A region in urokinase plasminogen receptor domain III controlling a functional association with α5β1 integrin and tumor growth

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

Research output: Contribution to journalArticlepeer-review

110 Scopus citations

Abstract

Highly expressed urokinase plasminogen activator receptor (uPAR) can interact with α5β1 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 α5β1 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 α5β1 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 theuPARintegrin interaction leading to down-regulation of ERK activity. The relevance of this binding site, and of the lateral uPAR-α5β1 integrin interaction, to ERK pathway activation and tumor growth implicates it as a possible specific target for cancer therapy.

Original languageEnglish (US)
Pages (from-to)14852-14863
Number of pages12
JournalJournal of Biological Chemistry
Volume281
Issue number21
DOIs
StatePublished - May 26 2006
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'A region in urokinase plasminogen receptor domain III controlling a functional association with α5β1 integrin and tumor growth'. Together they form a unique fingerprint.

Cite this