Article

Nuclear but not cytosolic phosphoinositide 3-kinase beta has an essential function in cell survival

Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin 3, Campus de Cantoblanco, Madrid E-28049, Spain.
Molecular and Cellular Biology (Impact Factor: 5.04). 03/2011; 31(10):2122-33. DOI: 10.1128/MCB.01313-10
Source: PubMed

ABSTRACT 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 p110α and p110β that have nonredundant functions in embryonic development and cell division. However, whereas p110α concentrates in the cytoplasm, p110β localizes to the nucleus and modulates nuclear processes such as DNA replication and repair. At present, the structural features that determine p110β nuclear localization remain unknown. We describe here that association with the p85β regulatory subunit controls p110β nuclear localization. We identified a nuclear localization signal (NLS) in p110β C2 domain that mediates its nuclear entry, as well as a nuclear export sequence (NES) in p85β. Deletion of p110β induced apoptosis, and complementation with the cytoplasmic C2-NLS p110β mutant was unable to restore cell survival. These studies show that p110β NLS and p85β NES regulate p85β/p110β nuclear localization, supporting the idea that nuclear, but not cytoplasmic, p110β controls cell survival.

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    • "However, measurement of PIP 3 levels revealed that BYL719 did not fully suppress PIP 3 levels in PIK3CA mutant cells, especially after 24 hr, and combined inhibition of p110a and p110b resulted in stronger reduction of PIP 3 levels than BYL719 alone (Figure 4C). Because p110b has been shown to induce phosphorylation of nuclear AKT (Kumar et al., 2011), we determined if inhibition of p110b affected AKT signaling specifically in the nucleus, which may have been missed in assessments of AKT phosphorylation in whole cell lysates (Figure 4B). However, in the PIK3CA mutant cell line MCF7, p110b did not control AKT phosphorylation in either the cytoplasm or the nucleus (Figure S4A). "
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