Cell signaling and activation - CNRS URA2582  

  HEADProf. ISRAEL Alain / aisrael@pasteur.fr
Dr LAPLANTINE Emmanuel / LOBRY Camille / Dr LOGEAT Frédérique / Dr WEIL Robert

  Annual Report

SMAC (Signalisation moléculaire et activation cellulaire) is involved in the study of two signaling pathways, NF-κB and Notch, using essentially biochemical, genetic and cell biology approaches. These pathways have in common the involvement of inducible proteolysis events that lead to the nuclear translocation of transcription factors. NF-κB activation represents a general stress response pathway, involved among others in the immune, inflammatory and anti-apoptotic responses. NF-κB activity is controled by cytoplasmic retention through inhibitory molecules, which get degraded in response to multiple signals. Our projects are focused on T Cell Receptor-mediated NF-κB activation, and in particular on the role of phosphorylation and ubiquitination events. We have for example demonstrated that the IKK kinase complex, thought to be the central positive regulator of the NF-κB cascade, is also involved into negative regulatory functions. In parallel we have set up a system that results in constitutive NF-κB activation in T cells, and we are currently testing the consequences of this activation on the proliferation and potential immortalisation of primary T cells.

Another project involves the functional characterization of the protein NRP/optineurin, which shows very strong homologies with NEMO, the core element of the IKK complex, but is associated with the Golgi apparatus and seems to be involved into a different type of signaling activity.

The second signaling cascade we study centers around the Notch family of receptors, which plays an important role in a large variety of developmental events. Signaling through Notch requires a series of three proteolytic events which lead to the nuclear translocation of the intracellular part of the receptor, which behaves as a transcriptional co-activator. We have pursued 3 directions of research: i) we have initiated a functional characterization of a series of ubiquitin-ligases and kinases known to be involved in the early steps of the pathway ; ii) we have set up a genetic screen to identify new components of the γ-secretase activity, responsible for the last of the 3 proteolysis steps mentioned above ; iii) we have pursued the study of the cell-autonomous function of the ligands of the Notch receptor.



Publications 2006 of the unit on Pasteur's references database

Activity Reports 2006 - Institut Pasteur
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