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Group leader: Pascale Zimmermann
Pharmacist, School of Pharmacy, Université Catholique de Louvain (U.C.L.), Belgium
PhD: I.C.P. Christian de Duve Institute, U.C.L., Brussels, Belgium, 95
Postdocs: Univ. of Leuven, Belgium; Univ. of Gent, Belgium; Austrian Academy of Science, Austria
Research Professor Univ. of Leuven since 2002, full-time since 2006
EMBO Young Investigator 2008-2010
Current team
Ph.D & Research Project
Ylva Ivarsson (EMBO long-term fellow) 'Integration of peptide and lipid signaling by PDZ scaffolds'
Ane Marcos Carcavilla ‘Developing models to target syntenin pathways in cancer’
Ph.D. Students & Research project
Annelies Geeraerts (IWT PhD Student, also member of the Group Science, Engineering and Technology) 'Dynamics and High-resolution microscopy of syntenin 2'
Antoine Hubert ‘Function of phosphoinositide-PDZ domain interactions in the nucleus’
Anna Wawrzyniak (FWO aspirant) 'The role of the interaction of the PDZ protein syntenin 2 with nuclear lipids and nucleic acids’
Stijn Van Dyck ‘The syntenin pathway in cell polarity'
Master Students & Research project
Marie Raport ‘Biochemical characterization of PDZ-lipid interactions’
Technicians
Elke Vermeiren 'responsible for the Lab materials’
Dimitri Jordens 'responsible for the Lab equipment’
Research interests
Living cells display complex signal processing behaviours mediated by networks of proteins specialized for signal transduction. The wiring of the signalling pathways, or the input-ouput relationship, is coordinated by scaffold proteins. These proteins contain multiple interaction domains and act as organizing platforms that recruit specific signalling components and their upstream/downstream partners to the same complex. We focus on two classes of scaffold proteins, syndecan heparan sulfate proteoglycans and PDZ proteins. Syndecans are extracellular scaffolds and work as co-receptors for a plethora of growth factors (FGF, Wnt, BMP…) and adhesion molecules (Fibronectin, collagens…). PDZ proteins are intracellular scaffolds crucial for cell polarity. PDZ domains function as protein-interaction modules that recognize short sequences at the C-terminal end of transmembrane receptors. Importantly, we found that PDZ domains can also interact with phosphoinositides, lipids that control subcellular compartmentalization and signalling events at the membrane and in the nucleus. In particular, we have established that the PDZ domains of syntenin-1 and syntenin-2 bind to phosphatidylinositol 4, 5-bisphosphate (PIP2) with high-affinity and specificity. We have shown that syntenin-1/PIP2 interaction mediates syndecan and syndecan-cargo recycling, supporting a more dynamic view of PDZ protein function. We found that syntenin-2 shuttles between plasma membrane PIP2 and nuclear PIP2 in nucleoli and nuclear speckles. Screening for phosphoinositide interactors, we identified other candidate PDZ proteins interacting with PIP2, at the membrane and in the nucleus. This indicates that PDZ proteins integrate peptide and lipid signalling at the membrane and in the nucleus.
We currently conduct 3 lines of research (i) establishing the function of syntenin-syndecan pathways in endocytosis, exocytosis, development and cancer (ii) clarifying the functional role of PDZ-lipid interaction in particular in the nucleus and (iii) unravelling how PDZ proteins integrate protein and lipid signalling at the molecular level. We thereby expect to (i) identify novel mechanisms important for development and acquired diseases, (ii) unravel novel aspects of the biology of PDZ proteins and contribute to a better understanding of nuclear-phosphoinositide signalling and (iii) propose novel pharmacological approaches.
Technological approaches
We combine structural, biophysical, cell biological and developmental approaches. We have a quite broad expertise in standard approaches of molecular biology, cell biology (in particular fluorescence confocal and live imaging), biochemistry (in particular surface plasmon resonance/Biacore) and animal models (zebrafish and mouse). We have ongoing collaborations for NMR, crystallisation, drug discovery, and cancer studies.
Our services – hightech shared facilities
Live Imaging: Wide-Field (Leica ASMDW) and Confocal (Olympus FluoVIEW 1000) fluorescence microscopy
Surface Plasmon Resonance : Biacore 2000 and Biacore T100
Key Publications
Gallardo R, Ivarsson I, Schymkowitz J, Rousseau F, Zimmermann P. Structural Diversity of PDZ-Lipid Interactions. Chembiochem 2010, 11:456-467.
Lambaerts K, Wilcox-Adelman SA, Zimmermann P. The signaling mechanisms of syndecan heparan sulfate proteoglycans. Curr Opin Cell Biol. 2009, 21:662-669.
Wawrzak D, Luyten A, Lambaerts K, Zimmermann P. Frizzled-PDZ scaffold interactions in the control of Wnt signaling. Adv Enzyme Regul. 2009, 49:98-106.
Luyten A, Mortier E, Van Campenhout C, Taelman V, Degeest G, Wuytens G, Lambaerts K, David G, Bellefroid EJ, Zimmermann P. The postsynaptic density 95/disc-large/zona occludens protein syntenin directly interacts with frizzled 7 and supports noncanonical Wnt signaling. Mol Biol Cell. 2008, 19:1594-604.
Mortier E., Wuytens G., Leenaerts I., Degeest G., Heung M.Y., David G. and Zimmermann P. Nuclear speckles and nucleoli targeting by PIP2-PDZ domain interactions. EMBO J. 2005, 24:2556-65.
Zimmermann P, Zhang Z, Degeest G, Mortier E, Leenaerts I, Coomans C, Schulz J, N'Kuli F, Courtoy PJ and David G. Syndecan recycling is controlled by syntenin-PIP2 interaction and Arf6. Dev. Cell, 2005, 3:377-88.
Zimmermann P, Meerschaert K, Reekmans G, Leenaerts I, Small JV, Vandekerckhove J, David G, Gettemans J. PIP(2)-PDZ domain binding controls the association of syntenin with the plasma membrane. Mol Cell. 2002, 6:1215-25.
Research team
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