Journal articles: 'Inositol polyphosphate phosphatases'

1

Eramo, Matthew J., and Christina A. Mitchell. "Regulation of PtdIns(3,4,5)P3/Akt signalling by inositol polyphosphate 5-phosphatases." Biochemical Society Transactions 44, no. 1 (February 9, 2016): 240–52. http://dx.doi.org/10.1042/bst20150214.

Full text

Abstract:

The phosphoinositide 3-kinase (PI3K) generated lipid signals, PtdIns(3,4,5)P3 and PtdIns(3,4)P2, are both required for the maximal activation of the serine/threonine kinase proto-oncogene Akt. The inositol polyphosphate 5-phosphatases (5-phosphatases) hydrolyse the 5-position phosphate from the inositol head group of PtdIns(3,4,5)P3 to yield PtdIns(3,4)P2. Extensive work has revealed several 5-phosphatases inhibit PI3K-driven Akt signalling, by decreasing PtdIns(3,4,5)P3 despite increasing cellular levels of PtdIns(3,4)P2. The roles that 5-phosphatases play in suppressing cell proliferation and transformation are slow to emerge; however, the 5-phosphatase PIPP [proline-rich inositol polyphosphate 5-phosphatase; inositol polyphosphate 5-phosphatase (INPP5J)] has recently been identified as a putative tumour suppressor in melanoma and breast cancer and SHIP1 [SH2 (Src homology 2)-containing inositol phosphatase 1] inhibits haematopoietic cell proliferation. INPP5E regulates cilia stability and INPP5E mutations have been implicated ciliopathy syndromes. This review will examine 5-phosphatase regulation of PI3K/Akt signalling, focussing on the role PtdIns(3,4,5)P3 5-phosphatases play in developmental diseases and cancer.

APA, Harvard, Vancouver, ISO, and other styles

2

Zhang, Qingxiu, and Francois X. Claret. "Phosphatases: The New Brakes for Cancer Development?" Enzyme Research 2012 (October 31, 2012): 1–11. http://dx.doi.org/10.1155/2012/659649.

Full text

Abstract:

The phosphatidylinositol 3-kinase (PI3K) pathway plays a pivotal role in the maintenance of processes such as cell growth, proliferation, survival, and metabolism in all cells and tissues. Dysregulation of the PI3K/Akt signaling pathway occurs in patients with many cancers and other disorders. This aberrant activation of PI3K/Akt pathway is primarily caused by loss of function of all negative controllers known as inositol polyphosphate phosphatases and phosphoprotein phosphatases. Recent studies provided evidence of distinct functions of the four main phosphatases—phosphatase and tensin homologue deleted on chromosome 10 (PTEN), Src homology 2-containing inositol 5′-phosphatase (SHIP), inositol polyphosphate 4-phosphatase type II (INPP4B), and protein phosphatase 2A (PP2A)—in different tissues with respect to regulation of cancer development. We will review the structures and functions of PTEN, SHIP, INPP4B, and PP2A phosphatases in suppressing cancer progression and their deregulation in cancer and highlight recent advances in our understanding of the PI3K/Akt signaling axis.

APA, Harvard, Vancouver, ISO, and other styles

3

Jia, Qi, Defeng Kong, Qinghua Li, Song Sun, Junliang Song, Yebao Zhu, Kangjing Liang, Qingming Ke, Wenxiong Lin, and Jinwen Huang. "The Function of Inositol Phosphatases in Plant Tolerance to Abiotic Stress." International Journal of Molecular Sciences 20, no. 16 (August 16, 2019): 3999. http://dx.doi.org/10.3390/ijms20163999.

Full text

Abstract:

Inositol signaling is believed to play a crucial role in various aspects of plant growth and adaptation. As an important component in biosynthesis and degradation of myo-inositol and its derivatives, inositol phosphatases could hydrolyze the phosphate of the inositol ring, thus affecting inositol signaling. Until now, more than 30 members of inositol phosphatases have been identified in plants, which are classified intofive families, including inositol polyphosphate 5-phosphatases (5PTases), suppressor of actin (SAC) phosphatases, SAL1 phosphatases, inositol monophosphatase (IMP), and phosphatase and tensin homologue deleted on chromosome 10 (PTEN)-related phosphatases. The current knowledge was revised here in relation to their substrates and function in response to abiotic stress. The potential mechanisms were also concluded with the focus on their activities of inositol phosphatases. The general working model might be that inositol phosphatases would degrade the Ins(1,4,5)P3 or phosphoinositides, subsequently resulting in altering Ca2+ release, abscisic acid (ABA) signaling, vesicle trafficking or other cellular processes.

APA, Harvard, Vancouver, ISO, and other styles

4

Astle, Megan V., Kristy A. Horan, Lisa M. Ooms, and Christina A. Mitchell. "The inositol polyphosphate 5-phosphatases: traffic controllers, waistline watchers and tumour suppressors?" Biochemical Society Symposia 74 (January 12, 2007): 161–81. http://dx.doi.org/10.1042/bss2007c15.

Full text

Abstract:

Phosphoinositide signals regulate cell proliferation, differentiation, cytoskeletal rearrangement and intracellular trafficking. Hydrolysis of PtdIns(4,5)P2 and PtdIns(3,4,5)P3, by inositol polyphosphate 5-phosphatases regulates synaptic vesicle recycling (synaptojanin-1), hematopoietic cell function [SHIP1(SH2-containing inositol polyphosphate 5-phosphatase-1)], renal cell function [OCRL (oculocerebrorenal syndrome of Lowe)] and insulin signalling (SHIP2). We present here a detailed review of the characteristics of the ten mammalian 5-phosphatases. Knockout mouse phenotypes and underexpression studies are associated with significant phenotypic changes, indicating non-redundant roles, despite, in many cases, overlapping substrate specificity and tissue expression. The extraordinary complexity in the control of phosphoinositide signalling continues to be revealed.

APA, Harvard, Vancouver, ISO, and other styles

5

Chellapandi, Paulchamy, and Jayachandrabal Balachandramohan. "Computational Evaluation of Designed Phosphatase from Conserved Sequence Scratch for Diverse Substrate Specificity." International Journal Bioautomation 26, no. 3 (September 2022): 297–310. http://dx.doi.org/10.7546/ijba.2022.26.3.000553.

Full text

Abstract:

The ability to design efficient enzymes for a broad class of different reactions would be of tremendous practical interest in both science and industry. Computer-assisted designing is a novel approach to generating industrial enzymes for biotechnological applications. Objectives: The main aim of this study was to design an enzyme construct with diverse substrate-binding specificity based on the evolutionary conservation of archaeal vanadium-dependent phosphatases. Materials and methods: A rational 3D structural model of enzyme construct was developed from conserved sequence scratch encompassing a vanadium-binding site and functional domain. Substrate-binding specificity of the designed enzyme was computed with different myo-inositol polyphosphate analogous by a molecular docking program. Results: A designed enzyme has shown more substrate-binding specificity with 1D-myo-inositol 3, 4, 5, 6-tetrakisphosphate. Its catalytic function closely resembled myo-inositol polyphosphate-5-phosphatase and multiple inositol polyphosphate phosphatases. Moreover, the enzyme construct was energetically stable with a low degree of conformational changes upon substrate-binding. Conclusion: Substrate specificity and catalytic competence of designed enzymes were computationally evaluated for further biotechnological applications.

APA, Harvard, Vancouver, ISO, and other styles

6

Mitchell, Christina A., Rajendra Gurung, Anne M. Kong, Jennifer M. Dyson, April Tan, and Lisa M. Ooms. "Inositol Polyphosphate 5-Phosphatases: Lipid Phosphatases With Flair." IUBMB Life (International Union of Biochemistry and Molecular Biology: Life) 53, no. 1 (January 1, 2002): 25–36. http://dx.doi.org/10.1080/15216540210815.

Full text

APA, Harvard, Vancouver, ISO, and other styles

7

Mitchell, C. A. "THE REGULATION OF INOSITOL TRISPHOSPHATE BY INOSITOL POLYPHOSPHATE 5-PHOSPHATASES." Biochemical Society Transactions 24, no. 4 (November 1, 1996): 621S. http://dx.doi.org/10.1042/bst024621sa.

