Underexpression of the 43 kDa inositol polyphosphate 5-phosphatase is associated with cellular transformation.

Speed, Caroline J.; Little, Peter J.; Hayman, John; Mitchell, Christina A.

doi:10.1002/j.1460-2075.1996.tb00866.x

Cited by 55 publications

(54 citation statements)

References 59 publications

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“…Type I inositol polyphosphate 5-phosphatase is the enzyme that hydrolyzes the calcium-mobilizing messenger inositol 1,4,5-trisphosphate (Ins-1,4,5-P 3 ). Cells stably transfected with an antisense cDNA for this enzyme have elevated levels of Ins-1,4,5-P 3 and display a transformed phenotype (1). Drosophila mutants lacking inositol polyphosphate 1-phosphatase, a lithium-inhibited phosphatase, have a ''shaker'' phenotype (2).…”

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Overexpression of the inositol phosphatase SopB in human 293 cells stimulates cellular chloride influx and inhibits nuclear mRNA export

Feng¹

2001

Proceedings of the National Academy of Sciences

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SopB is an inositol phosphate phosphatase that is a virulence factor in Salmonella species. We have overexpressed SopB cDNA in a tetracycline-dependent system in human embryonic 293 cells, and used this model system to directly analyze the role of SopB in altering inositol metabolite levels in vivo. Addition of tetracycline to these cells resulted in the rapid induction of SopB expression, which was coincident with perturbations in the cellular levels of multiple soluble inositol phosphates. All of the changes induced by SopB expression were reversed within 24 h on removal of tetracycline from media. Specifically, cellular inositol 1,3,4,5,6-pentakisphosphate (InsP 5) and inositol hexakisphosphate (InsP6) levels were depleted within 4 to 6 h after inducing SopB expression. A transient rise in cellular inositol 1,4,5,6-tetrakisphosphate was also observed and was accompanied by increased chloride channel activity. This indicates that SopB alone is sufficient for changes in chloride channel function in cells infected with Salmonella organisms. Depletion of inositol phosphates, including InsP 5 and InsP6 metabolites, was coincident with the accumulation of polyadenylated RNA in the nucleus. This suggested that a defect in nuclear export had occurred. Moreover, the penetrance of the export defect required localization of SopB to the nucleus. These results provide evidence that inositol phosphate productions may be required for efficient mRNA export in mammalian cells.

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Overexpression of the inositol phosphatase SopB in human 293 cells stimulates cellular chloride influx and inhibits nuclear mRNA export

Feng¹

2001

Proceedings of the National Academy of Sciences

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“…Mice deficient in both OCRL and 5-phosphatase II die in utero (12). Underexpression of the 43-kDa 5-phosphatase using an antisense strategy results in enhanced intracellular calcium oscillations and cellular transformation (13,14).Although the 5-phosphatase enzymes are defined by their ability to remove the 5-position phosphate from the inositol ring, the catalytic mechanism and substrate-binding sites of the 5-phosphatases have yet to be defined. The various isoforms show specificity for discrete substrates, which include the water-soluble inositol phosphates inositol 1,4,5-trisphosphate (Ins (1,4,5)P 3 ) and inositol 1,3,4,5-tetrakisphosphate (Ins (1,3,4,5)P 4 ), and phosphatidylinositol-derived messenger molecules PtdIns (4,5)P 2 , phosphatidylinositol 3,4,5-trisphosphate (PtdIns (3,4,5)P 3 ) and phosphatidylinositol 3,5-bisphosphate (PtdIns (3,5)P 2 ).…”

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The Inositol Polyphosphate 5-Phosphatases and the Apurinic/Apyrimidinic Base Excision Repair Endonucleases Share a Common Mechanism for Catalysis

Whisstock¹,

Romero²,

Gurung³

et al. 2000

Journal of Biological Chemistry

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Inositol polyphosphate 5-phosphatases (5-phosphatase) hydrolyze the 5-position phosphate from the inositol ring of phosphatidylinositol-derived signaling molecules; however, the mechanism of catalysis is only partially characterized. These enzymes play critical roles in regulating cell growth, apoptosis, intracellular calcium oscillations, and post-synaptic vesicular trafficking. The UCLA fold recognition server (threader) predicted that the conserved 300-amino acid catalytic domain, common to all 5-phosphatases, adopts the fold of the apurinic/apyrimidinic (AP) base excision repair endonucleases. PSI-BLAST searches of GENPEPT, using the amino acid sequence of AP endonuclease exonuclease III, identified all members of the 5-phosphatase family with highly significant scores. A sequence alignment between exonuclease III and all known 5-phosphatases revealed six highly conserved motifs containing residues that corresponded to the catalytic residues in the AP endonucleases. Mutation of each of these residues to alanine in the mammalian 43-kDa, or yeast Inp52p 5-phosphatase, resulted in complete loss of enzyme activity. We predict the 5-phosphatase enzymes share a similar mechanism of catalysis to the AP endonucleases, consistent with other common functional similarities such as an absolute requirement for magnesium for activity. Based on this analysis, functional roles have been assigned to conserved residues in all 5-phosphatase enzymes.The phosphoinositide signaling cascade regulates many essential cellular processes including secretion, cellular proliferation, actin polymerization, vesicular and protein trafficking, cell growth, and inhibition of apoptosis (1-5). The inositol polyphosphate 5-phosphatases (5-phosphatases) 1 are a large family of enzymes that specifically hydrolyze the 5-position phosphate from the inositol ring from both inositol phosphates and phosphoinositides (5). Nine mammalian enzymes have been cloned and characterized, and four yeast homologues have been identified in Saccharomyces cerevisiae (6 -8).The 5-phosphatases play a significant role in the regulation of many phosphoinositide signaling events and in the pathogenesis of human diseases. Recent characterization of mice or humans lacking functional 5-phosphatase isoforms has identified the role specific 5-phosphatases play in regulating cell growth, post-synaptic vesicular trafficking, and apoptosis. The Src homology 2 domain containing 5-phosphatase SHIP is exclusively expressed in hematopoietic cells. Gene-targeted deletion of SHIP in mice leads to early death from a syndrome that resembles chronic myeloid leukemia (9). In primary cell lines derived from Philadelphia-positive chronic myeloid leukemia patients, the expression of SHIP is reduced or absent (10). The pre-synaptic 5-phosphatase synaptojanin associates with endocytic-coated intermediates and regulates synaptic vesicle recycling. Synaptojanin-deficient mice demonstrate neurological impairment and die shortly after birth (2). Lowe's oculocerebrorenal (OCRL) syndrome is a human...

