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Analysis of Transduction Pathways (ATP)

Keywords : migration, GTPases, signalling, networks, cytokinesis, apoptosis, polarity

Group leader : Jacques Camonis

Read the scientific activity report. (pdf 68Ko, last update 17th, february 2010)


Our team is questioning molecular mechanisms involved in the appearance, survival and proliferation of cancer cells. We are working, in particular, on signalling networks and are seeking to identify critical points whose therapeutic targeting would make fragile cancer cells without or limited adverse effects on normal cells. One of the most frequently mutated proteins in human cancers is the Ras protein. Its permanent activation causes a cascade of intracellular signals whose components required for cancerous transformation have long been debated. It appears, both in experimental oncology and in human cancers, that the signalling route for another GTPase, Ral, is mobilised downstream of Ras. Our team's activity is organised around the question of the role of the Ral GTPase in oncogenic transformation and in physiological homeostasis.

The Ral GTPases have progressed from a status of molecular curiosity to a status of key player in oncogenesis. Ral exists neither in plants, nor in single-cell organisms. It is an essential link for the hypersignalling driven by oncogenic deregulated receptors or Ras mutants. Even better: cancer cells appear to be extremely susceptible to drops in Ral activity, leading to their death.

Our activity is structured around two parallel approaches, taking advantage of the functional and physical conservation of the Ral signalling pathways between flies and mammals. In an ex vivo cellular approach, we apply biochemistry and cell biology techniques to vertebrate cells harbouring defined properties of “normal” or transformed cells. A genetic approach uses the fruitfly Drosophila melanogaster as a model organism.

 

Exploring the plasticity of the Ral networks. In various cellular “normal” or transformed human cell lines (HeLa, HBEC, RPE1), we are determining the impact of potentiel Ral interactomers, depleted by siRNA, on Ral-dependent phentoypes. The Ral interactomExploring the plasticity of the Ral networks. In various cellular “normal” or transformed human cell lines (HeLa, HBEC, RPE1), we are determining the impact of potentiel Ral interactomers, depleted by siRNA, on Ral-dependent phentoypes. The Ral interactom

Spatial and temporal organization of Ral proteins and the exocyst during cytokinesis: a schematic.Spatial and temporal organization of Ral proteins and the exocyst during cytokinesis: a schematic.

The work conducted by my team has enabled us to identify proteins organised in networks and involved in Ras oncogene-dependent transduction routes. We have achieved this by a molecular approach via the Drosoman screening project aimed at defining the protein-protein interactions of more than 150 proteins of critical importance to oncogenesis or to cell life. A genetic screen in Drosophila has completed this data set: starting from cell death caused by a Ral mutation, we have identified a number of genes that either exacerbate the death rate, or conversely prevent death. The aim is now to define the features of these protein or genetic partnerships. We are tackling this issue the two ends: by cutting edge “craftmanship” in cell and molecular biology, and biochemistry and fly genetics, and by a high-throughput phenotypic characterisation approach based on the Biophenics automatic cell manipulation, imaging and image analysis platform.

Flies mutated in Ral display a loss of mechano-sensoriel organs on the notum (A; upper view of a notum). Identifying genes whose perturbation either suppresses (B) or enhances (C) this phenotype allows to define interaction maps and understand the moleculFlies mutated in Ral display a loss of mechano-sensoriel organs on the notum (A; upper view of a notum). Identifying genes whose perturbation either suppresses (B) or enhances (C) this phenotype allows to define interaction maps and understand the molecul