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J. Biol. Chem., Vol. 281, Issue 21, 14852-14863, May 26, 2006

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A Region in Urokinase Plasminogen Receptor Domain III Controlling a Functional Association with 51 Integrin and Tumor Growth^*

Pratima Chaurasia, Julio A. Aguirre-Ghiso¹, Olin D. Liang², Henrik Gardsvoll^¶, Michael Ploug^¶, and Liliana Ossowski³

From the Department of Medicine, Division of Hematology/Oncology, Mount Sinai School of Medicine, New York, New York 10029, the Institut fur Biochemie, Fachbereich Humanmedizin, Justus-Liebig-Universitat, Friedrichstrasse 24, D-35392 Giessen, Germany, and the ^¶Finsen Laboratory, Copenhagen University Hospital, Strandboulevarden 49, DK-2100 Copenhagen, Denmark

Highly expressed urokinase plasminogen activator receptor (uPAR) can interact with 51 integrin leading to persistent ERK activation and tumorigenicity. Disrupting this interaction reduces ERK activity, forcing cancer cells into dormancy. We identified a site in uPAR domain III that is indispensable for these effects. A 9-mer peptide derived from a sequence in domain III (residues 240-248) binds purified 51 integrin. Substituting a single amino acid (S245A) in this peptide, or in full-length soluble uPAR, impairs binding of the purified integrin. In the recently solved crystal structure of uPAR the Ser-245 is confined to the large external surface of the receptor, a location that is well separated from the central urokinase plasminogen binding cavity. The impact of this site on 51 integrin-dependent cell functions was examined by comparing cells induced to express uPAR^wt or the uPAR^S245A mutant. Transfecting uPAR^wt into cells with low endogenous levels of uPAR, inactive integrin, low ERK activity, and a dormant phenotype in vivo restores these functions and reinstates growth in vivo. In contrast, transfection of the same cells with uPAR^S245A elicits only very small changes. Incubation of highly malignant cells with the wild-type, but not the S245A mutant peptide, disrupts the uPAR integrin interaction leading to down-regulation of ERK activity. The relevance of this binding site, and of the lateral uPAR-51 integrin interaction, to ERK pathway activation and tumor growth implicates it as a possible specific target for cancer therapy.

Received for publication, November 16, 2005 , and in revised form, March 14, 2006.

^* This work was supported by USPHS Research Grant CA-40578 and the Samuel Waxman Cancer Research Foundation (to L. O.), and by the John and Birthe Meyer Foundation, The Lundbeck Foundation, The Danish Cancer Society, and EU contract LSHC-CT2003-503297 (to M. P.). 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 Current address: Department of Biomedical Sciences, Center for Excellence in Cancer Genomics, State University of New York at Albany, DB Wing, Room DB219, One University Place, Rensselaer, NY 12144-2345.

² Current address: Division of Newborn Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115.

³ To whom correspondence should be addressed: Dept. of Medicine, Div. of Hematology/Oncology, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029. Tel.: 212-241-5899; Fax: 212-996-5787; E-mail: Liliana.Ossowski{at}mssm.edu.

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