Disruption of the mouse inositol 1,3,4,5,6-pentakisphosphate 2-kinase gene, associated lethality, and tissue distribution of 2-kinase expression

Verbsky, John W.; Lavine, Kory J.; Majerus, Philip W.

doi:10.1073/pnas.0503656102

Cited by 64 publications

(70 citation statements)

References 16 publications

(19 reference statements)

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“…Soluble inositol phosphates were extracted according to the method previously described (27). Briefly, cells were lysed in 500 l of methanol and 0.5 N HCl mixture (methanol, 0.5 N HCl ϭ 2:1) and inositol phosphates were extracted with 335 l of chloroform.…”

Section: Methodsmentioning

confidence: 99%

Inositol Pentakisphosphate Mediates Wnt/β-Catenin Signaling

Gao

Wang

2007

Journal of Biological Chemistry

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Section: Methodsmentioning

confidence: 99%

Inositol Pentakisphosphate Mediates Wnt/β-Catenin Signaling

Gao

Wang

2007

Journal of Biological Chemistry

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“…Yes. Recent studies of several IPKs have demonstrated their essential involvement in organism development and function (17,(36)(37)(38)(39)(40)(41). Given the highly orchestrated nature of these processes, it is reasonable to conclude that the production of an IP code that emerges from IP 3 is involved in the execution of these instructions.…”

Section: G Protein Activation Along With Expression Of the Four Evolmentioning

confidence: 99%

Alterations in an inositol phosphate code through synergistic activation of a G protein and inositol phosphate kinases

Otto

Kelly

Chiou

et al. 2007

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

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In mammals, many cellular stimuli evoke a response through G protein activation of phospholipase C, which results in the lipidderived production of inositol 1,4,5-trisphosphate (IP3). Although it is well established that IP3 is converted to numerous inositol phosphates (IPs) and pyrophosphates (PP-IPs) through the action of up to six classes of inositol phosphate kinases (IPKs), it is not clear that these metabolites are influenced by G protein signaling. Here we report that activation of G␣q leads to robust stimulation of IP3 to IP8 metabolism. To expose flux through these pathways, genetic perturbation was used to alter IP homeostasis. Coupled expression of a constitutively active G␣qQL and one or more IPK gene products synergistically generated dramatic changes in the patterns of intracellular IP messengers. Many distinct IP profiles were observed through the expression of different combinations of IPKs, including changes in previously unappreciated pools of IP 5 and IP6, two molecules widely viewed as stable metabolites. Our data link the activation of a trimeric G protein to a plethora of metabolites downstream of IP3 and provide a framework for suggesting that cells possess the machinery to produce an IPK-dependent IP code. We imply, but do not prove, that agonist-induced alterations in such a code would theoretically be capable of enhancing signaling complexity and specificity. The essential roles for IPKs in organism development and cellular adaptation are consistent with our hypothesis that such an IP code may be relevant to signaling pathways.Gq ͉ metabolomics ͉ phospholipase C ͉ signal transduction ͉ G protein-coupled receptor I n mammals, hundreds of G protein-coupled receptors (GPCR) and receptor tyrosine kinases (RTKs) are present and link to numerous intracellular signaling modules that, in combination, enable selective cellular responses. One of the most commonly activated signaling modules is the generation of the second messengers inositol 1,4,5-trisphosphate (IP 3 ) and 1,2-diacylglycerol by the action of phospholipase C isozymes (PLCs) on phosphatidylinositol 4,5-bisphosphate (PIP 2 ) (1-5). The ubiquity of PLC activation in response to a wide range of stimuli supports its central role in signaling, but also emphasizes that the production of two messengers alone, IP 3 and diacylglycerol, is insufficient to encode the breadth of specific cellular responses necessary for survival and adaptation. Therefore, it has been postulated that further signaling diversity could theoretically arise from the conversion of IP 3 to numerous inositol tetrakisphosphate (IP 4 ), inositol pentakisphosphate (IP 5 ), inositol hexakisphosphate (IP 6 ), and inositol pyrophosphate (PP-IP) molecules (2, 6-9). The production of these regulators occurs through the action of up to six classes of evolutionarily conserved IP kinase (IPK) gene products that include: IPMK/IPK2 (10-14), IPK1 (15-17), , ITPK/IP56K (21, 22), IP6K/ IHPK (23-25), and VIP1 (25-27) (Fig. 1). Genetic and biochemical studies of IPKs have provided v...

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“…We did not use RNA interference to reduce expression of the InsP 5 kinase that synthesizes InsP 6 . This decision was based on previous experiments showing that "knockdown" of mammalian InsP 5 2-kinase expression induces gross changes in nuclear morphology (41), is pro-apoptotic (42), and generally toxic (43,44). Instead, we overexpressed MINPP, an InsP 6 phosphatase.…”

Section: The Effect Of Minpp Upon Insp 6 Levels and Nucleolinmentioning

confidence: 99%

The Nucleolus Exhibits an Osmotically Regulated Gatekeeping Activity That Controls the Spatial Dynamics and Functions of Nucleolin

Yang

Reece²,

Cho

et al. 2008

Journal of Biological Chemistry

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We demonstrate that physiologically relevant perturbations in the osmotic environment rheostatically regulate a gatekeeping function for the nucleolus that controls the spatial dynamics and functions of nucleolin. HeLa cells and U2-OS osteosarcoma cells were osmotically challenged with 100 -200 mM sorbitol, and the intranuclear distribution of nucleolin was monitored by confocal microscopy. Nucleolin that normally resides in the innermost fibrillar core of the nucleolus, where it assists rDNA transcription and replication, was expelled within 30 min of sorbitol addition. The nucleolin was transferred into the nucleoplasm, but it distributed there non-uniformly; locally high levels accumulated in 4,6-diamidino-2-phenylindole-negative zones containing euchromatic (transcriptionally active) DNA. Inositol pyrophosphates also responded within 30 min of hyperosmotic stress: levels of bisdiphosphoinositol tetrakisphosphate increased 6-fold, and this was matched by decreased levels of its precursor, diphosphoinositol pentakisphosphate. Such fluctuations in inositol pyrophosphate levels are of considerable interest, because, according to previously published in vitro data, they regulate the degree of phosphorylation of nucleolin through a novel kinase-independent phosphotransferase reaction (Saiardi, A., Bhandari, A., Resnick, R., Cain, A., Snowman, A. M., and Snyder, S. H. (2004) Science 306, 2101-2105). However, by pharmacologically intervening in inositol pyrophosphate metabolism, we found that it did not supervise the osmotically driven switch in the biological activities of nucleolin in vivo.

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Disruption of the mouse inositol 1,3,4,5,6-pentakisphosphate 2-kinase gene, associated lethality, and tissue distribution of 2-kinase expression

Cited by 64 publications

References 16 publications

Inositol Pentakisphosphate Mediates Wnt/β-Catenin Signaling

Inositol Pentakisphosphate Mediates Wnt/β-Catenin Signaling

Alterations in an inositol phosphate code through synergistic activation of a G protein and inositol phosphate kinases

The Nucleolus Exhibits an Osmotically Regulated Gatekeeping Activity That Controls the Spatial Dynamics and Functions of Nucleolin

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