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: 4.78). 03/2011; 31(10):2122-33. DOI: 10.1128/MCB.01313-10
Source: PubMed


Class IA 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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Available from: Vicente Pérez-García, Mar 06, 2014
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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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    ABSTRACT: BYL719, which selectively inhibits the alpha isoform of the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (p110a), is currently in clinical trials for the treatment of solid tumors, especially luminal breast cancers with PIK3CA mutations and/or HER2 amplification. This study reveals that, even among these sensitive cancers, the initial efficacy of p110α inhibition is mitigated by rapid re-accumulation of the PI3K product PIP3 produced by the p110β isoform. Importantly, the reactivation of PI3K mediated by p110β does not invariably restore AKT phosphorylation, demonstrating the limitations of using phospho-AKT as a surrogate to measure PI3K activation. Consistently, we show that the addition of the p110β inhibitor to BYL719 prevents the PIP3 rebound and induces greater antitumor efficacy in HER2-amplified and PIK3CA mutant cancers. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Dec 2014 · Cancer Cell
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    • "This is supported by a recent report [46] that p110β is mostly involved in DNA replication through both kinase-dependent and -independent mechanisms . Third, a nuclear localization sequence (NLS) has been identified in p110β C2 domain ( 310 KVNTTKSTK 318 ) but it is missing in p110α and this nuclear localized p110β is essential for cell survival [49] and chromosome segregation during mitosis [50]. In addition, p110β but not p110α was recently shown to be involved in osteoclastic resorption in bone [51] [52] and in male fertility as evidenced by testicular hypotrophy and impaired spermatogenesis in p110β inactivated mice [53]. "
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    ABSTRACT: Prostate cancers in the castration-resistant stage are life-threatening because they are not curable in clinic. The novel androgen receptor inhibitor Xandi (Enzalutamide) and the new CYP17 inhibitor Zytiga (Abiraterone) prolonged patient survival only a few months in advanced prostate cancers. Therefore, novel therapeutic agents for advanced prostate cancers are urgently needed. PI-3 kinases are major intracellular signaling molecules that regulate multiple signal pathways related to cellular metabolism, cytokinesis, growth and survival. Accumulating evidence in the literature indicates that some isoforms of this kinase family are oncogenic and abnormally expressed in various human cancers, including prostate cancers. Recent extensive studies from our group and others showed that PI-3 kinase p110β is aberrantly overexpressed in advanced prostate cancers and is critical for prostate cancer development and progression as demonstrated in cell-based and animal models. Importantly, novel p110β-specific inhibitors have been developed and are currently been testing in clinical trials. In this article, we will briefly summarize recent developments in this regard.
    Full-text · Article · Nov 2014
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    • "Recombinant and endogenous p85a yielded a similar pattern, although the exogenous protein was expressed at higher levels (Fig. 1A). In contrast, p85b localized in the nucleus, as reported (Kumar et al., 2011), as well as in the first confocal zsection in contact with the matrix, where endogenous and recombinant p85b showed similar dotted staining patterns (Fig. 1A). Preincubation of cells with the p85b Ab plus its antigenic peptide eliminated most of the p85b signal, indicating Ab signal specificity (Fig. 1A). "
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    ABSTRACT: The acquisition of invasiveness is characteristic of tumor progression. Numerous genetic changes are associated with metastasis, but the mechanism by which a cell becomes invasive remains unclear. Expression of p85β, a regulatory subunit of phosphoinositide-3-kinase, markedly increases in advanced carcinoma, but its mode of action is unknown. We postulated that p85β might facilitate cell invasion. We show that p85β localized at cell adhesions in complex with focal adhesion kinase and enhanced stability and maturation of cell adhesions. In addition, p85β induced development at cell adhesions of an F-actin core that extended several microns into the cell z-axis resembling the skeleton of invadopodia. p85β lead to F-actin polymerization at cell adhesions by recruiting active Cdc42/Rac at these structures. In accordance with p85β function in invadopodium-like formation, p85β levels increased in metastatic melanoma and p85β depletion reduced invadopodium formation and invasion. These results show that p85β enhances invasion by inducing cell adhesion development into invadopodia-like structures explaining the metastatic potential of tumors with increased p85β levels.
    Full-text · Article · Sep 2014 · Biology Open
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