Journal
NATURE CELL BIOLOGY
Volume 11, Issue 6, Pages 739-U93Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb1880
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Funding
- Ligue Contre le Cancer
- Agence Nationale de la Recherche
- Institut National du Cancer
- Rhone-Alpes Region
- Centre National de la Recherche Scientifique
- EU
- NIH [NS45093, AI56324]
- Rhone-Alpes Region fellowship
- Association pour la Recherche sur le Cancer fellowship
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Sonic hedgehog (Shh) and its main receptor, Patched (Ptc), are implicated in both neural development and tumorigenesis(1,2). Besides its classic morphogenic activity, Shh is also a survival factor(3,4). Along this line, Ptc has been shown to function as a dependence receptor; it induces apoptosis in the absence of Shh, whereas its pro-apoptotic activity is blocked in the presence of Shh(5). Here we show that, in the absence of its ligand, Ptc interacts with the adaptor protein DRAL (downregulated in rhabdomyosarcoma LIM-domain protein; also known as FHL2). DRAL is required for the pro-apoptotic activity of Ptc both in immortalized cells and during neural tube development in chick embryos. We demonstrate that, in the absence of Shh, Ptc recruits a protein complex that includes DRAL, one of the caspase recruitment (CARD)-domain containing proteins TUCAN (family member, 8) or NALP1 (NLR family, pyrin domain containing 1) and apical caspase-9. Ptc triggers caspase-9 activation and enhances cell death through a caspase-9-dependent mechanism. Thus, we propose that in the absence of its ligand Shh the dependence receptor Ptc serves as the anchor for a caspase-activating complex that includes DRAL, and caspase-9.
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