Inositol Pyrophosphates Mediate Chemotaxis in Dictyostelium via Pleckstrin Homology Domain-PtdIns(3,4,5)P3 Interactions

Inositol phosphates are well-known signaling molecules, whereas the inositol pyrophosphates, such as diphosphoinositol pentakisphosphate (InsP7/IP7) and bis-diphosphoinositol tetrakisphosphate (InsP8/IP8), are less well characterized. We demonstrate physiologic regulation of Dictyostelium chemotaxis...

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Bibliographic Details
Published in:	Cell Vol. 114; no. 5; pp. 559 - 572
Main Authors:	Luo, Hongbo R, Huang, Yi Elaine, Chen, Jianmeng C, Saiardi, Adolfo, Iijima, Miho, Ye, Keqiang, Huang, Yunfei, Nagata, Eiichiro, Devreotes, Peter, Snyder, Solomon H
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 05-09-2003
Subjects:	Amino Acid Sequence Animals Blotting, Northern Blotting, Southern Blotting, Western Cell Membrane - metabolism Chemotaxis Chromatography, High Pressure Liquid Cloning, Molecular Cyclic AMP - metabolism Dictyostelium Dictyostelium - physiology DNA - metabolism Dose-Response Relationship, Drug Gene Deletion Green Fluorescent Proteins Guanosine 5'-O-(3-Thiotriphosphate) - metabolism Inositol Phosphates - metabolism Inositol Phosphates - physiology Luminescent Proteins - metabolism Models, Genetic Molecular Sequence Data Mutation Phosphatidylinositol Phosphates - metabolism Protein Binding Protein Structure, Tertiary Protein Transport Sequence Homology, Amino Acid Signal Transduction Time Factors
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Summary:	Inositol phosphates are well-known signaling molecules, whereas the inositol pyrophosphates, such as diphosphoinositol pentakisphosphate (InsP7/IP7) and bis-diphosphoinositol tetrakisphosphate (InsP8/IP8), are less well characterized. We demonstrate physiologic regulation of Dictyostelium chemotaxis by InsP7 mediated by its competition with PtdIns(3,4,5)P3 for binding pleckstrin homology (PH) domain-containing proteins. Chemoattractant stimulation triggers rapid and sustained elevations in InsP7/InsP8 levels. Depletion of InsP7 and InsP8 by deleting the gene for InsP6 kinase (InsP6K/IP6K), which converts inositol hexakisphosphate (InsP6/IP6) to InsP7, causes rapid aggregation of mutant cells and increased sensitivity to cAMP. Chemotaxis is mediated by membrane translocation of certain PH domain-containing proteins via specific binding to PtdIns(3,4,5)P3. InsP7 competes for PH domain binding with PtdIns(3,4,5)P3 both in vitro and in vivo. InsP7 depletion enhances PH domain membrane translocation and augments downstream chemotactic signaling activity.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0092-8674 1097-4172
DOI:	10.1016/S0092-8674(03)00640-8