If you are experiencing problems downloading PDF or HTML fulltext, our helpdesk recommend clearing your browser cache and trying again. If you need help in clearing your cache, please click here . Still need help? Email help@ingentaconnect.com

Dimerization of endogenous MT1-MMP is a regulatory step in the activation of the 72 kDa gelatinase, MMP-2, on fibroblasts and fibrosarcoma cells

$48.00 plus tax (Refund Policy)

Download / Buy Article:

Abstract:

Matrix metalloproteases (MMPs) are centrally engaged in the processes of extracellular matrix turnover that occur during cancer invasion. An important MMP cascade reaction is initiated by the membrane-anchored matrix metalloprotease, MT1-MMP, which serves to activate the proenzyme form of the secreted gelatinase, matrix metalloprotease-2 (MMP-2). This reaction occurs in an interplay with the matrix metalloprotease inhibitor, TIMP-2, and the proposed mechanism involves two molecules of MT1-MMP in complex with one TIMP-2 molecule. To study this, as well as other roles of MT1-MMP, we have now raised a panel of monoclonal antibodies against the protein. These antibodies have been raised in MT1-MMP knock-out mice and react against conserved epitopes in murine and human MT1-MMP. Using one of these antibodies we provide positive evidence that proMMP-2 activation is governed by dimerization of MT1-MMP on the surface of fibroblasts and fibrosarcoma cells. The antibody in question binds specifically to MT1-MMP on the cell surface, as shown by immunofluorescence experiments. It is directed against the hemopexin domain of MT1-MMP and has no effect on the catalytic activity of the protease domain. The antibody induces dimerization of the endogenous MT1-MMP on the cell surface. Through this reaction, it markedly stimulates the formation of the 62 kDa active MMP-2 and the processing into a 59 kDa product that retains gelatinolytic activity. This effect is indeed a consequence of MT1-MMP dimerization because it requires the divalent monoclonal antibody with no effect being obtained with monovalent Fab fragments. Since only a negligible level of proMMP-2 activation is obtained with MT1-MMP expressing cells in the absence of dimerization, our results identify the dimerization event as a critical level of proteolytic cascade regulation.

Document Type: Abstract

DOI: http://dx.doi.org/10.1111/j.1600-0463.2008.001165_47.x

Affiliations: 1: Finsenlaboratoriet, Rigshospitalet, Ole Maaløes Vej 5, 2200 København N, Danmark 2: Oral & Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA

Publication date: May 1, 2008

Related content

Tools

Favourites

Share Content

Access Key

Free Content
Free content
New Content
New content
Open Access Content
Open access content
Subscribed Content
Subscribed content
Free Trial Content
Free trial content
Cookie Policy
X
Cookie Policy
ingentaconnect website makes use of cookies so as to keep track of data that you have filled in. I am Happy with this Find out more