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J. Biol. Chem., Vol. 281, Issue 33, 23367-23376, August 18, 2006

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Characterization of the GbpD-activated Rap1 Pathway Regulating Adhesion and Cell Polarity in Dictyostelium discoideum^*

Arjan Kortholt, Holger Rehmann, Helmut Kae^¶, Leonard Bosgraaf, Ineke Keizer-Gunnink, Gerald Weeks^¶1, Alfred Wittinghofer^||, and Peter J. M. Van Haastert²

From the Department of Molecular Cell Biology, University of Groningen, Kerklaan 30, 9751 NN Haren, the Netherlands, Department of Physiological Chemistry and Centre of Biomedical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands, ^¶Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada, and ^||Max-Planck-Institut für Molekulare Physiologie, Otto-Hahn-Strasse 11, D-44227 Dortmund, Germany

The regulation of cell polarity plays an important role in chemotaxis. GbpD, a putative nucleotide exchange factor for small G-proteins of the Ras family, has been implicated in adhesion, cell polarity, and chemotaxis in Dictyostelium. Cells overexpressing GbpD are flat, exhibit strongly increased cell-substrate attachment, and extend many bifurcated and lateral pseudopodia. These cells overexpressing GbpD are severely impaired in chemotaxis, most likely due to the induction of many protrusions rather than an enhanced adhesion. The GbpD-overexpression phenotype is similar to that of cells overexpressing Rap1. Here we demonstrate that GbpD activates Rap1 both in vivo and in vitro but not any of the five other characterized Ras proteins. In a screen for Rap1 effectors, we overexpressed GbpD in several mutants defective in adhesion or cell polarity and identified Phg2 as Rap1 effector necessary for adhesion, but not cell polarity. Phg2, a serine/threonine-specific kinase, directly interacts with Rap1 via its Ras association domain.

Received for publication, January 26, 2006 , and in revised form, May 24, 2006.

^* The studies were supported in part by a grant from Canadian Institutes of Health Research (to G. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains one supplemental figure.

¹ Supported by the Chemical Sciences of the Netherlands Organization for Scientific Research (NWO-CW) recipient of the Otto-Hahn-Medaille of the Max-Planck-Gesellschaft.

² To whom correspondence should be addressed. Tel.: 31-50-3634172; Fax: 31-50-3634165; E-mail: P.J.M.van.Haastert{at}rug.nl.

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