Proteolysis as a Regulatory Event in Pathophysiology

Sonderforschungsbereich 877

An der Christian-Albrechts-Universität zu Kiel

Group photograph

   


 The CRC 877 goes into the second funding  period (July 2014 - June 2018, see press  release of the University of Kiel)

 

Long-term and connective research goals

Proteases constitute 1%–5% of eukaryotic genes and the human genome encodes 566 predicted proteolytic enzymes. The functions of proteases are essential in many physiological processes,including development, blood coagulation, and cell death, as well as many pathophysiologic events such as cancer and infectious diseases.

The general aim of the collaborative research centre is to obtain a profound understanding of proteolytic processes in cellular regulation and signaling and define the involvement of such processes in human pathophysiology.

Time Scale of SFB 877

The process of proteolysis is, in contrast to other posttranslational modifications such as protein phosphorylation, protein lipidation or protein methylation, completely irreversible. Therefore – at least theoretically – it might represent an entirely different and presumably higher level of regulation than the other mentioned protein modifications.

Our hypothesis is that there are proteolytic reactions, which represent master switches in the regulation of the immune system, in neuronal development, in neurodegeneration, in apoptosis and in cancer development.

Therefore we plan to analyze proteolytic reactions in molecular detail, which are an integral part of signaling processes. Examples are the cleavage of cytokines, cell adhesion molecules, growth factors and their cognate receptors by membrane proteases and the importance of these events in development, modulation of the immune system and cancer. Further, we plan to study the involvement of caspases, ubiquitin ligation and proteasomal protein degradation in the regulation of apoptotic and caspase-independent programmed cell death. Lastly we will study the regulation of epithelial barrier function, autophagy and other fundamental cell biology functions by proteolytic processes.

Since cytokines, growth factors, apoptosis, cellular barrier function and autophagy have been implied in the development of numerous chronic inflammatory or neurodegenerative diseases, our hypothesis is that proteolysis is a crucial and decisive factor in the pathophysiology of infection, skin disorders, neurodegeneration, inflammation and cancer.

Composition of SFB 877

Composition of SFB 877

A few examples should be mentioned, which support our view of proteolysis as an integral part of inter- and intracellular signaling pathways.

Within the large family of ADAM (A Disintegrin and Metalloprotease) proteases, ADAM10 and ADAM17 share the highest sequence similarity. ADAM10 and ADAM17 have been defined as the major shedding proteases for substrates such as ligands of the epidermal growth factor receptor (EGF-R), Notch, L-selectin, E-cadherin, N-cadherin, VE-cadherin, Fas-Ligand and many others. Using novel mouse models we could now demonstrate that the major role of ADAM10 is the regulation of developmental processes whereas ADAM17 is rather a master switch in the coordination of responses of the organism to wounding and immunological stress.

The pro-inflammatory cytokine tumor necrosis factor α (TNFα) can induce pro- and anti-apoptotic signaling pathways. The balance between these two opposing pathways is governed by various proteolytic steps involving several caspases as well as cathepsin D. These proteolytic cascades therefore determine whether TNFα exhibits pro- or anti-apoptotic properties.

Signal-Peptide-Peptidase-like 2a (SPPL2a) and b (SPPL2b) are two novel intramembrane proteases with largely unknown function. They are localized in lysosomal/endosomal compartments and at the cell surface. Gene targeting experiments now revealed that these proteases play a major role in the immune system.

These examples show that proteolysis plays a key role in many signaling processes and is often a key event in pathophysiology.

The goal of our planned collaborative research centre is to define the molecular mechanisms regulating the proteolytic steps in signaling cascades and to understand the conceptional difference between proteolytic steps and other fast and reversible signaling events such as phosphorylation and methylation. Such an understanding will not only help us to define pathophysiologic situations mediated by cytokines and growth factors but also to define points of intervention for the development of novel therapeutic principles.

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