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

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.

ACKNOWLEDGMENTS

We thank M. White for the myc-p110α plasmid, B. Vanhaesebroeck for the p110β plasmid, A. Klippel for anti-p110 Ab, F. Pazos for support in p85β/p110β structure prediction, and C. Mark for editorial assistance.

A.K. held a predoctoral fellowship associated with a project financed by the Fundación Ramón Areces. J.R.-M. has a JAE postdoctoral fellowship from the Spanish National Research Council (CSIC). V.P.-G received a predoctoral FPI fellowship associated with a project financed by the Spanish Ministry of Science and Innovation (MICINN). This study was financed by grants from the Spanish Association Against Cancer (AECC), the MICINN (SAF2007-63624 and SAF2010-21019 and Network of Cooperative Research in Cancer RD07/0020/2020), the Madrid regional government (S-BIO-0189/06), the Sandra Ibarra Foundation, and Genoma España.