Extracellular proteinases are critical regulators of cell function. It has long been recognised that the serine proteinases of the plasminogen activator (PA)-plasmin network and the Zn-dependent matrix metalloproteinases (MMPs) conspire via interlocked activation cascades in the control of degradation of the extracellular matrix (ECM). Through their effects on ECM integrity and metabolism, these cellular proteinases are mediators of the cell-cell and cell-ECM interactions that regulate morphogenesis, differentiation, proliferation and apoptosis. Moreover, in various human diseases, including cancer, arthritis and cardiovascular disease, loss of control of extracellular proteolysis is causally linked with pathological events. Proteolysis of the ECM provides the mechanism for cell invasion during metastasis and angiogenesis, as well as acting as a trigger for apoptosis of differentiated epithelial cells. But there are also more subtle actions of proteinases in the extracellular milieu, including the generation of bioactive fragments of matrix that influence cell motility or suppress angiogenesis. Also, initiation of cell signalling can occur through proteolytic mobilisation of ECM- and cell-associated growth factors (GFs), and cleavage of GF-binding proteins can modulate factor bioavailability. In addition, proteases can dramatically change the functions of extracellular signalling ligands, an example being MMP-mediated cleavage of the chemokine MCP-3 (monocyte chemoattractant protein-3) that generates an antagonist of several chemokine receptors, thus potentially suppressing inflammatory responses. In the PA system, binding of PAs to cell surface receptors such as the urokinase PA receptor (uPAR) can both directly activate cell signalling pathways and modulate cell adhesion. There is also evidence that the Tissue Inhibitors of Metalloproteinases (TIMPs), whose primary recognised role is to limit the function of the MMPs, can act directly on cells to stimulate cell growth and apoptosis.
We are only beginning to understand the biological functions of the cellular proteinases and their inhibitors, but this knowledge is essential for the rational development of pharmacologic agents for intervention in numerous diseases. This issue is highlighted by experience with the first generation synthetic metalloproteinase inhibitors (MPIs) such as British Biotech’s marimastat. These compounds have drawn attention to other classes of susceptible metalloproteinase, notably the mammalian adamalysins (ADAMs, a disintegrin and metalloproteinase) which have biological roles that likely encompass cellular recognition and direct engagement of the intracellular signalling machinery, as well as processing of cell membrane receptors, cytokine precursors and other components. The inadvertent inhibition of ADAMs and related adamalysin-thrombospondin (ADAMTS) proteinases as well as MMPs may mitigate the therapeutic effectiveness of the MPIs, contributing to the disappointing performance of the inhibitors in phase III cancer trials. We are aware of 23 human MMPs, 28 ADAMs and 19 ADAMTSs. A recently identified family of transmebrane serine proteinases appear likely to have both important functions in regulating the activity of the PA system and processing functions similar to the ADAMs.
The philosophy of the Cellular Protease Group at UEA is that we need to understand in detail the precise physiological and pathological roles of the enzymes that comprise the DEGRADOME – the repertoire of proteases elaborated by cells and tissues – as a prelude to the development of the next generations of therapeutic agents.