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).

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

PhD fellowships in cell and cancer biology

The Cancer Research Center of Marseille (CRCM), France is pleased to announce that two PhD fellowships will be available from 1 January 2017 or as soon as possible thereafter. The application deadline is November 30th 2016.

 

Applications are invited for the three-year fellowship from applicants who hold or expect to hold a master´s degree in a field relevant to the following PhD projects: A. PDZ-mediated syndecan-phosphoinositide networks in trafficking and signaling; B. PDZ network associated with Vangl and Scribble cell polarity proteins and implication in cancer.

 

Project description

PDZ proteins co-evolved with multicellularity and control various aspects of receptor signaling and trafficking, both known to be deregulated during cancer progression. The two present projects aim to address how PDZ-supported networks impact on cell-cell communication (including via exosomes), and on cell polarity. This work should contribute our understanding of the role of PDZ-networks in physiology and systemic diseases like cancer.

 

Project A aims at providing a comprehensive map of interactions between syndecans, PDZ domain proteins and phospholipids, and investigating their role in subcellular membrane trafficking, exosome secretion and the signaling of various receptors (in part with Systasy).

 

Project B aims at elucidating the role of PDZ interactions of Vangl on the trafficking of the receptor and thereby to gain fundamental insight into how Vangl trafficking is involved in breast cancer. We expect to develop peptide inhibitors of the PDZ domains of Scribble and establish the functional consequences of inhibiting the Vangl-Scribble interaction in cancer models.

 

These PhD fellowships are part of the EU-funded project, PDZnet, which is an ambitious inter- and multidisciplinary European Training Network under the H2020 Marie Skłodowska-Curie Actions (www.pdznet.eu) offering training for 14 PhD fellows. The PDZnet consortium contains 12 different partners in 6 EU countries (Denmark, Sweden, Germany, France, Italy, Portugal). The PDZnet training program involves a range of network wide training activities.

 

Required qualifications

The successful candidate must:

·         hold a Master´s degree in a relevant subject area prior to the starting date

·         be fluent in English and have excellent communication skills

 

Preferred qualifications

We are looking for a highly motivated individual with a background in molecular, biochemical, cellular and/or cancer biology, ideally with some experience in microscopy, cell fractionation and/or exosome purification.

 

Supervisors

Project A. Prof Pascale ZIMMERMANN, pascale.zimmermann(at)inserm(dot)fr, Team ”Spatio-temporal regulation of cell signaling”

Project B. Prof Jean-paul BORG, jean-paul.borg(at)inserm(dot)fr, Team “Cell polarity, signaling and cancer”

 

General job description

Your key tasks as a PhD fellow at Cancer Center of Marseille are to:

·         manage and carry through your research project

·         take PhD courses

·         write scientific articles and your PhD thesis

·         participate in national and international congresses and scientific meetings

·         stay at an external research institution, preferably abroad

·         teach and disseminate your research

 

Key criteria for the assessment of applicants

·         Professional qualifications relevant to the PhD programme

·         Relevant work experience

·         Previous publications

·         The grade point average achieved

·         Other professional activities

·         Language skills

·         The successful applicant is also required to be enterprising and to possess good interpersonal skills

 

Formal requirements

The position is available for a three-year period for applicants holding a relevant master´s degree.

 

The candidate should have less than 4 years of research experience and must not have resided or carried out his/her main activity in France for more than 12 months during the last 3 years immediately prior to the recruitment.

 

The successful applicant will be requested to formally apply for enrolment as a PhD student at Aix-Marseille University.

 

The PhD student is expected to be affiliated to the graduate programme of Aix-Marseille University.

 

Questions

For further information, applicants may contact the supervisors Pascale Zimmerman and/or Jean-Paul Borg.

 

How to apply

Send CV, motivation letter and the coordinates of 2 referees by email to Pascale Zimmerman and/or Jean-Paul Borg.

Deadline for applications: 30 November 2016.

An answer as to the granting of the fellowship can be expected approx. 4 weeks after application deadline.

 

The Cancer Research Center of Marseille wishes to encourage everyone interested in this post to apply, regardless of personal background.