The Experts below are selected from a list of 297 Experts worldwide ranked by ideXlab platform
Philip W. Majerus - One of the best experts on this subject based on the ideXlab platform.
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sopb a protein required for virulence of salmonella dublin is an Inositol phosphate phosphatase
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: F A Norris, Monita P Wilson, Timothy S Wallis, Edouard E Galyov, Philip W. MajerusAbstract:Several proteins secreted by enteric bacteria are thought to contribute to virulence by disturbing the signal transduction of infected cells. Here, we report that SopB, a protein secreted by Salmonella dublin, has sequence homology to mammalian Inositol polyphosphate 4-phosphatases and that recombinant SopB has Inositol phosphate phosphatase activity in vitro. SopB hydrolyzes phosphatidylInositol 3,4,5-trisphosphate, an inhibitor of Ca2+-dependent chloride secretion. In addition, SopB hydrolyzes Inositol 1,3,4,5,6 pentakisphosphate to yield Inositol 1,4,5,6-tetrakisphosphate, a signaling molecule that increases chloride secretion indirectly by antagonizing the inhibition of chloride secretion by phosphatidylInositol 3,4,5-trisphosphate [Eckmann, L., Rudolf, M. T., Ptasznik, A., Schultz, C., Jiang, T., Wolfson, N., Tsien, R., Fierer, J., Shears, S. B., Kagnoff, M. F., et al. (1997) Proc. Natl. Acad. Sci. USA 94, 14456–14460]. Mutation of a conserved cysteine that abolishes phosphatase activity of SopB results in a mutant strain, S. dublin SB c/s, with decreased ability to induce fluid secretion in infected calf intestine loops. Moreover, HeLa cells infected with S. dublin SB c/s do not accumulate high levels of Inositol 1,4,5,6-tetrakisphosphate that are characteristic of wild-type S. dublin-infected cells. Therefore, SopB mediates virulence by interdicting Inositol phosphate signaling pathways.
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sopb a protein required for virulence of salmonella dublin is an Inositol phosphate phosphatase
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: F A Norris, Monita P Wilson, Timothy S Wallis, Edouard E Galyov, Philip W. MajerusAbstract:Several proteins secreted by enteric bacteria are thought to contribute to virulence by disturbing the signal transduction of infected cells. Here, we report that SopB, a protein secreted by Salmonella dublin, has sequence homology to mammalian Inositol polyphosphate 4-phosphatases and that recombinant SopB has Inositol phosphate phosphatase activity in vitro. SopB hydrolyzes phosphatidylInositol 3,4,5-trisphosphate, an inhibitor of Ca2+-dependent chloride secretion. In addition, SopB hydrolyzes Inositol 1,3,4,5,6 pentakisphosphate to yield Inositol 1,4,5,6-tetrakisphosphate, a signaling molecule that increases chloride secretion indirectly by antagonizing the inhibition of chloride secretion by phosphatidylInositol 3,4,5-trisphosphate [Eckmann, L., Rudolf, M. T., Ptasznik, A., Schultz, C., Jiang, T., Wolfson, N., Tsien, R., Fierer, J., Shears, S. B., Kagnoff, M. F., et al. (1997) Proc. Natl. Acad. Sci. USA 94, 14456–14460]. Mutation of a conserved cysteine that abolishes phosphatase activity of SopB results in a mutant strain, S. dublin SB c/s, with decreased ability to induce fluid secretion in infected calf intestine loops. Moreover, HeLa cells infected with S. dublin SB c/s do not accumulate high levels of Inositol 1,4,5,6-tetrakisphosphate that are characteristic of wild-type S. dublin-infected cells. Therefore, SopB mediates virulence by interdicting Inositol phosphate signaling pathways.
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the 145 kda protein induced to associate with shc by multiple cytokines is an Inositol tetraphosphate and phosphatidylInositol 3 4 5 triphosphate 5 phosphatase
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Jacqueline E Damen, Philip W. Majerus, P Rosten, R K Humphries, Ann B Jefferson, Gerald KrystalAbstract:A 145-kDa tyrosine-phosphorylated protein that becomes associated with Shc in response to multiple cytokines has been purified from the murine hemopoietic cell line B6SUtA1. Amino acid sequence data were used to clone the cDNA encoding this protein from a B6SUtA1 library. The predicted amino acid sequence encodes a unique protein containing an N-terminal src homology 2 domain, two consensus sequences that are targets for phosphotyrosine binding domains, a proline-rich region, and two motifs highly conserved among Inositol polyphosphate 5-phosphatases. Cell lysates immunoprecipitated with antiserum to this protein exhibited both phosphatidylInositol 3,4,5-trisphosphate and Inositol 1,3,4,5-tetrakisphosphate polyphosphate 5-phosphatase activity. This novel signal transduction intermediate may serve to modulate both Ras and Inositol signaling pathways. Based on its properties, we suggest the 145-kDa protein be called SHIP for SH2-containing Inositol phosphatase.
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Inositol phosphate biochemistry
Annual Review of Biochemistry, 1992Co-Authors: Philip W. MajerusAbstract:PERSPECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 C ONVENTIONAL PHOSPHA TIDYLIN OSITOLS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 PHOSPHOLIPASE C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . .. . . . . . . . . . . 227 ACTIVATION Of PHOSPHOLIPASE C BY GaQ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . .. . 227 ACTIVATI ON OF PLCy BY TYR OSINE PHOSPHORYLATI ON . . . . . . . . . . . . . . . . . . . . . . . . 229 Inositol POLYPHOSPHATE 5-PHOSPHATASE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 1 INS ( 1 ,4,5)P3 3·KINASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 Inositol POLYPHOSPHATE I·PHOSPHATASE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 Inositol POLYPHOSPHATE 4·PHOSPHATASE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 Inositol P OLYPHOSPHATE 3·PHOSPHATASE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 Inositol M ON OPHOSP HATA SE . . . . . . . . . . . .. . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . 236 Inositol ( 1 :2 CYCLIC) PHOSPHATE 2 PHOSPHOHYDROLASE AND IN OSITOL CYCLIC PHOSPHATES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236 OTHER ENZYMES OF IN OSITOL PHOSPHATE METAB OLISM . . . . . . . . . . . . . . . . . . . . . . . 238 IN OSITOL PENTAPHOSPHATE AN D HE XAPHOSPHATE METAB OLISM . . . . . . . . . . 238 IN OSITOL PHOSPHATE-BIN DIN G PROTEINS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 PHOSPHATIDYLInositol 3·PHOSPHATE PATHWAy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
I M Bird - One of the best experts on this subject based on the ideXlab platform.
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studies of hormone sensitive and insensitive pools of phosphoinositides in cultured bovine zona fasciculata reticularis cells evidence that acetylcholine and angiotensin ii stimulate the breakdown of a common pool of phosphoinositides
Biochemical Pharmacology, 1992Co-Authors: Colin Clyne, S W Walker, Brent C Williams, I M BirdAbstract:Abstract The effects of acetylcholine (ACh) and manganese pre-incubation on angiotensin II (AII)-stimulated incorporation of [ 3 H]Inositol into phosphoinositide, phosphoInositol and free Inositol fractions of adrenocortical cells isolated from the bovine zona fasciculata/reticularis (zfr) were investigated. In cells pre-labelled for 6 hr with [ 3 H]Inositol, ACh and AII stimulated the incorporation of cytosolic [ 3 H]Inositol into a common hormone-sensitive pool of phosphoinositides, which was distinct from the non-hormone-sensitive pool labelled in the presence of manganese. Regression analysis of the cortisol versus [ 3 H]Inositol headgroup responses for both AII (10 −11 –10 −7 M) and ACh (10 −9 –10 −3 M) showed that the gradients of these responses were not significantly different. These data provide strong evidence that in cultured bovine zfr cells, ACh and AII stimulate the breakdown and resynthesis of a common pool of phosphoinositides.
