The Patched dependence receptor triggers apoptosis through a DRAL-caspase-9 complex.
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.
Mille
Frédéric
F
Apoptosis, Cancer and Development Laboratory, Equipe labellisée La Ligue, CNRS UMR5238, Université de Lyon, Centre Leon Bérard, 69008 Lyon, France.
Thibert
Chantal
C
Fombonne
Joanna
J
Rama
Nicolas
N
Guix
Catherine
C
Hayashi
Hideki
H
Corset
Véronique
V
Reed
John C
JC
Mehlen
Patrick
P
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism*; D002460:Cell Line; D002642:Chick Embryo; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D060850:LIM-Homeodomain Proteins; D046912:Multiprotein Complexes / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D000070576:NLR Proteins; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D000072079:Patched Receptors; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; C455623:CARD8 protein, human; C105987:FHL2 protein, human; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D046912:Multiprotein Complexes; D009124:Muscle Proteins; D000070576:NLR Proteins; C427903:NLRP1 protein, human; D009363:Neoplasm Proteins; D000072079:Patched Receptors; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; C509239:SHH protein, human; D014157:Transcription Factors; D053453:Caspase 9