Inositol lipids are regulated during cell cycle progression in the nuclei of murine erythroleukaemia cells

Clarke, Jonathan H.; Letcher, Andrew J.; D’Santos, Clive S.; Halstead, Jonathan R.; Irvine, Robin F.; Divecha, Nullin

doi:10.1042/bj3570905

Cited by 110 publications

(78 citation statements)

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“…Accumulative evidence supports that cell cycle progression and nuclear phosphoinositide metabolism are linked. Although the levels of total cellular phosphoinositides remain constant throughout the cell cycle, nuclear phosphoinositides fluctuate significantly in a cell-cycledependent manner (30,31). Our finding that Aly is a downstream target of nuclear PI3K, namely phosphorylation by nuclear Akt and association with nuclear phosphoinositol lipids, provides a molecular mechanism for how nuclear PI3K mediates cell cycle progression and cell proliferation.…”

Section: Discussionmentioning

confidence: 82%

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

Okada

Jang

2008

Proc. Natl. Acad. Sci. U.S.A.

103

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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.nuclear PI 3-kinase ͉ nuclear speckle ͉ nuclear Akt ͉ T219 phosphorylation P I3K and Akt predominantly locate in the cytoplasm, but they also occur in the nucleus or translocate there upon stimulation. Most of phosphoinositol lipid metabolic enzymes and PI3K signaling machinery occur in the nucleus. For example, PI-PLC (1, 2), phosphatidylinositol phosphate kinases (3, 4), PDK1 (5), PTEN (6 -8), and Akt (9, 10). Nuclear phosphoinositides play critical roles in cell growth and differentiation (11). In addition to nuclear membrane, phosphoinositides also associate with the nuclear speckles, a peculiar nuclear subcompartment enriched in small ribonucleoprotein (RNP) particles and various splicing factors (12), where many elements of nuclear phosphoinositide metabolism, including PI(4,5)P 2 , are concentrated (4,13,14). Nuclear phosphoinositides may be implicated in pre-mRNA splicing and chromatin structure (11). It has been shown before that nuclear PI(4,5)P 2 assembles in a mitotically regulated particle involved in pre-mRNA splicing (14). Elements of the transcriptional and pre-mRNA processing machinery interact with this pool of nuclear PI(4,5)P 2 , and PI(4,5)P 2 immunoprecipitates contain intermediates and products of the splicing reaction. Alternative splicing of pre-mRNAs can be regulated by extracellular signals such as growth factors, cytokines, hormones, and stress stimuli (15). For instance, insulin-activated PI3K signaling has been shown to implicate in mammary epithelial-mesenchymal interaction, which regulates fibronectin alternative splicing (16).Splicing of pre-mRNA and export of mRNA are normally coupled (17-19). Pre-mRNA splicing has been proposed to stimulate mRNA export (17,20). Based on genetic and biochemical evidence, Reed et al. (21) proposed a model for mRNA export: nascent pre-mRNA is first packaged into heterogeneous nuclear RNP (hnRNP) particles. During spliceosome assembly,...

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Section: Discussionmentioning

confidence: 82%

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

Okada

Jang

2008

Proc. Natl. Acad. Sci. U.S.A.

103

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“…PtdIns-5-P was shown to exist in cells relatively recently, and its cellular-signaling function is poorly understood (6). It is known that PtdIns-5-P levels increase in the nucleus during the G 1 phase of the cell cycle (17), increase in platelets in response to thrombin stimulation (18), and also increase after insulin stimulation of adipocytes (19). Hypoosmotic shock and histamine decrease PtdIns-5-P levels (7,20), and hyperosmotic shock increases PtdIns-5-P levels in L6 myotubes overexpressing the myotubularin protein MTM1 (9).…”

Section: Discussionmentioning

confidence: 99%

The identification and characterization of two phosphatidylinositol-4,5-bisphosphate 4-phosphatases

