Spatio-Temporal Regulation of Cell Signaling – Scaffolds & Phosphoinositides
At a glance
Our aim is to identify novel mechanisms of cellular signaling important in cancer and to propose innovative diagnostic and therapeutic approaches.
We are investigating novel pathways controlling cell signaling and cell-cell communication and exploring their potential benefit for the cancer field. We concentrate our studies on scaffold proteins (heparan sulfate proteoglycans and PDZ proteins) and signaling lipids (phosphoinositides) that are important molecules for the spatio-temporal organisation of cell signaling.
In particular we study their effect on the half-life of signaling receptors, their role in cell-cell communication and their impact on nuclear processes. We thereby hope to pave the way for innovative therapeutic approaches.
Main research fields and interests
Cell signalling, scaffold proteins, signalling lipids, membrane compartmentalization, nuclear processes, cell biology, biochemistry, model organisms, cancer, drug discovery.
Specific research projects
Living cells display complex signal processing behaviors mediated by networks of proteins specialized for signal transduction. The wiring of the signaling 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, namely syndecan heparan sulfate proteoglycans and PDZ proteins and on one class of lipids, namely phosphoinositides. Syndecans are extracellular scaffolds and work as co-receptors for a plethora of growth factors (like FGF, Wnt, BMP) and adhesion molecules (like 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 signaling events 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) unraveling how PDZ proteins integrate protein and lipid signaling at the molecular level. We thereby expect to (i) identify novel mechanisms important for development and acquired diseases, in particular cancer (ii) unravel novel aspects of the biology of PDZ proteins and contribute to a better understanding of nuclear-phosphoinositide signaling and (iii) propose novel pharmacological approaches.
We combine structural, biophysical, cell biological and model organisms’ 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, crystallization, drug discovery, and cancer studies.
POST-DOC position in EV molecular/cellular biology
The Cancer Research Center Marseille (CRCM) common goal is to advance our understanding of the biology of cancer and to improve treatment. CRCM combines access to high education in immunology and oncology, state-of-the-art technological support (platforms & resources) and a collegial set of teams offering a fertile and outstanding environment to develop fundamental, translational or clinical project. Our multidisciplinary teams of about 400 researchers are housed on the campus of the Institut Paoli-Calmettes, one of the largest university-affiliated cancer centers in France with 1,500 staff-members (http://www.institutpaolicalmettes.fr/en/research/).
At CRCM, the team of Pascale Zimmermann is investigating novel pathways controlling cell signaling and cell-cell communication and exploring their potential benefit for the cancer field. The team provided major contributions to our understanding of the importance of membrane trafficking for the biology of heparan sulfate proteoglycans, the role of phospholipids in the function of PDZ proteins and more recently the molecular mechanisms of exosome biogenesis (e.g. Baietti et al., Nat Cell Biol 2012; Ghossoub et al., Nat Commun 2014; Imjeti et al., PNAS 2017).
We are recruiting a young post-doc interested in understanding the mechanisms controlling the molecular and functional diversity of extracellular vesicles and in particular at investigating the crosstalk between membrane scaffolds tetraspanins, syndecans and PDZ proteins. Financial support is foreseen for up to 3 years and candidate are encouraged to apply for competitive fellowships (EMBO, Marie-Curie or French agencies). This work is supported by the ANR project SynTEV which is a joined effort with the group of Clotilde Théry and Eric Rubinstein.
PhD in Biochemistry, Molecular Biology, Cell Biology or equivalent
Strong background in imaging methods (microscopy and/or FACS) and protein/membrane work
Proficient in written and spoken English
Strong organizational and interpersonal skills
How to apply?
Motivated candidates are asked to apply by email to pascale.zimmermann(at)inserm(dot)fr (subject Post-Doc SynTEV) and to send applications including CV, research experience, and at least two names and contact information for references.
For more information, you can contact Pascale Zimmermann (by email).
About the team leader
- 1995 PhD in Pharmacy, I.C.P. and Christian de Duve Institute, U.C.L., Belgium
- 1999-2005 Post-Doctoral Fellow of the Science Foundation Flanders, Belgium
- 2001-2002 Post-Doc, Austrian Academy of Science, Salzburg, Austria.
- 2002-2006 V.I.B. Project leader, Belgium
- 2006- Research Professor K.U.Leuven, Belgium, Head Laboratory for Signal Integration in Cell Fate Decision.
- 2011- Directeur de Recherche Inserm, France
- Academic Award for Fundamental Research in Medicine Period 2003-2006 (Belgium)
- European Molecular Biology Organization (EMBO) Young Investigator Program (YIP)
- Identification of the PDZ scaffold protein syntenin
- Discovery of PDZ-lipid interactions
- Documenting the role of vesicular trafficking in the function of heparan sulfate proteoglycans
- Discovery of the interaction of PDZ domains with nuclear lipids