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J. Biol. Chem. 278 (14): 12495-12506

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

Novel Mechanism of the Co-regulation of Nuclear Transport of SmgGDS and Rac1*

Cathy Cole Lanning, Rebecca Ruiz-Velasco, and Carol L. WilliamsDagger

From the Molecular Pharmacology Laboratory, Guthrie Research Institute, Sayre, Pennsylvania 18840

The armadillo protein SmgGDS promotes guanine nucleotide exchange by small GTPases containing a C-terminal polybasic region (PBR), such as Rac1 and RhoA. Because the PBR resembles a nuclear localization signal (NLS) sequence, we investigated the nuclear transport of SmgGDS with Rac1 or RhoA. We show that the Rac1 PBR has significant NLS activity when it is fused to green fluorescent protein (GFP) or in the context of full-length Rac1. In contrast, the RhoA PBR has very poor NLS activity when it is fused to GFP or in the context of full-length RhoA. The nuclear accumulation of both Rac1 and SmgGDS is enhanced by Rac1 activation and diminished by mutation of the Rac1 PBR. Conversely, SmgGDS nuclear accumulation is diminished by interactions with RhoA. An SmgGDS nuclear export signal sequence that we identified promotes SmgGDS nuclear export. These results suggest that SmgGDS· Rac1 complexes accumulate in the nucleus because the Rac1 PBR has NLS activity and because Rac1 supplies the appropriate GTP-dependent signal. In contrast, SmgGDS·RhoA complexes accumulate in the cytoplasm because the RhoA PBR does not have NLS activity. This model may be applicable to other armadillo proteins in addition to SmgGDS, because we demonstrate that activated Rac1 and RhoA also provide stimulatory and inhibitory signals, respectively, for the nuclear accumulation of p120 catenin. These results indicate that small GTPases with a PBR can regulate the nuclear transport of armadillo proteins.

* This work was supported by grants (to C. L. W.) from the NHLBI/National Institutes of Health (Grant RO1 HL63921) and the Pennsylvania/Delaware Affiliate of the American Heart Association (Grant 9951305U).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Molecular Pharmacology Laboratory, One Guthrie Square, Sayre, PA 18840. Tel.: 570-882-4650; Fax: 570-882-4643; E-mail: williams_carol@guthrie.org.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

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