Proteolysis as a Regulatory Event in Pathophysiology

Sonderforschungsbereich 877

An der Christian-Albrechts-Universität zu Kiel

Research Area A

 

Schematic Overview - Projects of Research Area A

(Click on picture for a larger version)

Proteases at the Plasma Membrane: Structure, Function and Mechanisms of Pathophysiology
(overview)

 A1 (visit project website)
Chalaris / Rose-John (Biochemisches Institut, CAU Kiel):
Analysis of the role to the shedding protease ADAM17 in vivo
(Fachrichtung Biochemie)
 A2 (visit project website)
Scheller (Institut für Biochemie und Molekularbiologie II, Universität Düsseldorf):
Mechanisms of ADAM activation in the context of IL-6/sIL-6R biology
(Fachrichtung Biochemie)
 A3 (visit project website)
Saftig (Biochemisches Institut, CAU Kiel):
Analysis of the postnatal and tissue-specific role of the protease ADAM10
(Fachrichtung Biochemie)
 A4 (visit project website)
Reiß (Hautklinik CAU Kiel):
Regulation and functional relevance of ADAM10- and ADAM17-mediated proteolysis (Fachrichtung Dermatologie, Biochemie)
 A5 (visit project website)
Koch-Nolte (Institut für Immunologie, UKE Hamburg):
Molecular mechanisms and functional consequences of ADAM protease activation induced by extracellular NAD or ATP
(Fachrichtung Molekulare Immunologie
 A6 (visit project website)
Grötzinger (Biochemisches Institut, CAU Kiel):
Structure-function analysis of the extracellular part of ADAM17
(Fachrichtung Biochemie)
 A7 (visit project website)
Kabelitz (Institut für Immunologie, UKSH Kiel):
Mechanisms and implications of NKG2D ligand shedding
A9 (visit project website)
Becker-Pauly (Biochemisches Institut, CAU Kiel)
Function of the metalloproteases meprin α and meprin β in pathophysiology (Fachrichtung Biochemie)

 

Overview

Research area A is devoted to the understanding of the general and specific mechanisms of cell surface protein processing by proteases, which mainly but not exclusively belong to the ADAM familiy of metalloproteases. In the projects of Rose-John (A1) and Saftig (A3) sophisticated genetic mouse models were generated to study the function of ADAM17 and ADAM10. The project of Grötzinger (A6) studies structural aspects of substrate recognition by ADAM17 and tries to rationally design antagonists of this protease. The proteases ADAM10 and ADAM17 have been implicated in the shedding of various substrates such as TNFa, TNF-receptor-II, L-selectin, cadherins, NCAM, L1 IL- 6R, the Alzheimer protein APP, ligands of the EGF-receptor, ART2.2, Notch and Notch-ligands. The project of Scheller (A2) studies the functional consequences of shedding of the IL-6R. The project of Reiß (A4) is dealing with the regulation of the activity of ADAM10 and ADAM17, which is poorly characterized so far. The projects of Koch-Nolte (A5)and Kabelitz (A7) will analyze functional and clinical consequences of shedding reactions, which are involved in the reaction of immune cells to extracellular ATP or NAD (A5) and in activation of T-lymphocyte subsets via the NKG2D ligands (A7).

The common theme of these projects is that proteolytic reactions, which are most likely performed by proteases of the ADAM family, are triggering steps of extracellular and intracellular signaling cascades. These activation steps leading to protease activation are mostly unknown. The molecular mechanisms leading to activation of ADAM proteases are poorly understood. Disturbance of membrane integrity seems to be one possibility leading to ADAM activation. In addition, several intracellular pathways such as the MAP kinase pathway and the calmodulin pathway have been implicated in the activation of these proteases.

The range of Research Area A reaches from protein-structural aspects of substrate recognition and protease inhibition to the cell biology of the proteases involved. Novel substrates will be defined and the clinical consequences of ADAM activation and inhibition will be studied. It is the aim of this Research Area to identify similarities and differences between the initiation of the above mentioned signaling pathways. We anticipate that there is cross-talk at the level of protease activation, which leads to the coordination of multiple signaling pathways, which are – so far – thought to be completely unrelated and independent.