Regulation of Ins(3,4,5,6)P4 Signaling by a Reversible Kinase/Phosphatase

Ho, Melissa W. Y.; Yang, Xiao; Carew, Mark; Zhang, Tong; Hua, Len; Kwon, Young‐Uk; Chung, Sung‐Kee; Adelt, Stephan; Vogel, Günter; Riley, Andrew M.; Potter, Barry V. L.; Shears, Stephen B.

doi:10.1016/s0960-9822(02)00713-3

Cited by 57 publications

(84 citation statements)

References 23 publications

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“…1A). This is a biologically significant phenomenon that enables Ins(1,3,4)P 3 to regulate Ins(3,4,5,6)P 4 accumulation in vivo (8), but it has not previously been rationalized at a molecular level. We now show that Ins(1,3,4)P 3 considerably reduced the quantity of [ Fig.…”

Section: Resultsmentioning

confidence: 99%

“…2). These reactions have been demonstrated to be reversible: ITPK1 can also dephosphorylate Ins(1,3,4,5,6)P 5 back to Ins(3,4,5,6)P 4 (8). An especially puzzling aspect of this phenomenon is that dephosphorylation of Ins(1,3,4,5,6)P 5 by human ITPK1 is stimulated, rather than competitively inhibited, by one of its alternate substrates, Ins(1,3,4)P 3 (8).…”

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confidence: 99%

“…In this way Ins (3,4,5,6)P 4 regulates a range of biological processes, including salt and fluid secretion, neurotransmission, and insulin secretion from pancreatic ␤-cells (8,(11)(12)(13). Recently it was shown that changes in ITPK1 * This work was based on experiments conducted at beamlines 5.0.3 and 5.0.2 of the Advanced Light Source (ALS).…”

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confidence: 99%

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Integration of Inositol Phosphate Signaling Pathways via Human ITPK1

Chamberlain

Qian

Stiles

et al. 2007

Journal of Biological Chemistry

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105

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Inositol 1,3,4-trisphosphate 5/6-kinase (ITPK1) is a reversible, poly-specific inositol phosphate kinase that has been implicated as a modifier gene in cystic fibrosis. Upon activation of phospholipase C at the plasma membrane, inositol 1,4,5-trisphosphate enters the cytosol and is inter-converted by an array of kinases and phosphatases into other inositol phosphates with diverse and critical cellular activities. In mammals it has been established that inositol 1,3,4-trisphosphate, produced from inositol 1,4,5-trisphosphate, lies in a branch of the metabolic pathway that is separate from inositol 3,4,5,6-tetrakisphosphate, which inhibits plasma membrane chloride channels. We have determined the molecular mechanism for communication between these two pathways, showing that phosphate is transferred between inositol phosphates via ITPK1-bound nucleotide. Intersubstrate phosphate transfer explains how competing substrates are able to stimulate each others' catalysis by ITPK1. We further show that these features occur in the human protein, but not in plant or protozoan homologues. The high resolution structure of human ITPK1 identifies novel secondary structural features able to impart substrate selectivity and enhance nucleotide binding, thereby promoting intersubstrate phosphate transfer. Our work describes a novel mode of substrate regulation and provides insight into the enzyme evolution of a signaling mechanism from a metabolic role.Cellular inositol phosphate metabolism is an intricate web of kinase and phosphatase reactions that produces a number of important signaling molecules (for review see Ref. 1). A now classic example of these signaling activities is the release of Ca 2ϩ into the cytoplasm through an intracellular channel that is gated by inositol 1,4,5-trisphosphate (Ins(1,4,5)P 3 ) 4 (2). Additional roles are continually being discovered: inositol phosphates have recently been shown to be critical to the activity of RNA-editing enzymes (3), to participate in telomere maintenance (4), and to be the phosphate donors in certain protein phosphorylation events (5). It is of critical interest, therefore, to establish the regulatory mechanisms that govern the metabolism of inositol phosphates.An interesting feature of inositol phosphate metabolism is the promiscuity with which several key kinases phosphorylate multiple substrates (6). For example, ITPK1 (also known as inositol 1,3,4-trisphosphate 5/6-kinase) adds either a 5-or 6-phosphate to Ins(1,3,4)P 3 and also attaches a 1-phosphate to Ins(3,4,5,6)P 4 (6, 7) (inositol phosphate structures shown in Fig. 2). These reactions have been demonstrated to be reversible: ITPK1 can also dephosphorylate Ins(1,3,4,5,6)P 5 back to Ins(3,4,5,6)P 4 (8). An especially puzzling aspect of this phenomenon is that dephosphorylation of Ins(1,3,4,5,6)P 5 by human ITPK1 is stimulated, rather than competitively inhibited, by one of its alternate substrates, Ins(1,3,4)P 3 (8).The fact that mammalian ITPK1 reversibly phosphorylates both Ins(3,4,5,6)P 4 and Ins(1,3,4)P 3 takes on...