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evidence for two distinct hormone sensitive 3h phosphoinositide pools in bovine adrenocortical zona fasciculata reticularis cells stimulated with angiotensin ii
Journal of Molecular Endocrinology, 1992Co-Authors: I M Bird, Bryan Williams, S W WalkerAbstract:: Bovine adrenocortical cells from the zona fasciculata/reticularis were isolated and their phosphoinositides labelled to a steady state with [3H]Inositol in primary culture. Experiments performed on these cells in the presence of Li+ have shown that, over a period of 60 min, angiotensin II (AII; 10(-7) M) stimulated a linear increase in [3H]Inositol phosphates that was sustained through the utilization of two hormone-sensitive subpools of prelabelled lipid (30% and 45% respectively), and a rapid resynthesis of [3H]phosphoinositide into one of these pools using cytosolic [3H]Inositol. The 30% pool was used immediately on stimulation, and was sustained at a steady-state size of 10-15% during the first 30 min of stimulation through rapid resynthesis using cytosolic [3H]Inositol. Only after 30 min, when the cytosolic [3H]Inositol was depleted and resynthesis could no longer occur, did the additional 45% pool start to supply further substrate to the phospholipase C, thereby further sustaining the generation of [3H]Inositol phosphates. Once this pool was depleted however (by approximately 60 min), [3H]Inositol phosphate generation finally ceased. These findings establish the differential use of two metabolically distinct hormone-sensitive pools of phosphoinositide following AII stimulation in bovine adrenocortical cells, events which are dependent upon the availability of cytosolic Inositol for phosphoinositide resynthesis.
S W Walker - One of the best experts on this subject based on the ideXlab platform.
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studies of hormone sensitive and insensitive pools of phosphoinositides in cultured bovine zona fasciculata reticularis cells evidence that acetylcholine and angiotensin ii stimulate the breakdown of a common pool of phosphoinositides
Biochemical Pharmacology, 1992Co-Authors: Colin Clyne, S W Walker, Brent C Williams, I M BirdAbstract:Abstract The effects of acetylcholine (ACh) and manganese pre-incubation on angiotensin II (AII)-stimulated incorporation of [ 3 H]Inositol into phosphoinositide, phosphoInositol and free Inositol fractions of adrenocortical cells isolated from the bovine zona fasciculata/reticularis (zfr) were investigated. In cells pre-labelled for 6 hr with [ 3 H]Inositol, ACh and AII stimulated the incorporation of cytosolic [ 3 H]Inositol into a common hormone-sensitive pool of phosphoinositides, which was distinct from the non-hormone-sensitive pool labelled in the presence of manganese. Regression analysis of the cortisol versus [ 3 H]Inositol headgroup responses for both AII (10 −11 –10 −7 M) and ACh (10 −9 –10 −3 M) showed that the gradients of these responses were not significantly different. These data provide strong evidence that in cultured bovine zfr cells, ACh and AII stimulate the breakdown and resynthesis of a common pool of phosphoinositides.
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evidence for two distinct hormone sensitive 3h phosphoinositide pools in bovine adrenocortical zona fasciculata reticularis cells stimulated with angiotensin ii
Journal of Molecular Endocrinology, 1992Co-Authors: I M Bird, Bryan Williams, S W WalkerAbstract:: Bovine adrenocortical cells from the zona fasciculata/reticularis were isolated and their phosphoinositides labelled to a steady state with [3H]Inositol in primary culture. Experiments performed on these cells in the presence of Li+ have shown that, over a period of 60 min, angiotensin II (AII; 10(-7) M) stimulated a linear increase in [3H]Inositol phosphates that was sustained through the utilization of two hormone-sensitive subpools of prelabelled lipid (30% and 45% respectively), and a rapid resynthesis of [3H]phosphoinositide into one of these pools using cytosolic [3H]Inositol. The 30% pool was used immediately on stimulation, and was sustained at a steady-state size of 10-15% during the first 30 min of stimulation through rapid resynthesis using cytosolic [3H]Inositol. Only after 30 min, when the cytosolic [3H]Inositol was depleted and resynthesis could no longer occur, did the additional 45% pool start to supply further substrate to the phospholipase C, thereby further sustaining the generation of [3H]Inositol phosphates. Once this pool was depleted however (by approximately 60 min), [3H]Inositol phosphate generation finally ceased. These findings establish the differential use of two metabolically distinct hormone-sensitive pools of phosphoinositide following AII stimulation in bovine adrenocortical cells, events which are dependent upon the availability of cytosolic Inositol for phosphoinositide resynthesis.
