Related Experiment Video

Updated: Jun 28, 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

2.2K

TAK1 inhibition leads to RIPK1-dependent apoptosis in immune-activated cancers

Helene Damhofer1,2,3, Tülin Tatar1,3, Benjamin Southgate4

  • 1Division of Cancer Biology, The Institute of Cancer Research, London, UK.

Cell Death & Disease
|April 17, 2024
PubMed

Insights

Targeting TGFβ activated kinase (TAK1) offers a new therapeutic strategy for glioblastoma (GBM) by inducing apoptosis in glioma stem cells (GSCs). This approach shows promise for immune-activated cancers, including mesenchymal GBM.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Stem Cell Biology

Background:

  • Glioblastoma (GBM) exhibits poor survival rates and limited treatment responses, largely due to persistent glioma stem cells (GSCs).
  • Identifying novel therapeutic targets within GSCs is crucial for improving GBM patient outcomes.

Purpose of the Study:

  • To identify novel therapeutic targets in glioblastoma stem cells.
  • To investigate the role of TGFβ activated kinase (TAK1) as a survival factor in GSCs.
  • To explore therapeutic strategies targeting TAK1 in GBM.

Main Methods:

  • CRISPR/Cas9 knockout screens were employed to identify GSC survival factors.
  • Investigated the mechanism of TAK1 loss-induced apoptosis, including RIPK1, Caspase-8, FADD, TNFα, and TNFR signaling.
  • Identified a transcriptional signature for predicting sensitivity to TAK1 inhibition.
  • Assessed the impact of pro-inflammatory cytokines (IFNγ, TNFα) on GSC sensitivity to TAK1 inhibition.

Main Results:

  • TGFβ activated kinase (TAK1) was identified as a selective survival factor for a subset of GSCs.
  • Loss of TAK1 kinase activity triggers RIPK1-dependent apoptosis via Caspase-8/FADD activation, mediated by autocrine TNFα and TNFR signaling.
  • A specific transcriptional signature associated with immune activation and mesenchymal GBM subtypes predicts sensitivity to TAK1 inhibition.
  • Pro-inflammatory cytokines IFNγ and TNFα can sensitize resistant GSCs to TAK1 inhibition.

Conclusions:

  • TAK1 kinase activity is a novel vulnerability in immune-activated cancers, particularly mesenchymal GBM.
  • Targeting TAK1 represents a promising therapeutic strategy for glioblastoma.
  • The identified transcriptional signature can predict therapeutic response to TAK1 inhibitors like HS-276.

More Related Videos

Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis08:55

Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis

Published on: August 7, 2018

10.8K
Evaluation of Caspase Activation to Assess Innate Immune Cell Death10:23

Evaluation of Caspase Activation to Assess Innate Immune Cell Death

Published on: January 20, 2023

3.2K

Related Concept Videos

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...
6.5K
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...
6.3K
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
8.8K
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...
3.5K
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
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.4K