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J. Biol. Chem., Vol. 281, Issue 32, 23060-23065, August 11, 2006

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Constitutive and UV-induced Fibronectin Degradation Is a Ubiquitination-dependent Process Controlled by -TrCP^*

Dipankar Ray¹, Evan C. Osmundson, and Hiroaki Kiyokawa^¶

From the Department of Molecular Pharmacology and Biological Chemistry, ^¶Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611 and Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60607

Loss of fibronectin (FN) assembly in the extracellular matrix has long been recognized as a feature of cellular transformation. However, such assembly is regulated not only by FN synthesis but also by its post-translational modifications. The mechanism controlling FN protein stability has remained unclear so far. Recently it was demonstrated that FN matrix turnover occurs intracellularly at the lysosome following caveolin-1-dependent endocytosis. Although FN was reported to undergo ubiquitindependent degradation, the ubiquitin ligase responsible for FN ubiquitination is unknown. In this study, we have identified -TrCP as the ubiquitin ligase for lysosomal degradation of FN. We found two conserved -TrCP recognition motif (DSGVVYS and DSGSIVVS) in the primary amino acid sequence of human, mouse, and rat FN. Down-regulation of either -TrCP1 or -TrCP2 by small interference (siRNA) caused significant accumulation of FN. Immunolocalization studies showed intracellular accumulation of FN in -TrCP siRNA-treated cells without showing much alteration in its matrix association. We also observed that exposure of cells to UV irradiation effectively down-regulated FN following increased ubiquitination, which was significantly inhibited either by lysosomal inhibitor or by siRNA-mediated down-regulation of -TrCP. Taken together, constitutive FN degradation, as well as UV-induced degradation, is ubiquitination dependent and controlled by -TrCP.

Received for publication, May 5, 2006 , and in revised form, June 6, 2006.

^* This work was supported by National Institutes of Health Grants RO1 CA100204, CA112282, and HD38085 (to H. K.). 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 To whom correspondence should be addressed: Dept. of Molecular Pharmacology and Biological Chemistry, 303 E. Superior, Rm. 3-220, Northwestern University, Chicago, IL 60611. Tel.: 312-503-0704; Fax: 312-503-0700; E-mail: dipankar-ray{at}northwestern.edu.

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