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J. Biol. Chem., Vol. 282, Issue 16, 11874-11884, April 20, 2007

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Role of Phosphatidylinositol 3-Kinases in Chemotaxis in Dictyostelium^*

Kosuke Takeda, Atsuo T. Sasaki¹, Hyunjung Ha², Hyun-A Seung², and Richard A. Firtel³

From the Section of Cell and Developmental Biology, Division of Biological Sciences and Center for Molecular Genetics, University of California, San Diego, La Jolla, California 92093-0380

Experiments in several cell types revealed that local accumulation of phosphatidylinositol 3,4,5-triphosphate mediates the ability of cells to migrate during gradient sensing. We took a systematic approach to characterize the functions of the six putative Class I phosphatidylinositol 3-kinases (PI3K1–6) in Dictyostelium by creating a series of gene knockouts. These studies revealed that PI3K1–PI3K3 are the major PI3Ks for chemoattractant-mediated phosphatidylinositol 3,4,5-triphosphate production. We studied chemotaxis of the pi3k1/2/3 triple knock-out strain (pi3k1/2/3 null cells) to cAMP under two distinct experimental conditions, an exponential gradient emitted from a micropipette and a shallow, linear gradient in a Dunn chamber, using four cAMP concentrations ranging over a factor of 10,000. Under all conditions tested pi3k1/2/3 null cells moved slower and had less polarity than wild-type cells. pi3k1/2/3 null cells moved toward a chemoattractant emitted by a micropipette, although persistence was lower than that of wild-type or pi3k1/2 null cells. In shallow linear gradients, pi3k1/2 null cells had greater directionality defects, especially at lower chemoattractant concentrations. Our studies suggest that although PI3K is not essential for directional movement under some chemoattractant conditions, it is a key component of the directional sensing pathway and plays a critical role in linear chemoattractant gradients, especially at low chemoattractant concentrations. The relative importance of PI3K in chemotaxis is also dependent on the developmental stage of the cells. Our data suggest that the output of other signaling pathways suffices to mediate directional sensing when cells perceive a strong signal, but PI3K signaling is crucial for detecting weaker signals.

Received for publication, November 29, 2006 , and in revised form, February 5, 2007.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) XM_642316 [GenBank] , XM_635069 [GenBank] , and XM_630307 [GenBank] .

^* This work was supported by United States Public Health Service grants (to R. A. F.). 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.

¹ Present address: Lewis Cantley Laboratory, Harvard Medical School, New Research Building Room 152, 77 Ave. Louis Pasteur, Boston, MA 02115.

² Present address: Dept. of Biochemistry, School of Life Sciences, Chungbuk National University, Cheongju 361-762, Korea.

³ To whom correspondence should be addressed: Natural Sciences Bldg. Rm. 6316, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0380. Tel.: 858-534-2788; Fax: 858-822-5900; E-mail: rafirtel{at}ucsd.edu.

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