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“…These data were obtained using an antisense strategy in rat kidney cells (49). The antisense-transfected cells had 2-4 fold elevated levels of both Ins(l,4,5)P 3 and Ins(l,3,4,5)P 4 , and there was a corresponding 2-fold increase in cytosolic [Ca 2+ ].…”

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confidence: 79%

“…The antisense-transfected cells had 2-4 fold elevated levels of both Ins(l,4,5)P 3 and Ins(l,3,4,5)P 4 , and there was a corresponding 2-fold increase in cytosolic [Ca 2+ ]. These cells demonstrated a transformed phenotype that formed tumors in mice (49).…”

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The Structural and Functional Versatility of Inositol Phosphates

Caffrey

Safrany

Yang

et al. 1998

ACS Symposium Series

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This review presents a summary of our current knowledge of inositol phosphate turnover in animal cells. In the Figure 1, the various metabolic reactions are sub-divided into several distinct groups; each of these is discussed in turn in this review, in an effort to illustrate the functional versatility of these polyphosphates.The Ins(l,4,5)P 3 / Ins(l,3,4,5)P 4 cycleThe discovery of inositol phosphate-mediated cellular Ca 2+ mobilization was a pivotal development in the field of signal transduction (/), but this breakthrough also owes much to the persistence of some other workers who had the foresight to develop and promote the idea of receptor-activated inositide signaling. It was the Hokins who first discovered that muscarinic agonists accelerate the turnover of Ptdlns in tissue slices from brain and pancreas (2). It was unfortunate that their dedication to characterizing this effect over the following 20 years did not lead them to ascribe its biological function. Indeed, there was little general interest in this so-called "phosphoinositide effect", until Michell (3) proposed that it might drive receptor-dependent Ca 2+ influx into the cell. Later, Michell and his colleagues showed mat an accelerated PtdIns(4,5)P 2 turnover immediately followed receptor-occupation by Ca 2+ -mobilizing hormones (4,5). The modem era of inositide research was now bom: Berridge (6) recognized that the Ins(l,4,5)P 3 formed by hydrolysis of PtdIns(4,5)P 2 was a candidate intracellular signal, and so it was discovered that Ins(l,4,5)/\ released Ca 2+ from endoplasmic reticulum (ER) (7). This intracellular release of Ca was found to be co-ordinated with an increase in the rate of Ca 2+ influx into the cell (7) -which finally confirmed the essence of the original idea (3) that inositol lipid turnover regulated Ca 2+ entry.Ins(l,4,5)P 3 -induced Ca 2+ release mediates an abundance of cellular responses as diverse as fertilization, cell growth and differentiation, neuronal signaling, secretion, and phototransduction. The distinct signaling requirements of individual cells are served by cell-and agonist-specific spatiotemporal patterns of Ca 2+ signaling. These arise not just from the binding of Ins(l,4,5)P 3 to its receptor, but also by modulation of this ligand/protein interaction by both cytosolic and ER-luminal Ca 2+ , and there is also input from the process of Ca 2+ entry, and Ins(l,4,5)P 3 metabolism (8). There is also regulatory diversity between the three major forms of the Ins(l,4,5)P 3 receptors that are currently recognized (see reference 9 for a review).

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Underexpression of the 43 kDa inositol polyphosphate 5-phosphatase is associated with cellular transformation.

Cited by 55 publications

References 59 publications

Overexpression of the inositol phosphatase SopB in human 293 cells stimulates cellular chloride influx and inhibits nuclear mRNA export

Overexpression of the inositol phosphatase SopB in human 293 cells stimulates cellular chloride influx and inhibits nuclear mRNA export

The Inositol Polyphosphate 5-Phosphatases and the Apurinic/Apyrimidinic Base Excision Repair Endonucleases Share a Common Mechanism for Catalysis

The Structural and Functional Versatility of Inositol Phosphates

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