期刊
NATURE CELL BIOLOGY
卷 11, 期 6, 页码 739-U93出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb1880
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资金
- 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
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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