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J. Biol. Chem., Vol. 281, Issue 47, 35954-35964, November 24, 2006

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Pak-interacting Exchange Factor-mediated Rac1 Activation Requires smgGDS Guanine Nucleotide Exchange Factor in Basic Fibroblast Growth Factor-induced Neurite Outgrowth^*

Eun-Young Shin¹, Chan-Soo Lee¹, Tae Goo Cho, Young Gyu Kim, Sukgil Song^¶, Yong-Sung Juhnn^||, Sang Chul Park^||, Ed Manser^**2, and Eung-Gook Kim³

From the Departments of Biochemistry and Neurosurgery, College of Medicine, Chungbuk National University, Cheongju 361-763, Korea, ^¶College of Pharmacy, Chungbuk National University, Cheongju 361-763, Korea, the ^||Department of Biochemistry, Seoul National University College of Medicine, Seoul 110-799, Korea, and ^**GlaxoSmithKline-Institute of Molecular and Cell Biology Group, Institute of Molecular and Cell Biology, Proteos Building, 61 Biopolis Drive, Singapore 138673, Singapore

Neuritogenesis requires active actin cytoskeleton rearrangement in which Rho GTPases play a pivotal role. In a previous study (Shin, E. Y., Woo, K. N., Lee, C. S., Koo, S. H., Kim, Y. G., Kim, W. J., Bae, C. D., Chang, S. I., and Kim, E. G. (2004) J. Biol. Chem. 279, 1994-2004), we demonstrated that Pak-interacting exchange factor (PIX) guanine nucleotide exchange factor (GEF) mediates basic fibroblast growth factor (bFGF)-stimulated Rac1 activation through phosphorylation of Ser-525 and Thr-526 at the GIT-binding domain (GBD). However, the mechanism by which this phosphorylation event regulates the Rac1-GEF activity remained elusive. We show here that PIX binds to Rac1 via the GBD and also activates the GTPase via an associated GEF, smgGDS, in a phosphorylation-dependent manner. Notably, the Rac1-GEF activity of PIX persisted for an extended period of time following bFGF stimulation, unlike other Rho GEFs containing the Dbl homology domain. We demonstrate that C-PIX, containing proline-rich, GBD, and leucine zipper domains can interact with Rac1 via the GBD in vitro and in vivo and also mediated bFGF-stimulated Rac1 activation, as determined by a modified GEF assay and fluorescence resonance energy transfer analysis. However, nonphosphorylatable C-PIX (S525A/T526A) failed to generate Rac1-GTP. Finally, PIX is shown to form a trimeric complex with smgGDS and Rac1; down-regulation of smgGDS expression by short interfering RNA causing significant inhibition of PIX-mediated Rac1 activation and neurite outgrowth. These results provide evidence for a new and unexpected mechanism whereby PIX can regulate Rac1 activity.

Received for publication, March 14, 2006 , and in revised form, August 18, 2006.

^* This work was supported in part by the Regional Research Centers Program of the Ministry of Education and Human Resources Development in Korea, Grant R01-2006-000-10386-0 from the Basic Research Program of the Korea Science and Engineering Foundation, Grant RTI04-03-06 from the Regional Technology Innovation Program of the Ministry of Commerce, Industry, and Energy, and Grant KRF-2002-002-E00018 from the Korean Research Foundation. 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 Both authors contributed equally to this paper.

² Supported by the GlaxoSmithKline-Singapore Research fund.

³ To whom correspondence should be addressed. Tel.: 82-43-261-2848; Fax: 82-43-274-9710; E-mail: egkim{at}chungbuk.ac.kr.

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