An extracellular stimulus evokes a specific response from its target cell - for example, it may command the release or uptake of nutrient, promote neurotransmitter release, or initiate muscle contraction. The information inherent in the stimulus is frequently translated into a format that can then be conveyed by intracellular emissaries: the intracellular levels and hence the activities of these """"""""second messengers"""""""" are regulated according to the strength and duration of the original stimulus. This process - signal transduction - is fundamental to how an organism responds and adapts to changes in the environment. Unfortunately, there are many ways it can be disrupted in disease states and by environmental toxins. The adequate treatment of such disturbances requires us to have an understanding of the precise molecular mechanisms that are involved. We study the physiological actions of the inositol polyphosphate second messengers, particularly metabolites of InsP5 and InsP6. We have discovered that InsP5 is metabolically poised to respond to an appropriate cell stimulus by being metabolized to a novel second messenger - an InsP4 - that regulates Ca2+-dependent Cl- channels in the plasma membrane. These ion channels participate in salt and fluid secretion, smooth muscle contraction, neurotransmission, bone remodeling, tumor cell migration, osmoregulation and volume-dependent metabolic effects. With regards to InsP6, we have shown it is a precursor for other important derivatives: the """"""""pyrophosphorylated"""""""" polyphosphates. We are exploring the significance of these novel metabolites, and the information uncovered to date strongly suggests they are """"""""high-energy"""""""" molecules that act as sensors of specific environmental stress stimulii and nutrient deprivation. Recent data also suggest roles in tissue repair.

Project Start
Project End
Budget Start
Budget End
Support Year
25
Fiscal Year
2013
Total Cost
$1,743,917
Indirect Cost
City
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Nair, Vasudha S; Gu, Chunfang; Janoshazi, Agnes K et al. (2018) Inositol Pyrophosphate Synthesis by Diphosphoinositol Pentakisphosphate Kinase-1 is Regulated by Phosphatidylinositol(4,5)bisphosphate. Biosci Rep :
Yousaf, Rizwan; Gu, Chunfang; Ahmed, Zubair M et al. (2018) Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse. PLoS Genet 14:e1007297
Rajasekaran, Subu Surendran; Kim, Jaeyoon; Gaboardi, Gian-Carlo et al. (2018) Inositol hexakisphosphate kinase 1 is a metabolic sensor in pancreatic ?-cells. Cell Signal 46:120-128
Rajasekaran, Subu Surendran; Kim, Jaeyoon; Gaboardi, Gian-Carlo et al. (2018) Corrigendum to 'Inositol hexakisphosphate kinase 1 is a metabolic sensor in pancreatic ?-cells' [Cellular Signalling 46 (2018) 120-128]. Cell Signal :
Shears, Stephen B; Hayakawa, Yoichi (2018) The Drosophila cytokine, GBP: A model that illuminates the yin-yang of inflammation and longevity in humans? Cytokine 110:298-300
Wang, Huanchen; Gu, Chunfang; Rolfes, Ronda J et al. (2018) Structural and biochemical characterization of Siw14: A protein-tyrosine phosphatase fold that metabolizes inositol pyrophosphates. J Biol Chem 293:6905-6914
Rajasekaran, Subu Surendran; Illies, Christopher; Shears, Stephen B et al. (2018) Protein kinase- and lipase inhibitors of inositide metabolism deplete IP7 indirectly in pancreatic ?-cells: Off-target effects on cellular bioenergetics and direct effects on IP6K activity. Cell Signal 42:127-133
Shears, Stephen B (2018) Intimate connections: Inositol pyrophosphates at the interface of metabolic regulation and cell signaling. J Cell Physiol 233:1897-1912
Gu, Chunfang; Nguyen, Hoai-Nghia; Hofer, Alexandre et al. (2017) The Significance of the Bifunctional Kinase/Phosphatase Activities of Diphosphoinositol Pentakisphosphate Kinases (PPIP5Ks) for Coupling Inositol Pyrophosphate Cell Signaling to Cellular Phosphate Homeostasis. J Biol Chem 292:4544-4555
Wang, Huanchen; Shears, Stephen B (2017) Structural features of human inositol phosphate multikinase rationalize its inositol phosphate kinase and phosphoinositide 3-kinase activities. J Biol Chem 292:18192-18202

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