title: 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.
abstract: 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.
authors.affiliation: Institute of Biochemistry and Molecular Biology I-Cellular Signal Transduction, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany. nalaskowski@uke.uni-hamburg.de
authors.forename: Marcus M
authors.initials: MM
authors.lastname: Nalaskowski
authors.forename: Ralf
authors.initials: R
authors.lastname: Fliegert
authors.forename: Olga
authors.initials: O
authors.lastname: Ernst
authors.forename: Maria A
authors.initials: MA
authors.lastname: Brehm
authors.forename: Werner
authors.initials: W
authors.lastname: Fanick
authors.forename: Sabine
authors.initials: S
authors.lastname: Windhorst
authors.forename: Hongying
authors.initials: H
authors.lastname: Lin
authors.forename: Susanne
authors.initials: S
authors.lastname: Giehler
authors.forename: Jamin
authors.initials: J
authors.lastname: Hein
authors.forename: Yuan-Na
authors.initials: YN
authors.lastname: Lin
authors.forename: Georg W
authors.initials: GW
authors.lastname: Mayr
mesh_terms: D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D002462:Cell Membrane / Q000201:enzymology* / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D028884:Karyopherins / Q000235:genetics / Q000378:metabolism; D009685:Nuclear Envelope / Q000201:enzymology* / Q000235:genetics; D049790:Nuclear Export Signals / Q000502:physiology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D000097606:Exportin 1 Protein
chemical_list: D002118:Calcium; D015544:Inositol 1,4,5-Trisphosphate; D007527:Isoenzymes; D028884:Karyopherins; D049790:Nuclear Export Signals; D017853:Phosphotransferases (Alcohol Group Acceptor); D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C051038:Inositol 1,4,5-trisphosphate 3-kinase