Caspase-8 tyrosine-380 phosphorylation inhibits CD95 DISC function by preventing procaspase-8 maturation and cycling within the complex
Open accessAbstract
Caspase-8 is a key initiator of apoptotic cell death where it functions as the apical protease in death receptor-mediated apoptosis triggered via the death-inducing signalling complex (DISC). However, the observation that caspase-8 is upregulated in many common tumour types led to the discovery of alternative non-apoptotic, pro-survival functions, many of which are contingent on phosphorylation of a tyrosine residue (Y380) found in the linker region between the two catalytic domains of the enzyme. Furthermore, Src-mediated Y380 phosphorylation leads to increased resistance to CD95-induced apoptosis; however, the mechanism underlying this impaired response to extrinsic apoptotic stimuli has not been identified. Consequently, we have employed a number of model systems to further dissect this protective mechanism. First, using an in vitro DISC model together with recombinant procaspase-8 variants, we show that Y380 phosphorylation inhibits procaspase-8 activation at the CD95 DISC, thereby preventing downstream activation of the caspase cascade. Second, we validated this finding in a cellular context using transfected neuroblastoma cell lines deficient in caspase-8. Reconstitution of these lines with phosphomimetic-caspase-8 results in increased resistance to CD95-mediated apoptosis and enhanced cell migration. When the in vitro DISC is assembled in the presence of cell lysate, caspase-8 Y380 phosphorylation attenuates DISC activity by inhibiting procaspase-8 autoproteolytic activity but not recruitment or homodimerization of caspase-8 within the complex. Once incorporated into the DISC, phosphorylated caspase-8 is unable to be released from the complex; this inhibits further cycling and release of active catalytic subunits into the cytoplasm, thus resulting in increased apoptotic resistance. Taken together, our novel findings expand our understanding of the key mechanisms underlying the anti-apoptotic functions of caspase-8 which may act as a critical block to existing antitumour therapies. Importantly, reversal or inhibition of caspase-8 phosphorylation may prove a valuable avenue to explore for sensitization of resistant tumours to extrinsic apoptotic stimuli.
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Phosphorylation of CASP8 at Y380 inhibits its autoproteolytic activity upon FAS activation.
“(1) phosphorylation at Y380, which inhibits the autoproteolytic activity of CASP8 upon FAS activation [306]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [306]
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Cites
Cellular Mechanisms Controlling Caspase Activation and FunctionPreprint
Parrish, A. B., Freel, C. D., & Kornbluth, S. A. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a008672 · Cited by 629 · see citing works
Caspases and Kinases in a Death Grip
Kurokawa, M., & Kornbluth, S. A. (2009) · Cell · doi:10.1016/j.cell.2009.08.021 · Cited by 476 · see citing works
Dickens, L. S., Boyd, R. S., Jukes-Jones, R., Hughes, M. A., Robinson, G. L., Fairall, L., Schwabe, J. W. R., Cain, K., & MacFarlane, M. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.05.004 · Cited by 349 · see citing works
Self-citationTargeting Src family kinases in anti-cancer therapies: turning promise into triumph
Zhang, S., & Yu, D. (2011) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2011.11.002 · Cited by 323 · see citing works
Inactivating mutations of caspase-8 gene in colorectal carcinomas
Kim, H. S., Lee, J. W., Soung, Y. H., Park, W. S., Kim, S. Y., Lee, J., Park, J. Y., Cho, Y. G., Kim, C. J., Jeong, S. W., et al. (2003) · Gastroenterology · doi:10.1016/s0016-5085(03)01059-x · Cited by 230 · see citing works
Oberst, A., Pop, C., Tremblay, A. G., Blais, V., Denault, J.-B., Salvesen, G. S., & Green, D. R. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.095083 · Cited by 214 · see citing works
p38-MAPK Signals Survival by Phosphorylation of Caspase-8 and Caspase-3 in Human Neutrophils
Alvarado-Kristensson, M., Melander, F., Leandersson, K., Rönnstrand, L., Wernstedt, C., & Andersson, T. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20031771 · Cited by 213 · see citing works
Harper, N. W., Hughes, M. A., MacFarlane, M., & Cohen, G. M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m303399200 · Cited by 209 · see citing works
Self-citationThe ‘complexities’ of life and death: Death receptor signalling platforms
Dickens, L. S., Powley, I. R., Hughes, M. A., & MacFarlane, M. (2012) · Experimental Cell Research · doi:10.1016/j.yexcr.2012.04.005 · Cited by 208 · see citing works
Self-citationSrc kinase phosphorylates Caspase‐8 on Tyr380: a novel mechanism of apoptosis suppression
Cursi, S., Rufini, A., Stagni, V., Condò, I., Matafora, V., Bachi, A., Bonifazi, A. P., Coppola, L., Superti‐Furga, G., Testi, R., et al. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601085 · Cited by 205 · see citing works
Schleich, K., Warnken, U., Fricker, N., Öztürk, S., Richter, P., Kammerer, K., Schnölzer, M., Krammer, P. H., & Lavrik, I. N. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.05.006 · Cited by 198 · see citing works
