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 tumorigenesis1,2. Besides its classic morphogenic activity, Shh is also a survival factor3,4. 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 Shh5. 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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: The pro-apoptotic domain of Ptc interacts with DRAL.
Figure 2: DRAL is required for Ptc pro-apoptotic activity.
Figure 3: Ptc–DRAL serves as a platform to recruit TUCAN or NALP1 and caspase-9.
Figure 4: TUCAN/NALP1 and caspase-9 are required for Ptc-induced apoptosis.
Figure 5: Ptc pro-apoptotic complex recruits and activates caspase-9.


  1. 1

    Jessell, T. M. Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nature Rev. Genet. 1, 20–29 (2000).

    CAS  Article  Google Scholar 

  2. 2

    Murone, M., Rosenthal, A. & de Sauvage, F. J. Sonic hedgehog signaling by the patched-smoothened receptor complex. Curr. Biol. 9, 76–84 (1999).

    CAS  Article  Google Scholar 

  3. 3

    Charrier, J. B., Lapointe, F., Le Douarin, N. M. & Teillet, M. A. Anti-apoptotic role of Sonic hedgehog protein at the early stages of nervous system organogenesis. Development 128, 4011–4020 (2001).

    CAS  PubMed  Google Scholar 

  4. 4

    Litingtung, Y. & Chiang, C. Specification of ventral neuron types is mediated by an antagonistic interaction between Shh and Gli3. Nature Neurosci. 3, 979–985 (2000).

    CAS  Article  Google Scholar 

  5. 5

    Thibert, C. et al. Inhibition of neuroepithelial patched-induced apoptosis by sonic hedgehog. Science 301, 843–846 (2003).

    CAS  Article  Google Scholar 

  6. 6

    Mehlen, P. et al. The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis. Nature 395, 801–804 (1998).

    CAS  Article  Google Scholar 

  7. 7

    Bredesen, D. E., Mehlen, P. & Rabizadeh, S. Apoptosis and dependence receptors: a molecular basis for cellular addiction. Physiol. Rev. 84, 411–430 (2004).

    CAS  Article  Google Scholar 

  8. 8

    Mehlen, P. & Bredesen, D. E. The dependence receptor hypothesis. Apoptosis 9, 37–49 (2004).

    CAS  Article  Google Scholar 

  9. 9

    Tauszig-Delamasure, S. et al. The TrkC receptor induces apoptosis when the dependence receptor notion meets the neurotrophin paradigm. Proc.Natl Acad. Sci. USA 104, 13361–13366 (2007).

    CAS  Article  Google Scholar 

  10. 10

    Furne, C. et al. EphrinB3 is an Anti-apoptotic Ligand that Inhibits the Dependence Receptor Functions of EphA4 Receptors during adult neurogenesis Biochem. Biophys. Acta 1793 (2), 231–238 (2009).

    Article  Google Scholar 

  11. 11

    Hahn, H. et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85, 841–851 (1996).

    CAS  Article  Google Scholar 

  12. 12

    Goodrich, L. V., Milenkovic, L., Higgins, K. M. & Scott, M. P. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277, 1109–1113 (1997).

    CAS  Article  Google Scholar 

  13. 13

    Forcet, C. et al. The dependence receptor DCC (deleted in colorectal cancer) defines an alternative mechanism for caspase activation. Proc. Natl Acad. Sci.USA 98, 3416–3421 (2001).

    CAS  Article  Google Scholar 

  14. 14

    Zimmermann, K. C. & Green, D. R. How cells die: apoptosis pathways. J. Allergy Clin. Immunol. 108, S99–103 (2001).

    CAS  Article  Google Scholar 

  15. 15

    Johannessen, M., Moller, S., Hansen, T., Moens, U. & Van Ghelue, M. The multifunctional roles of the four-and-a-half-LIM only protein FHL2. Cell. Mol. Life Sci. 63, 268–284 (2006).

    CAS  Article  Google Scholar 

  16. 16

    Scholl, F. A., McLoughlin, P., Ehler, E., de Giovanni, C. & Schafer, B. W. DRAL is a p53-responsive gene whose four and a half LIM domain protein product induces apoptosis. J. Cell Biol. 151, 495–506 (2000).

    CAS  Article  Google Scholar 

  17. 17

    Stilo, R. et al. TUCAN/CARDINAL and DRAL participate in a common pathway for modulation of NF-kappaB activation. FEBS Lett. 521, 165–169 (2002).

