Dataset Information

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 p110? and p110? that have nonredundant functions in embryonic development and cell division. However, whereas p110? concentrates in the cytoplasm, p110? localizes to the nucleus and modulates nuclear processes such as DNA replication and repair. At present, the structural features that determine p110? nuclear localization remain unknown. We describe here that association with the p85? regulatory subunit controls p110? nuclear localization. We identified a nuclear localization signal (NLS) in p110? C2 domain that mediates its nuclear entry, as well as a nuclear export sequence (NES) in p85?. Deletion of p110? induced apoptosis, and complementation with the cytoplasmic C2-NLS p110? mutant was unable to restore cell survival. These studies show that p110? NLS and p85? NES regulate p85?/p110? nuclear localization, supporting the idea that nuclear, but not cytoplasmic, p110? controls cell survival.

SUBMITTER: Kumar A

PROVIDER: S-EPMC3133359 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Kumar Amit A Redondo-Muñoz Javier J Perez-García Vicente V Cortes Isabel I Chagoyen Monica M Carrera Ana C AC

Molecular and cellular biology 20110307 10

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 r ...[more]

PMID: 21383062

Similar Datasets

Project description:The dual specificity protein/lipid kinase, phosphoinositide 3-kinase (PI3K), promotes growth factor-mediated cell survival and is frequently deregulated in cancer. However, in contrast to canonical lipid-kinase functions, the role of PI3K protein kinase activity in regulating cell survival is unknown. We have employed a novel approach to purify and pharmacologically profile protein kinases from primary human acute myeloid leukemia (AML) cells that phosphorylate serine residues in the cytoplasmic portion of cytokine receptors to promote hemopoietic cell survival. We have isolated a kinase activity that is able to directly phosphorylate Ser585 in the cytoplasmic domain of the interleukin 3 (IL-3) and granulocyte macrophage colony stimulating factor (GM-CSF) receptors and shown it to be PI3K. Physiological concentrations of cytokine in the picomolar range were sufficient for activating the protein kinase activity of PI3K leading to Ser585 phosphorylation and hemopoietic cell survival but did not activate PI3K lipid kinase signaling or promote proliferation. Blockade of PI3K lipid signaling by expression of the pleckstrin homology of Akt1 had no significant impact on the ability of picomolar concentrations of cytokine to promote hemopoietic cell survival. Furthermore, inducible expression of a mutant form of PI3K that is defective in lipid kinase activity but retains protein kinase activity was able to promote Ser585 phosphorylation and hemopoietic cell survival in the absence of cytokine. Blockade of p110α by RNA interference or multiple independent PI3K inhibitors not only blocked Ser585 phosphorylation in cytokine-dependent cells and primary human AML blasts, but also resulted in a block in survival signaling and cell death. Our findings demonstrate a new role for the protein kinase activity of PI3K in phosphorylating the cytoplasmic tail of the GM-CSF and IL-3 receptors to selectively regulate cell survival highlighting the importance of targeting such pathways in cancer.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets