmic, p110 beta controls cell survival.