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Patched dependence receptor triggers apoptosis through ubiquitination of caspase-9.
Fombonne J., Bissey P.-A., Guix C., Sadoul R., Thibert C., Mehlen P.
Proceedings- National Academy of Sciences Usa 109, 26 (2012) 10510-5 - http://www.hal.inserm.fr/inserm-00721053
Patched dependence receptor triggers apoptosis through ubiquitination of caspase-9.
Joanna Fombonne1, Pierre-Antoine Bissey1, Catherine Guix1, Rémy Sadoul2, Chantal Thibert2, Patrick Mehlen () 1
1 :  CRCL - Centre de Recherche en Cancérologie de Lyon
CNRS : UMR5286 – INSERM : U1052 – Université Claude Bernard - Lyon I (UCBL) – CLB Centre Léon Bérard
28 rue laennec Bat Cheney 69373 Cedex 08 Lyon
2 :  GIN - U836 - Grenoble Institut des Neurosciences
INSERM : U836 – Université Joseph Fourier - Grenoble I – CHU Grenoble – CEA : DSV/IRTSV
UJF - Site Santé La Tronche - BP 170 - 38042 Grenoble Cedex 9
INSERM U836, équipe 2, Neurodégénérescence et plasticité
Patched (Ptc), the main receptor for Sonic Hedgehog, is a tumor suppressor. Ptc has been shown to be a dependence receptor, and as such triggers apoptosis in the absence of its ligand. This apoptosis induction occurs through the recruitment by the Ptc intracellular domain of a caspase-activating complex, which includes the adaptor proteins DRAL and TUCAN, and the apical caspase-9. We show here that this caspase-activating complex also includes the E3 ubiquitin ligase NEDD4. We demonstrate that Ptc-mediated apoptosis and Ptc-induced caspase-9 activation require NEDD4. We show that Ptc, but not Bax, the prototypical inducer of the intrinsic cell-death pathway, triggers polyubiquitination of caspase-9. Moreover, a caspase-9 mutant that could not be ubiquitinated failed to mediate Ptc-induced apoptosis. Taken together, these data support the view that the Ptc dependence receptor specifically allows the activation of caspase-9 via its ubiquitination, which occurs via the recruitment by Ptc of NEDD4.
Sciences du Vivant/Biochimie, Biologie Moléculaire

Articles dans des revues avec comité de lecture
Proceedings- National Academy of Sciences Usa

posttranslational modification – protease – signalisation
Apoptosis – Caspase 3 – Cell Line – Humans – Mutagenesis – Site-Directed – Real-Time Polymerase Chain Reaction – Two-Hybrid System Techniques – Ubiquitination
This work was supported by institutional grants from the Ligue Contre le Cancer, INCA, ANR, and IP ApoSys.
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