Requirement of Inositol Pyrophosphates for Full Exocytotic Capacity in Pancreatic β Cells

Illies, Christopher; Gromada, Jesper; Fiume, Roberta; Leibiger, Barbara; Yu, Jia; Juhl, Kirstine; Yang, Shao Nian; Barma, D. K.; Falck, John R.; Saiardi, Adolfo; Barker, Christopher J.; Berggren, Per Olof

doi:10.1126/science.1146824

Cited by 168 publications

(213 citation statements)

References 23 publications

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“…3c). This data correlates with the observations of Illies et al (25) that RNA silencing of IP6K1 in pancreatic beta cells inhibits exocytosis of insulin-containing granules from the readily releasable pool. There- …”

Section: Resultssupporting

confidence: 81%

“…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 targeted deletion of the exon encoding the C-terminal catalytic domain.…”

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confidence: 99%

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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.

129

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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Section: Resultssupporting

confidence: 81%

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.

129

186

View full text Add to dashboard Cite

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“…Recent studies indicated that the size of the primed vesicle pool in insulin-secreting pancreatic ␤ cells was dependent on the level of diphosphoinositol pentakisphosphate (48), which non-enzymatically pyrophosphorylates proteins on phosphoSer residues within CK2 consensus sites (49). Whether CAPS is further activated by diphosphoinositol pentakisphosphatemediated pyrophosphorylation to enhance vesicle priming will require further study.…”

Section: Discussionmentioning

confidence: 99%

CAPS Activity in Priming Vesicle Exocytosis Requires CK2 Phosphorylation

Nojiri

Loyet²,

Klenchin

et al. 2009

Journal of Biological Chemistry

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CAPS (Ca 2؉ -dependent activator protein for secretion) functions in priming Ca 2؉ -dependent vesicle exocytosis, but the regulation of CAPS activity has not been characterized. Here we show that phosphorylation by protein kinase CK2 is required for CAPS activity. Dephosphorylation eliminated CAPS activity in reconstituting Ca 2؉ -dependent vesicle exocytosis in permeable and intact PC12 cells. Ser-5, -6, and -7 and Ser-1281 were identified by mass spectrometry as the major phosphorylation sites in the 1289 residue protein. Ser-5, -6, and -7 but not Ser-1281 to Ala substitutions abolished CAPS activity. Protein kinase CK2 phosphorylated CAPS in vitro at these sites and restored the activity of dephosphorylated CAPS. CK2 is the likely in vivo CAPS protein kinase based on inhibition of phosphorylation by tetrabromo-2-benzotriazole in PC12 cells and by the identity of in vivo and in vitro phosphorylation sites. CAPS phosphorylation by CK2 was constitutive, but the elevation of Ca 2؉ in synaptosomes increased CAPS Ser-5 and -6 dephosphorylation, which terminates CAPS activity. These results identify a functionally important N-terminal phosphorylation site that regulates CAPS activity in priming vesicle exocytosis.Regulated neurotransmitter secretion is central to intercellular communication in the nervous system. Two types of secretory vesicles mediate neurotransmitter release; that is, synaptic vesicles that release transmitters such as glutamate at synapses and dense-core vesicles that release modulatory transmitters and neuropeptides at non-synaptic sites. Both types of secretory vesicles are recruited to docking sites on the plasma membrane where they are primed to a ready release state to undergo fusion in response to Ca 2ϩ elevations. Many of the proteins that mediate the targeting, docking, priming, and Ca 2ϩ -dependent fusion of vesicles with the plasma membrane function in both synaptic vesicle and dense-core vesicle pathways (1). CAPS-1 2 (also known as Cadps1) is a 1289-residue protein that reconstitutes Ca 2ϩ -triggered dense-core vesicle exocytosis in permeable neuroendocrine cells at a priming step (2-4). CAPS is required for secretion of a subset of transmitters in Caenorhabditis elegans (5) and Drosophila melanogaster (6) and for priming dense-core vesicle exocytosis in neuroendocrine cells (7) and synaptic vesicle exocytosis in neurons (8). Vesicle priming reactions are extensively modulated during physiological demand (9), but mechanisms that regulate CAPS function remain to be identified.Reversible protein phosphorylation is a major mechanism for the regulation of cellular processes including vesicle exocytosis. Many proteins that function in evoked vesicle exocytosis are phosphoproteins (10, 11). The neuronal SNARE proteins syntaxin 1A, VAMP-2, and SNAP-25 are phosphorylated by several protein kinases in vitro (12)(13)(14). Protein kinase C and protein kinase A sites on SNAP-25 affect refilling rates and size, respectively, of the primed pool of vesicles in chromaffin cells (15,16). Several SNARE...

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“…In mammalian cells, InsP7 has been implicated in several cellular functions, including vesicular trafficking and exocytosis (26,27), apoptosis (28)(29)(30)(31), insulin disposition (32), insulin sensitivity, and weight gain (33). We recently showed that InsP7 also represents a mechanism for controlling optimal PtdIns(3,4,5)P3/Akt pathway activation in neutrophils.…”

Section: Discussionmentioning

confidence: 99%

“…Total and phosphorylated Akt were detected by Western blot using anti-Akt and anti-phospho-Akt (Ser473) antibodies, respectively. Relative amounts of phosphorylated Akt were quantified using NIH Image software as described (26). All samples were normalized to the amount of total Akt.…”

Section: Effects Of Cse and Nicotine On Neutrophil Spontaneous Death mentioning

confidence: 99%

Cigarette smoke (CS) and nicotine delay neutrophil spontaneous death via suppressing production of diphosphoinositol pentakisphosphate

Bajrami

et al. 2013

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

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Diphosphoinositol pentakisphosphate (InsP7), a higher inositol phosphate containing energetic pyrophosphate bonds, is beginning to emerge as a key cellular signaling molecule. However, the various physiological and pathological processes that involve InsP7 are not completely understood. Here we report that cigarette smoke (CS) extract and nicotine reduce InsP7 levels in aging neutrophils. This subsequently leads to suppression of Akt deactivation, a causal mediator of neutrophil spontaneous death, and delayed neutrophil death. The effect of CS extract and nicotine on neutrophil death can be suppressed by either directly inhibiting the PtdIns(3,4,5)P3/Akt pathway, or increasing InsP7 levels via overexpression of InsP6K1, an inositol hexakisphosphate (InsP6) kinase responsible for InsP7 production in neutrophils. Delayed neutrophil death contributes to the pathogenesis of CS-induced chronic obstructive pulmonary disease. Therefore, disruption of InsP6K1 augments CS-induced neutrophil accumulation and lung damage. Taken together, these results suggest that CS and nicotine delay neutrophil spontaneous death by suppressing InsP7 production and consequently blocking Akt deactivation in aging neutrophils. Modifying neutrophil death via this pathway provides a strategy and therapeutic target for the treatment of tobacco-induced chronic obstructive pulmonary disease.

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Requirement of Inositol Pyrophosphates for Full Exocytotic Capacity in Pancreatic β Cells

Cited by 168 publications

References 23 publications

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

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

CAPS Activity in Priming Vesicle Exocytosis Requires CK2 Phosphorylation

Cigarette smoke (CS) and nicotine delay neutrophil spontaneous death via suppressing production of diphosphoinositol pentakisphosphate

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