Köhn Group
Investigation of phosphatases using chemical biology tools
Investigation of disease-promoting phosphatases
Previous and current research
Protein and second messenger dephosphorylation by phosphatases is fundamental to a vast number of cellular signalling 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 specifi city and the lack of tools to selectively study particular phosphatases. Despite major accomplishments in the field, understanding of phosphatase function, regulation and substrate interaction is in general still limited. Our main interest is thus to control and investigate phosphatases with the help of chemical tools, based on phosphoinositide (PIP) and peptide synthetic organic chemistry as well as protein semisynthesis, and also with molecular biology approaches. Thereby, we are focusing on phosphatases that promote diseases.
We are working on the design of inhibitors/modulators for phosphatases based on chemical modification of substrates and interacting proteins. PIPs are a major substrate class of interest in our research. We have developed a novel solid phase synthesis strategy that accelerates access to these compounds and their analogues. One goal is to achieve a detailed picture of substrate specificities of lipid phosphatases in biochemical structure-activity relationship (SAR) studies using a library of PIP analogues. Information about specific substrate preferences will help to design specific inhibitors of lipid phosphatases.
The PRL family of phosphatases is of particular interest to us because it is involved in several types of cancer. We apply protein semisynthesis, imaging, and molecular and genome biology approaches to obtain information about natural substrates, regulation and networks of these oncogenic phosphatases. Furthermore, in collaboration with Mathieu Bollen (KU Leuven, Belgium), we are employing new ways to modulate the ubiquitous phosphatase PP1. A general understanding of phosphatase and kinase networks is still very incomplete. In collaboration with Matthias Wilmanns, and Janet Thornton, we use computational, biochemical and structural approaches to view, predict and validate these networks.
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 lipid phosphatases in cells by applying the modulators resulting from our SAR studies. Developing modulators for highly non-specific serine/threonine phosphatases is a long-term goal and we already successfully developed modulators for PP1 and have begun to pursue this for PP2C in collaboration with José Márquez.
The lab consists of an equal number of molecular biologists and organic chemists at both 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.
10 years of the human genome
EMBL scientists mark a decade since the first draft human genome sequence. Click on the image to play.
Duration: 6 mins.