Abstract
Sonic hedgehog (Shh) and its main receptor, Patched (Ptc), are implicated in both neural development and tumorigenesis. Besides its classic morphogenic activity, Shh is also a survival factor. 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. 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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CARD Signaling Adaptor Proteins / genetics
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CARD Signaling Adaptor Proteins / metabolism
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Caspase 9 / metabolism*
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Cell Line
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Chick Embryo
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Hedgehog Proteins / genetics
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Hedgehog Proteins / metabolism*
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism*
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Humans
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LIM-Homeodomain Proteins
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Multiprotein Complexes / metabolism
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Muscle Proteins / genetics
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Muscle Proteins / metabolism*
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NLR Proteins
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Patched Receptors
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism*
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Signal Transduction / physiology
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Two-Hybrid System Techniques
Substances
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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CARD Signaling Adaptor Proteins
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CARD8 protein, human
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FHL2 protein, human
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Hedgehog Proteins
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Homeodomain Proteins
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LIM-Homeodomain Proteins
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Multiprotein Complexes
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Muscle Proteins
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NLR Proteins
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NLRP1 protein, human
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Neoplasm Proteins
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Patched Receptors
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RNA, Small Interfering
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Receptors, Cell Surface
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SHH protein, human
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Transcription Factors
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Caspase 9