The Patched dependence receptor triggers apoptosis through a DRAL–caspase-9 complex
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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.
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In absence of ligands, PTCH1 interacts with FHL2, favoring assembly of CASP9-activating complex consisting of CARD8 and NEDD4.
“(2) PTCH1 interacts with the cytosolic adaptor four and a half LIM domains 2 (FHL2; best known as DRAL), hence favoring the assembly of a CASP9-activating complex consisting of caspase recruitment domain family member 8 (CARD8; also known as TUCAN) and neural precursor cell expressed, developmentally down-regulated 4, E3 ubiquitin protein ligase (NEDD4) [352–354]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [354]
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- Authors
- Mille, F., Thibert, C., Fombonne, J., Rama, N., Guix, C., Hayashi, H., Corset, V., Reed, J. C., & Mehlen, P.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Mehlen, Patrick
- Venue
- Nature Cell Biology
- Published
- 2009-05-24
- Volume
- 11
- Issue
- 6
- Pages
- 739-746
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC2844407
- OpenAlex
- W2000992130
- Cited by
- 154
- References
- 30
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 5 · 2023: 3 · 2022: 7 · 2021: 7 · 2020: 11 · 2019: 8 · 2018: 12 · 2017: 8 · 2016: 11 · 2015: 11 · 2014: 15 · 2013: 14 · 2012: 11
- FWCI
- 5.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI056324, AI 56324)
- National Institute of Neurological Disorders and Stroke (R01NS045093, NS-45093)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- Patched receptor, Sonic hedgehog, dependence receptors, apoptosis, FHL2, caspase-9, TUCAN, NALP1, CARD domain, neural tube development, chick embryo, cell survival signaling
- MeSH terms
- NLR Proteins, Patched Receptors, Animals, Cell Line, Chick Embryo, Humans, Muscle Proteins, Neoplasm Proteins, Receptors, Cell Surface, Transcription Factors, Signal Transduction, Apoptosis, Homeodomain Proteins, Two-Hybrid System Techniques, RNA, Small Interfering, Multiprotein Complexes, Adaptor Proteins, Signal Transducing, Apoptosis Regulatory Proteins, Caspase 9, CARD Signaling Adaptor Proteins, Hedgehog Proteins, LIM-Homeodomain Proteins
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