New Horizons in Cellular Regulation by Inositol Polyphosphates: Insights from the Pancreatic<i>β</i>-Cell

Barker, Christopher J.; Berggren, Per Olof

doi:10.1124/pr.112.006775

Cited by 33 publications

(36 citation statements)

References 205 publications

(359 reference statements)

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“…That is, the prevailing levels of 5-InsP 7 may reflect the degree of the cell’s bioenergetic well-being. In pancreatic β-cells this may be a significant event in organismal metabolic homeostasis: increased transport of serum glucose into β-cells stimulates the rate of glycolytic ATP production, elevating levels of 5-InsP 7 , which promotes exocytic insulin secretion (Barker and Berggren, 2013; Illies et al, 2007; Nagel et al, 2010). It is tempting to rationalize the significance of the multiple phosphates of 5-InsP 7 as their being fundamental to the polyphosphate’s “energetic” properties that closely ties its synthesis to cellular ATP availability, aided by the enzymology of IP6Ks (i.e., their low ATP affinity).…”

Section: The Relationship Between Pp-insp Turnover and Cellular Bioenmentioning

confidence: 99%

Inositol pyrophosphates: Why so many phosphates?

Shears

2015

Advances in Biological Regulation

115

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The inositol pyrophosphates (PP-InsPs) are a specialized group of “energetic” signaling molecules found in yeasts, plants and animals. PP-InsPs boast the most crowded three dimensional phosphate arrays found in Nature; multiple phosphates and diphosphates are crammed around the six-carbon, inositol ring. Yet, phosphate esters are also a major energy currency in cells. So the synthesis of PP-InsPs, and the maintenance of their levels in the face of a high rate of ongoing turnover, all requires significant bioenergetic input. What are the particular properties of PP-InsPs that repay this investment of cellular energy? Potential answers to that question are discussed here, against the backdrop of a recent hypothesis that signaling by PP-InsPs is evolutionarily ancient. The latter idea is extended herein, with the proposal that the primordial origins of PP-InsPs is reflected in the apparent lack of isomeric specificity of certain of their actions. Nevertheless, there are other aspects of signaling by these polyphosphates that are more selective for a particular PP-InsP isomer. Consideration of the nature of both specific and non-specific effects of PP-InsPs can help rationalize why such molecules possess so many phosphates.

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Section: The Relationship Between Pp-insp Turnover and Cellular Bioenmentioning

confidence: 99%

Inositol pyrophosphates: Why so many phosphates?

Shears

2015

Advances in Biological Regulation

115

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“…The myo-inositol phosphates (InsPs) are signaling molecules that are critically important in eukaryotes, functioning in a wide array of processes such as hormonal signaling, stress responses, telomere maintenance, vesicular trafficking, phosphorus sensing, homeostasis and storage (Tsui and York, 2010;Shears et al, 2012;Barker and Berggren, 2013;Gillaspy, 2013). In plants, several signals such as gravitropism, drought and salt treatment perturb levels of InsPs, which are thought to provide a chemical code critical for plant response to these signals (Perera et al, 2001(Perera et al, , 2004(Perera et al, , 2006(Perera et al, , 2008Munnik and Vermeer, 2010).…”

Section: Introductionmentioning

confidence: 99%

Two inositol hexakisphosphate kinases drive inositol pyrophosphate synthesis in plants

et al. 2014

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SUMMARYInositol pyrophosphates are unique cellular signaling molecules with recently discovered roles in energy sensing and metabolism. Studies in eukaryotes have revealed that these compounds have a rapid turnover, and thus only small amounts accumulate. Inositol pyrophosphates have not been the subject of investigation in plants even though seeds produce large amounts of their precursor, myo-inositol hexakisphosphate (InsP 6 ). Here, we report that Arabidopsis and maize InsP 6 transporter mutants have elevated levels of inositol pyrophosphates in their seed, providing unequivocal identification of their presence in plant tissues. We also show that plant seeds store a little over 1% of their inositol phosphate pool as InsP 7 and InsP 8 . Many tissues, including, seed, seedlings, roots and leaves accumulate InsP 7 and InsP 8 , thus synthesis is not confined to tissues with high InsP 6 . We have identified two highly similar Arabidopsis genes, AtVip1 and AtVip2, which are orthologous to the yeast and mammalian VIP kinases. Both AtVip1 and AtVip2 encode proteins capable of restoring InsP 7 synthesis in yeast mutants, thus AtVip1 and AtVip2 can function as bonafide InsP 6 kinases. AtVip1 and AtVip2 are differentially expressed in plant tissues, suggesting nonredundant or non-overlapping functions in plants. These results contribute to our knowledge of inositol phosphate metabolism and will lay a foundation for understanding the role of InsP 7 and InsP 8 in plants.

