Patched dependence receptor triggers apoptosis through ubiquitination of caspase-9
Open accessAbstract
Patched (Ptc), the main receptor for Sonic Hedghog, is a tumor suppressor. Ptc has been shown to be a dependence receptor, and as such triggers apoptosis in the absence of its ligand. This apoptosis induction occurs through the recruitment by the Ptc intracellular domain of a caspase-activating complex, which includes the adaptor proteins DRAL and TUCAN, and the apical caspase-9. We show here that this caspase-activating complex also includes the E3 ubiquitin ligase NEDD4. We demonstrate that Ptc-mediated apoptosis and Ptc-induced caspase-9 activation require NEDD4. We show that Ptc, but not Bax, the prototypical inducer of the intrinsic cell-death pathway, triggers polyubiquitination of caspase-9. Moreover, a caspase-9 mutant that could not be ubiquitinated failed to mediate Ptc-induced apoptosis. Taken together, these data support the view that the Ptc dependence receptor specifically allows the activation of caspase-9 via its ubiquitination, which occurs via the recruitment by Ptc of NEDD4.
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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 [353]
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Cites
Mechanisms of caspase activation
Boatright, K. M., & Salvesen, G. S. (2003) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2003.10.009 · Cited by 1,374 · see citing works
The apoptosome: Signalling platform of cell death
Riedl, S. J., & Salvesen, G. S. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2153 · Cited by 1,097 · see citing works
A Unified Model for Apical Caspase Activation
Boatright, K. M., Renatus, M., Scott, F. L., Sperandio, S., Shin, H., Pedersen, I. M., Ricci, J., Edris, W. A., Sutherlin, D. P., Green, D. R., et al. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00051-0 · Cited by 963 · see citing works
The central executioners of apoptosis: caspases or mitochondria?
Green, D. R., & Kroemer, G. (1998) · Trends in Cell Biology · doi:10.1016/s0962-8924(98)01273-2 · Cited by 775 · see citing works
Jin, Z., Li, Y., Pitti, R. M., Lawrence, D. A., Pham, V. C., Lill, J. R., & Ashkenazi, A. (2009) · Cell · doi:10.1016/j.cell.2009.03.015 · Cited by 588 · see citing works
Marsden, V. S., O'Connor, L., O'Reilly, L. A., Silke, J., Metcalf, D., Ekert, P. G., Huang, D. C. S., Cecconi, F., Kuida, K., Tomaselli, K. J., et al. (2002) · Nature · doi:10.1038/nature01101 · Cited by 578 · see citing works
Ubiquitylation in apoptosis: a post-translational modification at the edge of life and death
Vucic, D., Dixit, V. M., & Wertz, I. E. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3143 · Cited by 451 · see citing works
Regulation of the Apaf-1–caspase-9 apoptosome
Bratton, S. B., & Salvesen, G. S. (2010) · Journal of Cell Science · doi:10.1242/jcs.073643 · Cited by 434 · see citing works
Inhibition of Neuroepithelial Patched-Induced Apoptosis by Sonic Hedgehog
Thibert, C., Teillet, M., Lapointe, F., Mazelin, L., Douarin, N. M. L., & Mehlen, P. (2003) · Science · doi:10.1126/science.1085405 · Cited by 328 · see citing works
Self-citationSignaling to NF- B: Regulation by UbiquitinationPreprint
Wertz, I. E., & Dixit, V. M. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a003350 · Cited by 298 · see citing works
The Apoptosome Activates Caspase-9 by Dimerization
Pop, C., Timmer, J. C., Sperandio, S., & Salvesen, G. S. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.03.009 · Cited by 294 · see citing works
Apoptosis regulators and their role in tumorigenesis
Zörnig, M., Hueber, A., Baum, W., & Evan, G. I. (2001) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/s0304-419x(01)00031-2 · Cited by 239 · see citing works
Forcet, C., Ye, X., Granger, L., Corset, V., Shin, H., Bredesen, D. E., & Mehlen, P. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.051378298 · Cited by 208 · see citing works
