Resnick, A. C. et al. Inositol polyphosphate multikinase is a nuclear PI3-kinase with transcriptional regulatory activity. Proc. Natl Acad. Sci. USA 102, 12783-12788

Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2005; 102(36):12783-8. DOI: 10.1073/pnas.0506184102
Source: PubMed


Phosphatidylinositol 3,4,5-trisphosphate is a major intracellular messenger molecule thought to be formed almost exclusively by cytosolic, wortmannin-inhibited phosphoinositide 3-kinase family members. Inositol polyphosphate multikinase was identified as an enzyme that generates a series of water-soluble inositol phosphates. We now report the robust, physiologic, and evolutionarily conserved phosphoinositide 3-kinase activity of inositol polyphosphate multikinase, which is localized to nuclei and unaffected by wortmannin. In yeast, this inositol lipid kinase activity physiologically regulates transcription.

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Available from: Adolfo Saiardi, Jan 09, 2014
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    • "LRH-1 is known to bind PIP2 and PIP3 in vitro (Krylova et al., 2005), making IPMK and PTEN activity possible in cells. LRH-1 and IPMK are both highly expressed in the human liver (Chang et al., 2002), and both reside in the nucleus (Resnick et al., 2005), however it remains to be determined if IPMK and/or PTEN directly regulate LRH-1 (Fig 6B). The PPARs (a, b/d and g) are also nuclear receptors that are well established to bind lipids and be regulated by them (Baker et al., 2005; Issemann and Green, 1990; Wahli and Michalik, 2012). "
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    ABSTRACT: An unresolved problem in biological signal transduction is how particular branches of highly interconnected signaling networks can be decoupled, allowing activation of specific circuits within complex signaling architectures. Although signaling dynamics and spatiotemporal mechanisms serve critical roles, it remains unclear if these are the only ways cells achieve specificity within networks. The transcription factor Steroidogenic Factor-1 (SF-1) is an excellent model to address this question, as it forms dynamic complexes with several chemically distinct lipid species (phosphatidylinositols, phosphatidylcholines and sphingolipids). This property is important since lipids bound to SF-1 are modified by lipid signaling enzymes (IPMK & PTEN), regulating SF-1 biological activity in gene expression. Thus, a particular SF-1/lipid complex can interface with a lipid signaling enzyme only if SF-1 has been loaded with a chemically compatible lipid substrate. This mechanism permits dynamic downstream responsiveness to constant upstream input, disentangling specific pathways from the full network. The potential of this paradigm to apply generally to nuclear lipid signaling is discussed, with particular attention given to the nuclear receptor superfamily of transcription factors and their phospholipid ligands.
    Full-text · Article · Oct 2013
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    • "Mammalian IPMK catalyzes the synthesis of IPs, as well as PIP 3 (Maag et al., 2011; Resnick et al., 2005; Saiardi et al., 2001), and there is emerging evidence that inositol pyrophosphates affect HR (Jadav et al., 2013). However, little is known about the biological significance of the PI3K activity of IPMK that synthesizes PIP 3 , although it has recently been implicated in lipid-mediated signaling in the cell nucleus (Blind et al., 2012; Resnick et al., 2005). In this light, future investigation of the effects of IPMK-mediated PIP 3 synthesis on nuclear mRNA export and other biologic processes is desirable but is unlikely to be straightforward using currently available genetic models. "
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    ABSTRACT: Messenger RNA (mRNA) export from the nucleus is essential for eukaryotic gene expression. Here we identify a transcript-selective nuclear export mechanism affecting certain human transcripts, enriched for functions in genome duplication and repair, controlled by inositol polyphosphate multikinase (IPMK), an enzyme catalyzing inositol polyphosphate and phosphoinositide turnover. We studied transcripts encoding RAD51, a protein essential for DNA repair by homologous recombination (HR), to characterize the mechanism underlying IPMK-regulated mRNA export. IPMK depletion or catalytic inactivation selectively decreases RAD51 protein abundance and the nuclear export of RAD51 mRNA, thereby impairing HR. Recognition of a sequence motif in the untranslated region of RAD51 transcripts by the mRNA export factor ALY requires IPMK. Phosphatidylinositol (3,4,5)-trisphosphate (PIP3), an IPMK product, restores ALY recognition in IPMK-depleted cell extracts, suggesting a mechanism underlying transcript selection. Our findings implicate IPMK in a transcript-selective mRNA export pathway controlled by phosphoinositide turnover that preserves genome integrity in humans.
    Full-text · Article · Sep 2013 · Molecular cell
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    • "The kinase that showed the greatest effect on SopB-mediated Akt activation in HeLa cells was IPMK. IPMK is reported to have PI3-kinase activity and it was shown to phosphorylate PI(4,5) P2 to generate PI(3–5) P3 [37]. Also, IPMK was shown to activate Akt [26]. "
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    ABSTRACT: SopB is a type 3 secreted effector with phosphatase activity that Salmonella employs to manipulate host cellular processes, allowing the bacteria to establish their intracellular niche. One important function of SopB is activation of the pro-survival kinase Akt/protein kinase B in the infected host cell. Here, we examine the mechanism of Akt activation by SopB during Salmonella infection. We show that SopB-mediated Akt activation is only partially sensitive to PI3-kinase inhibitors LY294002 and wortmannin in HeLa cells, suggesting that Class I PI3-kinases play only a minor role in this process. However, depletion of PI(3,4) P2/PI(3-5) P3 by expression of the phosphoinositide 3-phosphatase PTEN inhibits Akt activation during Salmonella invasion. Therefore, production of PI(3,4) P2/PI(3-5) P3 appears to be a necessary event for Akt activation by SopB and suggests that non-canonical kinases mediate production of these phosphoinositides during Salmonella infection. We report that Class II PI3-kinase beta isoform, IPMK and other kinases identified from a kinase screen all contribute to Akt activation during Salmonella infection. In addition, the kinases required for SopB-mediated activation of Akt vary depending on the type of infected host cell. Together, our data suggest that Salmonella has evolved to use a single effector, SopB, to manipulate a remarkably large repertoire of host kinases to activate Akt for the purpose of optimizing bacterial replication in its host.
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