Full text

APA, Harvard, Vancouver, ISO, and other styles

8

Noakes, Christopher J., Grace Lee, and Martin Lowe. "The PH domain proteins IPIP27A and B link OCRL1 to receptor recycling in the endocytic pathway." Molecular Biology of the Cell 22, no. 5 (March 2011): 606–23. http://dx.doi.org/10.1091/mbc.e10-08-0730.

Full text

Abstract:

Mutation of the inositol polyphosphate 5-phosphatase OCRL1 results in two disorders in humans, namely Lowe syndrome (characterized by ocular, nervous system, and renal defects) and type 2 Dent disease (in which only the renal symptoms are evident). The disease mechanisms of these syndromes are poorly understood. Here we identify two novel OCRL1-binding proteins, termed inositol polyphosphate phosphatase interacting protein of 27 kDa (IPIP27)A and B (also known as Ses1 and 2), that also bind the related 5-phosphatase Inpp5b. The IPIPs bind to the C-terminal region of these phosphatases via a conserved motif similar to that found in the signaling protein APPL1. IPIP27A and B, which form homo- and heterodimers, localize to early and recycling endosomes and the trans-Golgi network (TGN). The IPIPs are required for receptor recycling from endosomes, both to the TGN and to the plasma membrane. Our results identify IPIP27A and B as key players in endocytic trafficking and strongly suggest that defects in this process are responsible for the pathology of Lowe syndrome and Dent disease.

APA, Harvard, Vancouver, ISO, and other styles

9

Drayer, A. L., X. Pesesse, F. De Smedt, D. Communi, C. Moreau, and C. Erneux. "The family of inositol and phosphatidylinositol polyphosphate 5-phosphatases." Biochemical Society Transactions 24, no. 4 (November 1, 1996): 1001–5. http://dx.doi.org/10.1042/bst0241001.

Full text

APA, Harvard, Vancouver, ISO, and other styles

10

Antibus, Robert K., Robert L. Sinsabaugh, and Arthur E. Linkins. "Phosphatase activities and phosphorus uptake from inositol phosphate by ectomycorrhizal fungi." Canadian Journal of Botany 70, no. 4 (April 1, 1992): 794–801. http://dx.doi.org/10.1139/b92-101.

Full text

Abstract:

To better understand the physiological importance of acid phosphatase activity we examined the effects of inorganic and organic phosphorus growth sources on enzyme activity and 32P uptake in several ectomycorrhizal fungi. Mycelium of eight isolates from four basidiomycete species demonstrated optimal p-nitrophenyl phosphatase activity at pH 4.5 or 5.0. Acid phosphatase activities varied between strains of Scleroderma citrinum and between the species examined. Interspecific differences in isozyme patterns of whole cell extracts were apparent in native polyacrylamide gels. The isoelectric points of the predominant phosphatases in whole cell extracts were in the pH 5.0 to 5.5 range. Growth of fungi on inositol hexaphosphate versus inorganic P did not affect the isozyme patterns detected by either electrophoretic method. Growth on inositol hexaphosphate affected surface and soluble activities towards p-nitrophenyl phosphate and inositol phosphate to different degrees in species examined. Phytase activity was sufficient to produce a net release of P in all isolates. Growth on inositol hexaphosphate was associated with increased uptake of 32P from inositol polyphosphate in four of five species examined. Acid phosphatase, measured with p-nitrophenyl phosphate, was positively correlated with 32P uptake. Decreased phytase activities measured for inositol hexaphosphate grown mycelium were associated with increased P influx in such mycelium. Both phosphatase activity and 32P uptake were subject to inorganic P inhibition with 32P uptake demonstrating a greater sensitivity. These results provide further evidence for the role of surface acid phosphatases in organic P utilization by ectomycorrhizal fungi. Key words: acid phosphatase, ectomycorrhizal fungi, phytase.

APA, Harvard, Vancouver, ISO, and other styles

11

Ooms, Lisa M., Kristy A. Horan, Parvin Rahman, Gillian Seaton, Rajendra Gurung, Dharini S. Kethesparan, and Christina A. Mitchell. "The role of the inositol polyphosphate 5-phosphatases in cellular function and human disease." Biochemical Journal 419, no. 1 (March 13, 2009): 29–49. http://dx.doi.org/10.1042/bj20081673.

Full text

Abstract:

Phosphoinositides are membrane-bound signalling molecules that regulate cell proliferation and survival, cytoskeletal reorganization and vesicular trafficking by recruiting effector proteins to cellular membranes. Growth factor or insulin stimulation induces a canonical cascade resulting in the transient phosphorylation of PtdIns(4,5)P2 by PI3K (phosphoinositide 3-kinase) to form PtdIns(3,4,5)P3, which is rapidly dephosphorylated either by PTEN (phosphatase and tensin homologue deleted on chromosome 10) back to PtdIns(4,5)P2, or by the 5-ptases (inositol polyphosphate 5-phosphatases), generating PtdIns(3,4)P2. The 5-ptases also hydrolyse PtdIns(4,5)P2, forming PtdIns4P. Ten mammalian 5-ptases have been identified, which share a catalytic mechanism similar to that of the apurinic/apyrimidinic endonucleases. Gene-targeted deletion of 5-ptases in mice has revealed that these enzymes regulate haemopoietic cell proliferation, synaptic vesicle recycling, insulin signalling, endocytosis, vesicular trafficking and actin polymerization. Several studies have revealed that the molecular basis of Lowe's syndrome is due to mutations in the 5-ptase OCRL (oculocerebrorenal syndrome of Lowe). Futhermore, the 5-ptases SHIP [SH2 (Src homology 2)-domain-containing inositol phosphatase] 2, SKIP (skeletal muscle- and kidney-enriched inositol phosphatase) and 72-5ptase (72 kDa 5-ptase)/Type IV/Inpp5e (inositol polyphosphate 5-phosphatase E) are implicated in negatively regulating insulin signalling and glucose homoeostasis in specific tissues. SHIP2 polymorphisms are associated with a predisposition to insulin resistance. Gene profiling studies have identified changes in the expression of various 5-ptases in specific cancers. In addition, 5-ptases such as SHIP1, SHIP2 and 72-5ptase/Type IV/Inpp5e regulate macrophage phagocytosis, and SHIP1 also controls haemopoietic cell proliferation. Therefore the 5-ptases are a significant family of signal-modulating enzymes that govern a plethora of cellular functions by regulating the levels of specific phosphoinositides. Emerging studies have implicated their loss or gain of function in human disease.

APA, Harvard, Vancouver, ISO, and other styles

12

Erneux, Christophe, Somadri Ghosh, Ana Raquel Ramos, and William`s Elong Edimo. "New Functions of the Inositol Polyphosphate 5-Phosphatases in Cancer." Current Pharmaceutical Design 22, no. 16 (April 27, 2016): 2309–14. http://dx.doi.org/10.2174/1381612822666160226132512.

Full text

APA, Harvard, Vancouver, ISO, and other styles

13

Astle, Megan, Gillian Seaton, Elizabeth Davies, Clare Fedele, Parvin Rahman, Laima Arsala, and Christina Mitchell. "Regulation of phosphoinositide signaling by the inositol polyphosphate 5-phosphatases." IUBMB Life (International Union of Biochemistry and Molecular Biology: Life) 58, no. 8 (August 1, 2006): 451–56. http://dx.doi.org/10.1080/15216540600871159.

Full text

APA, Harvard, Vancouver, ISO, and other styles

14

Mitchell, C. A., S. Brown, J. K. Campbell, A. D. Munday, and C. J. Speed. "Regulation of second messengers by the inositol polyphosphate 5-phosphatases." Biochemical Society Transactions 24, no. 4 (November 1, 1996): 994–1000. http://dx.doi.org/10.1042/bst0240994.

Full text

APA, Harvard, Vancouver, ISO, and other styles

15

Braun, Werner, and Catherine H. Schein. "Membrane Interaction and Functional Plasticity of Inositol Polyphosphate 5-Phosphatases." Structure 22, no. 5 (May 2014): 664–66. http://dx.doi.org/10.1016/j.str.2014.04.008.

