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First published online June 23, 2005
doi: 10.1242/10.1242/jcs.02432

Journal of Cell Science 118, 2975-2986 (2005)
Published by The Company of Biologists 2005
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Research Article

Phospholipase D2 stimulates integrin-mediated adhesion via phosphatidylinositol 4-phosphate 5-kinase I{gamma}b

Dale J. Powner1,*, Roberta M. Payne1, Trevor R. Pettitt1, M. Luisa Giudici2, Robin F. Irvine2 and Michael J. O. Wakelam1

1 CRUK Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
2 Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD, UK

* Author for correspondence (e-mail: d.j.powner.20{at}bham.ac.uk)

Accepted 4 April 2005

Cellular adhesion can be regulated by, as yet, poorly defined intracellular signalling events. Phospholipase D enzymes generate the messenger lipid phosphatidate and here we demonstrate that suppression of this reaction inhibits cellular adhesion. This effect was reversed by the addition of cell-permeable analogues of either phosphatidate or phosphatidylinositol 4,5-bisphosphate. By contrast, neither diacylglycerol nor lysophosphatidic acid were able to reverse this effect suggesting that phosphatidate itself acts directly on a target protein(s) to regulate adhesion rather than as the result of its conversion to either of these metabolite lipids. Antibodies that block ß1 and ß2 integrin-substrate interactions inhibited adhesion stimulated by both phosphatidate and phosphatidylinositol 4,5-bisphosphate indicating that these lipids regulate ß1 and ß2 integrin-mediated adhesion. In vivo, these lipids can be generated by phospholipase D2 and phosphatidylinositol 4-phosphate 5-kinase I{gamma}b, respectively, and over-expression of catalytically-functional forms of these enzymes dose-dependently stimulated adhesion while siRNA depletion of PLD2 levels inhibited adhesion. Furthermore the ability of over-expressed phospholipase D2 to stimulate adhesion was inhibited by a dominant-negative version of phosphatidylinositol 4-phosphate 5-kinase I{gamma}b. Consistent with this, phosphatidylinositol 4-phosphate 5-kinase I{gamma}b-mediated adhesion was dependent upon phospholipase D2's product, phosphatidate indicating that phosphatidylinositol 4-phosphate 5-kinase I{gamma}b is downstream of, and necessary for, phospholipase D2's regulation of adhesion. It is likely that this phospholipase D2-generated phosphatidate directly stimulates phosphatidylinositol 4-phosphate 5-kinase I{gamma}b to generate phosphatidylinositol 4,5-bisphosphate as this mechanism has previously been demonstrated in vitro. Thus, our data indicates that during the initial stages of adhesion, phospholipase D2-derived phosphatidate stimulates phosphatidylinositol 4-phosphate 5-kinase I{gamma}b to generate phosphatidylinositol 4,5-bisphosphate and that consequently this inositol phospholipid promotes adhesion through its regulation of cell-surface integrins.

Key words: Adhesion, Integrin, Phospholipase D2, Phosphatidylinositol 4-phosphate 5-kinase I{gamma}b, Phosphatidylinositol 4, 5-bisphosphate




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