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Akt phosphorylation and nuclear phosphoinositide association mediate mRNA export and cell proliferation activities by ALY.

ABSTRACT: Nuclear PI3K and its downstream effectors play essential roles in a variety of cellular activities including cell proliferation, survival, differentiation, and pre-mRNA splicing. Aly is a nuclear speckle protein implicated in mRNA export. Here we show that Aly is a physiological target of nuclear PI3K signaling, which regulates its subnuclear residency, cell proliferation, and mRNA export activities through nuclear Akt phosphorylation and phosphoinositide association. Nuclear Akt phosphorylates Aly on threonine-219, which is required for its interaction with Akt. Aly binds phosphoinositides, and this action is regulated by Akt-mediated phosphorylation. Phosphoinositide binding but not Akt phosphorylation dictates Aly's nuclear speckle residency. Depletion of Aly results in cell growth suppression and mRNA export reduction. Inhibition of Aly phosphorylation substantially decreases cell proliferation and mRNA export. Furthermore, disruption of phosphoinositide association with Aly also significantly reduces these activities. Thus, nuclear PI3K signaling mediates both cell proliferation and mRNA export functions of Aly.

SUBMITTER: Okada M

PROVIDER: S-EPMC2438396 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Akt phosphorylation and nuclear phosphoinositide association mediate mRNA export and cell proliferation activities by ALY.

Okada Masashi M Jang Sang-Wuk SW Ye Keqiang K

Proceedings of the National Academy of Sciences of the United States of America 20080617 25

Nuclear PI3K and its downstream effectors play essential roles in a variety of cellular activities including cell proliferation, survival, differentiation, and pre-mRNA splicing. Aly is a nuclear speckle protein implicated in mRNA export. Here we show that Aly is a physiological target of nuclear PI3K signaling, which regulates its subnuclear residency, cell proliferation, and mRNA export activities through nuclear Akt phosphorylation and phosphoinositide association. Nuclear Akt phosphorylates ...[more]

PMID: 18562279

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Project description:AimOxidative stress induced by free fatty acids (FFA) contributes to metabolic syndrome-associated development of cardiovascular diseases, yet molecular mechanisms remain poorly understood. This study aimed at establishing whether phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and its subcellular location play a role in FFA-induced endothelial oxidative stress.ResultsExposing human endothelial cells (ECs) with FFA activated mammalian target of rapamycin (mTOR)/S6K pathway, and upon activation, S6K directly phosphorylated PTEN at S380. Phosphorylation of PTEN increased its interaction with its deubiquitinase USP7 in the nucleus, leading to PTEN deubiquitination and nuclear export. The reduction of PTEN in the nucleus, in turn, decreased p53 acetylation and transcription, reduced the expression of the p53 target gene glutathione peroxidase-1 (GPX1), resulting in reactive oxygen species (ROS) accumulation and endothelial damage. Finally, C57BL/6J mice fed with high-fat atherogenic diet (HFAD) showed PTEN nuclear export, decreased p53 and GPX1 protein expressions, elevated levels of ROS, and significant lesions in aortas. Importantly, inhibition of mTOR or S6K effectively blocked these effects, suggesting that mTOR/S6K pathway mediates HFAD-induced oxidative stress and vascular damage via PTEN/p53/GPX1 inhibition in vivo.InnovationOur study demonstrated for the first time that S6K directly phosphorylated PTEN at S380 under high FFA conditions, and this phosphorylation mediated FFA-induced endothelial oxidative stress. Furthermore, we showed that S380 phosphorylation affected PTEN monoubiquitination and nuclear localization, providing the first example of coordinated regulation of PTEN nuclear localization via phosphorylation and ubiquitination.ConclusionOur studies provide a novel mechanism by which hyperlipidemia causes vascular oxidative damage through the phosphorylation of PTEN, blocking of PTEN nuclear function, and inhibition of p53/GPX1 activity.

Dataset Information

Akt phosphorylation and nuclear phosphoinositide association mediate mRNA export and cell proliferation activities by ALY.

Publications

Akt phosphorylation and nuclear phosphoinositide association mediate mRNA export and cell proliferation activities by ALY.

Similar Datasets

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