Subcellular localisation of human inositol 1,4,5-trisphosphate 3-kinase C: species-specific use of alternative export sites for nucleo-cytoplasmic shuttling indicates divergent roles of the catalytic and N-terminal domains

Nalaskowski, Marcus M.; Windhorst, Sabine; Stockebrand, Malte; Mayr, Georg W.

doi:10.1515/bc.2006.075

Cited by 11 publications

(7 citation statements)

References 48 publications

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“…This isoform is the least regulated by feedback from Ca 2ϩ /CaM and lacks a consensus phosphorylation site for CaM kinase. Thus, it has been suggested that IP 3 KC is adapted for regulating the resting Ins(1,4,5)P 3 levels in cells (42,43). The reported K m values for mammalian IP 3 Ks range from about 0.2 to 10 M (28, 38), whereas the K m reported for dmIP 3 K␤ is 25 nM (11).…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

“…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%

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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“…The secondary ␣-rabbit antibody was labeled with Alexa Fluor 488. DAPI staining and examination of the intracellular localization by epifluorescence microscopy were previously described by Nalaskowski et al (29). Transient transfection of eukaryotic cells was performed using the Metafectene reagent according to the manufacturer's instructions (Biontex Laboratories, Munich, Germany).…”

Section: Cloning and Mutagenesis Of Egfp Fusion Gene Expressionmentioning

confidence: 99%

“…Signal-The C isoform of human and rat IP3K is actively imported into and actively exported out of the nucleus of mammalian cells (29,30). Its nuclear export is mediated by leucine-rich nuclear export signals (NES).…”

Section: Active Nuclear Export Of Ip3kb Is Mediated By a Leucinerich mentioning

confidence: 99%

Human Inositol 1,4,5-Trisphosphate 3-Kinase Isoform B (IP3KB) Is a Nucleocytoplasmic Shuttling Protein Specifically Enriched at Cortical Actin Filaments and at Invaginations of the Nuclear Envelope

Nalaskowski

Fliegert

Ernst

et al. 2011

Journal of Biological Chemistry

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Recent studies have shown that inositol 1,4,5-trisphosphate 3-kinase isoform B (IP3KB) possesses important roles in the development of immune cells. IP3KB can be targeted to multiple cellular compartments, among them nuclear localization and binding in close proximity to the plasma membrane. The B isoform is the only IP3K that is almost ubiquitously expressed in mammalian cells. Detailed mechanisms of its targeting regulation will be important in understanding the role of Ins(1,4,5)P 3 phosphorylation on subcellular calcium signaling and compartment-specific initiation of pathways leading to regulatory active higher phosphorylated inositol phosphates. Here, we identified an exportin 1-dependent nuclear export signal ( 134 LQRELQNVQV) and characterized the amino acids responsible for nuclear localization of IP3KB ( 129 RKLR). These two targeting domains regulate the amount of nuclear IP3KB in cells. We also demonstrated that the localization of IP3KB at the plasma membrane is due to its binding to cortical actin structures. Intriguingly, all three of these targeting activities reside in one small polypeptide segment (amino acids 104 -165), which acts as a multitargeting domain (MTD). Finally, a hitherto unknown subnuclear localization of IP3KB could be demonstrated in rapidly growing H1299 cells. IP3KB is specifically enriched at nuclear invaginations extending perpendicular between the apical and basal surface of the nucleus of these flat cells. Such nuclear invaginations are known to be involved in Ins(1,4,5)P 3 -mediated Ca 2؉ signaling of the nucleus. Our findings indicate that IP3KB not only regulates cytoplasmic Ca 2؉ signals by phosphorylation of subplasmalemmal and cytoplasmic Ins(1,4,5)P 3 but may also be involved in modulating nuclear Ca 2؉ signals generated from these nuclear envelope invaginations.It is well established that the highly inositol 1,4,5-trisphosphate (Ins(1,4,5)P 3 ) 2 -specific IP3Ks remove the Ca 2ϩ -releasing second messenger Ins(1,4,5)P 3 by phosphorylating it to Ins(1,3,4,5)P 4 (1) supporting the formation of higher phosphorylated inositols in the cell (2). So far, three isoforms of IP3K, termed A (3), B (4), and C (5), have been identified in mammals. Full-length cDNAs encoding IP3K isoform B (IP3KB) were cloned from man (6) and rat (7). IP3KB was mapped to the telomeric end of human chromosome 1 (8, 9) and identified as a candidate gene in the pathogenesis of multiple sclerosis (10), Alzheimer disease (11), and malignant melanoma (12). But most importantly, IP3KB is a promising new target in immune disorders (13). Transgenic disruption of the IP3KB gene in mice causes a significant decrease in Ins(1,3,4,5)P 4 levels in thymocytes leading to a block of positive selection and consequently to a severe T cell deficiency (14). Recent studies described additional functions of IP3KB in selection and survival of B cells (15, 16), signaling of neutrophils (17), and modulation of myelopoiesis (18). In mammalian cells, multiple intracellular localizations of IP3KB, namely to the plasma membr...

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“…This is specific for ITPKC and was not observed with ITPKA and ITPKB. The mouse endogenous ITPKC protein was never detected in the nucleus, in contrast to previously reported data of transfected rat and human ITPKC in NRK 52E renal cells (Nalaskowski et al, 2003(Nalaskowski et al, , 2006. We also analyzed multiciliated tracheal epithelial cells and spermatozoa for ITPKC protein function in our Itpkc þ/þ and Itpkc À/-mice.…”

Section: Discussionmentioning

confidence: 73%

Specific expression and function of inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) in wild type and knock-out mice

Scoumanne

Molina-Ortíz

Monteyne

et al. 2016

Advances in Biological Regulation

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a b s t r a c tInositol 1,4,5-trisphosphate 3-kinase C (ITPKC) is the last identified member of the inositol 1,4,5-trisphosphate 3-kinases family which phosphorylates inositol 1,4,5-trisphosphate into inositol 1,3,4,5-tetrakisphosphate. Although expression and function of the two other family members ITPKA and ITPKB are rather well characterized, similar information is lacking for ITPKC. Here, we first defined the expression of Itpkc mRNA and protein in mouse tissues and cells using in situ hybridization and new antibodies. Surprisingly, we found that cells positive for ITPKC in the studied tissues express either a multicilium (tracheal and bronchial epithelia, brain ependymal cells), microvilli forming a brush border (small and large intestine, and kidney proximal tubule cells) or a flagellum (spermatozoa), suggesting a role for ITPKC either in the development or the function of these specialized cellular structures. Given this surprising expression, we then analyzed ITPKC function in multiciliated tracheal epithelial cells and sperm cells using our Itpkc knock-out mouse model. Unfortunately, no significant difference was observed between control and mutant mice for any of the parameters tested, leaving the exact in vivo function of this third Ins(1,4,5)P3 3-kinase still open.

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Subcellular localisation of human inositol 1,4,5-trisphosphate 3-kinase C: species-specific use of alternative export sites for nucleo-cytoplasmic shuttling indicates divergent roles of the catalytic and N-terminal domains

Cited by 11 publications

References 48 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

Human Inositol 1,4,5-Trisphosphate 3-Kinase Isoform B (IP3KB) Is a Nucleocytoplasmic Shuttling Protein Specifically Enriched at Cortical Actin Filaments and at Invaginations of the Nuclear Envelope

Specific expression and function of inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) in wild type and knock-out mice

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