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Christina Anne Mitchell - One of the best experts on this subject based on the ideXlab platform.
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regulation of ptdins 3 4 5 p3 akt signalling by inositol polyphosphate 5 Phosphatases
Biochemical Society Transactions, 2016Co-Authors: Matthew J Eramo, Christina Anne MitchellAbstract:The phosphoinositide 3-kinase (PI3K) generated lipid signals, PtdIns(3,4,5) P 3 and PtdIns(3,4) P 2, 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) P 3 to yield PtdIns(3,4) P 2. Extensive work has revealed several 5-Phosphatases inhibit PI3K-driven Akt signalling, by decreasing PtdIns(3,4,5) P 3 despite increasing cellular levels of PtdIns(3,4) P 2. 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) P 3 5-Phosphatases play in developmental diseases and cancer. * 3AC, : 3-a-aminocholestane; 5-Phosphatases, : inositol polyphosphate 5-Phosphatases; AURKA, : aurora kinase A; BJAB, : human B-cell lymphoma cell line; BMMC, : bone marrow-derived mast cells; CHO, : Chinese hamster ovary; EGF, : epidermal growth factor; ENU, : N -ethyl- N -nitrosourea; ER, : estrogen receptor; FoxO, : forkhead box, class O; GLUT4, : glucose transporter type 4; Gpr161, : G-protein-coupled receptor 161; HEK, : human embryonic kidney; IGF-1, : insulin-like growth factor-1; IL-3, : interleukin-3; LPS, : lipopolysaccharide; MEF, : mouse embryonic fibroblast; MM, : multiple myeloma; mTORC, : mammalian target of rapamycin complex; NFAT, : nuclear factor of activated T cells; OCRL, : oculocerebrorenal syndrome of Lowe; Pak1, : P21-activated kinase 1; PDK1, : phosphoinositide-dependent kinase 1; PH, : pleckstrin homology; 1PIE, : (2-phenyl-benzo[ h ]quinolin-4-yl)-[2]piperidyl-methanol hydrochloride; 2PIQ, : 1-[(chlorophenyl)methyl]-2-methyl-5-(methylthio)-1H-indole-3-ethanamine hydrochloride; 6PTQ, : (2-adamantan-1-yl-6,8-dichloro-quinolin-4-yl)-pyridin-2-yl-methanol hydrochloride; PI3K, : phosphoinositide 3-kinase; PIPP, : proline-rich inositol polyphosphate 5-phosphatase; PRAS40, : proline-rich Akt substrate of 40 kDa; PTEN, : phosphatase and tensin homologue deleted on chromosome 10; PyMT, : polyoma middle T; Rheb, : Ras homologue enriched in brain; RhoGAP, : Rho GTP-ase activating protein; SAG, : smoothened agonist; Shh, : sonic hedgehog; SHIP, : SH2-containing inositol phosphatase; SKICH, : SKIP carboxy homology; SKIP, : skeletal muscle- and kidney-enriched inositol phosphatase; TNFα, : tumour necrosis factor α; TSC, : tuberous sclerosis; TULP3, : Tubby-like protein 3
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inositol polyphosphate Phosphatases in human disease
Current Topics in Microbiology and Immunology, 2012Co-Authors: Sandra Hakim, Micka C Bertucci, Sarah E Conduit, David L Vuong, Christina Anne MitchellAbstract:Phosphoinositide signalling molecules interact with a plethora of effector proteins to regulate cell proliferation and survival, vesicular trafficking, metabolism, actin dynamics and many other cellular functions. The generation of specific phosphoinositide species is achieved by the activity of phosphoinositide kinases and Phosphatases, which phosphorylate and dephosphorylate, respectively, the inositol headgroup of phosphoinositide molecules. The phosphoinositide Phosphatases can be classified as 3-, 4- and 5-Phosphatases based on their specificity for dephosphorylating phosphates from specific positions on the inositol head group. The SAC Phosphatases show less specificity for the position of the phosphate on the inositol ring. The phosphoinositide Phosphatases regulate PI3K/Akt signalling, insulin signalling, endocytosis, vesicle trafficking, cell migration, proliferation and apoptosis. Mouse knockout models of several of the phosphoinositide Phosphatases have revealed significant physiological roles for these enzymes, including the regulation of embryonic development, fertility, neurological function, the immune system and insulin sensitivity. Importantly, several phosphoinositide Phosphatases have been directly associated with a range of human diseases. Genetic mutations in the 5-phosphatase INPP5E are causative of the ciliopathy syndromes Joubert and MORM, and mutations in the 5-phosphatase OCRL result in Lowe’s syndrome and Dent 2 disease. Additionally, polymorphisms in the 5-phosphatase SHIP2 confer diabetes susceptibility in specific populations, whereas reduced protein expression of SHIP1 is reported in several human leukaemias. The 4-phosphatase, INPP4B, has recently been identified as a tumour suppressor in human breast and prostate cancer. Mutations in one SAC phosphatase, SAC3/FIG4, results in the degenerative neuropathy, Charcot-Marie-Tooth disease. Indeed, an understanding of the precise functions of phosphoinositide Phosphatases is not only important in the context of normal human physiology, but to reveal the mechanisms by which these enzyme families are implicated in an increasing repertoire of human diseases.
