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Molecular and Cellular Biology, May 2009, p. 2816-2827, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.01713-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Dual Role of Cdc42 in Spindle Orientation Control of Adherent Cells{triangledown} ,§

Masaru Mitsushima,1 Fumiko Toyoshima,1,2,3* and Eisuke Nishida1

Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan,1 PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, Saitama, Japan,2 Laboratory of Subcellular Biogenesis, Institute for Virus Research, Kyoto University, Shogoin-Kawahara cho, Sakyo-ku, Kyoto 606-8507, Japan3

Received 7 November 2008/ Returned for modification 11 December 2008/ Accepted 25 February 2009

The spindle orientation is regulated by the interaction of astral microtubules with the cell cortex. We have previously shown that spindles in nonpolarized adherent cells are oriented parallel to the substratum by an actin cytoskeleton- and phosphatidylinositol 3,4,5-triphosphate [PtdIns(3,4,5)P3]-dependent mechanism. Here, we show that Cdc42, a Rho family of small GTPases, has an essential role in this mechanism of spindle orientation by regulating both the actin cytoskeleton and PtdIns(3,4,5)P3. Knockdown of Cdc42 suppresses PI(3)K activity in M phase and induces spindle misorientation. Moreover, knockdown of Cdc42 disrupts the cortical actin structures in metaphase cells. Our results show that p21-activated kinase 2 (PAK2), a target of Cdc42 and/or Rac1, plays a key role in regulating actin reorganization and spindle orientation downstream from Cdc42. Surprisingly, PAK2 regulates spindle orientation in a kinase activity-independent manner. βPix, a guanine nucleotide exchange factor for Rac1 and Cdc42, is shown to mediate this kinase-independent function of PAK2. This study thus demonstrates that spindle orientation in adherent cells is regulated by two distinct pathways downstream from Cdc42 and uncovers a novel role of the Cdc42-PAK2-βPix-actin pathway for this mechanism.

* Corresponding author. Mailing address: Laboratory of Subcellular Biogenesis, Institute for Virus Research, Kyoto University, Shogoin-Kawahara cho, Sakyo-ku, Kyoto 606-8507, Japan. Phone: 81-75-751-4015. Fax: 81-75-751-4016. E-mail: ftoyoshi{at}virus.kyoto-u.ac.jp

{triangledown} Published ahead of print on 9 March 2009.

§ Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, May 2009, p. 2816-2827, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.01713-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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