Patched dependence receptor triggers apoptosis through ubiquitination of caspase-9

Patched (Ptc), the main receptor for Sonic Hedghog, 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.

[1]  John Calvin Reed,et al.  The Patched dependence receptor triggers apoptosis through a DRAL–caspase-9 complex , 2009, Nature Cell Biology.

[2]  D. Bredesen,et al.  Dependence Receptors: From Basic Research to Drug Development , 2011, Science Signaling.

[3]  P. Mehlen,et al.  Dependence receptors: a new paradigm in cell signaling and cancer therapy , 2010, Oncogene.

[4]  G. Salvesen,et al.  Regulation of the Apaf-1–caspase-9 apoptosome , 2010, Journal of Cell Science.

[5]  P. Mace,et al.  Molecular cell death platforms and assemblies. , 2010, Current opinion in cell biology.

[6]  G. Salvesen,et al.  Mechanisms of caspase activation. , 2003, Current opinion in cell biology.

[7]  D. Green,et al.  The central executioners of apoptosis: caspases or mitochondria? , 1998, Trends in cell biology.

[8]  V. Dixit,et al.  Signaling to NF-kappaB: regulation by ubiquitination. , 2010, Cold Spring Harbor perspectives in biology.

[9]  G. Evan,et al.  Apoptosis regulators and their role in tumorigenesis. , 2001, Biochimica et biophysica acta.

[10]  Keisuke Kuida,et al.  Apoptosis initiated by Bcl-2-regulated caspase activation independently of the cytochrome c/Apaf-1/caspase-9 apoptosome , 2002, Nature.

[11]  D. Lawrence,et al.  Cullin3-Based Polyubiquitination and p62-Dependent Aggregation of Caspase-8 Mediate Extrinsic Apoptosis Signaling , 2009, Cell.

[12]  G. Salvesen,et al.  The apoptosome activates caspase-9 by dimerization. , 2006, Molecular cell.

[13]  N. Donato,et al.  Bcr-Abl ubiquitination and Usp9x inhibition block kinase signaling and promote CML cell apoptosis. , 2011, Blood.

[14]  P. Mehlen,et al.  Inhibition of Neuroepithelial Patched-Induced Apoptosis by Sonic Hedgehog , 2003, Science.

[15]  D. Bredesen,et al.  Receptors that mediate cellular dependence , 2005, Cell Death and Differentiation.

[16]  G. Salvesen,et al.  The apoptosome: signalling platform of cell death , 2007, Nature Reviews Molecular Cell Biology.

[17]  Vishva M. Dixit,et al.  Ubiquitylation in apoptosis: a post-translational modification at the edge of life and death , 2011, Nature Reviews Molecular Cell Biology.

[18]  I. Melero,et al.  Lysine 63 Polyubiquitination in Immunotherapy and in Cancer-promoting Inflammation , 2009, Clinical Cancer Research.

[19]  D. Green,et al.  A unified model for apical caspase activation. , 2003, Molecular cell.

[20]  D. Bredesen,et al.  The dependence receptor DCC (deleted in colorectal cancer) defines an alternative mechanism for caspase activation , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[21]  T. Kornberg,et al.  The C-terminal tail of the Hedgehog receptor Patched regulates both localization and turnover. , 2006, Genes & development.