Members of the class IA family of phosphoinositide 3-kinases (PI3Ks) catalyze the production of phosphatidylinositol 3,4,5-trisphosphate (PIP3) and are involved in processes such as cell survival, proliferation, and migration. These enzymes consist of a p110 catalytic subunit that forms a heterodimer with a p85 regulatory subunit. The α and β isoforms are the most ubiquitously expressed PI3Ks, and they have nonredundant functions, which may, in part, be due to their differential localization; p110α is predominantly found in the cytoplasm, whereas p110β localizes to the nucleus. Kumar et al. investigated the mechanism by which p110β, which forms a heterodimer with p85β, localizes to the nucleus in mouse embryo fibroblasts (MEFs) and murine cell lines. Immunofluorescence microscopic analysis of p85β-deficient cells showed a reduction in the amount of nuclear p110β compared with that in wild-type cells, and that expression of p85β in p85β-deficient cells promoted the nuclear translocation of p110β. Sequence analysis and assays of mutant forms of p110β showed the presence of a functional nuclear localization sequence (NLS) in the C2 domain of p110β, which was proximal to the p85β subunit in the heterodimer and was required for nuclear localization of the heterodimer; however, p85β did not contain an NLS. Rather, p85β contained a nuclear export sequence (NES) in its N-terminal region, which was required for the nuclear exit of the p110β:p85β heterodimer. Depletion of p110β in NIH-3T3 cells by short hairpin RNA (shRNA) resulted in reduced cell survival in response to γ-irradiation, which was rescued by expression of an shRNA-resistant full-length p110β but not of an shRNA-resistant p110β with a mutated NLS. Together, these data suggest that binding to p85β renders the NLS of p110β functional and that nuclear, but not cytoplasmic, p110β promotes cell survival.
A. Kumar, J. Redondo-Muñoz, V. Perez-García, I. Cortes, M. Chagoyen, A. C. Carrera, Nuclear but not cytosolic phosphoinositide 3-kinase beta has an essential function in cell survival. Mol. Cell. Biol. 31, 2122–2133 (2011). [Abstract] [Full Text]