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Molecular and Cellular Biology, March 2001, p. 2118-2132, Vol. 21, No. 6
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.6.2118-2132.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

beta 3A-Integrin Downregulates the Urokinase-Type Plasminogen Activator Receptor (u-PAR) through a PEA3/ets Transcriptional Silencing Element in the u-PAR Promoter

Sandra Hapke,1 Meinrad Gawaz,2 Kerstin Dehne,1 Jenny Köhler,1 John F. Marshall,3 Henner Graeff,1 Manfred Schmitt,1 Ute Reuning,1 and Ernst Lengyel1,*

Department of Obstetrics and Gynecology1 and Department of Internal Medicine I, Deutsches Herzzentrum,2 Technische Universität München, Klinikum rechts der Isar, D-81675 Munich, Germany, and Richard Dimbleby Department of Cancer Research, ICRF Laboratory, St. Thomas's Hospital, London SE1 7EH, United Kingdom3

Received 15 February 2000/Returned for modification 18 April 2000/Accepted 8 December 2000

Migration of cells requires interactions with the extracellular matrix mediated, in part, by integrins, proteases, and their receptors. Previous studies have shown that beta 3-integrin interacts with the urokinase-type plasminogen activator receptor (u-PAR) at the cell surface. Since integrins mediate signaling into the cell, the current study was undertaken to determine if in addition beta 3-integrin regulates u-PAR expression. Overexpression of beta 3-integrin in CHO cells, which are avid expressers of the receptor, downregulated u-PAR protein and mRNA expression. The u-PAR promoter (-1,469 bp) that is normally constitutively active in CHO cells was downregulated by induced beta 3-integrin expression. A region between -398 and -197 bp of the u-PAR promoter was critical for beta 3-integrin-induced downregulation of u-PAR promoter activity. Deletion of the PEA3/ets motif at -248 bp substantially impaired the ability of beta 3-integrin to downregulate the u-PAR promoter, suggesting that the PEA3/ets site acts as a silencing element. An expression vector encoding the transcription factor PEA3 caused inhibition of the wild-type but not the PEA3/ets-deleted u-PAR promoter. The PEA3/ets site bound nuclear factors from CHO cells specifically, but binding was enhanced when beta 3-integrin was overexpressed. A PEA3 antibody inhibited DNA-protein complex formation, indicating the presence of PEA3. Downregulation of the u-PAR promoter was achieved by the beta 3A-integrin isoform but not by other beta 3-integrin isoforms and required the cytoplasmic membrane NITY759 motif. Moreover, overexpression of the short but not the long isoform of the beta 3-integrin adapter protein beta 3-endonexin blocked u-PAR promoter activity through the PEA3/ets binding site. Thus, besides the physical interaction of beta 3-integrin and u-PAR at the cell surface, beta 3 signaling is implicated in the regulation of u-PAR gene transcription, suggesting a mutual regulation of adhesion and proteolysis receptors.

* Corresponding author. Present address: University of California, San Francisco, UCSF Comprehensive Cancer Center and Cancer Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, 2340 Sutter St., San Francisco, CA 94143-0875. Phone: (415) 514-0231. Fax: (415) 514-0878. E-mail: elengyel{at}cc.ucsf.edu.

Molecular and Cellular Biology, March 2001, p. 2118-2132, Vol. 21, No. 6
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.6.2118-2132.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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