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J. Biol. Chem., Vol. 280, Issue 35, 30994-31002, September 2, 2005

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Regulation of p21-activated Kinase-independent Rac1 Signal Transduction by Nischarin^*

Peter J. Reddig, Dong Xu, and Rudy L. Juliano

From the Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NorthCarolina 27599

Nischarin regulates Rac1-dependent cell motility by interaction with and inhibition of the p21-activated kinase (PAK1). In addition to regulating the activation of PAK1, Rac1 controls multiple downstream pathways to regulate cell growth and differentiation, as well as cell motility. Signaling by a constitutively activated Rac1 mutant deficient in PAK binding (Rac1Q61L-40C) was examined to determine whether Nischarin impinges on these other Rac1 effector pathways. Nischarin formed immunoprecipitatable complexes with Rac1Q61L and Rac1Q61L-40C when the proteins were co-expressed. In NIH3T3 cells, Rac1Q61L and Rac1Q61L-40C stimulation of a minimal NF-B response element or the cyclin D1 promoter, a downstream target of NF-B, was inhibited by co-expression of Nischarin. Additionally, suppression of endogenous Nischarin protein with small interfering RNA in PC12 cells enhanced Rac1Q61L and Rac1Q61L-40C activation of NF-B. In further support of Nischarin suppressing PAK independent Rac signaling, foci formation in monolayers of NIH3T3 cells by Rac1Q61L-40C in cooperation with c-Raf/CAAX was inhibited by the presence of Nischarin. Nischarin alters the cellular localization of Rac1Q61L and Rac1Q61L-40C to vesicles and this positively correlates with the repression of the Rac1 signal. Thus, Nischarin, in addition to regulating the PAK strand of Rac1 signaling, can also regulate other links in the web of Rac1 signaling pathways.

Received for publication, March 8, 2005 , and in revised form, June 29, 2005.

^* This work was supported by National Institutes of Health Grants GM26165 and PO1-HL4500 (to R. L. J.) and American Cancer Society Fellowship PF-01-061-01-CSM (to P. J. R.). 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.

To whom correspondence should be addressed: Dept. of Pharmacology, School of Medicine, 1017 Mary Ellen Jones Bldg., CB 7365, University of North Carolina, Chapel Hill, NC 27599. Tel.: 919-966-4383; Fax: 919-966-5640; E-mail: arjay{at}med.unc.edu.

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