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M512311200v1
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Papers In Press, published online ahead of print March 17, 2006
J. Biol. Chem, 10.1074/jbc.M512311200
Submitted on November 16, 2005
Accepted on March 17, 2006

A region in uPAR domain III controlling a functional association with alpha 5beta 1-integrin and tumor growth

Pratima Chaurasia, Julio A. Aguirre-Ghiso, Olin D. Liang, Henrik Gardsvoll, Michael Ploug, and Liliana Ossowski

Medicine, Mount Sinai School of Medicine, New York, NY 10029

Corresponding Author: Liliana.Ossowski{at}mssm.edu

Highly expressed urokinase receptor (uPAR) can interact with a5b1-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 a5b1-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 S245 is confined to the large external surface of the receptor, a location that is well separated from the central uPA-binding cavity. The impact of this site on a5b1-integrin dependent cell functions was examined by comparing cells induced to express uPARwt or the uPARS245A mutant. Transfecting uPARwt 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 uPARS245A 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/a5b1-integrin interaction, to ERK pathway activation and tumor growth implicates it as possible specific target for cancer therapy.


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