Spatio-Temporal Regulation of Cell Signaling – Scaffolds & Phosphoinositides

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Mitochondria, potential new therapeutic targets in pancreatic cancer -

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.