Galila Agam - One of the best experts on this subject based on the ideXlab platform.
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acute intracerebroventricular Inositol does not reverse the effect of chronic lithium treatment in the forced swim test
Neuropsychobiology, 2013Co-Authors: Lilach Toker, Haim Einat, Robert H. Belmaker, Nirit Z Kara, Itay Hadas, Yuly Bersudsky, Galila AgamAbstract:Background: Lithium has numerous biochemical effects but it is difficult to dissect which of these is responsible for its therapeutic action in bipolar disorder. In the current study we aimed to address one of the major hypotheses, the Inositol depletion hypothesis. This hypothesis postulates that lithium's mood-stabilizing effect is mediated by the depletion of brain Inositol levels and the subsequent effect on cellular signaling. Methods: We studied whether acute intracerebroventricular (ICV) administration of myo-Inositol could reverse the antidepressant-like effect of chronic lithium treatment in the forced swim test (FST). Results: In contrast with our prediction, acute myo-Inositol administration did not reverse the effect of chronic lithium to decrease immobility in the FST. Conclusions: The results of the present study are limited due to the following: (1) Inositol was given acutely while possible events downstream of Inositol depletion might require a longer period and (2) ICV Inositol may not have reached those areas of the brain involved in the FST.
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human 1 d myo Inositol 3 phosphate synthase is functional in yeast
Journal of Biological Chemistry, 2004Co-Authors: Shulin Ju, Galila Agam, Galit Shaltiel, Alon Shamir, Miriam L GreenbergAbstract:Abstract We have cloned, sequenced, and expressed a human cDNA encoding 1-d-myo-Inositol-3-phosphate (MIP) synthase (hINO1). The encoded 62-kDa human enzyme converted d-glucose 6-phosphate to 1-d-myo-Inositol 3-phosphate, the rate-limiting step for de novo Inositol biosynthesis. Activity of the recombinant human MIP synthase purified from Escherichia coli was optimal at pH 8.0 at 37 °C and exhibited Km values of 0.57 mm and 8 μm for glucose 6-phosphate and NAD+, respectively. and K+ were better activators than other cations tested (Na+, Li+, Mg2+, Mn2+), and Zn2+ strongly inhibited activity. Expression of the protein in the yeast ino1Δ mutant lacking MIP synthase (ino1Δ/hINO1) complemented the Inositol auxotrophy of the mutant and led to Inositol excretion. MIP synthase activity and intracellular Inositol were decreased about 35 and 25%, respectively, when ino1Δ/hINO1 was grown in the presence of a therapeutically relevant concentration of the anti-bipolar drug valproate (0.6 mm). However, in vitro activity of purified MIP synthase was not inhibited by valproate at this concentration, suggesting that inhibition by the drug is indirect. Because Inositol metabolism may play a key role in the etiology and treatment of bipolar illness, functional conservation of the key enzyme in Inositol biosynthesis underscores the power of the yeast model in studies of this disorder.
Adolfo Saiardi - One of the best experts on this subject based on the ideXlab platform.
