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Mol. Cell. Biol. 31 (10): 2122-2133

Copyright © 2011 by the American Society for Microbiology. All rights reserved.

Nuclear but Not Cytosolic Phosphoinositide 3-Kinase Beta Has an Essential Function in Cell Survival{triangledown}

Amit Kumar,1,{dagger} Javier Redondo-Muñoz,1,{dagger} Vicente Perez-García,1,{dagger} Isabel Cortes,1 Monica Chagoyen,2, and Ana C. Carrera1*

Department of Immunology and Oncology,1 Computational Systems Biology Group, Centro Nacional de Biotecnología/CSIC, Cantoblanco, Madrid, Spain2

Received for publication 17 November 2010. Revision received 17 December 2010. Accepted for publication 18 February 2011.

Abstract: 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.

* Corresponding author. Mailing address: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin 3, Campus de Cantoblanco, Madrid E-28049, Spain. Phone: (34) 91 585-4846. Fax: (34) 91 372-0493. E-mail: acarrera{at}cnb.csic.es.

{dagger} A.K., J.R.-M., and V.P.-G. contributed equally to this study.

{triangledown} Published ahead of print on 7 March 2011.

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