Modulation of Breast Cancer Cell Function by Intracellular Signaling Through the Membrane-Type I Matrix Metalloproteinase

摘要

Membrane-type 1 matrix metalloproteinase (MT1 -MMP), a transmembrane proteinase with the catalytic domain exposed on the cell surface and a short cytoplasmic domain, has been implicated in the aggressiveness of a variety of human malignancies including mammary carcinoma. MT1-MMP forms a tri-molecular complex with matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinases-2 (TIMP-2), an interaction required for MMP-2 activation. Whereas the extracellular proteolytic activity of MT1 -MMP represents a proteolytic mechanism of tumor progression, its non- catalytic, cytoplasmic domain may serve as a transducer of intracellular signaling through a proteolysis-independent mechanism(s). This project aims to test the hypothesis that MT1-MMP binding of MMP-2 and/or TIMP-2 generates intracellular signaling through the cytoplasmic domain of MT1-MMP and thus regulates cell functions involved in breast carcinoma progression.