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J. Biol. Chem., Vol. 281, Issue 19, 13021-13029, May 12, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/19/13021    most recent M508526200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ghosh, S. Articles by Stack, M. S. Search for Related Content PubMed PubMed Citation Articles by Ghosh, S. Articles by Stack, M. S. Social Bookmarking                      What's this?

Functional Relevance of Urinary-type Plasminogen Activator Receptor-31 Integrin Association in Proteinase Regulatory Pathways^*

Supurna Ghosh, Jeff J. Johnson, Ratna Sen, Subhendu Mukhopadhyay, Yueying Liu, Feng Zhang, Ying Wei, Harold A. Chapman, and M. Sharon Stack^¶1

From the Department of Cell and Molecular Biology and the ^¶Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611 and the Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, California 94143

Squamous cell carcinoma of the oral cavity is characterized by persistent, disorganized expression of integrin 31 and enhanced production of urinary-type plasminogen activator (uPA) and its receptor (uPAR) relative to normal oral mucosa. Because multivalent aggregation of 31 integrin up-regulates uPA and induces a dramatic co-clustering of uPAR, we explored the hypothesis that lateral ligation of 31 integrin by uPAR contributes to uPA regulation in oral mucosal cells. To investigate mechanisms by which uPAR/31 binding enhances uPA expression, integrin-dependent signal activation was assessed. Both Src and ERK1/2 were phosphorylated in response to integrin aggregation, and blocking Src kinase activity completely abrogated ERK1/2 activation and uPA induction, whereas inhibition of epidermal growth factor receptor tyrosine kinase activity did not alter uPA expression. Proteinase up-regulation occurred at the transcriptional level and mutation of the AP1 (–1967) site in the uPA promoter blocked the uPAR/integrin-mediated transcriptional activation. Because uPAR is redistributed to clustered 31 integrins, the requirement for uPAR/31 interaction in uPA regulation was assessed. Clustering of 31 in the presence of a peptide (325) that disrupts uPAR/31 integrin binding prevented uPA induction. Depletion of cell surface uPAR using small interfering RNA also blocked uPA induction following integrin 31 clustering. These results were confirmed using a genetic strategy in which 3 null epithelial cells reconstituted with wild type 3 integrin, but not a mutant 3 unable to bind uPAR, induced uPA expression upon integrin clustering, confirming the critical role of uPAR in integrin-regulated proteinase expression. Disruption of uPAR/31 binding using peptide 325 or small interfering RNA blocked filopodia formation and matrix invasion, indicating that this interaction stimulates invasive behavior. Together these data support a model wherein matrix-induced clustering of31 integrin promotes uPAR/31 interaction, thereby potentiating cellular signal transduction pathways culminating in activation of uPA expression and enhanced uPA-dependent invasive behavior.

Received for publication, August 3, 2005 , and in revised form, February 28, 2006.

^* This work was supported by Grants RO1CA85870 (to M. S. S.), PO1DE12328 (to M. S. S.), and RO1HL44712 (to H. A. C.) from the National Institutes of Health and by funds from the H Foundation for Basic Science Research (to M. S. S.). 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 Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, 303 E. Superior St., Lurie Bldg. 3-111, Chicago, IL 60611. Tel.: 312-908-8216; Fax: 312-503-0386; E-mail: mss130{at}northwestern.edu.

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