Full text

APA, Harvard, Vancouver, ISO, and other styles

16

O'MALLEY, Cindy J., Brad K. McCOLL, Anne M. KONG, Sarah L. ELLIS, A. Primrose W. WIJAYARATNAM, Joe SAMBROOK, and Christina A. MITCHELL. "Mammalian inositol polyphosphate 5-phosphatase II can compensate for the absence of all three yeast Sac1-like-domain-containing 5-phosphatases." Biochemical Journal 355, no. 3 (April 24, 2001): 805–17. http://dx.doi.org/10.1042/bj3550805.

Full text

Abstract:

Phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] plays a complex role in generating intracellular signalling molecules, and also in regulating actin-binding proteins, vesicular trafficking and vacuolar fusion. Four inositol polyphosphate 5-phosphatases (hereafter called 5-phosphatases) have been identified in Saccharomyces cerevisiae: Inp51p, Inp52p, Inp53p and Inp54p. Each enzyme contains a 5-phosphatase domain which hydrolyses PtdIns(4,5)P2, forming PtdIns4P, while Inp52p and Inp53p also express a polyphosphoinositide phosphatase domain within the Sac1-like domain. Disruption of any two yeast 5-phosphatases containing a Sac1-like domain results in abnormalities in actin polymerization, plasma membrane, vacuolar morphology and bud-site selection. Triple null mutant 5-phosphatase strains are non-viable. To investigate the role of PtdIns(4,5)P2 in mediating the phenotype of double and triple 5-phosphatase null mutant yeast, we determined whether a mammalian PtdIns(4,5)P2 5-phosphatase, 5-phosphatase II, which lacks polyphosphoinositide phosphatase activity, could correct the phenotype of triple 5-phosphatase null mutant yeast and restore cellular PtdIns(4,5)P2 levels to near basal values. Mammalian 5-phosphatase II expressed under an inducible promoter corrected the growth, cell wall, vacuolar and actin polymerization defects of the triple 5-phosphatase null mutant yeast strains. Cellular PtdIns(4,5)P2 levels in various 5-phosphatase double null mutant strains demonstrated significant accumulation (4.5-, 3- and 2-fold for ∆inp51∆inp53, ∆inp51∆inp52 and ∆inp52∆inp53 double null mutants respectively), which was corrected significantly following 5-phosphatase II expression. Collectively, these studies demonstrate the functional and cellular consequences of PtdIns(4,5)P2 accumulation and the evolutionary conservation of function between mammalian and yeast PtdIns(4,5)P2 5-phosphatases.

APA, Harvard, Vancouver, ISO, and other styles

17

Zhang, Zaibao, Yuting Li, Zhaoyi Luo, Shuwei Kong, Yilin Zhao, Chi Zhang, Wei Zhang, Hongyu Yuan, and Lin Cheng. "Expansion and Functional Divergence of Inositol Polyphosphate 5-Phosphatases in Angiosperms." Genes 10, no. 5 (May 22, 2019): 393. http://dx.doi.org/10.3390/genes10050393.

Full text

Abstract:

Inositol polyphosphate 5-phosphatase (5PTase), a key enzyme that hydrolyzes the 5′ position of the inositol ring, has essential functions in growth, development, and stress responses in plants, yeasts, and animals. However, the evolutionary history and patterns of 5PTases have not been examined systematically. Here, we report a comprehensive molecular evolutionary analysis of the 5PTase gene family and define four groups. These four groups are different from former classifications, which were based on in vitro substrate specificity. Most orthologous groups appear to be conserved as single or low-copy genes in all lineages in Groups II–IV, whereas 5PTase genes in Group I underwent several duplication events in angiosperm, resulting in multiple gene copies. Whole-genome duplication (WGD) was the main mechanism for 5PTase duplications in angiosperm. Plant 5PTases have more members than that of animals, and most plant 5PTase genes appear to have evolved under strong purifying selection. The paralogs have diverged in substrate specificity and expression pattern, showing evidence of selection pressure. Meanwhile, the increase in 5PTases and divergences in sequence, expression, and substrate might have contributed to the divergent functions of 5PTase genes, allowing the angiosperms to successfully adapt to a great number of ecological niches.

APA, Harvard, Vancouver, ISO, and other styles

18

Erneux, Christophe, Cédric Govaerts, David Communi, and Xavier Pesesse. "The diversity and possible functions of the inositol polyphosphate 5-phosphatases." Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1436, no. 1-2 (December 1998): 185–99. http://dx.doi.org/10.1016/s0005-2760(98)00132-5.

Full text

APA, Harvard, Vancouver, ISO, and other styles

19

Jefferson, Anne Bennett, and Philip W. Majerus. "Mutation of the Conserved Domains of Two Inositol Polyphosphate 5-Phosphatases†." Biochemistry 35, no. 24 (January 1996): 7890–94. http://dx.doi.org/10.1021/bi9602627.

Full text

APA, Harvard, Vancouver, ISO, and other styles

20

Horan, Kristy A., Megan V. Astle, Lisa M. Ooms, and Christina A. Mitchell. "The inositol polyphosphate 5-phosphatases: traffic controllers, waistline watchers and tumour suppressors?" Biochemical Society Symposium 74, no. 1 (December 1, 2007): 161. http://dx.doi.org/10.1042/bss0740161.

Full text

APA, Harvard, Vancouver, ISO, and other styles

21

Whisstock, J. C., F. Wiradjaja, J. E. Waters, and R. Gurung. "The Structure and Function of Catalytic Domains Within Inositol Polyphosphate 5-Phosphatases." IUBMB Life (International Union of Biochemistry and Molecular Biology: Life) 53, no. 1 (January 1, 2002): 15–23. http://dx.doi.org/10.1080/15216540210814.

Full text

APA, Harvard, Vancouver, ISO, and other styles

22

Stolz, Leslie E., Chau V. Huynh, Jeremy Thorner, and John D. York. "Identification and Characterization of an Essential Family of Inositol Polyphosphate 5-Phosphatases (INP51, INP52 and INP53 Gene Products) in the Yeast Saccharomyces cerevisiae." Genetics 148, no. 4 (April 1, 1998): 1715–29. http://dx.doi.org/10.1093/genetics/148.4.1715.

Full text

Abstract:

Abstract We recently demonstrated that the S. cerevisiae INP51 locus (YIL002c) encodes an inositol polyphosphate 5-phosphatase. Here we describe two related yeast loci, INP52 (YNL106c) and INP53 (YOR109w). Like Inp51p, the primary structures of Inp52p and Inp53p resemble the mammalian synaptic vesicle-associated protein, synaptojanin, and contain a carboxy-terminal catalytic domain and an amino-terminal SAC1-like segment. Inp51p (108 kD), Inp52p (136 kD) and Inp53p (124 kD) are membrane-associated. Single null mutants (inp51, inp52, or inp53) are viable. Both inp51 inp52 and inp52 inp53 double mutants display compromised cell growth, whereas an inp51 inp53 double mutant does not. An inp51 inp52 inp53 triple mutant is inviable on standard medium, but can grow weakly on media supplemented with an osmotic stabilizer (1 M sorbitol). An inp51 mutation, and to a lesser degree an inp52 mutation, confers cold-resistant growth in a strain background that cannot grow at temperatures below 15°. Analysis of inositol metabolites in vivo showed measurable accumulation of phosphatidylinositol 4,5-bisphosphate in the inp51 mutant. Electron microscopy revealed plasma membrane invaginations and cell wall thickening in double mutants and the triple mutant grown in sorbitol-containing medium. A fluorescent dye that detects endocytic and vacuolar membranes suggests that the vacuole is highly fragmented in inp51 inp52 double mutants. Our observations indicate that Inp51p, Inp52p, and Inp53p have distinct functions and that substrates and/or products of inositol polyphosphate 5-phosphatases may have roles in vesicle trafficking, membrane structure, and/or cell wall formation.

APA, Harvard, Vancouver, ISO, and other styles

23

Bertelli, Daniela F., Eliana P. Araújo, Maristela Cesquini, Graziela R. Stoppa, Miriam Gasparotto-Contessotto, Marcos H. Toyama, Jorge V. C. Felix, et al. "Phosphoinositide-Specific Inositol Polyphosphate 5-Phosphatase IV Inhibits Inositide Trisphosphate Accumulation in Hypothalamus and Regulates Food Intake and Body Weight." Endocrinology 147, no. 11 (November 1, 2006): 5385–99. http://dx.doi.org/10.1210/en.2006-0280.

Full text

Abstract:

The enzyme phosphatidylinositol 3-kinase (PI3-kinase) exerts an important role in the transduction of the anorexigenic and thermogenic signals delivered by insulin and leptin to first-order neurons of the arcuate nucleus in the hypothalamus. The termination of the intracellular signals generated by the activation of PI3-kinase depends on the coordinated activity of specific inositol phosphatases. Here we show that phosphoinositide-specific inositol polyphosphate 5-phosphatase IV (5ptase IV) is highly expressed in neurons of the arcuate and lateral nuclei of the hypothalamus. Upon intracerebroventricular (ICV) treatment with insulin, 5ptase IV undergoes a time-dependent tyrosine phosphorylation, which follows the same patterns of canonical insulin signaling through the insulin receptor, insulin receptor substrate-2, and PI3-kinase. To evaluate the participation of 5ptase IV in insulin action in hypothalamus, we used a phosphorthioate-modified antisense oligonucleotide specific for this enzyme. The treatment of rats with this oligonucleotide for 4 d reduced the hypothalamic expression of 5ptase IV by approximately 80%. This was accompanied by an approximately 70% reduction of insulin-induced tyrosine phosphorylation of 5ptase IV and an increase in basal accumulation of phosphorylated inositols in the hypothalamus. Finally, inhibition of hypothalamic 5ptase IV expression by the antisense approach resulted in reduced daily food intake and body weight loss. Thus, 5ptase IV is a powerful regulator of signaling through PI3-kinase in hypothalamus and may become an interesting target for therapeutics of obesity and related disorders.

APA, Harvard, Vancouver, ISO, and other styles

24

Nakajima, Toshio, Shun Hosoyamada, Takehiko Kobayashi, and Yukio Mukai. "Secreted acid phosphatases maintain replicative lifespan via inositol polyphosphate metabolism in budding yeast." FEBS Letters 596, no. 2 (December 5, 2021): 189–98. http://dx.doi.org/10.1002/1873-3468.14245.

Full text

APA, Harvard, Vancouver, ISO, and other styles

25

Gunesekera, Bhadra, Javad Torabinejad, Jamille Robinson, and Glenda E. Gillaspy. "Inositol Polyphosphate 5-Phosphatases 1 and 2 Are Required for Regulating Seedling Growth." Plant Physiology 143, no. 3 (January 19, 2007): 1408–17. http://dx.doi.org/10.1104/pp.106.089474.

Full text

APA, Harvard, Vancouver, ISO, and other styles

26

Conduit, Sarah E., Jennifer M. Dyson, and Christina A. Mitchell. "Inositol polyphosphate 5-phosphatases; new players in the regulation of cilia and ciliopathies." FEBS Letters 586, no. 18 (July 21, 2012): 2846–57. http://dx.doi.org/10.1016/j.febslet.2012.07.037.

Full text

APA, Harvard, Vancouver, ISO, and other styles

27

Maeda, Akito, Mari Kurosaki, Masao Ono, Toshiyuki Takai, and Tomohiro Kurosaki. "Requirement of SH2-containing Protein Tyrosine Phosphatases SHP-1 and SHP-2 for Paired Immunoglobulin-like Receptor B (PIR-B)–mediated Inhibitory Signal." Journal of Experimental Medicine 187, no. 8 (April 20, 1998): 1355–60. http://dx.doi.org/10.1084/jem.187.8.1355.

Full text

Abstract:

Paired immunoglobulin-like receptor B (PIR-B) (p91) molecule has been proposed to function as an inhibitory receptor in B cells and myeloid lineage cells. We demonstrate here that the cytoplasmic region of PIR-B is capable of inhibiting B cell activation. Mutational analysis of five cytoplasmic tyrosines indicate that tyrosine 771 in the motif VxYxxL plays the most crucial role in mediating the inhibitory signal. PIR-B–mediated inhibition was markedly reduced in the SH2-containing protein tyrosine phosphatases SHP-1 and SHP-2 double-deficient DT40 B cells, whereas this inhibition was unaffected in the inositol polyphosphate 5′-phosphatase SHIP-deficient cells. These data demonstrate that PIR-B can negatively regulate B cell receptor activation and that this PIR-B–mediated inhibition requires redundant functions of SHP-1 and SHP-2.

APA, Harvard, Vancouver, ISO, and other styles

28

Ooms, Lisa M., Brad K. McColl, Fenny Wiradjaja, A. P. W. Wijayaratnam, Paul Gleeson, Mary Jane Gething, Joe Sambrook, and Christina A. Mitchell. "The Yeast Inositol Polyphosphate 5-Phosphatases Inp52p and Inp53p Translocate to Actin Patches following Hyperosmotic Stress: Mechanism for Regulating Phosphatidylinositol 4,5-Bisphosphate at Plasma Membrane Invaginations." Molecular and Cellular Biology 20, no. 24 (December 15, 2000): 9376–90. http://dx.doi.org/10.1128/mcb.20.24.9376-9390.2000.

Full text

Abstract:

ABSTRACT The Saccharomyces cerevisiae inositol polyphosphate 5-phosphatases (Inp51p, Inp52p, and Inp53p) each contain an N-terminal Sac1 domain, followed by a 5-phosphatase domain and a C-terminal proline-rich domain. Disruption of any two of these 5-phosphatases results in abnormal vacuolar and plasma membrane morphology. We have cloned and characterized the Sac1-containing 5-phosphatases Inp52p and Inp53p. Purified recombinant Inp52p lacking the Sac1 domain hydrolyzed phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] and PtdIns(3,5)P2. Inp52p and Inp53p were expressed in yeast as N-terminal fusion proteins with green fluorescent protein (GFP). In resting cells recombinant GFP-tagged 5-phosphatases were expressed diffusely throughout the cell but were excluded from the nucleus. Following hyperosmotic stress the GFP-tagged 5-phosphatases rapidly and transiently associated with actin patches, independent of actin, in both the mother and daughter cells of budding yeast as demonstrated by colocalization with rhodamine phalloidin. Both the Sac1 domain and proline-rich domains were able to independently mediate translocation of Inp52p to actin patches, following hyperosmotic stress, while the Inp53p proline-rich domain alone was sufficient for stress-mediated localization. Overexpression of Inp52p or Inp53p, but not catalytically inactive Inp52p, which lacked PtdIns(4,5)P2 5-phosphatase activity, resulted in a dramatic reduction in the repolarization time of actin patches following hyperosmotic stress. We propose that the osmotic-stress-induced translocation of Inp52p and Inp53p results in the localized regulation of PtdIns(3,5)P2 and PtdIns(4,5)P2 at actin patches and associated plasma membrane invaginations. This may provide a mechanism for regulating actin polymerization and cell growth as an acute adaptive response to hyperosmotic stress.

APA, Harvard, Vancouver, ISO, and other styles

29

McConnell, F. M., L. R. Stephens, and S. B. Shears. "Multiple isomers of inositol pentakisphosphate in Epstein-Barr-virus- transformed (T5-1) B-lymphocytes. Identification of inositol 1,3,4,5,6-pentakisphosphate, d-inositol 1,2,4,5,6-pentakisphosphate and l-inositol 1,2,4,5,6-pentakisphosphate." Biochemical Journal 280, no. 2 (December 1, 1991): 323–29. http://dx.doi.org/10.1042/bj2800323.

Full text

Abstract:

Substantial amounts of three [3H]InsP5 isomers were detected in [3H]inositol-labelled human lymphoblastoid (T5-1) cells. Their structures were determined by h.p.l.c. [Phillippy & Bland (1988) Anal. Biochem. 175, 162-166], and by utilizing a stereospecific D-inositol 1,2,4,5,6-pentakisphosphate 3-kinase from Dictyostelium discoideum [Stephens & Irvine (1990) Nature (London) 346, 580-583]. The structures were: inositol 1,3,4,5,6-pentakisphosphate, D-inositol 1,2,4,5,6-pentakisphosphate and L-inositol 1,2,4,5,6-pentakisphosphate. The relative proportions of these isomers (approx. 73:14:14 respectively) were unaffected by cross-linking anti-IgD receptors. The T5-1 cells also contained InsP6 and three Ins P4s, which were identified as the 1,3,4,5, 1,3,4,6 and 3,4,5,6 isomers. In incubations with permeabilized T5-1 cells, both 1,3,4,6 and 3,4,5,6 isomers of InsP4 were phosphorylated solely to Ins(1,3,4,5,6)P5. Permeabilized cells also dephosphorylated InsP6, even in the presence of a large excess of glucose 6-phosphate to saturate non-specific phosphatases. In the latter experiments the following isomers of InsP5 accumulated: D- and/or L-Ins(1,2,3,4,5)P5, plus D- and/or L-Ins(1,2,4,5,6)P5. This demonstration that multiple isomers of InsP5 may be formed in vivo and in vitro by a transformed lymphocyte cell line adds a new level of complexity to the study of inositol polyphosphate metabolism and function.

APA, Harvard, Vancouver, ISO, and other styles

30

Hejna, James A., Hiroshi Saito, Louise S. Merkens, Thomas V. Tittle, Petra M. Jakobs, Michael A. Whitney, Markus Grompe, Andrew S. Friedberg, and Robb E. Moses. "Cloning and Characterization of a Human cDNA (INPPL1) Sharing Homology with Inositol Polyphosphate Phosphatases." Genomics 29, no. 1 (September 1995): 285–87. http://dx.doi.org/10.1006/geno.1995.1247.

Full text

APA, Harvard, Vancouver, ISO, and other styles

31

Sitaram, Uyemura, Malarkannan, and Riese. "Beyond the Cell Surface: Targeting Intracellular Negative Regulators to Enhance T cell Anti-Tumor Activity." International Journal of Molecular Sciences 20, no. 23 (November 20, 2019): 5821. http://dx.doi.org/10.3390/ijms20235821.

Full text

Abstract:

It is well established that extracellular proteins that negatively regulate T cell function, such as Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA-4) and Programmed Cell Death protein 1 (PD-1), can be effectively targeted to enhance cancer immunotherapies and Chimeric Antigen Receptor T cells (CAR-T cells). Intracellular proteins that inhibit T cell receptor (TCR) signal transduction, though less well studied, are also potentially useful therapeutic targets to enhance T cell activity against tumor. Four major classes of enzymes that attenuate TCR signaling include E3 ubiquitin kinases such as the Casitas B-lineage lymphoma proteins (Cbl-b and c-Cbl), and Itchy (Itch), inhibitory tyrosine phosphatases, such as Src homology region 2 domain-containing phosphatases (SHP-1 and SHP-2), inhibitory protein kinases, such as C-terminal Src kinase (Csk), and inhibitory lipid kinases such as Src homology 2 (SH2) domain-containing inositol polyphosphate 5-phosphatase (SHIP) and Diacylglycerol kinases (DGKs). This review describes the mechanism of action of eighteen intracellular inhibitory regulatory proteins in T cells within these four classes, and assesses their potential value as clinical targets to enhance the anti-tumor activity of endogenous T cells and CAR-T cells.

APA, Harvard, Vancouver, ISO, and other styles

32

Batty, Ian H., Jeroen van der Kaay, Alex Gray, Joan F. Telfer, Miles J. Dixon, and C. Peter Downes. "The control of phosphatidylinositol 3,4-bisphosphate concentrations by activation of the Src homology 2 domain containing inositol polyphosphate 5-phosphatase 2, SHIP2." Biochemical Journal 407, no. 2 (September 25, 2007): 255–66. http://dx.doi.org/10.1042/bj20070558.

Full text

Abstract:

Activation of class Ia PI3K (phosphoinositide 3-kinase) produces PtdInsP3, a vital intracellular mediator whose degradation generates additional lipid signals. In the present study vanadate analogues that inhibit PTPs (protein tyrosine phosphatases) were used to probe the mechanisms which regulate the concentrations of these molecules allowing their independent or integrated function. In 1321N1 cells, which lack PtdInsP3 3-phosphatase activity, sodium vanadate or a cell permeable derivative, bpV(phen) [potassium bisperoxo(1,10-phenanthroline)oxovanadate (V)], increased the recruitment into anti-phosphotyrosine immunoprecipitates of PI3K activity and of the p85 and p110α subunits of class Ia PI3K and enhanced the recruitment of PI3K activity stimulated by PDGF (platelet-derived growth factor). However, neither inhibitor much increased cellular PtdInsP3 concentrations, but both diminished dramatically the accumulation of PtdInsP3 stimulated by PDGF or insulin and markedly increased the control and stimulated concentrations of PtdIns(3,4)P2. These actions were accounted for by the ability of PTP inhibitors to stimulate the activity of endogenous PtdInsP3 5-phosphatase(s), particularly SHIP2 (Src homology 2 domain containing inositol polyphosphate 5-phosphatase 2) and to inhibit types I and II PtdIns(3,4)P2 4-phosphatases. Thus bpV(phen) promoted the translocation of SHIP2 from the cytosol to a Triton X-100-insoluble fraction and induced a marked (5–10-fold) increase in SHIP2 specific activity mediated by enhanced tyrosine phosphorylation. The net effect of these inhibitors was, therefore, to switch the signal output of class I PI3K from PtdInsP3 to PtdIns(3,4)P2. A key component controlling this shift in the balance of lipid signals is the activation of SHIP2 by increased tyrosine phosphorylation, an effect observed in HeLa cells in response to both PTP inhibitors and epidermal growth factor.

APA, Harvard, Vancouver, ISO, and other styles

33

Ooms, Lisa M., Clare G. Fedele, Megan V. Astle, Ivan Ivetac, Vanessa Cheung, Richard B. Pearson, Meredith J. Layton, Ariel Forrai, Harshal H. Nandurkar, and Christina A. Mitchell. "The Inositol Polyphosphate 5-Phosphatase, PIPP, Is a Novel Regulator of Phosphoinositide 3-Kinase-dependent Neurite Elongation." Molecular Biology of the Cell 17, no. 2 (February 2006): 607–22. http://dx.doi.org/10.1091/mbc.e05-05-0469.

Full text

Abstract:

The spatial activation of phosphoinositide 3-kinase (PI3-kinase) signaling at the axon growth cone generates phosphatidylinositol 3,4,5 trisphosphate (PtdIns(3,4,5)P3), which localizes and facilitates Akt activation and stimulates GSK-3β inactivation, promoting microtubule polymerization and axon elongation. However, the molecular mechanisms that govern the spatial down-regulation of PtdIns(3,4,5)P3 signaling at the growth cone remain undetermined. The inositol polyphosphate 5-phosphatases (5-phosphatase) hydrolyze the 5-position phosphate from phosphatidylinositol 4,5 bisphosphate (PtdIns(4,5)P2) and/or PtdIns(3,4,5)P3. We demonstrate here that PIPP, an uncharacterized 5-phosphatase, hydrolyzes PtdIns(3,4,5)P3 forming PtdIns(3,4)P2, decreasing Ser473-Akt phosphorylation. PIPP is expressed in PC12 cells, localizing to the plasma membrane of undifferentiated cells and the neurite shaft and growth cone of NGF-differentiated neurites. Overexpression of wild-type, but not catalytically inactive PIPP, in PC12 cells inhibited neurite elongation. Targeted depletion of PIPP using RNA interference (RNAi) resulted in enhanced neurite differentiation, associated with neurite hyperelongation. Inhibition of PI3-kinase activity prevented neurite hyperelongation in PIPP-deficient cells. PIPP targeted-depletion resulted in increased phospho-Ser473-Akt and phospho-Ser9-GSK-3β, specifically at the neurite growth cone, and accumulation of PtdIns(3,4,5)P3 at this site, associated with enhanced microtubule polymerization in the neurite shaft. PIPP therefore inhibits PI3-kinase-dependent neurite elongation in PC12 cells, via regulation of the spatial distribution of phospho-Ser473-Akt and phospho-Ser9-GSK-3β signaling.

APA, Harvard, Vancouver, ISO, and other styles

34

Pöhlmann, Jennifer, and Ursula Fleig. "Asp1, a Conserved 1/3 Inositol Polyphosphate Kinase, Regulates the Dimorphic Switch in Schizosaccharomyces pombe." Molecular and Cellular Biology 30, no. 18 (July 12, 2010): 4535–47. http://dx.doi.org/10.1128/mcb.00472-10.

Full text

Abstract:

ABSTRACT The ability to undergo dramatic morphological changes in response to extrinsic cues is conserved in fungi. We have used the model yeast Schizosaccharomyces pombe to determine which intracellular signal regulates the dimorphic switch from the single-cell yeast form to the filamentous invasive growth form. The S. pombe Asp1 protein, a member of the conserved Vip1 1/3 inositol polyphosphate kinase family, is a key regulator of the morphological switch via the cAMP protein kinase A (PKA) pathway. Lack of a functional Asp1 kinase domain abolishes invasive growth which is monopolar, while an increase in Asp1-generated inositol pyrophosphates (PP) increases the cellular response. Remarkably, the Asp1 kinase activity encoded by the N-terminal part of the protein is regulated negatively by the C-terminal domain of Asp1, which has homology to acid histidine phosphatases. Thus, the fine tuning of the cellular response to environmental cues is modulated by the same protein. As the Saccharomyces cerevisiae Asp1 ortholog is also required for the dimorphic switch in this yeast, we propose that Vip1 family members have a general role in regulating fungal dimorphism.

APA, Harvard, Vancouver, ISO, and other styles

35

Wang, Ruobing, Yan Jiao, Yanqing Li, Siyang Ye, Guoqiang Pan, Shanshan Qin, Fang Hua, and Yahui Liu. "The Prediction and Prognostic Significance of INPP5K Expression in Patients with Liver Cancer." BioMed Research International 2020 (April 27, 2020): 1–9. http://dx.doi.org/10.1155/2020/9519235.

Full text

Abstract:

Liver cancer is a devastating disease for humans with poor prognosis. Although the survival rate of patients with liver cancer has improved in the past decades, the recurrence and metastasis of liver cancer are still obstacles for us. Inositol polyphosphate-5-phosphatase K (INPP5K) belongs to the family of phosphoinositide 5-phosphatases (PI 5-phosphatases), which have been reported to be associated with cell migration, polarity, adhesion, and cell invasion, especially in cancers. However, there have been few studies on the correlation of INPP5K and liver cancer. In this study, we explored the prognostic significance of INPP5K in liver cancer through bioinformatics analysis of data collected from The Cancer Genome Atlas (TCGA) database. Chi-square and Fisher exact tests were used to evaluate the relationship between INPP5K expression and clinical characteristics. Our results showed that low INPP5K expression was correlated with poor outcomes in liver cancer patients. Univariate and multivariate Cox analyses demonstrated that low INPP5K mRNA expression played a significant role in shortening overall survival (OS) and relapse-free survival (RFS), which might serve as the useful biomarker and prognostic factor for liver cancer. In conclusion, low INPP5K mRNA expression is an independent risk factor for poor prognosis in liver cancer.

APA, Harvard, Vancouver, ISO, and other styles

36

Malbec, Odile, Dana C. Fong, Martin Turner, Victor L. J. Tybulewicz, John C. Cambier, Wolf H. Fridman, and Marc Daëron. "Fcε Receptor I-Associated lyn-Dependent Phosphorylation of Fcγ Receptor IIB During Negative Regulation of Mast Cell Activation." Journal of Immunology 160, no. 4 (February 15, 1998): 1647–58. http://dx.doi.org/10.4049/jimmunol.160.4.1647.

Full text

Abstract:

Abstract FcγRIIB are low-affinity receptors for IgG whose intracytoplasmic domain contains an immunoreceptor tyrosine-based inhibition motif (ITIM). FcγRIIB inhibit cell activation triggered by receptors that signal via immunoreceptor tyrosine-based activation motifs. This inhibition requires ITIM tyrosyl phosphorylation and is correlated with the binding of SH2 domain-containing phosphatases that may mediate the inhibitory signal. In the present work, we investigated the mechanism of FcγRIIB phosphorylation and its consequences in mast cells. We demonstrate that the phosphorylation of FcγRIIB requires coaggregation with FcεRI and that, once phosphorylated, FcγRIIB selectively recruit the inositol polyphosphate 5 phosphatase SHIP, in vivo. In vitro, however, the phosphorylated FcγRIIB ITIM binds not only SHIP, but also the two protein tyrosine phosphatases, SHP-1 and SHP-2. We show that the coaggregation of FcγRIIB with FcεRI does not prevent FcεRI-mediated activation of lyn and syk. Both kinases can phosphorylate FcγRIIB in vitro. However, when coaggregated with FcεRI, FcγRIIB was in vivo phosphorylated in syk-deficient mast cells, but not in lyn-deficient mast cells. When FcεRI are coaggregated with FcγRIIB by immune complexes, FcεRI-associated lyn may thus phosphorylate FcγRIIB. By this mechanism, FcεRI initiate ITIM-dependent inhibition of intracellular propagation of their own signals.

APA, Harvard, Vancouver, ISO, and other styles

37

Jia, Qi, Song Sun, Defeng Kong, Junliang Song, Lumei Wu, Zhen Yan, Lin Zuo, et al. "Ectopic Expression of Gs5PTase8, a Soybean Inositol Polyphosphate 5-Phosphatase, Enhances Salt Tolerance in Plants." International Journal of Molecular Sciences 21, no. 3 (February 4, 2020): 1023. http://dx.doi.org/10.3390/ijms21031023.

Full text

Abstract:

Inositol polyphosphate 5-phosphatases (5PTases) function in inositol signaling by regulating the catabolism of phosphoinositol derivatives. Previous reports showed that 5PTases play a critical role in plant development and stress responses. In this study, we identified a novel 5PTase gene, Gs5PTase8, from the salt-tolerance locus of chromosome 3 in wild soybean (Glycine soja). Gs5PTase8 is highly up-regulated under salt treatment. It is localized in the nucleus and plasma membrane with a strong signal in the apoplast. Ectopic expression of Gs5PTase8 significantly increased salt tolerance in transgenic BY-2 cells, soybean hairy roots and Arabidopsis, suggesting Gs5PTase8 could increase salt tolerance in plants. The overexpression of Gs5PTase8 significantly enhanced the activities of catalase and ascorbate peroxidase under salt stress. The seeds of Gs5PTase8-transgenic Arabidopsis germinated earlier than the wild type under abscisic acid treatment, indicating Gs5PTase8 would alter ABA sensitivity. Besides, transcriptional analyses showed that the stress-responsive genes, AtRD22, AtRD29A and AtRD29B, were induced with a higher level in the Gs5PTase8-transgenic Arabidopsis plants than in the wild type under salt stress. These results reveal that Gs5PTase8 play a positive role in salt tolerance and might be a candidate gene for improving soybean adaptation to salt stress.

APA, Harvard, Vancouver, ISO, and other styles

38

Trésaugues, Lionel, Camilla Silvander, Susanne Flodin, Martin Welin, Tomas Nyman, Susanne Gräslund, Martin Hammarström, Helena Berglund, and Pär Nordlund. "Structural Basis for Phosphoinositide Substrate Recognition, Catalysis, and Membrane Interactions in Human Inositol Polyphosphate 5-Phosphatases." Structure 22, no. 5 (May 2014): 744–55. http://dx.doi.org/10.1016/j.str.2014.01.013.

Full text

APA, Harvard, Vancouver, ISO, and other styles

39

Marshall, Aaron J., Sen Hou, Xun Wu, and Hongzhao Li. "Control of B cell activation and migration by PI 3-kinase: role of inositol polyphosphate 4-phosphatases." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 198.5. http://dx.doi.org/10.4049/jimmunol.196.supp.198.5.

Full text

Abstract:

Abstract Balanced activation of the PI3K pathway by antigen and other stimuli is required for effective humoral immunity while avoiding autoimmunity and lymphoproliferative disease. The critical regulatory phosphatase SHIP dephosphorylates the PIP3 generated by PI3K to produce a distinct molecule PI(3,4)P2. A number of key signaling molecules bind to PIP3, including the protein kinase Btk; however much less is known about the function of PI(3,4)P2. The inositol phosphatase INPP4A can specifically hydrolyze PI(3,4)P2; however the functions of this phosphatase in B cell activation are unknown. We hypothesized that INPP4A can provide a tool to deplete PI(3,4)P2 and determine its range of functions. Human B lymphocytes over-expressing active or phosphatase-dead INPP4A were generated, and the cells expressing active enzyme were found to generate lower levels of PI(3,4)P2 upon chemokine or BCR stimulation. Chemokine-induced migration responses were inhibited by active, but not inactive INPP4A. An assessment of BCR signaling was carried out that compared BCR-stimulated cells expressing active versus inactive INPP4A in a screen encompassing over 800 protein phosphorylation sites. The results indicate that active INPP4A can suppress phosphorylation of Akt and known Akt targets. We are currently assessing whether PDK1, a major kinase upstream of Akt which also directly binds PI(3,4)P2, is regulated by INPP4A. Interestingly, other kinases known to interact with PDK1 (PKCdelta, RSK) or to be directly phosphorylated by PDK1 (PKCgamma) showed decreased phosphorylation in cells expressing active INPP4A. We are currently testing the hypothesis that PDK1/Akt and Btk/PLCγ2 signal osomes are differentially regulated by INPP4A.

APA, Harvard, Vancouver, ISO, and other styles

40

Csolle, Mariah P., Lisa M. Ooms, Antonella Papa, and Christina A. Mitchell. "PTEN and Other PtdIns(3,4,5)P3 Lipid Phosphatases in Breast Cancer." International Journal of Molecular Sciences 21, no. 23 (December 2, 2020): 9189. http://dx.doi.org/10.3390/ijms21239189.

Full text

Abstract:

The phosphoinositide 3-kinase (PI3K)/AKT signalling pathway is hyperactivated in ~70% of breast cancers. Class I PI3K generates PtdIns(3,4,5)P3 at the plasma membrane in response to growth factor stimulation, leading to AKT activation to drive cell proliferation, survival and migration. PTEN negatively regulates PI3K/AKT signalling by dephosphorylating PtdIns(3,4,5)P3 to form PtdIns(4,5)P2. PtdIns(3,4,5)P3 can also be hydrolysed by the inositol polyphosphate 5-phosphatases (5-phosphatases) to produce PtdIns(3,4)P2. Interestingly, while PTEN is a bona fide tumour suppressor and is frequently mutated/lost in breast cancer, 5-phosphatases such as PIPP, SHIP2 and SYNJ2, have demonstrated more diverse roles in regulating mammary tumourigenesis. Reduced PIPP expression is associated with triple negative breast cancers and reduced relapse-free and overall survival. Although PIPP depletion enhances AKT phosphorylation and supports tumour growth, this also inhibits cell migration and metastasis in vivo, in a breast cancer oncogene-driven murine model. Paradoxically, SHIP2 and SYNJ2 are increased in primary breast tumours, which correlates with invasive disease and reduced survival. SHIP2 or SYNJ2 overexpression promotes breast tumourigenesis via AKT-dependent and independent mechanisms. This review will discuss how PTEN, PIPP, SHIP2 and SYNJ2 distinctly regulate multiple functional targets, and the mechanisms by which dysregulation of these distinct phosphoinositide phosphatases differentially affect breast cancer progression.

APA, Harvard, Vancouver, ISO, and other styles

41

Gurung, Rajendra, April Tan, Lisa M. Ooms, Meagan J. McGrath, Richard D. Huysmans, Adam D. Munday, Mark Prescott, James C. Whisstock, and Christina A. Mitchell. "Identification of a Novel Domain in Two Mammalian Inositol-polyphosphate 5-Phosphatases That Mediates Membrane Ruffle Localization." Journal of Biological Chemistry 278, no. 13 (January 20, 2003): 11376–85. http://dx.doi.org/10.1074/jbc.m209991200.

Full text

APA, Harvard, Vancouver, ISO, and other styles

42

Zhong, Ruiqin, and Zheng-Hua Ye. "Molecular and Biochemical Characterization of Three WD-Repeat-Domain-containing Inositol Polyphosphate 5-Phosphatases in Arabidopsis thaliana." Plant and Cell Physiology 45, no. 11 (November 15, 2004): 1720–28. http://dx.doi.org/10.1093/pcp/pch187.

Full text

APA, Harvard, Vancouver, ISO, and other styles

43

Acquistapace, Isabella M., Monika A. Zi¸etek, Arthur W. H. Li, Melissa Salmon, Imke Kühn, Mike R. Bedford, Charles A. Brearley, and Andrew M. Hemmings. "Snapshots during the catalytic cycle of a histidine acid phytase reveal an induced-fit structural mechanism." Journal of Biological Chemistry 295, no. 51 (October 14, 2020): 17724–37. http://dx.doi.org/10.1074/jbc.ra120.015925.

Full text

Abstract:

Highly engineered phytases, which sequentially hydrolyze the hexakisphosphate ester of inositol known as phytic acid, are routinely added to the feeds of monogastric animals to improve phosphate bioavailability. New phytases are sought as starting points to further optimize the rate and extent of dephosphorylation of phytate in the animal digestive tract. Multiple inositol polyphosphate phosphatases (MINPPs) are clade 2 histidine phosphatases (HP2P) able to carry out the stepwise hydrolysis of phytate. MINPPs are not restricted by a strong positional specificity making them attractive targets for development as feed enzymes. Here, we describe the characterization of a MINPP from the Gram-positive bacterium Bifidobacterium longum (BlMINPP). BlMINPP has a typical HP2P-fold but, unusually, possesses a large α-domain polypeptide insertion relative to other MINPPs. This insertion, termed the U-loop, spans the active site and contributes to substrate specificity pockets underpopulated in other HP2Ps. Mutagenesis of U-loop residues reveals its contribution to enzyme kinetics and thermostability. Moreover, four crystal structures of the protein along the catalytic cycle capture, for the first time in an HP2P, a large ligand-driven α-domain motion essential to allow substrate access to the active site. This motion recruits residues both downstream of a molecular hinge and on the U-loop to participate in specificity subsites, and mutagenesis identified a mobile lysine residue as a key determinant of positional specificity of the enzyme. Taken together, these data provide important new insights to the factors determining stability, substrate recognition, and the structural mechanism of hydrolysis in this industrially important group of enzymes.

APA, Harvard, Vancouver, ISO, and other styles

44

Whisstock, James C., Susana Romero, Rajendra Gurung, Harshal Nandurkar, Lisa M. Ooms, Stephen P. Bottomley, and Christina A. Mitchell. "The Inositol Polyphosphate 5-Phosphatases and the Apurinic/Apyrimidinic Base Excision Repair Endonucleases Share a Common Mechanism for Catalysis." Journal of Biological Chemistry 275, no. 47 (August 28, 2000): 37055–61. http://dx.doi.org/10.1074/jbc.m006244200.

Full text

APA, Harvard, Vancouver, ISO, and other styles

45

Zhang, Yanyan, Anne-Sophie Wavreille, Andrew R. Kunys, and Dehua Pei. "The SH2 Domains of Inositol Polyphosphate 5-Phosphatases SHIP1 and SHIP2 Have Similar Ligand Specificity but Different Binding Kinetics." Biochemistry 48, no. 46 (November 24, 2009): 11075–83. http://dx.doi.org/10.1021/bi9012462.

Full text

APA, Harvard, Vancouver, ISO, and other styles

46

COMMUNI, David, and Christophe ERNEUX. "Identification of an active site cysteine residue in human type I Ins(1,4,5)P3 5-phosphatase by chemical modification and site-directed mutagenesis." Biochemical Journal 320, no. 1 (November 15, 1996): 181–86. http://dx.doi.org/10.1042/bj3200181.

Full text

Abstract:

Chemical modification using thiol-directed agents and site-directed mutagenesis have been used to investigate the crucial role of an active site cysteine residue within the substrate-binding domain of human type I Ins(1,4,5)P3 5-phosphatase. Irreversible inhibition of enzymic activity is provoked by chemical modification of the enzyme by N-ethylmaleimide (NEM), 5,5´-dithio-2-nitrobenzoic acid, iodoacetate and to a much smaller extent by iodoacetamide. The alkylation reaction by NEM is prevented in the presence of Ins(1,4,5)P3. The results indicate that NEM binds at the active site of the enzyme with a stoichiometry of 0.9 mol of NEM per mol of enzyme. A single [14C]NEM-modified peptide was isolated after α-chymotrypsin proteolysis of the radiolabelled enzyme and reverse-phase HPLC. Sequence analysis of the active site-labelled peptide (i.e. MNTRCPAWCD) demonstrated that Cys348 contained the radiolabel. Furthermore two mutant enzymes were obtained by site-directed mutagenesis of the cysteine residue to serine and alanine respectively. Both mutant enzymes had identical UV CD spectra. The two mutants (i.e. Cys348 → Ser and Cys348 → Ala) show a marked loss of enzymic activity (more than 98% compared with the wild-type enzyme). Thus we have directly identified a reactive cysteine residue as part of the active site, i.e. the substrate-binding domain, of Ins(1,4,5)P3 5-phosphatase. This cysteine residue is part of a sequence 10 amino acids long that is well conserved among the primary structures of inositol and phosphatidylinositol polyphosphate 5-phosphatases.

