Related Experiment Video
Updated: Jun 22, 2025
05:33
High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
Published on: November 9, 2020
9.6K
Intrinsic signaling pathways modulate targeted protein degradation.
Yuki Mori1,2, Yoshino Akizuki1,2, Rikuto Honda1,2
1Laboratory of Protein Degradation, Institute for Advanced Life Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
Nature Communications
|July 2, 2024
Summary
Targeted protein degradation can be enhanced by inhibiting cellular signaling pathways. Inhibitors of PARG, PERK, and HSP90 boost the degradation of cancer targets like BRD4, sensitizing cells to apoptosis.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Targeted protein degradation is a promising drug discovery approach.
- Regulatory mechanisms controlling targeted protein degradation are not fully understood.
Purpose of the Study:
- To identify cellular signaling pathways that modulate targeted protein degradation of BRD4 and related neosubstrates.
- To investigate the mechanisms by which signaling pathway inhibitors enhance PROTAC-mediated degradation.
Main Methods:
- Utilized Proteolysis-Targeting Chimeras (PROTACs) based on CRL2-VHL and CRL4-CRBN.
- Investigated the effects of inhibitors targeting poly-ADP ribosylation (PARG), unfolded protein response (PERK), and heat shock protein 90 (HSP90).
- Analyzed ubiquitylation patterns and ternary complex formation.
Main Results:
- PARG inhibition (PDD00017273) promotes BRD4 degradation by facilitating chromatin dissociation and enhancing ternary complex formation.
- HSP90 inhibition (luminespib) enhances BRD4 degradation post-ubiquitylation.
- PERK inhibition (GSK2606414) also enhances degradation.
- These signal inhibitors sensitized cells to PROTAC-induced apoptosis.
Conclusions:
- Cell-intrinsic signaling pathways can counteract chemically induced target degradation at multiple steps.
- Inhibitors of specific signaling pathways can overcome these counteracting mechanisms, enhancing targeted protein degradation.
- This study reveals a druggable strategy to potentiate PROTAC efficacy in cancer therapy.
More Related Videos
Related Concept Videos
02:58Regulated Protein Degradation
7.2K
It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
7.2K
01:22Amplifying Signals via Enzymatic Cascade
8.5K
When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
8.5K
01:19Interactions Between Signaling Pathways
6.3K
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.3K
01:31The Intrinsic Apoptotic Pathway
6.5K
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
6.5K
01:13The Proteasome
827
Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
827
01:17The Extrinsic Apoptotic Pathway
6.3K
The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
6.3K