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.

 

Overview

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.

Technological 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.

Figure 1

The syntenin-syndecan trafficking pathway allows a plethora of cell signaling receptor systems to escape degradation. It boosts signaling in cis (receptor recycling) and in trans (cell-cell communication via exosomes).
We are currently investigating the impact of the deregulation of this pathway in cancer signaling.
We are also trying to identify druggable compounds inhibiting this pathway.

Offre Master 2 : Etudes des réseaux Syndecan/Tetraspanin dans le trafic membranaire et la signalisation cellulaire

Encadrant : Rania Ghossoub – Directrice du laboratoire : Pascale Zimmermann

La signalisation cellulaire est régulée par le confinement des récepteurs de signalisation dans des compartiments membranaires. Une meilleure caractérisation des mécanismes moléculaires qui régulent ces processus est essentielle à notre compréhension du vivant et serait porteuse de nouveaux espoirs en thérapeutique. Les Syndecans (SDCs) et les Tetraspanines (TSPNs) sont des protéines transmembranaires qui permettent de dicter la destination et la localisation de nombreux récepteurs de signalisation. Les SDCs interagissent directement avec les facteurs de croissance et molécules d’adhésion grâce à leurs chaines heparan sulfate. Les TSPNs forment une famille de 33 protéines qui sont connues pour coordonner des réseaux protéiques membranaires. Les TSPNs permettent ainsi de réguler le trafic et la signalisation de nombreuses molécules d’adhésion et récepteurs à facteur de croissance. Nous avons pu mettre en évidence une collaboration TSPNs-SDCs. Le projet a pour but de mieux comprendre comment les SDCs et les TSPNs communiquent pour réguler le trafic vésiculaire et donc l’activité des récepteurs associés. Répondre à ces questions permettra d’évaluer l’impact des réseaux SDCs/TSPNs sur la signalisation cellulaire et en biologie du cancer. Le candidat se familiarisera avec les expériences de clonage moléculaire, de culture cellulaire, d’étude de perte et de gain de fonction de protéine et de microscopie.

About the team leader

Pascale Zimmermann

Education

  • 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

Scientific Awards

  • Academic Award for Fundamental Research in Medicine Period 2003-2006 (Belgium)
  • European Molecular Biology Organization (EMBO) Young Investigator Program (YIP)

Main achievements

  • 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