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Molecular and Cellular Biology, August 2003, p. 5331-5345, Vol. 23, No. 15
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.15.5331-5345.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

RNF5, a RING Finger Protein That Regulates Cell Motility by Targeting Paxillin Ubiquitination and Altered Localization

Christine Didier,1 Limor Broday,1 Anindita Bhoumik,1 Sharon Israeli,1 Shoichi Takahashi,1 Koh Nakayama,1 Sheila M. Thomas,2 Christopher E. Turner,3 Scott Henderson,4 Hisataka Sabe,5 and Ze'ev Ronai1*

Ruttenberg Cancer Center,1 Brookdale Center for Molecular Cellular and Developmental Biology, Mount Sinai School of Medicine, New York, New York,4 Cancer Biology Program, Beth Israel Deaconess Medical Center/Harvard Medical School, Cambridge, Massachusetts,2 Department of Anatomy and Cell Biology, State University of New York Syracuse, Syracuse, New York,3 Department of Molecular Biology, Osaka Bioscience Institute, Osaka, Japan5

Received 26 November 2002/ Returned for modification 13 January 2003/ Accepted 6 May 2003

RNF5 is a RING finger protein found to be important in the growth and development of Caenorhabditis elegans. The search for RNF5-associated proteins via a yeast two-hybrid screen identified a LIM-containing protein in C. elegans which shows homology with human paxillin. Here we demonstrate that the human homologue of RNF5 associates with the amino-terminal domain of paxillin, resulting in its ubiquitination. RNF5 requires intact RING and C-terminal domains to mediate paxillin ubiquitination. Whereas RNF5 mediates efficient ubiquitination of paxillin in vivo, protein extracts were required for in vitro ubiquitination, suggesting that additional modifications and/or an associated E3 ligase assist RNF5 targeting of paxillin ubiquitination. Mutant Ubc13 efficiently inhibits RNF5 ubiquitination, suggesting that RNF5 generates polychain ubiquitin of the K63 topology. Expression of RNF5 increases the cytoplasmic distribution of paxillin while decreasing its localization within focal adhesions, where it is primarily seen under normal growth. Concomitantly, RNF5 expression results in inhibition of cell motility. Via targeting of paxillin ubiquitination, which alters its localization, RNF5 emerges as a novel regulator of cell motility.

* Corresponding author. Mailing address: Ruttenberg Cancer Center and Brookdale Center for Molecular, Cellular and Developmental Biology, Mount Sinai School of Medicine, New York, NY 10029. Phone: (212) 849-2425. Fax: (212) 849-2425. E-mail: zeev.ronai{at}mssm.edu.

Molecular and Cellular Biology, August 2003, p. 5331-5345, Vol. 23, No. 15
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.15.5331-5345.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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