Akt phosphorylation and nuclear phosphoinositide association mediate mRNA export and cell proliferation activities by ALY. Proceedings of the National Academy of Sciences of the United States of America

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2008; 105(25):8649-54. DOI: 10.1073/pnas.0802533105
Source: PubMed


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.

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Available from: Masashi Okada
    • "Finally, nuclear PIs were also connected to RNA maturation through the activity of PIP5Ks. PI(4,5)P 2 modulates polymerase I-mediated transcription of ribosomal RNA, regulates Star-PAP, a poly(A)polymerase involved in the transcription of stress-related enzymes, and targets REF/ALY, a component of the TREX complex that binds spliced RNAs and controls their export in the cytoplasmic compartment (Mellman et al., 2008; Okada et al., 2008; Dias et al., 2010). All these evidences describe PIs as able to modulate many aspects of gene transcription machinery affecting chromatin remodeling, transcription complex formation, and RNA modifications. "
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    • "Polyphosphoinositides have been shown to modulate the intracellular localization and functions of various nuclear proteins (Manzoli et al., 1976; Fraschini et al., 1999; Hammond et al., 2004; Gonzales and Anderson, 2006). Phosphatidylinositol- 4,5-bisphosphate [PtdIns(4) (5)P 2 ] binds effector proteins to affect their nuclear localization, gene expression, RNA processing, mRNA export, and chromatin unfolding in animal cells (Yu et al., 1998; Zhao et al., 1998; Krylova et al., 2005; Mellman et al., 2008; Okada et al., 2008; Barlow et al., 2010). Phosphatidylinositol-5- bisphosphate [PtdIns(5)P] has been reported to promote protein translocation to the nucleus (Gozani et al., 2003) and also from the nucleus to the cytoplasm (Alvarez-Venegas et al., 2006; Viiri et al., 2009; Dieck et al., 2012). "
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    • "IPMK deletion causes a marked reduction in cellular PIP 3 levels, accompanied by impaired activation of the enzyme AKT (Maag et al., 2011). Because AKT activity has been implicated in the binding of ALY to phosphoinositides (Okada et al., 2008), and in the regulation of nuclear mRNA export via TREX components (Okada et al., 2008), we tested the effect of chemical inhibition of AKT on ALY recognition of the 3 0 UTR of RAD51. Interestingly, we find that AKT inhibition causes a decrease in ALY recognition, and that this can be partially restored by the addition of PIP 3 despite the continuing presence of the AKT inhibitor (Figure S6D). "
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