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the Inositol hexakisphosphate kinases ip6k1 and 2 regulate human cellular phosphate homeostasis including xpr1 mediated phosphate export
Journal of Biological Chemistry, 2019Co-Authors: Miranda S C Wilson, Henning J Jessen, Adolfo SaiardiAbstract:Phosphate's central role in most biochemical reactions in a living organism requires carefully maintained phosphate homeostasis. Although phosphate homeostasis in mammals has long been studied at the organismal level, the intracellular mechanisms controlling phosphate metabolism are not well understood. Inositol pyrophosphates have emerged as important regulatory elements controlling yeast phosphate homeostasis. To verify whether Inositol pyrophosphates also regulate mammalian cellular phosphate homeostasis, here we knocked out Inositol hexakisphosphate kinase (IP6K) 1 and IP6K2 to generate human HCT116 cells devoid of any Inositol pyrophosphates. Using PAGE and HPLC analysis, we observed that the IP6K1/2-knockout cells have non-detectable levels of the IP6-derived IP7 and IP8 and also exhibit reduced synthesis of the IP5-derived PP-IP4 Nucleotide analysis showed that the knockout cells contain increased amounts of ATP, while the Malachite green assay found elevated levels of free intracellular phosphate. Furthermore, [32Pi] pulse labeling experiments uncovered alterations in phosphate flux, with both import and export of phosphate being decreased in the knockout cells. Functional analysis of the phosphate exporter xenotropic and polytropic retrovirus receptor 1 (XPR1) revealed that it is regulated by Inositol pyrophosphates, which can bind to its SPX domain. We conclude that IP6K1 and -2 together control Inositol pyrophosphate metabolism and thereby physiologically regulate phosphate export and other aspects of mammalian cellular phosphate homeostasis.
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crosstalk between ras and Inositol phosphate signaling revealed by lithium action on Inositol monophosphatase in schizophyllum commune
Advances in biological regulation, 2019Co-Authors: Reyna Murry, Adolfo Saiardi, Olaf Kniemeyer, Katrin Krause, Erika KotheAbstract:Abstract Mushroom forming basidiomycete Schizophyllum commune has been used as a tractable model organism to study fungal sexual development. Ras signaling activation via G-protein-coupled receptors (GPCRs) has been postulated to play a significant role in the mating and development of S. commune. In this study, a crosstalk between Ras signaling and Inositol phosphate signaling by Inositol monophosphatase (IMPase) is revealed. Constitutively active Ras1 leads to the repression of IMPase transcription and lithium action on IMPase activity is compensated by the induction of IMPase at transcriptome level. Astonishingly, in S. commune lithium induces a considerable shift to Inositol phosphate metabolism leading to a massive increase in the level of higher phosphorylated Inositol species up to the Inositol pyrophosphates. The lithium induced metabolic changes are not observable in a constitutively active Ras1 mutant. In addition to that, proteome profile helps us to elucidate an overview of lithium action to the broad aspect of fungal metabolism and cellular signaling. Taken together, these findings imply a crosstalk between Ras and Inositol phosphate signaling.
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phosphate Inositol and polyphosphates
Biochemical Society Transactions, 2016Co-Authors: Thomas M Livermore, Cristina Azevedo, Bernadett Kolozsvari, Miranda S C Wilson, Adolfo SaiardiAbstract:Eukaryotic cells have ubiquitously utilized the myo -Inositol backbone to generate a diverse array of signalling molecules. This is achieved by arranging phosphate groups around the six-carbon Inositol ring. There is virtually no biological process that does not take advantage of the uniquely variable architecture of phosphorylated Inositol. In Inositol biology, phosphates are able to form three distinct covalent bonds: phosphoester, phosphodiester and phosphoanhydride bonds, with each providing different properties. The phosphoester bond links phosphate groups to the Inositol ring, the variable arrangement of which forms the basis of the signalling capacity of the Inositol phosphates. Phosphate groups can also form the structural bridge between myo -Inositol and diacylglycerol through the phosphodiester bond. The resulting lipid-bound Inositol phosphates, or phosphoinositides, further expand the signalling potential of this family of molecules. Finally, Inositol is also notable for its ability