Self-citationDependence receptors: a new paradigm in cell signaling and cancer therapy
Goldschneider, D., & Mehlen, P. (2010) · Oncogene · doi:10.1038/onc.2010.13 · Cited by 169 · see citing works
Self-citationThe Patched dependence receptor triggers apoptosis through a DRAL–caspase-9 complex
Mille, F., Thibert, C., Fombonne, J., Rama, N., Guix, C., Hayashi, H., Corset, V., Reed, J. C., & Mehlen, P. (2009) · Nature Cell Biology · doi:10.1038/ncb1880 · Cited by 154 · see citing works
Self-citationBcr-Abl ubiquitination and Usp9x inhibition block kinase signaling and promote CML cell apoptosis
Sun, H., Kapuria, V., Peterson, L. F., Fang, D., Bornmann, W. G., Bartholomeusz, G. A., Talpaz, M., & Donato, N. J. (2011) · Blood · doi:10.1182/blood-2010-03-276477 · Cited by 112 · see citing works
The C-terminal tail of the Hedgehog receptor Patched regulates both localization and turnoverPreprint
Lu, X., Liu, S., & Kornberg, T. B. (2006) · Genes & Development · doi:10.1101/gad.1461306 · Cited by 95 · see citing works
Molecular cell death platforms and assemblies
Mace, P. D., & Riedl, S. J. (2010) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2010.08.004 · Cited by 90 · see citing works
Receptors that mediate cellular dependence
Bredesen, D. E., Mehlen, P., & Rabizadeh, S. (2005) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401680 · Cited by 89 · see citing works
Self-citationDependence Receptors: From Basic Research to Drug Development
Mehlen, P., & Bredesen, D. E. (2011) · Science Signaling · doi:10.1126/scisignal.2001521 · Cited by 72 · see citing works
Self-citationLysine 63 Polyubiquitination in Immunotherapy and in Cancer-promoting Inflammation
Martínez‐Forero, I., Rouzaut, A., Palazón, A., Dubrot, J., & Melero, I. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-1225 · Cited by 49 · see citing works
Apoptosis regulators and their role in tumorigenesis.
Zörnig, M., Hueber, A., Baum, W., & Evan, G. I. (2002) · American Journal of Ophthalmology · doi:10.1016/s0002-9394(01)01388-5 · Cited by 17 · see citing works
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Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
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Lossi, L. (2022) · Biochemical Journal · doi:10.1042/bcj20210854 · Cited by 355 · see citing works
NEDD4: The founding member of a family of ubiquitin-protein ligases
Boase, N. A., & Kumar, S. (2014) · Gene · doi:10.1016/j.gene.2014.12.020 · Cited by 157 · see citing works
Luchino, J., Hocine, M., Amoureux, M., Gibert, B., Bernet, A., Royet, A., Treilleux, I., Lécine, P., Borg, J., Mehlen, P., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.09.010 · Cited by 129 · see citing works
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Galluzzi, L., Kepp, O., & Kroemer, G. (2016) · Microbial Cell · doi:10.15698/mic2016.03.483 · Cited by 106 · see citing works
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Yue, S., Tang, L.-Y., Tang, Y., Tang, Y., Shen, Q.-H., Ding, J., Chen, Y., Zhang, Z., Yu, T.-T., Zhang, Y. E., et al. (2014) · eLife · doi:10.7554/elife.02555 · Cited by 94 · see citing works
Targeting sonic hedgehog signaling in neurological disorders
Patel, S. S., Tomar, S., Sharma, D., Mahindroo, N., & Malairaman, U. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.01.008 · Cited by 83 · see citing works
Hedgehog signaling pathway: Epigenetic regulation and role in disease and cancer development
Fattahi, S., Langroudi, M. P., & Akhavan‐Niaki, H. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.26506 · Cited by 79 · see citing works
CHEN, Q., Li, P., Li, P., Xu, Y., LI, Y., & TANG, B. (2014) · Oncology Reports · doi:10.3892/or.2014.3626 · Cited by 75 · see citing works
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Gibert, B., & Mehlen, P. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-3652 · Cited by 73 · see citing works
Self-citationThe mechanism of chronic intracellular infection with Brucella spp.
Guo, X., Zeng, H., Li, M., Xiao, Y., Gu, G., Song, Z., Shuai, X., Guo, J., Huang, Q., Zhou, B., et al. (2023) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2023.1129172 · Cited by 69 · see citing works
Huang, G., Tang, B., TANG, K., Dong, X., Deng, J., Liao, L., Liao, Z., Yang, H., & He, S. (2014) · Oncology Reports · doi:10.3892/or.2014.3099 · Cited by 66 · see citing works
RetractedThe hedgehog pathway and ocular developmental anomalies
Cavodeassi, F., Creuzet, S., & Etchevers, H. (2018) · Human Genetics · doi:10.1007/s00439-018-1918-8 · Cited by 64 · see citing works
Szczepny, A., Rogers, S., Jayasekara, W. S. N., Park, K., McCloy, R. A., Cochrane, C. R., Ganju, V., Cooper, W. A., Sage, J., Peacock, C. D., et al. (2017) · Oncogene · doi:10.1038/onc.2017.173 · Cited by 59 · see citing works
Role and inhibition of GLI1 protein in cancer
Mastrangelo, E., & Milani, M. (2018) · Lung Cancer Targets and Therapy · doi:10.2147/lctt.s124483 · Cited by 55 · see citing works
Chen, F., CHEN, X., Yang, D., Che, X., WANG, J., Li, X., Zhang, Z., Wang, Q., Zheng, W., Wang, L., et al. (2016) · Oncology Reports · doi:10.3892/or.2016.4794 · Cited by 54 · see citing works
RetractedNon-Canonical Roles of Apoptotic Caspases in the Nervous System
Dehkordi, M. H., Munn, R. G. K., & Fearnhead, H. O. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.840023 · Cited by 55 · see citing works
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Dependence receptors and colorectal cancer
Mehlen, P., & Tauszig-Delamasure, S. (2014) · Gut · doi:10.1136/gutjnl-2013-306704 · Cited by 44 · see citing works
Self-citationChen, X. L., Chinchilla, P., Fombonne, J., Ho, L., Guix, C., Keen, J. H., Mehlen, P., & Galdo, N. A. R. (2014) · Molecular and Cellular Biology · doi:10.1128/mcb.00960-14 · Cited by 42 · see citing works
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Vial, J., Royet, A., Cassier, P. A., Tortereau, A., Dinvaut, S., Maillet, D., Gratadou, L., Creveaux, M., Sadier, A., Tondeur, G., et al. (2018) · Cell Death and Differentiation · doi:10.1038/s41418-018-0128-1 · Cited by 31 · see citing works
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Hsia, E. Y. C., Gui, Y., & Zheng, X. (2015) · Frontiers in Biology · doi:10.1007/s11515-015-1343-5 · Cited by 32 · see citing works
Brucella infection inhibits macrophages apoptosis via Nedd4-dependent degradation of calpain2
Cui, G., Wei, P., Zhao, Y., Guan, Z., Li, Y., Sun, W., Wang, S., & Peng, Q. (2014) · Veterinary Microbiology · doi:10.1016/j.vetmic.2014.08.033 · Cited by 31 · see citing works
N4BP3 promotes breast cancer metastasis via NEDD4-mediated E-cadherin ubiquitination and degradation
Luo, M., Li, J., Yang, Q., Xu, S., Zhang, K., Chen, J., Zhang, S., Zheng, S. S., & Zhou, J. (2022) · Cancer Letters · doi:10.1016/j.canlet.2022.215926 · Cited by 27 · see citing works
Royet, A., Broutier, L., Coissieux, M., Malleval, C., Gadot, N., Maillet, D., Gratadou, L., Bernet, A., Nony, P., Treilleux, I., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.16077 · Cited by 25 · see citing works
Self-citationBlocking SHH/Patched Interaction Triggers Tumor Growth Inhibition through Patched-Induced Apoptosis
Bissey, P.-A., Mathot, P., Guix, C., Jasmin, M., Goddard, I., Costechareyre, C., Gadot, N., Delcros, J., Mali, S. M., Fasan, R., et al. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-1340 · Cited by 23 · see citing works
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Rodrigue‐Gervais, I. G., & Saleh, M. (2012) · Trends in Immunology · doi:10.1016/j.it.2012.09.005 · Cited by 19 · see citing works
Kim, S., Choe, J., & Park, K.-Y. (2016) · Inflammation · doi:10.1007/s10753-016-0387-2 · Cited by 19 · see citing works
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Katić, J., Loers, G., Tosic, J., Schachner, M., & KLEENE, R. B. (2017) · Journal of Cell Science · doi:10.1242/jcs.194563 · Cited by 12 · see citing works
Kim, S., Choe, J., & Park, K.-Y. (2016) · Inflammation · doi:10.1007/s10753-016-0403-6 · Cited by 11 · see citing works
Yamaki, Y., Kagawa, H., Hatta, T., Natsume, T., & Kawahara, H. (2016) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-015-2643-4 · Cited by 9 · see citing works
Cullin-4B E3 ubiquitin ligase mediates Apaf-1 ubiquitination to regulate caspase-9 activity
Ohta, E., Itoh, M., Ueda, M., Hida, Y., Wang, M.-X., Hayakawa-Ogura, M., Li, S., Nishida, E., Ohta, K., Tana, T., et al. (2019) · PLoS ONE · doi:10.1371/journal.pone.0219782 · Cited by 9 · see citing works
Kanaki, N., Matsuda, A., Dejima, K., Murata, D., Nomura, K. H., Ohkura, T., Gengyo‐Ando, K., Yoshina, S., Mitani, S., & Nomura, K. (2018) · Glycobiology · doi:10.1093/glycob/cwy104 · Cited by 7 · see citing works
Leung, A. O.-W., Poon, A. C. H., Wang, X., Feng, C., Chen, P., Zheng, Z., To, M. K.-T., Chan, W. C. W., Cheung, M. C. H., & Chan, D. T.-M. (2024) · Nature Communications · doi:10.1038/s41467-024-45053-0 · Cited by 5 · see citing works
Morales-Alcala, C. C., Georgiou, I. C., Timmis, A. J., & Galdo, N. A. R. (2021) · Cells · doi:10.3390/cells10082003 · Cited by 5 · see citing works
Apoptosis is an obstacle to the differentiation of adipose-derived stromal cells into astrocytes
Yuan, X., Sun, Q., Ou, Y., Wang, S., Zhang, W., Deng, H., Wu, X., & Zhang, L. (2014) · Neural Regeneration Research · doi:10.4103/1673-5374.131600 · Cited by 4 · see citing works
Tsenkina, Y., Tapanes, S. A., Díaz, M. M., Titus, D. J., Gajavelli, S., Bullock, R., Atkins, C. M., & Liebl, D. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa175 · Cited by 4 · see citing works
Galasso, A., Iakovleva, D., & Baena-López, L. A. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/722330 · Cited by 3 · see citing works
Pergel, E., Tóth, D. J., Baukál, D., Veres, I., & Czirják, G. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25168879 · Cited by 2 · see citing works
Tan, M., Tan, H. K., & Muhammad, T. S. T. (2014) · Springer eBooks · doi:10.1007/978-3-662-44006-3_13 · Cited by 2 · see citing works
Tan, M., Hamid, S. B. S., Abduraman, M. A., & Tan, H. K. (2020) · Springer eBooks · doi:10.1007/978-3-030-30845-2_17 · Cited by 1 · see citing works
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Hedgehog Signalling in Development and Disease
Jenkins, D. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-821618-7.00124-3
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Self-citationArgüelles, C. (2017) · theses.fr (ABES) · doi:10.70675/a4e93013z2a18z44f2za36bzc050bc632a48
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- Authors
- Fombonne, J., Bissey, P.-A., Guix, C., Sadoul, R., Thibert, C., & Mehlen, P.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-06-07
- Volume
- 109
- Issue
- 26
- Pages
- 10510-10515
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3387056
- OpenAlex
- W1982722652
- Cited by
- 56
- References
- 22
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 6 · 2021: 1 · 2020: 4 · 2019: 2 · 2018: 8 · 2017: 7 · 2016: 5 · 2015: 3 · 2014: 9 · 2013: 4 · 2012: 1
- FWCI
- 2.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- HAL (submittedVersion, other-oa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- Patched receptor, Sonic hedgehog, dependence receptors, apoptosis, caspase-9, ubiquitination, NEDD4, E3 ubiquitin ligase, TUCAN, tumor suppressor, polyubiquitination, Bax
- MeSH terms
- Cell Line, Humans, Mutagenesis, Site-Directed, Apoptosis, Two-Hybrid System Techniques, Caspase 3, Ubiquitination, Real-Time Polymerase Chain Reaction
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