Hughes, M. A., Harper, N. W., Butterworth, M., Cain, K., Cohen, G. M., & MacFarlane, M. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.06.012 · Cited by 185 · see citing works
Self-citationCASPASE-8 Gene Is Inactivated by Somatic Mutations in Gastric Carcinomas
Soung, Y. H., Lee, J. W., Kim, S. Y., Jang, J., Park, Y. G., Park, W. S., Nam, S. W., Lee, J. Y., Yoo, N. J., & Lee, S. H. (2005) · Cancer Research · doi:10.1158/0008-5472.815.65.3 · Cited by 177 · see citing works
Functions of caspase 8: The identified and the mysterious
Salvesen, G. S., & Walsh, C. M. (2014) · Seminars in Immunology · doi:10.1016/j.smim.2014.03.005 · Cited by 136 · see citing works
MacFarlane, M., Cain, K., Sun, X., et al. (1997) · The Journal of Cell Biology · doi:10.1083/jcb.137.2.469 · Cited by 132 · see citing works
Self-citationSenft, J., Helfer, B. M., & Frisch, S. M. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-5755 · Cited by 120 · see citing works
Structural and Biochemical Studies on Procaspase-8: New Insights on Initiator Caspase Activation
Keller, N., Mareš, J., Zerbe, O., & Grütter, M. G. (2009) · Structure · doi:10.1016/j.str.2008.12.019 · Cited by 89 · see citing works
Jia, S. H., Parodo, J. C., Kapùs, A., Rotstein, O. D., & Marshall, J. C. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m706462200 · Cited by 82 · see citing works
Sequential Cdk1 and Plk1 phosphorylation of caspase‐8 triggers apoptotic cell death during mitosis
Matthess, Y., Raab, M., Knecht, R., Becker, S., & Strebhardt, K. (2014) · Molecular Oncology · doi:10.1016/j.molonc.2013.12.013 · Cited by 71 · see citing works
Src Kinase Inhibitors: Promising Cancer Therapeutics?
Creedon, H., & Brunton, V. G. (2012) · Critical Reviews™ in Oncogenesis · doi:10.1615/critrevoncog.v17.i2.20 · Cited by 69 · see citing works
Caspase 8 Promotes Peripheral Localization and Activation of Rab5
Torres, V. A., Mielgo, A., Barilà, D., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m805878200 · Cited by 55 · see citing works
Frisch, S. M. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-0952 · Cited by 55 · see citing works
Mandal, R., Raab, M., Matthess, Y., Becker, S., Knecht, R., & Strebhardt, K. (2013) · Molecular Oncology · doi:10.1016/j.molonc.2013.11.003 · Cited by 52 · see citing works
Cancer‐associated missense mutations of caspase‐8 activate nuclear factor‐κB signaling
Ando, M., Kawazu, M., Ueno, T., et al. (2013) · Cancer Science · doi:10.1111/cas.12191 · Cited by 44 · see citing works
Studies of the molecular mechanism of caspase-8 activation by solution NMR
Keller, N., Grütter, M. G., & Zerbe, O. (2009) · Cell Death and Differentiation · doi:10.1038/cdd.2009.155 · Cited by 42 · see citing works
Zonta, F., Pagano, M. A., Trentin, L., Tibaldi, E. V., Frezzato, F., Gattazzo, C., Martini, V., Trimarco, V., Mazzorana, M., Bordin, L., et al. (2013) · Blood · doi:10.1182/blood-2013-02-485540 · Cited by 29 · see citing works
Xu, J., Xu, Z., Zhou, J.-Y., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.508093 · Cited by 24 · see citing works
Isolation, characterisation and reconstitution of cell death signalling complexes
Hughes, M. A., Langlais, C., Cain, K., et al. (2013) · Methods · doi:10.1016/j.ymeth.2013.02.006 · Cited by 19 · see citing works
Self-citationLanglais, C., Hughes, M. A., Cain, K., et al. (2015) · Cold Spring Harbor Protocols · doi:10.1101/pdb.top070326 · Cited by 6 · see citing works
Self-citationActivation, Isolation, and Analysis of the Death-Inducing Signaling ComplexPreprint
Hughes, M. A., Langlais, C., Cain, K., et al. (2015) · Cold Spring Harbor Protocols · doi:10.1101/pdb.prot087098 · Cited by 3 · 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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- Authors
- Powley, I. R., Hughes, M. A., Cain, K., & MacFarlane, M.
- Corresponding author
- MacFarlane, M
- Venue
- Oncogene
- Published
- 2016-04-25
- Volume
- 35
- Issue
- 43
- Pages
- 5629-5640
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC5095593
- OpenAlex
- W2343871152
- Cited by
- 54
- References
- 30
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 7 · 2023: 5 · 2022: 5 · 2021: 4 · 2020: 4 · 2019: 8 · 2018: 2 · 2017: 5 · 2016: 2
- FWCI
- 2.94
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Oncogene (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Leicester Research Archive (University of Leicester) (submittedVersion, cc-by)
- Funders
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- caspase-8, Fas, death-inducing signalling complex, death receptor-mediated apoptosis, anti-apoptotic effects, apoptosis resistance, tumor resistance, cell migration, neuroblastoma cell lines
- MeSH terms
- Enzyme Activation, Humans, Models, Biological, Models, Molecular, Mutation, Phosphorylation, Protein Conformation, Tyrosine, Signal Transduction, Apoptosis, fas Receptor, src-Family Kinases, Jurkat Cells, Cell Line, Tumor, Caspase 8, Death Domain Receptor Signaling Adaptor Proteins, Protein Multimerization, Proteolysis
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