Modulation of Breast Cancer Cell Functions by Intracellular Signaling Through the Membrane Type-1 Matrix Metalloproteinase
Abstract
Membrane-type 1 matrix metalloproteinase (MT-MMPs), a member of the MMP family of proteinases, has been implicated in the invasive and metastatic potential of a variety of human malignancies, including mammary carcinoma Unlike the other members of the matrix metalloproteinase (MMP) family, which are secretory proteins, MT1-MMP is a transmembrane proteinase with the catalytic domain exposed on the cell surface and a short, 20 amino acid cytoplasmic domain. On the membrane of a variety of cell types including tumor cells MTl-MMP forms a tri-molecular complex with MMP-2 and its physiological inhibitor, the tissue inhibitor of metalloproteinases-2 (TIMP-2). in this complex the N- terminal, inhibitory domain of TlMP-2 directly interacts with the catalytic site of MTl-MMP. The C-terminal domain of TIMP-2 binds the C-terminal, hemopexin-like domain of MMP- 2. Thus, MTl-MMP acts as a membrane binding site for MMP-2-TIMP-2 complex. Binding of the enzyme-inhibitor complex to MTl-MMP is required for MMP-2 activation. MMP-2 interaction with MTl-MMP has analogy to the high-affinity binding of urokinase plasminogen activator (uPA) to its cell membrane receptor (uPAR). uPA and uPAR have also been implicated in the invasion and metastasis of a variety of tumors including breast carcinoma. Although uPAR is not a transmembrane protein , binding of uPA generates intracellular signals that control cell functions including migration and proliferation through mechanisms independent of the proteolytic activity of uPA. Other transmembrane proteins with short cytoplasmic domains similar to MT1-MMP the integrins also generate intracellular signals following interaction with their extracellular ligands . Based on these analogies, we hypothesized that MT1-MMP binding of TIMP-2 generates intracellular signaling through interaction of the cytoplasmic domain of MT1-MMP with signaling proteins, and thus regulates cell functions involved in breast cancers progression.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2002
- Accession Number
- ADA411529
Entities
People
- Paolo Mignatti
Organizations
- New York University