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MBC in Press, published online ahead of print October 3, 2007
Mol. Biol. Cell 10.1091/mbc.E07-05-0407

A more recent version of this article appeared on December 1, 2007 Originally published as MBC in Press, 10.1091/mbc.E07-05-0407 on September 26, 2007
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Submitted on May 4, 2007
Revised on August 6, 2007
Accepted on September 17, 2007

PLC Regulation of PI(3,4,5)P3-mediated Chemotaxis

Arjan Kortholt,*{dagger} Jason King,{dagger}{ddagger} Ineke Keizer-Gunnink,* Adrian Harwood,{ddagger} and Peter J.M. Van Haastert*

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

Monitoring Editor: John York

Generation of a 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 PI3K to increase PI(3,4,5)P3 on the membrane nearest the polarizing signal and PI(3,4,5)P3 dephosphorylation by PTEN elsewhere. Common to both of these enzymes is the lipid PI(4,5)P2, which is not only the substrate of PI3K and product of PTEN, but is also important for membrane binding of PTEN. Consequently, regulation of 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 PH-domain of CRAC (PHCRACGFP). 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.

{dagger}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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