Schultz Group
Chemical cell biology
Several reporter and modulator molecules developed in our lab, including small molecule sensors for lipases and proteases, genetically encoded reporters for kinase and phosphatase activities, membrane-permeant and photoactivatable lipid molecules as well as lipid derivatives that can be fluorescently labelled in living cells.
Previous and current research
Before joining EMBL, our research focused on finding novel ways to stimulate chloride and water secretion of epithelial cells to help with the genetic disease cystic fibrosis (CF). Our compounds helped to investigate some of the underlying intracellular signalling pathways and provided drug candidates to eventually treat CF patients. Especially, we developed chemical methods to convert highly polar signalling molecules such as cyclic nucleotides, inositol phosphates and phosphoinositides to membrane-permeant, bioactivatable derivatives (‘prodrugs’).
At EMBL, our interest has shift ed to the basic signalling network underlying epithelial secretion as well as receptor endocytosis and recycling. We have developed a wide range of fluorescent reporter molecules, either genetically encoded or as small molecule fluorescent probes (see figure). With these sensors, we hope to provide a more complete picture of the signalling network and to help find compounds that might be beneficial for unravelling basic principles in signal transduction and ultimately for CF patients. Currently, we use our prodrug approaches to dissect signalling networks by increasing the concentration of single lipids such as phosphoinositides in a non-invasive manner (Laketa et al., 2009). In addition, we introduced a novel method to fluorescently label lipids inside fixed and living cells (Neef & Schultz, 2009). These efforts to specifically manipulate and detect small molecules and proteins in cells are supported by novel ways to model intracellular signalling networks. The imaging abilities within the group are essential to validate these models and to support the emerging efforts towards systems biology at EMBL.
As a member of the Molecular Medicine Partnership Unit (MMPU) of EMBL and the University of Heidelberg, we are joining forces with Marcus Mall at the Medical School to test compounds in CF mouse. Small molecule fluorescent FRET probes are prepared to study intra- and extracellular enzyme activities with a focus on phospholipases and proteases, such as a probe to monitor matrix metallo proteinase 12 (MMP12) activity on the surface of macrophages, an enzyme crucial in the development of lung emphysema (Cobos- Correa et al., 2009).
Future projects and goals
In 2011, we will focus predominantly on lipid signalling and lipid-controlled cell biology. To examine the effect of phospholipids, i.e. phosphoinositides, on endocytosis, we are preparing membrane-permeant phospholipids to specifically increase cellular phosphoinositide levels in a non-disruptive way. Very recently, we succeeded in synthesising photoactivatable derivatives to provide an even more controlled way for manipulating lipid levels in living cells (Subramanian et al., 2010). Vesicle trafficking and endocytosis is investigated in collaboration with Rainer Pepperkok’s group. Finally, we are interested in how the plasma membrane is repaired after physical impact. We combine fluorescence microcopy of tagged proteins with electron microscopy (correlative microscopy), the latter a collaboration with Claude Antony.
Most projects rely on organic chemistry to produce the tools described above. The group therefore has a significant number of preparative chemists at the graduate student and postdoc level. The symbiosis of chemistry, biochemistry and cell biology opens new doors and grants novel insights into how cells function.