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Identification of Post-translational Modifications of Plant Protein Complexes
Published on: February 22, 2014
Post-translational modification of the death receptor complex as a potential therapeutic target in cancer
Kidong Kang1, So-Ra Lee1, Xuezhe Piao1
1Department of Pharmacology and Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea.
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.
Insights
Post-translational modifications (PTMs) regulate programmed cell death signaling complexes, particularly tumor necrosis factor receptor 1 (TNFR1). Understanding PTMs in TNFR1 complexes offers new cancer treatment strategies.
Area of Science:
- Molecular Biology
- Cell Biology
- Immunology
Background:
- Programmed cell death is essential for multicellular organisms, impacting development, immunity, and cancer.
- Death receptor (DR) signaling initiates apoptosis or necroptosis via protease cascades.
- Post-translational modifications (PTMs) of DR signaling components are complex and crucial for cell death regulation.
Purpose of the Study:
- To review the molecular mechanisms and consequences of PTMs in DR signaling complex formation, focusing on tumor necrosis factor receptor 1 (TNFR1).
- To characterize the role of PTMs in TNFR1 complexes I and II, emphasizing RIP1 ubiquitination and phosphorylation in cancer cell death.
- To discuss how PTMs dictate cell fate (life or death) upon DR ligation and explore therapeutic opportunities.
Main Methods:
- Literature review of molecular mechanisms and pathophysiological consequences of PTMs in DR signaling.
- Focus on TNFR1 signaling complexes (Complex I and II).
- Analysis of ubiquitination and phosphorylation of RIP1 in programmed cell death.
Main Results:
- PTMs on DR signaling components are critical for regulating cell death pathways.
- Ubiquitination and phosphorylation of RIP1 play key roles in TNFR1 complexes I and II.
- PTMs influence the balance between cell survival and death upon DR activation.
Conclusions:
- Concerted PTMs in TNFR1 complexes determine cell fate following DR ligation.
- Sequential cell death checkpoints mediated by RIP1 PTMs present novel therapeutic avenues for cancer treatment.
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