Ungewickell

Hugge

Kisseleva

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

107

103

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. Whereas the bacterial IpgD enzyme is known to catalyze this reaction, no such mammalian enzyme has been found. We have identified and characterized two previously undescribed human enzymes, PtdIns-4,5-P 2 4-phosphatase type I and type II, which catalyze the hydrolysis of PtdIns-4,5-P 2 to phosphatidylinositol-5-phosphate (PtdIns-5-P). Both enzymes are ubiquitously expressed and localize to late endosomal͞lysosomal membranes in epithelial cells. Overexpression of either enzyme in HeLa cells increases EGF-receptor degradation upon EGF stimulation.cell signaling ͉ lysosome ͉ phosphatidylinositol 5-phosphate I nositol-signaling molecules regulate many cellular processes, including actin cytoskeletal dynamics, apoptosis, cell division, and intracellular-membrane trafficking (1-4). Identification of the enzymes that regulate the levels of inositol second messengers is, therefore, important to understand how major cellular events are spatially and temporally coordinated.A large number of kinases and phosphatases have been described that regulate the levels of phosphatidylinositols in human cells (2,5). The production of PtdIns-5-P and its signaling functions are among the least well understood (6). Recent work implied that a significant amount of cellular PtdIns-5-P might be regulated by lipid phosphatases rather than kinases, because overexpression of the relevant phosphatidylinositol kinases did not significantly affect PtdIns-5-P levels in HeLa or Cos7 cells (7). Candidate human phosphatases include some of the myotubularins that convert phosphatidylinositol-3,5-bisphosphate to 9).Some bacterial pathogens, such as Salmonella dublin, secrete virulence factors (SopB) that are inositol polyphosphate phosphatases into host cells to modulate the inositol-signaling pathways and improve their survival and propagation (10). The Shigella flexneri virulence factor IpgD is an inositol polyphosphate 4-phosphatase that converts PtdIns-4,5-P 2 to PtdIns-5-P, leading to an accumulation of PtdIns-5-P in cells infected with the pathogen. Epithelial cells infected with Shigella flexneri exhibit membrane blebbing and actin cytoskeletal changes, indicating the importance of this reaction (11). Whether such a reaction normally occurs in mammalian cells and whether there are any endogenous enzymes that can catalyze this reaction have not been established.We now report the identification of two human PtdIns-4,5-P 2 4-phosphatases, PtdIns-4,5-P 2 4-phosphatase type I (PtdIns-4,5-P 2 4-Ptase I) and PtdIns-4,5-P 2 4-phosphatase type II (PtdIns-4,5-P 2 4-Ptase II). Both enzymes are ubiquitously expressed, localize to late endosomal͞lysosomal membranes, and appear to affect the lysosomal degradation of internalized plasma membrane receptors. We conclude that two different pathways exist in mammalian cells to degrade PtdIns-4,5-P 2 . One is catalyzed by inositol polyphosphate 5-phosphatases, leading to the production of PtdIns-4-P. The other pathway involves the type I and II PtdIns-4,5-P 2 4-Ptases and produces PtdIns-5-P. ¶ Antibodies and F...

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“…In addition, the signaling role of the nuclear PI-PLC might rely not only on the production of new lipid second messengers but on the regulation of the level of the nuclear substrate, as it is known that PtdIns(4,5)P 2 itself influences many nuclear processes directly (35). In murine erythroleukemia cells, the activity of enzymes responsible for the synthesis of PtdIns(4,5)P 2 increases during the progression through G 1 into S phase (13). Recent studies performed by Divecha and coworkers (23,38) suggest that Rb protein, a key regulator of G 1 /S phase transition, may provide a link between nuclear phospholipid signaling and cell cycle regulation as they demonstrate that pRb interacts with PtdIns(4)P 5-kinase, regulates the levels of the nuclear PtdIns(4,5)P 2 (23), and decreases the level of the nuclear DAG by activating the nuclear DAG kinase (38).…”

Section: The Role Of the Nuclear Pi-plc In Differentiation Mitogenesmentioning

confidence: 99%

Nuclear phospholipid signaling: phosphatidylinositol-specific phospholipase C and phosphoinositide 3-kinase

Višnjić

Banfíƈ

2007

Pflugers Arch - Eur J Physiol

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Over the last 20 years, numerous studies have demonstrated the existence of nuclear phosphoinositide signaling distinct from the one at the plasma membrane. The activation of phosphatidylinositol-specific phospholipase C (PI-PLC) and phosphoinositide 3-kinase (PI3K), the generation of diacylglycerol (DAG) and the accumulation of the 3-phosphorylated phosphoinositides have been documented in the nuclei of different cell types.In this review, we summarize some recent studies of the subnuclear localization, mechanisms of activation and the possible physiological roles of the nuclear PI-PLC and PI-3 kinases in the regulation of cell cycle, survival and differentiation.

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Inositol lipids are regulated during cell cycle progression in the nuclei of murine erythroleukaemia cells

Cited by 110 publications

References 0 publications

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

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

The identification and characterization of two phosphatidylinositol-4,5-bisphosphate 4-phosphatases

Nuclear phospholipid signaling: phosphatidylinositol-specific phospholipase C and phosphoinositide 3-kinase

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