Investigation of phosphatases using chemical biology tools
Figure 1: Our group’s approaches to the investigation of disease-promoting phosphatases
Figure 2: Solid phase synthesis of phosphoinositides for the preparation of libraries to enable SAR studies with lipid phosphatases. (B) A selective activator of PP1 in cells (collaboration with the Hart team and Bollen (KU Leuven) group)
The Köhn group combines molecular biology, biochemistry and synthetic chemistry to develop new approaches to study phosphatases, which can play a major role in cancer.
Previous and current research
Within intracellular signalling networks, phosphatases are counter players of kinases and play crucial roles in health and disease. The investigation of phosphatases is challenging, which is also due to the lack of tools to selectively study particular phosphatases. Understanding of phosphatase function, regulation and substrate interaction is therefore still quite limited. Our main interest is thus to control and investigate phosphatases using interdisciplinary approaches (figure 1). We are focusing on phosphatases that promote diseases.
Specifically, we are interested in the phosphatase of regenerating liver (PRL) enzymes. The PRL family consists of three oncogenes and is barely understood. My group studies biological pathways and the roles of this family using biochemical and molecular cell biology approaches. We aim to design inhibitors for PRL members. We have recently observed phosphoinositide-phosphatase activity in vitro for one member, PRL-3 (McParland et al., 2011). In this regard, we developed a solid phase synthesis strategy that accelerates access to phosphoinositides and their analogues (figure 2a, Bru et al., 2012). We aim to obtain a detailed picture of substrate specificities of lipid phosphatases in biochemical structure-activity relationship (SAR) studies using a library of phosphoinositide analogues. Information about specific substrate preferences will help to design specific inhibitors of lipid phosphatases.
Another interest is the tool development for protein phosphatase-1 (PP1), a ubiquitous phosphatase that is responsible for one third of all dephosphorylation reactions on Ser/Thr inside cells and is involved in many processes such as mitosis and cell cycle regulation. We have recently developed a peptide-based PP1 activator that targets protein–protein interactions (figure 2b, Chaterjee et al., 2012). All our chemical modulators are developed to be reliably active inside cells.
The understanding of phosphatase and kinase networks is still incomplete. We use computational, biochemical and structural approaches to view, predict and validate these networks (collaboration with the Thornton and Wilmanns groups).
Future projects and goals
Studying PRL biology will remain a focus of our lab in the future, with the goal of understanding the underlying mechanisms of oncogenesis caused by these phosphatases. We continue to develop chemical methods to enable us to apply peptides as well as inositides as phosphatase modulators inside cells. In addition to the phosphoinositide-based SAR studies, we have started to employ small molecules and medicinal chemistry for this purpose. Designing modulators for the highly complex serine/threonine phosphatases is another goal, and we continue to develop these for PP1 and have started this for PP2C (collaboration with Márquez team). The lab consists of an equal number of molecular biologists and organic chemists at pre- and postdoctoral level. The combination of biology and chemistry not only opens up new ways to approach challenging phosphatase research, but also broadens views and skills of every lab member.
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