APA, Harvard, Vancouver, ISO, and other styles

47

Dionisio, Giuseppe, Preben B. Holm, and Henrik Brinch-Pedersen. "Wheat (Triticum aestivum L.) and barley (Hordeum vulgare L.) multiple inositol polyphosphate phosphatases (MINPPs) are phytases expressed during grain filling and germination." Plant Biotechnology Journal 5, no. 2 (March 2007): 325–38. http://dx.doi.org/10.1111/j.1467-7652.2007.00244.x.

Full text

APA, Harvard, Vancouver, ISO, and other styles

48

Marjanovic, Jasna, Brad Rumancik, Luke Weber, Felix Wangmang, Dane Fickes, Dmitri Postnov, Dung Nguyen, Yoon Lee, Richard Ngo-Lam, and Monita Wilson. "Phosphatidylinositol-3,4-Bisphosphate-Akt Signaling Pathway Promotes Platelet Activation." Blood 132, Supplement 1 (November 29, 2018): 1131. http://dx.doi.org/10.1182/blood-2018-99-115066.

Full text

Abstract:

Abstract Phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P2) is a messenger that accumulates in platelets in a phosphoinositide 3-kinase and platelet aggregation-dependent manner. PtdIns(3,4)P2 is broken down by inositol polyphosphate 4-phosphatases, type I (INPP4A) and type II (INPP4B). These enzymes do not catalyze hydrolysis of phosphoinositides other than PtdIns(3,4)P2, and therefore provide unique means for studying the role of this lipid in platelet activation. We have found that the dominant isoform of 4-phosphatases expressed in platelets is INPP4A and we have generated radiation chimera mice with the deficiency in INPP4A restricted to hematopoietic cell lineage. Compared to wild type platelets, agonist-stimulated INPP4A-deficient platelets accumulated higher levels of PtdIns(3,4)P2. An increase in platelet aggregation in INPP4A-deficient platelets was observed with all tested agonists. To study platelet function in vivo, we performed carotid artery injury mouse thrombosis model experiments. Time to occlusion was dramatically reduced in mice with INPP4A deficiency. These data support the hypothesis that by regulating PtdIns(3,4)P2 levels, INPP4A downregulates platelet aggregation and thrombus formation. To investigate mechanisms mediating INPP4A-dependent signals, we compared levels of phosphorylated Akt and phosphorylated glycogen synthase kinase (GSK) in wild type and INPP4A-deficient platelets in response to agonist stimulation. An increase in phospho-Akt levels was observed in INPP4A-deficient platelets, suggesting that in addition to its well-characterized regulator, PtdIns(3,4,5)P3, PtdIns(3,4)P2 can promote Akt activation. Interestingly, this was not accompanied by a significant increase in phospho-GSK levels, suggesting a possible novel mechanism involved in platelet aggregation. Disclosures No relevant conflicts of interest to declare.

APA, Harvard, Vancouver, ISO, and other styles

49

Chi, Hongbo, Xiaonian Yang, Paul D. Kingsley, Regis J. O'Keefe, J. Edward Puzas, Randy N. Rosier, Stephen B. Shears, and Paul R. Reynolds. "Targeted Deletion of Minpp1 Provides New Insight into the Activity of Multiple Inositol Polyphosphate Phosphatase In Vivo." Molecular and Cellular Biology 20, no. 17 (September 1, 2000): 6496–507. http://dx.doi.org/10.1128/mcb.20.17.6496-6507.2000.

Full text

Abstract:

ABSTRACT Multiple inositol polyphosphate phosphatase (Minpp1) metabolizes inositol 1,3,4,5,6-pentakisphosphate (InsP5) and inositol hexakisphosphate (InsP6) with high affinity in vitro. However, Minpp1 is compartmentalized in the endoplasmic reticulum (ER) lumen, where access of enzyme to these predominantly cytosolic substrates in vivo has not previously been demonstrated. To gain insight into the physiological activity of Minpp1,Minpp1-deficient mice were generated by homologous recombination. Tissue extracts from Minpp1-deficient mice lacked detectable Minpp1 mRNA expression and Minpp1 enzyme activity. Unexpectedly, Minpp1-deficient mice were viable, fertile, and without obvious defects. Although Minpp1 expression is upregulated during chondrocyte hypertrophy, normal chondrocyte differentiation and bone development were observed inMinpp1-deficient mice. Biochemical analyses demonstrate that InsP5 and InsP6 are in vivo substrates for ER-based Minpp1, as levels of these polyphosphates inMinpp1-deficient embryonic fibroblasts were 30 to 45% higher than in wild-type cells. This increase was reversed by reintroducing exogenous Minpp1 into the ER. Thus, ER-based Minpp1 plays a significant role in the maintenance of steady-state levels of InsP5 and InsP6. These polyphosphates could be reduced below their natural levels by aberrant expression in the cytosol of a truncated Minpp1 lacking its ER-targeting N terminus. This was accompanied by slowed cellular proliferation, indicating that maintenance of cellular InsP5 and InsP6 is essential to normal cell growth. Yet, depletion of cellular inositol polyphosphates during erythropoiesis emerges as an additional physiological activity of Minpp1; loss of this enzyme activity in erythrocytes from Minpp1-deficient mice was accompanied by upregulation of a novel, substitutive inositol polyphosphate phosphatase.

APA, Harvard, Vancouver, ISO, and other styles

50

Horan, Kristy A., Ken-ichi Watanabe, Anne M. Kong, Charles G. Bailey, John E. J. Rasko, Takehiko Sasaki, and Christina A. Mitchell. "Regulation of FcγR-stimulated phagocytosis by the 72-kDa inositol polyphosphate 5-phosphatase: SHIP1, but not the 72-kDa 5-phosphatase, regulates complement receptor 3–mediated phagocytosis by differential recruitment of these 5-phosphatases to the phagocytic cup." Blood 110, no. 13 (December 15, 2007): 4480–91. http://dx.doi.org/10.1182/blood-2007-02-073874.

Full text

Abstract:

Macrophages phagocytose particles to resolve infections and remove apoptotic cells. Phosphoinositide 3-kinase generates phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P3] is restricted to the phagocytic cup, promoting phagocytosis. The PtdIns(3,4,5)P3 5-phosphatase (5-ptase) Src homology 2 (SH2) domain-containing inositol-5-phosphatase 1 (SHIP1) inhibits phagocytosis. We report here that another PtdIns(3,4,5)P3-5-ptase, the 72-kDa-5-phosphatase (72-5ptase), inhibits Fcγ receptor (FcγR)– but not complement receptor 3 (CR3)–mediated phagocytosis, affecting pseudopod extension and phagosome closure. In contrast, SHIP1 inhibited FcγR and CR3 phagocytosis with greater effects on CR3-stimulated phagocytosis. The 72-5ptase and SHIP1 were both dynamically recruited to FcγR-stimulated phagocytic cups, but only SHIP1 was recruited to CR3-stimulated phagocytic cups. To determine whether 5-ptases focally degrade PtdIns(3,4,5)P3 at the phagocytic cup after specific stimuli, time-lapse imaging of specific biosensors was performed. Transfection of dominant-negative 72-5ptase or 72-5ptase small interfering RNA (siRNA) resulted in amplified and prolonged PtdIns(3,4,5)P3 at the phagocytic cup in response to FcγR- but not CR3-stimulation. In contrast, macrophages from Ship1−/−/AktPH-GFP transgenic mice exhibited increased and sustained PtdIns(3,4,5)P3 at the cup in response to CR3 activation, with minimal changes to FcγR activation. Therefore, 72-5ptase and SHIP1 exhibit specificity in regulating FcγR- versus CR3-stimulated phagocytosis by controlling the amplitude and duration of PtdIns(3,4,5)P3 at the phagocytic cup.

APA, Harvard, Vancouver, ISO, and other styles

Journal articles on the topic 'Inositol polyphosphate phosphatases'

Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles