|Cell signaling and activation - CNRS URA 2582|
|HEAD||Prof ISRAËL Alain / firstname.lastname@example.org|
|MEMBERS||AYTAC Marie-Dominique / Dr BROU Christel / CHASTAGNIER Patricia / CORTE-REAL FILIPE Josina
Dr GUPTA-ROSSI Neetu / HEUSS Sara / LAKISIC Goran / Dr LAPLANTINE Emmanuel
LOBRY Camille / Dr LOGEAT Frédérique / LOPEZ Tatiana / MAUGEIN Alicia / MORETTI Julien
MOURGUIN-NAGUIN Stéphanie / NDIAYE-LOBRY Delphine / VALLET Judith / Dr WEIL Robert
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. More recently we have focused our interest on the multiple types of ubiquitination events involved in the regulation of these two signaling cascades. 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 are 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. Finally we have initiated a structure-function analysis of the NEMO molecule, the regulatory element and the central core of the IKK complex.
Another project involves the functional characterization of the protein NRP/optineurin, which shows very strong homologies with NEMO, but is associated with the Golgi apparatus and seems to be involved into a different type of signaling activity. We have demonstrated that NRP is involved in the regulation of protein export to the plasma membrane, and in the control of the cell cycle.
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 initiated a proteomic approach aimed at identifying the proteins associated with the Notch receptor at various steps of the activation process ; iii) we have demonstrated that the intracellular region of the Delta family of Notch ligands and more specifically their ubiquitination pattern controls the trafficking and therefore the signaling activity of these molecules.
Keywords: Signal transduction, NF-kappaB, Notch, phosphorylation, ubiquitination
CHASTAGNIER, P., ISRAEL, A. and BROU, C. 2006. Itch/AIP4 mediates Deltex degradation through the formation of K29-linked polyubiquitin chains. EMBO Reports, , 7, 1147-1153
GUPTA-ROSSI, N., SIX, E., LEBAIL, O., LOGEAT, F., CHASTAGNER, P , OLRY, A., ISRAEL, A. & BROU, C. 2004. Monoubiquitination and endocytosis direct γ-secretase cleavage of activated Notch receptor. J Cell Biol, 166, 73-83
KALTSCHMIDT, B., NDIAYE, D., KORTE, M., POTHION, S., ARBIBE, L., PRÜLLAGE, M., PFEIFFER, J., LINDECKE, A., STAIGER, V., ISRAEL, A., KALTSCHMIDT, C. & MEMET, S. 2006. NF-κB regulates spatial memory formation and synaptic plasticity through PKA/CREB signaling. Mol Cell Biol, 26, 2936-2946
LOBRY, C., LOPEZ, T., ISRAEL, A. and WEIL, R. 2007. Negative feed back loop in T-cell activation through IκB kinase-induced phosphorylation and degradation of Bcl10. Proc Natl Acad Sci USA, 2007, 104, 908-913
SIX, E., NDIAYE, D., SAUER, G., LAABI, Y., ATHMAN, R., CUMANO, A., BROU, C., ISRAËL, A., & LOGEAT, F. 2004. The Notch ligand Delta1 recruits Dlg1 at cell-cell contacts and regulates cell migration. J Biol Chem, 279, 55818-55826
Activity Reports 2007 - Institut Pasteur
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