Regulation of the localization and activity of inositol 1,4,5-trisphosphate 3-kinase B in intact cells by proteolysis

Yu, Jowie C.H.; Lloyd-Burton, Samantha M.; Irvine, Robin F.; Schell, Michael J.

doi:10.1042/bj20050829

Cited by 16 publications

(19 citation statements)

References 31 publications

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“…4 illustrates the effects of intracellular localization on mammalian IP 3 K efficacy. As we previously reported, removal of the N-terminal 66 amino acids in isoform A makes it cytosolic (39), and this has a marked effect on its efficacy, as assessed either in a way similar to that used for IP 3 KB by Yu et al (25) (Fig. 4A, graph) or the population profile (Fig.…”

Section: Resultsmentioning

confidence: 73%

“…Regulation by Localization near Sites of Ins(1,4,5)P 3 Production-We have previously highlighted the significant effect that the plasma membrane localization (by virtue of its F-actin binding) of IP 3 KB has on its efficacy in HeLa cells (25). Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In neurons, for example, IP 3 KA is concentrated in dendritic spines by way of an interaction with the filamentous actin (Factin) cytoskeleton (39), a localization that is subject to dynamic regulation by Ca 2ϩ (40). Similarly, IP 3 KB can associate with F-actin (41), but it can also be targeted to the endoplasmic reticulum (24), a targeting that may be dynamically regulated by proteases (25). IP 3 KC has been reported to be cytosolic in humans (24), yet it is also reported to actively shuttle between the cytoplasm and the nucleus in the rat (42,43).…”

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confidence: 99%

“…We recently used IP 3 KB overexpression to demonstrate the differing efficacy of IP 3 KB when it is bound to the cytoskeleton compared with when is cytosolic (25), thus demonstrating that localization of IP 3 KB alters its ability to modulate Ins(1,4,5)P 3 levels. Here we report a more systematic exploration of IP 3 K function using the same simple assay system (25) …”

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confidence: 99%

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Regulation of Inositol 1,4,5-Trisphosphate 3-Kinases by Calcium and Localization in Cells

Lloyd-Burton

Irvine

et al. 2007

Journal of Biological Chemistry

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We also compared the effects of the these IP 3 Ks with other enzymes that metabolize Ins(1,4,5)P 3 , including the Type I Ins(1,4,5)P 3 5-phosphatase, in both membrane-targeted and soluble forms, the human inositol polyphosphate multikinase, and the two isoforms of IP 3 K found in Drosophila. All reduce the Ca 2؉ signal but to varying degrees. We demonstrate that the activity of only one of two IP 3 K isoforms from Drosophila is positively regulated by calmodulin and that neither isoform associates with the cytoskeleton. Together the data suggest that IP 3 Ks evolved to regulate kinetic and spatial aspects of Ins (1,4,5)P 3 signals in increasingly complex ways in vertebrates, consistent with their probable roles in the regulation of higher brain and immune function.The metabolism of the calcium-mobilizing second messenger inositol 1,4,5-trisphosphate (Ins(1,4,5)P 3 ) 5 proceeds via two biochemical pathways. Type I Ins(1,4,5)P 3 5-phosphatase catalyzes the dephosphorylation of Ins(1,4,5)P 3 , producing the inactive (1, 2) metabolite Ins(1,4)P 2 (3). Alternatively, Ins(1,4,5)P 3 can be further phosphorylated to Ins(1,3,4,5)P 4 , in a reaction catalyzed by Ins(1,4,5)P 3 3-kinase (IP 3 K) (4). Ins(1,3,4,5)P 4 does not mobilize Ca 2ϩ , but is suggested to have a number of second messenger functions, most notably in the immune system (5, 6) and in neurons (7, 8) (reviewed in Ref. 9). Furthermore, IP 3 Ks may initiate a chain of reactions responsible for the production of higher inositol phosphates, having diverse intracellular roles (10), although this view has been challenged (11, 12).The human genome encodes three differentially expressed isoforms of IP 3 K, denoted IP 3 KA, -B, and -C (13, 14). In addition, inositol polyphosphate multikinase (IPMK; also described as IPK2, and Arg82 in yeast) harbors a range of inositol phosphate kinase activities, including Ins (1,4,5)P 3 3-kinase activity (15, 16). Two IP 3 Ks occur in Drosophila melanogaster, denoted dmIP 3 K␣ (17) and dmIP 3 K␤ (11). One IP 3 K gene occurs in Caenorhabditis elegans, and genetic evidence from both worms and flies strongly argues that IP 3 Ks function as negative regulators of Ins(1,4,5)P 3 Ca 2ϩ signals through their ability to remove Ins(1,4,5)P 3 (17, 18). Expression studies in mammalian cells further support the consensus view that IP 3 Ks negatively regulate Ins(1,4,5)P 3 Ca 2ϩ signals by their ability to remove Ins(1,4,5)P 3 (19 -25). The product of these enzymes, Ins(1,3,4,5)P 4 , may further regulate Ca 2ϩ homeostasis, although exactly how it may do that remains controversial (10).From the first studies of the IP 3 Ks, it has been assumed that because they are enzymes with a higher affinity for Ins(1,4,5)P 3 than the Type I Ins(1,4,5)P 3 5-phosphatase (26) and differ from the 5-phosphatase in that they are positively regulated by CaM and CaM kinase (see Refs. 13,14,27, and 28 for reviews), they must play a preferential role in regulating the pools of Ins (1,4,5)P 3 involved in signaling. However, the exact nature of this contribution is st...

