Extracellular regulation of metalloproteinases

Matrix metalloproteinases (MMPs) and adamalysin-like metalloproteinase with thrombospondin motifs (ADAMTSs) belong to the metzincin superfamily of metalloproteinases and they play key roles in extracellular matrix catabolism, activation and inactivation of cytokines, chemokines, growth factors, and other proteinases at the cell surface and within the extracellular matrix. Their activities are tightly regulated in a number of ways, such as transcriptional regulation, proteolytic activation and interaction with tissue inhibitors of metalloproteinases (TIMPs). Here, we highlight recent studies that have illustrated novel mechanisms regulating the extracellular activity of these enzymes. These include allosteric activation of metalloproteinases by molecules that bind outside the active site, modulation of location and activity by interaction with cell surface and extracellular matrix molecules, and endocytic clearance from the extracellular milieu by low-density lipoprotein receptor-related protein 1 (LRP1). •Novel extracellular mechanisms regulating metalloproteinase activity are reviewed.•ProMMPs can be activated by molecules that bind to non-catalytic allosteric sites.•Binding to transmembrane molecules can localise activity to the cell surface.•Binding to glycosaminoglycans can localise activity to the extracellular matrix.•Extracellular availability can be modulated by endocytic clearance.