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J. Biol. Chem., Vol. 279, Issue 42, 44197-44210, October 15, 2004

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The Rac1 C-terminal Polybasic Region Regulates the Nuclear Localization and Protein Degradation of Rac1^*

Cathy Cole Lanning, Janelle L. Daddona, Rebecca Ruiz-Velasco, Shulamith H. Shafer, and Carol L. Williams

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

We observed evolutionary conservation of canonical nuclear localization signal sequences (K(K/R)X(K/R)) in the C-terminal polybasic regions (PBRs) of some Rac and Rho isoforms. Canonical D-box sequences (RXXL), which target proteins for proteasome-mediated degradation, are also evolutionarily conserved near the PBRs of these small GTPases. We show that the Rac1 PBR (PVKKRKRK) promotes Rac1 nuclear accumulation, whereas the RhoA PBR (RRGKKKSG) keeps RhoA in the cytoplasm. A mutant Rac1 protein named Rac1 (pbrRhoA), in which the RhoA PBR replaces the Rac1 PBR, has greater cytoplasmic localization, enhanced resistance to proteasome-mediated degradation, and higher protein levels than Rac1. Mutating the D-box by substituting alanines at amino acids 174 and 177 significantly increases the protein levels of Rac1 but not Rac1(pbrRhoA). These results suggest that Rac1 (pbrRhoA) is more resistant than Rac1 to proteasome-mediated degradative pathways involving the D-box. The cytoplasmic localization of Rac1(pbrRhoA) provides the most obvious reason for its resistance to proteasome-mediated degradation, because we show that Rac1(pbrRhoA) does not greatly differ from Rac1 in its ability to stimulate membrane ruffling or to interact with SmgGDS and IQGAP1-calmodulin complexes. These findings support the model that nuclear localization signal sequences in the PBR direct Rac1 to the nucleus, where Rac1 participates in signaling pathways that ultimately target it for degradation.

Received for publication, May 4, 2004 , and in revised form, July 8, 2004.

^* This work was supported by Grants R01 HL63921 and R01 HL63921-03S1 (Supplement to Promote Reentry into Biomedical and Behavioral Research Careers) from the NHLBI, National Institutes of Health, and Grant-in-aid 0355759U from the Pennsylvania/Delaware Affiliate of the American Heart Association. 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: Molecular Pharmacology Laboratory, One Guthrie Square, Sayre, PA 18840. Tel.: 570-882-4650; Fax: 570-882-4643; E-mail: williams_carol{at}guthrie.org.

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