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Section: Resultsmentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Regulation of Inositol 1,4,5-Trisphosphate 3-Kinases by Calcium and Localization in Cells

Lloyd-Burton

Irvine

et al. 2007

Journal of Biological Chemistry

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“…Rat brain microglia were prepared as described previously (Yu et al, 2005), and cells collected by shaking and plated onto uncoated coverslips or six-well plates. Rat brain endothelial cells (RBECs) were kindly provided by J. Lim (University of Cambridge, UK).…”

Section: Cell Culturementioning

confidence: 99%

Regulation of P2X4 receptors by lysosomal targeting, glycan protection and exocytosis

Qureshi

Paramasivam

et al. 2007

Journal of Cell Science

196

225

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The P2X4 receptor has a widespread distribution in the central nervous system and the periphery, and plays an important role in the function of immune cells and the vascular system. Its upregulation in microglia contributes to neuropathic pain following nerve injury. The mechanisms involved in its regulation are not well understood, although we have previously shown that it is constitutively retrieved from the plasma membrane and resides predominantly within intracellular compartments. Here, we show that the endogenous P2X4 receptors in cultured rat microglia, vascular endothelial cells and freshly isolated peritoneal macrophages are localized predominantly to lysosomes. Lysosomal targeting was mediated through a dileucine-type motif within the N-terminus, together with a previously characterized tyrosine-based endocytic motif within the C-terminus. P2X4 receptors remained stable within the proteolytic environment of the lysosome and resisted degradation by virtue of their N-linked glycans. Stimulation of phagocytosis triggered the accumulation of P2X4 receptors at the phagosome membrane. Stimulating lysosome exocytosis, either by incubating with the Ca2+ ionophore ionomycin, for normal rat kidney (NRK) cells and cultured rat microglia, or the weak base methylamine, for peritoneal macrophages, caused an upregulation of both P2X4 receptors and the lysosomal protein LAMP-1 at the cell surface. Lysosome exocytosis in macrophages potentiated ATP-evoked P2X4 receptor currents across the plasma membrane. Taken together, our data suggest that the P2X4 receptor retains its function within the degradative environment of the lysosome and can subsequently traffic out of lysosomes to upregulate its exposure at the cell surface and phagosome.

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Inositol trisphosphate 3-kinases: focus on immune and neuronal signaling

Schell

2010

Cell. Mol. Life Sci.

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The localized control of second messenger levels sculpts dynamic and persistent changes in cell physiology and structure. Inositol trisphosphate [Ins(1,4,5)P(3)] 3-kinases (ITPKs) phosphorylate the intracellular second messenger Ins(1,4,5)P(3). These enzymes terminate the signal to release Ca(2+) from the endoplasmic reticulum and produce the messenger inositol tetrakisphosphate [Ins(1,3,4,5)P(4)]. Independent of their enzymatic activity, ITPKs regulate the microstructure of the actin cytoskeleton. The immune phenotypes of ITPK knockout mice raise new questions about how ITPKs control inositol phosphate lifetimes within spatial and temporal domains during lymphocyte maturation. The intense concentration of ITPK on actin inside the dendritic spines of pyramidal neurons suggests a role in signal integration and structural plasticity in the dendrite, and mice lacking neuronal ITPK exhibit memory deficits. Thus, the molecular and anatomical features of ITPKs allow them to regulate the spatiotemporal properties of intracellular signals, leading to the formation of persistent molecular memories.

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Regulation of the localization and activity of inositol 1,4,5-trisphosphate 3-kinase B in intact cells by proteolysis

Cited by 16 publications

References 31 publications

Regulation of Inositol 1,4,5-Trisphosphate 3-Kinases by Calcium and Localization in Cells

Regulation of Inositol 1,4,5-Trisphosphate 3-Kinases by Calcium and Localization in Cells

Regulation of P2X4 receptors by lysosomal targeting, glycan protection and exocytosis

Inositol trisphosphate 3-kinases: focus on immune and neuronal signaling

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