Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article PDF (Full Text) Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by LeBrasseur, N. Search for Related Content PubMed Articles by LeBrasseur, N. Related Collections Related Article Social Bookmarking                      What's this?

PAI-1 (yellow) causes integrins (blue) associated with uPAR (red circles) to be recycled.

PAI-1 is unique among protease inhibitors because it binds to the matrix protein vitronectin (VN). PAI-1 binding blocks VN's binding site for the cell surface receptor uPAR and for integrin family members. Czekay et al. (page 781) now show that PAI-1 is also able to detach cells through a less direct approach.

Unlike the direct competition method, PAI-1 also disrupted integrin-mediated adhesion without ever contacting VN. Instead, PAI-1 bound to another uPAR ligand, the protease uPA. Binding of uPA to uPAR causes integrin recruitment into complexes with uPA and uPAR. PAI-1 disrupted adhesion by inactivating these complexes and triggering their endocytosis. Endocytosis required the low density lipoprotein receptor-related protein, but how PAI-1 triggers integrin inactivation has yet to be determined.

Integrins interact with other matrix molecules in addition to VN. So far, the authors have shown that PAI-1 also detaches cells from fibronectin and collagen, again by promoting integrin endocytosis. In each case, cells expressing high levels of uPAR were more susceptible to PAI-1–induced detachment, because more of their surface integrins were complexed with uPAR. This association could explain why a high level of PAI-1 indicates a poor prognosis for many metastatic cancers—unusual for a protease inhibitor, since proteases normally promote cell invasion.

Nicole LeBrasseur

lebrasn{at}rockefeller.edu

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Related Article

Plasminogen activator inhibitor-1 detaches cells from extracellular matrices by inactivating integrins

Ralf-Peter Czekay, Kathleen Aertgeerts, Scott A. Curriden, and David J. Loskutoff
J. Cell Biol. 2003 160: 781-791. [Abstract] [Full Text] [PDF]

This Article PDF (Full Text) Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by LeBrasseur, N. Search for Related Content PubMed Articles by LeBrasseur, N. Related Collections Related Article Social Bookmarking                      What's this?