Inositol pyrophosphates: metabolism and signaling

Bennett, Matthew; Onnebo, Sara Maria Nancy; Azevedo, Cristina; Saiardi, Adolfo

doi:10.1007/s00018-005-5446-z

Cited by 162 publications

(205 citation statements)

References 104 publications

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“…The predicted products of CrVIP1, InsP 7 and InsP 8 , are usually the lowest abundance InsPs in eukaryotic cells and difficult to detect (Bennett et al, 2006;Losito et al, 2009;Lin et al, 2009;Desai et al, 2014). Sensitive in vivo labeling procedures for InsP detection using radiolabeled 3H-inositol have been successful in other species Stevenson-Paulik et al, 2006), but proved unfeasible in Chlamydomonas, which does not take up this precursor.…”

Section: Vip1-1 Mutants Have Defects In Insp 7 and Insp 8 Accumulationmentioning

confidence: 99%

“…In fungi, the roles of InsPs have been dissected using mutants that block different steps in the biosynthetic pathway. InsP 7 and InsP 8 are produced by VIP1 and/ or KCS1 kinases whose animal homologs are PP-InsP5K and InsP6K, respectively, and play diverse roles in cell physiology, including signaling phosphate starvation, telomere length control, DNA repair, autophagy, environmental stress responses, cytoskeletal dynamics, and ribosome biogenesis (Bennett et al, 2006;Shears, 2009;Tsui and York, 2010;Wundenberg and Mayr, 2012;Wilson et al, 2013;Thota and Bhandari, 2015;Livermore et al, 2016).…”

Section: Chlamydomonas Vip1 Provides An Entrée Into Inositol Polyphosmentioning

confidence: 99%

“…Asterisks represent significant differences (P < 0.05) between means evaluated using Student's t test. species, including plants that also contain VIP proteins but no KCS1/InsP6K-like proteins (Bennett et al, 2006;Desai et al, 2014;Williams et al, 2015). Despite vip1-1 being a loss-of-function allele, the mutants still have some detectable InsP 7 and InsP 8 (Figures 3 and 8), indicating that there may be another route for InsP 7 and InsP 8 synthesis in these cells.…”

Section: Chlamydomonas Vip1 Provides An Entrée Into Inositol Polyphosmentioning

confidence: 99%

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Synergism between Inositol Polyphosphates and TOR Kinase Signaling in Nutrient Sensing, Growth Control, and Lipid Metabolism in Chlamydomonas

et al. 2016

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The networks that govern carbon metabolism and control intracellular carbon partitioning in photosynthetic cells are poorly understood. Target of Rapamycin (TOR) kinase is a conserved growth regulator that integrates nutrient signals and modulates cell growth in eukaryotes, though the TOR signaling pathway in plants and algae has yet to be completely elucidated. We screened the unicellular green alga Chlamydomonas reinhardtii using insertional mutagenesis to find mutants that conferred hypersensitivity to the TOR inhibitor rapamycin. We characterized one mutant, vip1-1, that is predicted to encode a conserved inositol hexakisphosphate kinase from the VIP family that pyrophosphorylates phytic acid (InsP 6 ) to produce the low abundance signaling molecules InsP 7 and InsP 8 . Unexpectedly, the rapamycin hypersensitive growth arrest of vip1-1 cells was dependent on the presence of external acetate, which normally has a growth-stimulatory effect on Chlamydomonas. vip1-1 mutants also constitutively overaccumulated triacylglycerols (TAGs) in a manner that was synergistic with other TAG inducing stimuli such as starvation. vip1-1 cells had reduced InsP 7 and InsP 8 , both of which are dynamically modulated in wild-type cells by TOR kinase activity and the presence of acetate. Our data uncover an interaction between the TOR kinase and inositol polyphosphate signaling systems that we propose governs carbon metabolism and intracellular pathways that lead to storage lipid accumulation.

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Section: Vip1-1 Mutants Have Defects In Insp 7 and Insp 8 Accumulationmentioning

confidence: 99%

Section: Chlamydomonas Vip1 Provides An Entrée Into Inositol Polyphosmentioning

confidence: 99%

Section: Chlamydomonas Vip1 Provides An Entrée Into Inositol Polyphosmentioning

confidence: 99%

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Synergism between Inositol Polyphosphates and TOR Kinase Signaling in Nutrient Sensing, Growth Control, and Lipid Metabolism in Chlamydomonas

et al. 2016

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“…Recent attention has focused on the inositol pyrophosphates, also designated inositol diphosphates, of which the best studied are diphosphoinositol pentakisphosphate [5-PP-I(1,2,3,4,6)P 5 , here designated IP 7 ] and bisdiphosphoinositol tetrakisphosphate ([PP] 2 -IP 4 , IP 8 ) (2)(3)(4). These compounds are synthesized by a family of three inositol hexakisphosphate (IP 6 ) kinases (IP6Ks) (5-7).…”

mentioning

confidence: 99%

Gene deletion of inositol hexakisphosphate kinase 1 reveals inositol pyrophosphate regulation of insulin secretion, growth, and spermiogenesis