to host more phosphates than it has carbons. These unusual organic molecules are commonly referred to as the Inositol pyrophosphates (PP-IPs), due to the presence of high-energy phosphoanhydride bonds (pyro- or diphospho-). PP-IPs themselves constitute a varied family of molecules with one or more pyrophosphate moiety/ies located around the Inositol. Considering the relationship between phosphate and Inositol, it is no surprise that members of the Inositol phosphate family also regulate cellular phosphate homoeostasis. Notably, the PP-IPs play a fundamental role in controlling the metabolism of the ancient polymeric form of phosphate, inorganic polyphosphate (polyP). Here we explore the intimate links between phosphate, Inositol phosphates and polyP, speculating on the evolution of these relationships. * DIPPs, : diphosphoInositol polyphosphate phosphohydrolases; FYVE, : Fab1, YOTB, Vac 1 and EEA1 homology; IP3R, : Inositol trisphosphate receptor; IP6K, : Inositol hexakisphosphate kinase; IPMK, : Inositol polyphosphate multikinase; PH, : pleckstrin homology; PHD, : plant homeodomain; PiUS, : Pi Uptake Stimulator; polyP, : inorganic polyphosphate; PP-IPs, : Inositol pyrophosphates; PX, : phox homology
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Inositol pyrophosphates between signalling and metabolism
Biochemical Journal, 2013Co-Authors: Miranda S C Wilso, Thomas M Livermore, Adolfo SaiardiAbstract:The present review will explore the insights gained into Inositol pyrophosphates in the 20 years since their discovery in 1993. These molecules are defined by the presence of the characteristic ‘high energy’ pyrophosphate moiety and can be found ubiquitously in eukaryotic cells. The enzymes that synthesize them are similarly well distributed and can be found encoded in any eukaryote genome. Rapid progress has been made in characterizing Inositol pyrophosphate metabolism and they have been linked to a surprisingly diverse range of cellular functions. Two decades of work is now beginning to present a view of Inositol pyrophosphates as fundamental, conserved and highly important agents in the regulation of cellular homoeostasis. In particular it is emerging that energy metabolism, and thus ATP production, is closely regulated by these molecules. Much of the early work on these molecules was performed in the yeast Saccharomyces cerevisiae and the social amoeba Dictyostelium discoideum , but the development of mouse knockouts for IP6K1 and IP6K2 [IP6K is IP 6 (Inositol hexakisphosphate) kinase] in the last 5 years has provided very welcome tools to better understand the physiological roles of Inositol pyrophosphates. Another recent innovation has been the use of gel electrophoresis to detect and purify Inositol pyrophosphates. Despite the advances that have been made, many aspects of Inositol pyrophosphate biology remain far from clear. By evaluating the literature, the present review hopes to promote further research in this absorbing area of biology.
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arginine transcriptional response does not require Inositol phosphate synthesis
Journal of Biological Chemistry, 2012Co-Authors: Daniel Bosch, Adolfo SaiardiAbstract:Inositol phosphates are key signaling molecules affecting a large variety of cellular processes. Inositol-polyphosphate multikinase (IPMK) is a central component of the Inositol phosphate biosynthetic routes, playing essential roles during development. IPMK phosphorylates Inositol 1,4,5-trisphosphate to Inositol tetrakisphosphate and subsequently to Inositol pentakisphosphate and has also been described to function as a lipid kinase. Recently, a catalytically inactive mammalian IPMK was reported to be involved in nutrient signaling by way of mammalian target of rapamycin and AMP-activated protein kinase. In yeast, the IPMK homologue, Arg82, is the sole Inositol-trisphosphate kinase. Arg82 has been extensively studied as part of the transcriptional complex regulating nitrogen sensing, in particular arginine metabolism. Whether this role requires Arg82 catalytic activity has long been a matter of contention. In this study, we developed a novel method for the real time study of promoter strength in vivo and used it to demonstrate that catalytically inactive Arg82 fully restored the arginine-dependent transcriptional response. We also showed that expression in yeast of catalytically active, but structurally very different, mammalian or plant IPMK homologue failed to restore arginine regulation. Our work indicates that Inositol phosphates do not regulate arginine-dependent gene expression.