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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Integration of Inositol Phosphate Signaling Pathways via Human ITPK1

Chamberlain

Qian

Stiles

et al. 2007

Journal of Biological Chemistry

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105

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“…We now report that the three other GmItpk isoforms also show this activity: type 1 = 403 ± 4, type 3 = 487 ± 47, type 4 = 88 ± 16 (lmol/ mg protein/min), albeit at rates 6-to 33-fold lower than that of the type 2 enzyme. Substrate cycling between Ins(3,4,5,6)P 4 and Ins(1,3,4,5,6)P 5 may serve a signaling role in plants, in which Ins(3,4,5,6)P 4 has been shown to regulate Cl À channel conductance [15], similar to the role of Ins(3,4,5,6)P 4 in animal cells [22].…”

Section: Synthesis Of Ins(3456)p 4 By Soybean Itpksmentioning

confidence: 97%

“…As well as exhibiting Ins(3,4,5,6)P 4 1-kinase activity, mammalian Itpk1 has been shown to dephosphorylate Ins(1,3,4,5,6)P 5 to Ins(3,4,5,6)P 4 [16,22]. We recently demonstrated that GmItpk2 can also dephosphorylate Ins(1,3,4,5,6)P 5 to Ins(3,4,5,6)P 4 (2932 ± 50 lmol/mg protein/min) [16].…”

Section: Synthesis Of Ins(3456)p 4 By Soybean Itpksmentioning

confidence: 99%

Metabolic and signaling properties of an Itpk gene family in Glycine max

et al. 2008

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We have cloned and characterized four Itpk genes from soybean. All four recombinant Itpk proteins showed canonical Ins(1,3,4)P 3 5/6-kinase activity, but a kinetic analysis raised questions about its biological significance. Instead, we provide evidence that one alternative biological role for soybean Itpks is to interconvert the Cl À channel inhibitor, Ins(3,4,5,6)P 4 , and its metabolic precursor, Ins(1,3,4,5,6)P 5 , within a substrate cycle. The soybean Itpks also phosphorylated Ins(3,4,6)P 3 to Ins(1,3,4,6)P 4 which was further phosphorylated to Ins(1,3,4,5,6)P 5 by soybean Ipk2. Thus, soybean Itpks may participate in an inositol lipid-independent pathway of InsP 6 synthesis.

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Inositol Polyphosphates

Resnick¹,

Saiardi²

2008

Wiley Encyclopedia of Chemical Biology

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Inositol polyphosphates comprise a large family of water‐soluble molecules derived from the combinatorial phophorylation of the six hydroxyls of myo ‐inositol. Second messenger roles for inositol polyphosphates in Ca 2+ mobilization were first identified for what is now the best characterized family member, inositol 1,4,5‐trisphosphate (InsP 3 ). Additional anabolic and catabolic metabolism of InsP 3 results in the formation of a large, diverse family of higher inositol polyphosphates whose signaling roles and biologic functionality remain largely undefined. However, the recent cloning and identification of the kinases and phosphatases involved in the combinatorial modification of inositol polyphosphates has served to further define and characterize this complex metabolic network and to identify its preeminence in nearly all aspects of cell biology. Conserved from yeast to humans, inositol polyphosphates regulate a wide array of processes, including ion‐channel conductance, membrane dynamics, transcription, nucleic acid metabolism, and protein phosphorylation.

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Regulation of Ins(3,4,5,6)P4 Signaling by a Reversible Kinase/Phosphatase

Cited by 57 publications

References 23 publications

Integration of Inositol Phosphate Signaling Pathways via Human ITPK1

Integration of Inositol Phosphate Signaling Pathways via Human ITPK1

Metabolic and signaling properties of an Itpk gene family in Glycine max

Inositol Polyphosphates

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