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Vol. 18, Issue 12, 4772-4779, December 2007

This Article Full Text Full Text (PDF) Supplemental Materials A correction has been published All Versions of this Article: E07-05-0407v1 E07-05-0407v2 18/12/4772    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kortholt, A. Articles by Van Haastert, P. J.M. Search for Related Content PubMed PubMed Citation Articles by Kortholt, A. Articles by Van Haastert, P. J.M.

Phospholipase C Regulation of Phosphatidylinositol 3,4,5-trisphosphate-mediated Chemotaxis

Arjan Kortholt^*,, Jason S. King^,, Ineke Keizer-Gunnink^*, Adrian J. Harwood, and Peter J.M. Van Haastert^*

*Department of Molecular Cell Biology, University of Groningen, 9751 NN Haren, The Netherlands; and School of Biosciences, Cardiff University, Cardiff CF10 3US, United Kingdom

Submitted May 4, 2007; Revised August 6, 2007; Accepted September 17, 2007
Monitoring Editor: John York

Generation of a phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P₃] gradient within the plasma membrane is important for cell polarization and chemotaxis in many eukaryotic cells. The gradient is produced by the combined activity of phosphatidylinositol 3-kinase (PI3K) to increase PI(3,4,5)P₃ on the membrane nearest the polarizing signal and PI(3,4,5)P₃ dephosphorylation by phosphatase and tensin homolog deleted on chromosome ten (PTEN) elsewhere. Common to both of these enzymes is the lipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P₂], which is not only the substrate of PI3K and product of PTEN but also important for membrane binding of PTEN. Consequently, regulation of phospholipase C (PLC) activity, which hydrolyzes PI(4,5)P₂, could have important consequences for PI(3,4,5)P₃ localization. We investigate the role of PLC in PI(3,4,5)P₃-mediated chemotaxis in Dictyostelium. plc-null cells are resistant to the PI3K inhibitor LY294002 and produce little PI(3,4,5)P₃ after cAMP stimulation, as monitored by the PI(3,4,5)P₃-specific pleckstrin homology (PH)-domain of CRAC (PH_CRACGFP). In contrast, PLC overexpression elevates PI(3,4,5)P₃ and impairs chemotaxis in a similar way to loss of pten. PI3K localization at the leading edge of plc-null cells is unaltered, but dissociation of PTEN from the membrane is strongly reduced in both gradient and uniform stimulation with cAMP. These results indicate that local activation of PLC can control PTEN localization and suggest a novel mechanism to regulate the internal PI(3,4,5)P₃ gradient.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E07-05-0407) on September 26, 2007.

These authors contributed equally to this work.

Address correspondence to: Peter J.M. van Haastert (p.j.m.van.haastert{at}rug.nl).

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