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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, 2000Co-Authors: Lisa M Ooms, Brad K Mccoll, Fenny Wiradjaja, A P W Wijayaratnam, Paul A Gleeson, Mary Jane Gething, Joseph Sambrook, Christina Anne MitchellAbstract:The actin cytoskeleton plays a fundamental role in regulating cytokinesis and organelle transport. In the budding yeast Saccharomyces cerevisiae genetic and morphological evidence indicates that actin regulates cell growth. In yeast filamentous actin is found in two morphologically identified forms, cables and patches (1, 24). Actin cables are found mainly in the mother cell and extend along the axis of growth, which is asymmetrical to the emerging daughter cell. Cables are involved in regulating organelle inheritance and vesicle targeting. Actin patches are associated with plasma membrane invaginations and are motile structures that move along the plasma membrane in response to osmotic stress (6, 33, 47). It has been speculated that actin patches may be necessary machinery for maintaining secretion or endocytosis. Actin cables and patches may form part of an integrated system, as their distributions often change simultaneously (23). However, the signaling mechanisms regulating the assembly and movement of actin cables and patches in response to osmotic and other stimuli are not well understood. The phosphoinositides are ubiquitous components of eukaryotic membranes and are critical regulators of the actin cytoskeleton and membrane trafficking (reviewed in references 11, 12, and 45). Phosphatidylinositol 4,5 bisphosphate [PtdIns(4,5)P2] serves as a precursor to a variety of second-messenger molecules and, via interactions with actin binding proteins, plays a critical role in regulating actin cytoskeletal rearrangement. The synthesis and degradation of PtdIns(4,5)P2 are mediated by a series of lipid phosphorylation and dephosphorylation reactions, governed by specific lipid kinases and Phosphatases. The enzyme family of inositol polyphosphate 5-Phosphatases (5-Phosphatases) regulate cellular PtdIns(4,5)P2 concentrations by dephosphorylating the position-5 phosphate from the inositol ring, forming PtdIns(4)P (28, 30). In addition, mammalian 5-Phosphatases dephosphorylate other position-5 phosphate phosphoinositides and inositol phosphates in a series of signal-terminating reactions that control intracellular calcium oscillations, apoptosis, synaptic vesicle recycling, and actin cytoskeletal rearrangement (28, 30). In S. cerevisiae, four genes encoding enzymes with amino acid sequence homology to the mammalian 5-Phosphatases have been identified. Three of these enzymes exhibit a structure similar to that of the mammalian 5-phosphatase, synaptojanin, and contain an N-terminal Sac1 domain, a central 5-phosphatase domain, and a C-terminal proline-rich domain. The coding sequences for these loci are designated SJL1, SJL2, and SJL3, respectively, for “synaptojanin-like” or INP51, INP52, and INP53, respectively, for inositol polyphosphate 5-Phosphatases 1 to 3 (42, 43). A fourth 5-phosphatase, encoded by INP54, contains significant homology to mammalian 5-Phosphatases but has no Sac1 or C-terminal proline-rich domain and specifically hydrolyzes only PtdIns(4,5)P2 (39). Several studies of S. cerevisiae have investigated the phenotype associated with deletion of genes encoding Sac1-containing 5-Phosphatases (42, 43). Single-gene disruption of any 5-phosphatase produces little change in the phenotype, suggesting the functional redundancy of these enzymes. Disruption of any two genes results in a phenotype comprising vacuolar fragmentation, abnormal plasma membrane morphology with massive plasma membrane invaginations, disorganization of polymerized actin, and cell wall thickening. Recent studies have also noted receptor-mediated and fluid-phase endocytosis abnormalities, which correlate with the severity of actin and polarity defects (41). Disruption of all three Sac1 domain-containing 5-Phosphatases is lethal. The biochemical mechanisms mediating the observed phenotype in the 5-phosphatase double mutants are currently being delineated. Disruption of the Sac1-containing 5-Phosphatases, individually or in pairs, results in decreased total cellular PtdIns(4,5)P2 5-phosphatase activity and variable increases in [3H]PtdIns(4,5)P2 levels (42, 43). The cellular requirement for four yeast 5-Phosphatases with overlapping phosphoinositide substrate specificities may be to localize each isoform to discrete intracellular compartments; however this has yet to be shown. In this study we investigated the intracellular location of the Sac1-containing 5-Phosphatases Inp52p and Inp53p. We present evidence that in the resting cell these enzymes localize to the Triton X-100-insoluble fraction of the cell, consistent with a cytoskeletal location. Following hyperosmotic stress, Inp52p and Inp53p enzymes translocate rapidly and transiently to actin patches in the mother and daughter cells. We propose that 5-phosphatase localization at actin patches facilitates the localized hydrolysis of PtdIns(4,5)P2 and thereby actin rearrangement, which may in turn transiently regulate cell growth during hyperosmotic stress.
