Related Experiment Video

Updated: Jul 16, 2025

Tyramide Signal Amplification for the Immunofluorescent Staining of ZBP1-Dependent Phosphorylation of RIPK3 and MLKL After HSV-1 Infection in Human Cells
09:15

Tyramide Signal Amplification for the Immunofluorescent Staining of ZBP1-Dependent Phosphorylation of RIPK3 and MLKL After HSV-1 Infection in Human Cells

Published on: October 20, 2022

2.3K

Small molecule activators of TAK1 promotes its activity-dependent ubiquitination and TRAIL-mediated tumor cell death

Weimin Sun1, Guowei Wu1, Xinyu Tian1

  • 1Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201203, China.

Proceedings of the National Academy of Sciences of the United States of America
|September 21, 2023
PubMed

Insights

Small molecules R406/R788 activate TAK1 (transforming growth factor-activated kinase 1), enhancing RIPK1-dependent cell death. These TAK1 activators potentiate TRAIL-based cancer therapies by promoting sustained TAK1 and RIPK1 activation.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Cancer Research

Background:

  • Transforming growth factor-activated kinase 1 (TAK1) is crucial for NF-κB and RIPK1 signaling pathways.
  • TAK1 activation mediates key phosphorylation events in the TNF signaling pathway, influencing cell death and survival.
  • Targeting RIPK1-mediated necroptosis is a potential strategy for cancer therapy.

Purpose of the Study:

  • To identify small molecules that activate RIPK1-mediated necroptosis.
  • To investigate the mechanism of action of novel TAK1 activators.
  • To evaluate the therapeutic potential of TAK1 activators in combination with TRAIL for cancer treatment.

Main Methods:

  • Screening for small molecule activators of RIPK1-mediated necroptosis.
  • Biochemical binding assays and click chemistry to determine TAK1 activation mechanism.
  • Assessment of cell sensitization to TNF-mediated necroptosis and apoptosis.
  • In vitro and in vivo studies evaluating combination therapy with TRAIL.

Main Results:

  • R406 and R788 were identified as small molecules promoting sustained TAK1 activation.
  • R406 directly binds and activates TAK1, independent of Syk kinase.
  • Treatment with R406 enhances RIPK1 activation, sensitizing cells to necroptosis and apoptosis.
  • R406/R788 promote TAK1 ubiquitination and interaction with RIPK1.
  • R406/R788 enhance the anti-cancer efficacy of TRAIL in vitro and in mouse models.

Conclusions:

  • Small molecule-mediated activation of TAK1 is a viable strategy to enhance RIPK1-dependent cell death.
  • R406/R788 represent promising compounds for potentiating TRAIL-based anticancer therapies.
  • Targeting TAK1 offers a novel approach to sensitize cancer cells to apoptosis and necroptosis.
Keywords:
RIPK1TAK1cell death

More Related Videos

Enhancement of Apoptotic and Autophagic Induction by a Novel Synthetic C-1 Analogue of 7-deoxypancratistatin in Human Breast Adenocarcinoma and Neuroblastoma Cells with Tamoxifen19:44

Enhancement of Apoptotic and Autophagic Induction by a Novel Synthetic C-1 Analogue of 7-deoxypancratistatin in Human Breast Adenocarcinoma and Neuroblastoma Cells with Tamoxifen

Published on: May 30, 2012

18.7K
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs10:44

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Published on: May 15, 2019

13.3K

Related Concept Videos

The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

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...
6.4K
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

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...
6.6K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.8K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
3.6K
Enzyme-linked Receptors01:00

Enzyme-linked Receptors

Enzyme-linked receptors are proteins that act as both receptor and enzyme, activating multiple intracellular signals. This is a large group of receptors that include the receptor tyrosine kinase (RTK) family. Many growth factors and hormones bind to and activate the RTKs.
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds...
78.7K
Cytotoxic T Cells-mediated Immune Response01:27

Cytotoxic T Cells-mediated Immune Response

Cytotoxic T cells are a vital component of the immune system. They have the remarkable ability to identify and target antigens on infected or abnormal cells. These antigens often originate from intracellular pathogens such as viruses or abnormal proteins cancer cells produce.
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...
956