Köhn Group
Investigation of phosphatases using chemical biology tools
Investigation of disease-promoting phosphatases
Previous and current research
Protein dephosphorylation by protein phosphatases (PPs) is fundamental to a vast number of cellular signaling processes and thus to physiological functions. Impairment of these processes contributes to the development of human diseases such as cancer and diabetes. The investigation of phosphatases is challenging, mainly due to their broad substrate specificity and the lack of tools to selectively study particular phosphatases. Therefore, knowledge of phosphatase function and substrate interaction is in general still quite limited. Our main interest is thus to control and investigate phosphatases with the help of chemical tools, based on phosphoinositide and peptide synthetic organic chemistry as well as protein semisynthesis, and also with molecular biology approaches. We are interested in phosphatases that promote diseases, focusing on protein tyrosine phosphatases (PTPs) and dual specificity phosphatases (DSPs). Furthermore, in collaboration with Mathieu Bollen at KU Leuven, Belgium, we are employing new ways to modulate the serine/ threonine phosphatase PP1.
We are working on the design of inhibitors for PTPs based on chemical modification of protein/peptide substrates. Thus, upon binding, the phosphatase cannot fulfill its function and is bound to themodified substrate with natural high affinity. In this way, one does not have to rely on the random discovery of effector molecules by for example exhaustive screening of large compound libraries. In addition, we are looking into phosphoinositides as natural substrates of lipid phosphatases and DSPs. We are working on new synthetic strategies to simplify access to these compounds as well as their analogues to achieve a detailed picture of substrate specificities of these phosphatases in biochemical structure-activity relationship (SAR) studies.
The PRL family of phosphatases is of particular interest to us, because it is involved in several types of cancer. We apply protein semisynthesis and molecular biology approaches to obtain information about natural substrates, regulation and networks of these oncogenic phosphatases in cell culture and zebrafish embryos, the latter in collaboration with Darren Gilmour's group.
Future projects and goals
We are interested in further developing chemical methods to stabilise peptides as well as inositides and in working on novel cell penetration concepts. Another goal is to control and investigate the function and interactions of human lipid phosphatases in cells by applying the modulators resulting from our SAR studies. Developing effector molecules for the highly non-specific PSTPs is a long-term goal. The activity of these phosphatases is controlled not only by active-site specificity, but majorly also by cofactors and cellular localisation, which adds to the challenge of finding tools to selectively target these phosphatases in the context of the cell.
The lab consists of an equal number of molecular biologists and organic chemists on the graduate student and postdoctoral level. The combination of molecular biology, biochemistry and synthetic chemistry not only opens up new ways to approach challenging phosphatase research, but also broadens the views and skills of every lab member.