Meiping Zhao - One of the best experts on this subject based on the ideXlab platform.
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Development of a high-throughput screening platform for DNA 3'-Phosphatases and their inhibitors based on a universal molecular beacon and quantitative real-time PCR.
Chemistry - An Asian Journal, 2010Co-Authors: Chen Song, Chen Zhang, Meiping ZhaoAbstract:DNA 3'-Phosphatases play a unique role in the repair of strand breaks induced by DNA damaging agents, such as ionizing radiation or oxidative stress. In this paper, we present an efficient detection system for rapid screening of DNA 3'-Phosphatases and their inhibitors. A unique template substrate has been designed to hybridize with the universal molecular beacon (U-MB), and the detection process is carried out in a quantitative real-time PCR. The method is successfully applied to monitor the activity and kinetics of two typical 3'-Phosphatases, that is, T4 polynucleotide kinase phosphatase (PNKP) and calf intestinal alkaline phosphatase (CIP). The inhibition effect of heparin on T4 PNKP and theophylline on CIP is also quantitatively characterized. The proposed method is demonstrated to be very useful for sensitive, high-throughput, and precise measurement of various 3'-Phosphatases and their inhibitors.
Zhao Mei-ping - One of the best experts on this subject based on the ideXlab platform.
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Development of a High-Throughput Screening Platform for DNA 3 '-Phosphatases and Their Inhibitors Based on a Universal Molecular Beacon and Quantitative Real-time PCR
chemistry an asian journal, 2010Co-Authors: Song Chen, Zhang Chen, Zhao Mei-pingAbstract:DNA 3'-Phosphatases play a unique role in the repair of strand breaks induced by DNA damaging agents, such as ionizing radiation or oxidative stress. In this paper, we present an efficient detection system for rapid screening of DNA 3'-Phosphatases and their inhibitors. A unique template substrate has been designed to hybridize with the universal molecular beacon (U-MB), and the detection process is carried out in a quantitative real-time PCR. The method is successfully applied to monitor the activity and kinetics of two typical 3'-Phosphatases, that is, T4 polynucleotide kinase phosphatase (PNKP) and calf intestinal alkaline phosphatase (CIP). The inhibition effect of heparin on T4 PNKP and theophylline on CIP is also quantitatively characterized. The proposed method is demonstrated to be very useful for sensitive, high-throughput, and precise measurement of various 3'-Phosphatases and their inhibitors.Chemistry, MultidisciplinarySCI(E)EI8ARTICLE51146-1151
Chen Song - One of the best experts on this subject based on the ideXlab platform.
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Development of a high-throughput screening platform for DNA 3'-Phosphatases and their inhibitors based on a universal molecular beacon and quantitative real-time PCR.
Chemistry - An Asian Journal, 2010Co-Authors: Chen Song, Chen Zhang, Meiping ZhaoAbstract:DNA 3'-Phosphatases play a unique role in the repair of strand breaks induced by DNA damaging agents, such as ionizing radiation or oxidative stress. In this paper, we present an efficient detection system for rapid screening of DNA 3'-Phosphatases and their inhibitors. A unique template substrate has been designed to hybridize with the universal molecular beacon (U-MB), and the detection process is carried out in a quantitative real-time PCR. The method is successfully applied to monitor the activity and kinetics of two typical 3'-Phosphatases, that is, T4 polynucleotide kinase phosphatase (PNKP) and calf intestinal alkaline phosphatase (CIP). The inhibition effect of heparin on T4 PNKP and theophylline on CIP is also quantitatively characterized. The proposed method is demonstrated to be very useful for sensitive, high-throughput, and precise measurement of various 3'-Phosphatases and their inhibitors.
Song Chen - One of the best experts on this subject based on the ideXlab platform.
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Development of a High-Throughput Screening Platform for DNA 3 '-Phosphatases and Their Inhibitors Based on a Universal Molecular Beacon and Quantitative Real-time PCR
chemistry an asian journal, 2010Co-Authors: Song Chen, Zhang Chen, Zhao Mei-pingAbstract:DNA 3'-Phosphatases play a unique role in the repair of strand breaks induced by DNA damaging agents, such as ionizing radiation or oxidative stress. In this paper, we present an efficient detection system for rapid screening of DNA 3'-Phosphatases and their inhibitors. A unique template substrate has been designed to hybridize with the universal molecular beacon (U-MB), and the detection process is carried out in a quantitative real-time PCR. The method is successfully applied to monitor the activity and kinetics of two typical 3'-Phosphatases, that is, T4 polynucleotide kinase phosphatase (PNKP) and calf intestinal alkaline phosphatase (CIP). The inhibition effect of heparin on T4 PNKP and theophylline on CIP is also quantitatively characterized. The proposed method is demonstrated to be very useful for sensitive, high-throughput, and precise measurement of various 3'-Phosphatases and their inhibitors.Chemistry, MultidisciplinarySCI(E)EI8ARTICLE51146-1151
