Patched dependence receptor triggers apoptosis through ubiquitination of caspase-9.
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.
Apoptosis, Cancer and Development Laboratory-Equipe labellisée La Ligue, LabEx DEVweCAN, Centre de Cancérologie de Lyon, Institut, Université de Lyon, 69008 Lyon, France.
Joanna
J
Fombonne
Pierre-Antoine
PA
Bissey
Catherine
C
Guix
Rémy
R
Sadoul
Chantal
C
Thibert
Patrick
P
Mehlen
D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D016297:Mutagenesis, Site-Directed; D060888:Real-Time Polymerase Chain Reaction; D020798:Two-Hybrid System Techniques; D054875:Ubiquitination
D053148:Caspase 3