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“…The highly electronegative and energetic properties of the PP-InsPs enable them to regulate protein function through electrostatic interactions (2) and by protein pyrophosphorylation (4,5). A number of biological effects have been attributed to the PP-InsPs, but evidence is emerging that a primary role is to regulate metabolic circuitry (1,2,(6)(7)(8) as part of an overarching process by which signaling cascades interface with cellular and organismal homeostasis (9).…”

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confidence: 99%

KO of 5-InsP ₇ kinase activity transforms the HCT116 colon cancer cell line into a hypermetabolic, growth-inhibited phenotype

Nguyen

Ganini

et al. 2017

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

104

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The inositol pyrophosphates 5-InsP (diphosphoinositol pentakisphosphate) and 1,5-InsP (bis-diphosphoinositol tetrakisphosphate) are highly energetic cellular signals interconverted by the diphosphoinositol pentakisphosphate kinases (PPIP5Ks). Here, we used CRISPR to KO PPIP5Ks in the HCT116 colon cancer cell line. This procedure eliminates 1,5-InsP and raises 5-InsP levels threefold. Expression of p53 and p21 was up-regulated; proliferation and G1/S cell-cycle transition slowed. Thus, PPIP5Ks are potential targets for tumor therapy. Deletion of the PPIP5Ks elevated [ATP] by 35%; both [ATP] and [5-InsP] were restored to WT levels by overexpression of PPIP5K1, and a kinase-compromised PPIP5K1 mutant had no effect. This covariance of [ATP] with [5-InsP] provides direct support for an energy-sensing attribute (i.e., 1 mM for ATP) of the 5-InsP-generating inositol hexakisphosphate kinases (IP6Ks). We consolidate this conclusion by showing that 5-InsP levels are elevated on direct delivery of ATP into HCT116 cells using liposomes. Elevated [ATP] in HCT116 cells is underpinned by increased mitochondrial oxidative phosphorylation and enhanced glycolysis. To distinguish between 1,5-InsP and 5-InsP as drivers of the hypermetabolic and p53-elevated phenotypes, we used RNAi and the pan-IP6K inhibitor,2-(-trifluorobenzyl), 6-(-nitrobenzyl) purine (TNP), to return 5-InsP levels in cells to those of WT cells without rescuing 1,5-InsP levels. Attenuation of IP6K restored p53 expression but did not affect the hypermetabolic phenotype. Thus, we conclude that 5-InsP regulates p53 expression, whereas 1,5-InsP regulates ATP levels. These findings attribute hitherto unsuspected functionality for 1,5-InsP to bioenergetic homeostasis.

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New Horizons in Cellular Regulation by Inositol Polyphosphates: Insights from the Pancreaticβ-Cell

Cited by 33 publications

References 205 publications

Inositol pyrophosphates: Why so many phosphates?

Inositol pyrophosphates: Why so many phosphates?

Two inositol hexakisphosphate kinases drive inositol pyrophosphate synthesis in plants

KO of 5-InsP ₇ kinase activity transforms the HCT116 colon cancer cell line into a hypermetabolic, growth-inhibited phenotype

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New Horizons in Cellular Regulation by Inositol Polyphosphates: Insights from the Pancreaticβ-Cell

Cited by 33 publications

References 205 publications

Inositol pyrophosphates: Why so many phosphates?

Inositol pyrophosphates: Why so many phosphates?

Two inositol hexakisphosphate kinases drive inositol pyrophosphate synthesis in plants

KO of 5-InsP 7 kinase activity transforms the HCT116 colon cancer cell line into a hypermetabolic, growth-inhibited phenotype

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KO of 5-InsP ₇ kinase activity transforms the HCT116 colon cancer cell line into a hypermetabolic, growth-inhibited phenotype