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Vol. 20, Issue 2, 699-707, January 15, 2009

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Dictyostelium Dock180-related RacGEFs Regulate the Actin Cytoskeleton during Cell Motility

Alessia Para^*, Miriam Krischke^*,, Sylvain Merlot, Zhouxin Shen, Michael Oberholzer, Susan Lee, Steven Briggs, and Richard A. Firtel

Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0380

Submitted September 2, 2008; Revised November 10, 2008; Accepted November 13, 2008
Monitoring Editor: Carole Parent

Cell motility of amoeboid cells is mediated by localized F-actin polymerization that drives the extension of membrane protrusions to promote forward movements. We show that deletion of either of two members of the Dictyostelium Dock180 family of RacGEFs, DockA and DockD, causes decreased speed of chemotaxing cells. The phenotype is enhanced in the double mutant and expression of DockA or DockD complements the reduced speed of randomly moving DockD null cells' phenotype, suggesting that DockA and DockD are likely to act redundantly and to have similar functions in regulating cell movement. In this regard, we find that overexpressing DockD causes increased cell speed by enhancing F-actin polymerization at the sites of pseudopod extension. DockD localizes to the cell cortex upon chemoattractant stimulation and at the leading edge of migrating cells and this localization is dependent on PI3K activity, suggesting that DockD might be part of the pathway that links PtdIns(3,4,5)P₃ production to F-actin polymerization. Using a proteomic approach, we found that DdELMO1 is associated with DockD and that Rac1A and RacC are possible in vivo DockD substrates. In conclusion, our work provides a further understanding of how cell motility is controlled and provides evidence that the molecular mechanism underlying Dock180-related protein function is evolutionarily conserved.

* These authors contributed equally to this work.

Present addresses: Department of Paediatric Haematology and Oncology, University Hospital Münster, Domagkstrasse 24, 48149 Münster, Germany;

Institut des Sciences du Végétal, CNRS, 1, Avenue de la Terrasse, 91190 Gif-sur-Yvette, France;

Department of Molecular and Cell Biology, Salk Institute for Biological Studies, P.O. Box 85800, San Diego, CA 92185.

Address correspondence to: Richard A. Firtel (rafirtel{at}ucsd.edu).

Abbreviations used: GEF, guanine nucleotide exchange factor; DHR, Dock-homology region; CZH, CDM(Ced-5 Dock180 Myoblast city)-zizimin homology; LatB, latrunculin B.

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