    CAS  Article  Google Scholar 

  18. 18

    Razmara, M. et al. CARD-8 protein, a new CARD family member that regulates caspase-1 activation and apoptosis. J. Biol. Chem. 277, 13952–13958 (2002).

    CAS  Article  Google Scholar 

  19. 19

    Pathan, N. et al. TUCAN, an antiapoptotic caspase-associated recruitment domain family protein overexpressed in cancer. J. Biol. Chem. 276, 32220–32229 (2001).

    CAS  Article  Google Scholar 

  20. 20

    Charrier, J. B., Teillet, M. A., Lapointe, F. & Le Douarin, N. M. Defining subregions of Hensen's node essential for caudalward movement, midline development and cell survival. Development 126, 4771–4783 (1999).

    CAS  PubMed  Google Scholar 

  21. 21

    Stamataki, D., Ulloa, F., Tsoni, S. V., Mynett, A. & Briscoe, J. A gradient of Gli activity mediates graded Sonic Hedgehog signaling in the neural tube. Genes Dev. 19, 626–641 (2005).

    CAS  Article  Google Scholar 

  22. 22

    Tschopp, J., Martinon, F. & Burns, K. NALPs: a novel protein family involved in inflammation. Nature Rev. Mol. Cell Biol. 4, 95–104 (2003).

    CAS  Article  Google Scholar 

  23. 23

    Liu, F. et al. Expression of NALP1 in cerebellar granule neurons stimulates apoptosis. Cell Signal 16, 1013–1021 (2004).

    CAS  Article  Google Scholar 

  24. 24

    Kinoshita, T., Wang, Y., Hasegawa, M., Imamura, R. & Suda, T. PYPAF3, a PYRIN-containing APAF-1-like protein, is a feedback regulator of caspase-1-dependent interleukin-1 β secretion. J. Biol. Chem. 280, 21720–21725 (2005).

    CAS  Article  Google Scholar 

  25. 25

    Faustin, B. et al. Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Mol. Cell 25, 713–724 (2007).

    CAS  Article  Google Scholar 

  26. 26

    Boatright, K. M. et al. A unified model for apical caspase activation. Mol. Cell 11, 529–541 (2003).

    CAS  Article  Google Scholar 

  27. 27

    Riedl, S. J. & Salvesen, G. S. The apoptosome: signalling platform of cell death. Nature Rev. Mol. Cell Biol. 8, 405–413 (2007).

    CAS  Article  Google Scholar 

  28. 28

    Tinel, A. & Tschopp, J. The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress. Science 304, 843–846 (2004).

    CAS  Article  Google Scholar 

  29. 29

    Chu, Z. L. et al. A novel enhancer of the Apaf1 apoptosome involved in cytochrome c-dependent caspase activation and apoptosis. J. Biol. Chem. 276, 9239–9245 (2001).

    CAS  Article  Google Scholar 

  30. 30

    Furne, C., Rama, N., Corset, V., Chedotal, A. & Mehlen, P. Netrin-1 is a survival factor during commissural neuron navigation. Proc. Natl Acad. Sci. USA 105, 14465–14470 (2008).

    CAS  Article  Google Scholar 

Download references


We thank J. Briscoe and N. Le Douarin for advice and reagents, B. W. Schafer, C. Sardet and R. Sadoul for reagents, K. Cywinska for technical work on immunoprecipitation experiments and L. Kremer for the 5e1 hybridoma cell line (protein tools service at the Centro Nacional de Biotecnologia of Madrid). This work was supported by the Ligue Contre le Cancer, the Agence Nationale de la Recherche, the Institut National du Cancer, the Rhône-Alpes Region, the Centre National de la Recherche Scientifique, the EU grants Hermione and APO-SYS, NIH grants to P.M. (NS45093) and J.C.R. (AI56324), and a Rhône-Alpes Region fellowship and an Association pour la Recherche sur le Cancer fellowship to F.M.

Author information




F.M., C.T., J.F., N.R., H.H. and V.C. performed experiments and analysed data; C.G. performed experiments; J.C.R. provided materials; C.T planned the project and P.M. planned the project, analysed data and wrote the manuscript.

Corresponding author

Correspondence to Patrick Mehlen.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 1000 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Mille, F., Thibert, C., Fombonne, J. et al. The Patched dependence receptor triggers apoptosis through a DRAL–caspase-9 complex. Nat Cell Biol 11, 739–746 (2009).

Download citation

Further reading


Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing