Final Report Summary - PROTEASYS (Protease Systems Biology in Tumorigenesis and Neurodegeneration) Proteases are enzymes that cleave other proteins. This activity may serve to remove the target proteins (called substrates).However, in many cases, proteases cleave only at very defined positions, yielding cleavage products that often have novel functions. This process is called limited proteolysis and has important regulatory functions. Humans have hundreds of proteases that simultaneously and continuously control the levels and activity status of other proteins. The importance of proteolysis is underlined by its tight control. Many proteases require specific activation (i.e. “switching on”) and once active, there are numerous inhibitors to capture excessive protease activity. However, in many diseases, protease activity is dysregulated. It is thus important to better understand the role of proteases in health and disease. Since proteases fulfill their function by cleaving other proteins, it is highly to identify their substrates. This can be achieved by dedicated methods that are based on a technique called mass spectrometry. Generally, technological developments have lately revolutionized the way we identify protease substrates, thus providing entirely new insight into their function. With this background, we sought to investigate several aspects of protease function.Firstly, we focused on a protease called fibroblast activation protein (FAP)-alpha.FAP-alpha is expressed in many solid tumors – however not by the actual tumor cells but by surrounding cells called cancer associated fibroblasts (CAFs). We have shown that FAP-alpha plays an important role in the interaction between tumor cells and CAFs . It contributes to stiffness of the extracellular matrix and may promote the formation of blood vessels in tumors. We have also show that FAP-alpha is not evenly spread out on the cell surface of CAFs bur rather localizes in small structures called lipid rafts. Further subprojects focussed on proteases made by actual tumor cells. For example, we have shown that so-called kallikrein proteases are liked to important extracellular signaling processes. These findings strengthen the interest into exploiting protease functionality for novel cancer therapies. In a second line of research we explored limited and degradative proteolysis in model systems consisting of differentiated, cultured neuron-like cells. We have confirmed an initially unexpected activity of an assumed protease and worked towards a better understanding how such neuronal cells dispose of their protein inventory.Generally, present project has contributed to a more solidified and up-to-date conceptual view on proteolytic processing.
