Ins(1,3,4,5)P4 negatively regulates PtdIns(3,4,5)P3 signaling in neutrophils

[en] Many neutrophil functions are regulated by phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) that mediates protein membrane translocation via binding to pleckstrin homolog (PH) domains within target proteins. Here we show that inositol 1,3,4,5-tetrakisphosphate(Ins(1,3,4,5)P4), a cytosolic small molecule, bound the same PH domain of target proteins and competed for binding to PtdIns(3,4,5)P3. In neutrophils, chemoattractant stimulation triggered rapid elevation in Ins(1,3,4,5)P4 concentration. Depletion of Ins(1,3,4,5)P4 by deleting the gene encoding InsP3KB, which converts Ins(1,4,5)P3 to Ins(1,3,4,5)P4, enhanced membrane translocation of the PtdIns(3,4,5)P3-specific PH domain. This led to enhanced sensitivity to chemoattractant stimulation, elevated superoxide production, and enhanced neutrophil recruitment to inflamed peritoneal cavity. On the contrary, augmentation of intracellular Ins(1,3,4,5)P4 concentrationblockedPHdomainmediated membrane translocation of target proteins and dramatically decreased the sensitivity of neutrophils to chemoattractant stimulation. These findings establish a role for Ins(1,3,4,5)P4 in cellular signal transduction pathways and provide another mechanism for modulating PtdIns(3,4,5)P3 signaling in neutrophils.

Disciplines :

Biochemistry, biophysics & molecular biology
Genetics & genetic processes

Author, co-author :

Jia, Y.; Harvard Medical School > Department of Pathology, Dana-Farber/Harvard Cancer Center, Department of Lab Medicine, Children’s Hospital Boston, Karp Family Research Building, Room 10214, Boston, MA 02115, USA

Subramanian, K. K.; Harvard Medical School > Department of Pathology, Dana-Farber/Harvard Cancer Center, Department of Lab Medicine, Children’s Hospital Boston, Karp Family Research Building, Room 10214, Boston, MA 02115, USA

Erneux, C.; Université Libre de Bruxelles - ULB > IRIBHM

Pouillon, V.; Université Libre de Bruxelles - ULB > IRIBHM

Hattori, H.; Harvard Medical School, Dana-Farber/Harvard Cancer Center, Department of Lab Medicine, Children’s Hospital Boston, Karp Family Research Building, Room 10214, Boston, MA 02115, USA > Department of Pathology, Dana-Farber/Harvard Cancer Center, Department of Lab Medicine, Children’s Hospital Boston, Karp Family Research Building, Room 10214, Boston, MA 02115, USA

Jo, H.; Harvard Medical School > Department of Pathology, Dana-Farber/Harvard Cancer Center, Department of Lab Medicine, Children’s Hospital Boston, Karp Family Research Building, Room 10214, Boston, MA 02115, USA

You, J.; Harvard Medical School > Department of Pathology, Dana-Farber/Harvard Cancer Center, Department of Lab Medicine, Children’s Hospital Boston, Karp Family Research Building, Room 10214, Boston, MA 02115, USA

Zhu, D.; Harvard Medical School > Department of Pathology, Dana-Farber/Harvard Cancer Center, Department of Lab Medicine, Children’s Hospital Boston, Karp Family Research Building, Room 10214, Boston, MA 02115, USA

Serhan, C.; Harvard Medical School > Department of Pathology, Dana-Farber/Harvard Cancer Center, Department of Lab Medicine, Children’s Hospital Boston, Karp Family Research Building, Room 10214, Boston, MA 02115, USA

Schurmans, Stéphane ; Université Libre de Bruxelles - ULB > IRIBHM

Luo, H. R.; Harvard Medical School > Dept of Pathology, Dana-Farber/Harvard Cancer Center, Department of Lab Medicine, Children’s Hospital Boston, Karp Family Research Building, Room 10214, Boston, MA 02115, USA

Language :

English

Title :

Ins(1,3,4,5)P4 negatively regulates PtdIns(3,4,5)P3 signaling in neutrophils

Publication date :

2007

Journal title :

Immunity

ISSN :

1074-7613

eISSN :

1097-4180

Publisher :

Cell Press, Cambridge, United States - Massachusetts

Volume :

Pages :

453-467

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 19 November 2009

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