Cell signaling and activation
Signalisation moléculaire et activation cellulaire
SMAC (Signalisation moléculaire et activation cellulaire) is involved in the study of three signaling pathways, NF-kB, Optineurin and Notch, using essentially biochemical, genetic and cell biology approaches. Group 6 is associated with SMAC, with an independent project. Recently part of our effort has focused on the multiple types of ubiquitination events involved in the regulation of two of these signaling cascades.
Group 1 (C. BROU) studies the Notch pathway, which is involved in the development and maintenance of organs and tissues. Contrary to a number of signaling pathways, Notch does not use a cascade of kinases, but relies on complex trafficking events targeting both the receptor and its ligands, and controlled by a network of ubiquitinated proteins and ubiquitin receptors. The group of C Brou specifically studies the mechanisms that control the maintenance of an active receptor at the plasma membrane, the production of active ligands, and the regulation of signal transduction after activation. They are particularly interested in the trafficking and post-translational modifications undergone by the Notch receptor and its ligands.
Group 2 (N. GUPTA-ROSSI) studies the role of the Notch pathway in liver differentiation under normal and pathological situations, using an ex vivo system of differentiation towards hepatocytes or cholangiocytes.
Groups 3-5 study the NF-kB and Optineurin pathways :
Group 3 (A. ISRAEL) : NF-kB activation represents a general stress response, involved among others in the immune, inflammatory and anti-apoptotic responses. Its dysfunction is associated with a number of pathologies, cancer being only one of them. The activity of the NF-kB cascade is controlled by a series of post-translational modifications, non-degradative ubiquitination being the last one to be discovered. Group 3 is currently studying the mechanisms that control the complex network of ubiquitinated molecules and ubiquitin receptors involved in NF-kB signaling, both under normal and pathological conditions. In particular they study the regulation of the activity of NEMO, the core element of the NF-kB signaling pathway, focusing on its ability to bind different types of polyubiquitin chains. They have identified a family of proteins which use the same ubiquitin-binding domains as NEMO, and are characterizing new members of this family (in collaboration with group 4).
Group 4 (F. AGOU), recently associated with SMAC (but a long time collaborator), uses physico-chemical approaches to perform a structure-function analysis of NEMO and other proteins of the same family, in connection with their ability to bind poly-ubiquitin chains.
Group 5 (R. WEIL) studies the activation of NF-kB by the antigen in T cells. They have identified a new upstream component of this cascade. They also study the protein Optineurin, which shows very strong homologies with NEMO, but is associated with the Golgi apparatus and seems to be involved in a different type of signaling activity. They have demonstrated that Optineurin is a new component of the innate antiviral response, and that it plays a critical role in the regulation of the cell cycle by controling the activity of the kinase Plk1.
Group 6 (A. GARCIA) studies the involvement of the protein phosphatases PP1 and PP2A and of peptides derived from these enzymes in apoptosis, especially of tumor cells, as well as the mechanisms by which viral proteins divert the activity of these phosphatases.
SMAC is part of CNRS URA 2582, headed by Alain ISRAËL