Bhandari

Juluri

Resnick

et al. 2008

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

133

186

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Inositol pyrophosphates, also designated inositol diphosphates, possess high-energy ␤-phosphates that can pyrophosphorylate proteins and regulate various cellular processes. They are formed by a family of inositol hexakisphosphate kinases (IP6Ks). We have created mice with a targeted deletion of IP6K1 in which production of inositol pyrophosphates is markedly diminished. Defects in the mutants indicate important roles for IP6K1 and inositol pyrophosphates in several physiological functions. Male mutant mice are sterile with defects in spermiogenesis. Mutant mice are smaller than wild-type despite normal food intake. The mutants display markedly lower circulating insulin.inositol phosphate kinase ͉ inositol polyphosphate ͉ knockout mouse N umerous inositol phosphates regulate biological functions with the best characterized, inositol-1,4,5-trisphosphate (IP 3 ), releasing intracellular calcium (1). Recent attention has focused on the inositol pyrophosphates, also designated inositol diphosphates, of which the best studied are diphosphoinositol pentakisphosphate [5-PP-I(1,2,3,4,6)P 5 , here designated IP 7 ] and bisdiphosphoinositol tetrakisphosphate ([PP] 2 -IP 4 , IP 8 ) (2-4). These compounds are synthesized by a family of three inositol hexakisphosphate (IP 6 ) kinases (IP6Ks) (5-7). Inositol pyrophosphates have been implicated in a variety of physiologic functions including apoptosis (8, 9), endocytosis (10, 11), telomere length maintenance (12, 13), and chemotaxis (14). Additionally, another form of IP 7 , tentatively identified as 4/6-PP-IP 5 , is formed by the Vip1 enzyme in yeast and is implicated in the regulation of cell morphology, cell growth, and phosphate homeostasis (15, 16). Shears et al. have established that the mammalian Vip1 ortholog physiologically synthesizes IP 8 , which is involved in osmotic regulation (17,18). Inositol pyrophosphates may exert their functions in two ways, by binding to proteins or via phosphorylation. IP 7 can directly bind cytosolic proteins, such as the cyclin-cyclin-dependent kinase (CDK)-CDK inhibitor (CKI) complex, required for phosphate homeostasis in yeast (19). IP 7 can also compete with membrane phosphoinositides for binding to phosphoinositide-binding modules such as PH domains, as observed during chemotactic regulation in Dictyostelium (14). In addition, IP 7 physiologically phosphorylates proteins in a nonenzymatic fashion, analogous to S-nitrosylation, whereby the ␤-phosphate is transferred from IP 7 to previously phosphorylated proteins; hence, IP 7 pyrophosphorylates proteins (20, 21).The various mammalian IP6Ks serve diverse functions. IP6K2 regulates apoptotic cell death (8,9,22,23). IP6K1 has been implicated in the disposition of insulin and glucose. A putative disruption of the IP6K1 gene has been described in a family with type 2 diabetes (24). Illies et al. recently showed that selective depletion of IP6K1 by RNA interference in pancreatic beta cells impairs insulin secretion (25). To elucidate the physiologic role of IP6K1, we created mice with a ta...

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“…IP6K-deficient yeast manifest major abnormalities in vesicular endocytosis (8)(9)(10) and telomere length (11,12). Abundant evidence implicates PP-IPs in vesicular trafficking.…”

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confidence: 99%

HSP90 regulates cell survival via inositol hexakisphosphate kinase-2

Chakraborty

Koldobskiy

Sixt

et al. 2008

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

108

119

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Heat-shock proteins (HSPs) are abundant, inducible proteins best known for their ability to maintain the conformation of proteins and to refold damaged proteins. Some HSPs, especially HSP90, can be antiapoptotic and the targets of anticancer drugs. Inositol hexakisphosphate kinase-2 (IP6K2), one of a family of enzymes generating the inositol pyrophosphate IP7 [diphosphoinositol pentakisphosphate (5-PP-IP5)], mediates apoptosis. Increased IP6K2 activity sensitizes cancer cells to stressors, whereas its depletion blocks cell death. We now show that HSP90 physiologically binds IP6K2 and inhibits its catalytic activity. Drugs and selective mutations that abolish HSP90 -IP6K2 binding elicit activation of IP6K2, leading to cell death. Thus, the prosurvival actions of HSP90 reflect the inhibition of IP6K2, suggesting that selectively blocking this interaction could provide effective and safer modes of chemotherapy.apoptosis ͉ cisplatin ͉ novobiocin ͉ inositol polyphosphate

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Inositol pyrophosphates: metabolism and signaling

Cited by 162 publications

References 104 publications

Synergism between Inositol Polyphosphates and TOR Kinase Signaling in Nutrient Sensing, Growth Control, and Lipid Metabolism in Chlamydomonas

Synergism between Inositol Polyphosphates and TOR Kinase Signaling in Nutrient Sensing, Growth Control, and Lipid Metabolism in Chlamydomonas

Gene deletion of inositol hexakisphosphate kinase 1 reveals inositol pyrophosphate regulation of insulin secretion, growth, and spermiogenesis

HSP90 regulates cell survival via inositol hexakisphosphate kinase-2

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