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Post-translational modification of the death receptor complex as a potential therapeutic target in cancer

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Abstract

Programmed cell death is critical to the physiological function of multi-cellular organisms, controlling development, immunity, inflammation, and cancer progression. Death receptor (DR)-mediated regulation of a protease functions as a second messenger to initiate a death signal cascade to induce apoptosis or necroptosis. Recently, it has become clear that post-translational modifications (PTMs) of signaling components in the DR complex are highly complex, temporally controlled, and tightly regulated, and play an important role in cell death signaling. This review focuses on the molecular mechanisms and pathophysiological consequences of PTMs on the formation of the DR signaling complex, especially with respect to tumor necrosis factor receptor 1 (TNFR1). Furthermore, characterization of the role of PTMs in spatially different TNFR1 complexes (complexes I and II), especially with respect to the role of ubiquitination and phosphorylation of receptor interacting protein 1 (RIP1) in programmed cell death in cancer cells, will be reviewed. By integrating recently gained insight of the functional importance of PTMs in complex I or II, this review discusses how the concerted action of PTMs results in life or death upon DR ligation. Finally, the emerging concept of a sequential cell death checkpoint by the PTMs of RIP1, which may reveal novel therapeutic opportunities for the treatment of some cancers, will be discussed.

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Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (Grant Nos. 2017R1A2A1A05001225, 2017R1A5A2015385).

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  1. Department of Pharmacology and Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea

    Kidong Kang, So-Ra Lee, Xuezhe Piao & Gang Min Hur

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  1. Kidong Kang
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  2. So-Ra Lee
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  3. Xuezhe Piao
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  4. Gang Min Hur
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Correspondence to Gang Min Hur.

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Kang, K., Lee, SR., Piao, X. et al. Post-translational modification of the death receptor complex as a potential therapeutic target in cancer. Arch. Pharm. Res. 42, 76–87 (2019). https://doi.org/10.1007/s12272-018-01107-8

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  • DOI: https://doi.org/10.1007/s12272-018-01107-8

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