Related Experiment Video

Updated: Jan 18, 2026

Combined Use of Tail Vein Metastasis Assays and Real-Time In Vivo Imaging to Quantify Breast Cancer Metastatic Colonization and Burden in the Lungs
10:32

Combined Use of Tail Vein Metastasis Assays and Real-Time In Vivo Imaging to Quantify Breast Cancer Metastatic Colonization and Burden in the Lungs

Published on: December 19, 2019

11.5K

Modulating TAK1 Expression Inhibits YAP and TAZ Oncogenic Functions in Pancreatic Cancer

Raffaela Santoro1, Marco Zanotto1, Francesca Simionato2

  • 1Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, Università degli studi di Verona, Verona, Italy.

Molecular Cancer Therapeutics
|September 29, 2019
PubMed

Insights

We discovered that targeting TGFβ-activated kinase 1 (TAK1) can reduce YAP/TAZ activity in pancreatic cancer. Inhibiting Glycogen synthase kinase 3 (GSK3) with LY2090314, combined with nab-paclitaxel, improved survival in mice.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • YAP/TAZ proteins are key drivers of pancreatic cancer malignancy but are currently undruggable.
  • TGFβ-activated kinase 1 (TAK1) integrates signals that promote pancreatic cancer aggressiveness and chemoresistance.
  • Glycogen synthase kinase 3 (GSK3) inhibition reduces TAK1 levels, suggesting a potential therapeutic strategy.

Purpose of the Study:

  • To investigate if TAK1 sustains the YAP/TAZ program in pancreatic cancer.
  • To determine if inhibiting GSK3 can modulate TAK1 and impair YAP/TAZ functions.
  • To evaluate the therapeutic potential of GSK3 inhibitors in combination with chemotherapy.

Main Methods:

  • Differential gene expression profiling and Ingenuity Pathway Analysis were used to assess TAK1's role.
  • TAK1 expression was modulated using shRNA and GSK3 inhibitors (e.g., LY2090314).
  • In vivo efficacy of LY2090314 with nab-paclitaxel was tested in an orthotopic pancreatic cancer mouse model.

Main Results:

  • TAK1 expression is linked to HIPPO and ubiquitination pathways, significantly impacting YAP/TAZ levels and their target genes.
  • TAK1 stabilizes YAP/TAZ via a complex with TRAF6, promoting K63-ubiquitination over K48-ubiquitination.
  • GSK3 inhibition decreased YAP/TAZ levels and oncogenic functions; LY2090314 plus nab-paclitaxel significantly improved survival in mice.

Conclusions:

  • TAK1 plays a critical role in regulating YAP/TAZ activity in pancreatic cancer.
  • LY2090314 demonstrates potential as a novel therapeutic agent for pancreatic cancer, particularly in combination with nab-paclitaxel.
  • Further clinical development of LY2090314 for pancreatic cancer treatment is warranted.

More Related Videos

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter11:32

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter

Published on: March 27, 2020

7.4K
All-optical Mechanobiology Interrogation of Yes-associated Protein in Human Cancer and Normal Cells using a Multi-functional System09:55

All-optical Mechanobiology Interrogation of Yes-associated Protein in Human Cancer and Normal Cells using a Multi-functional System

Published on: December 20, 2021

3.3K

Related Concept Videos

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...
4.6K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

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...
7.2K
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...
5.4K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
5.1K
TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
10.5K
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...
12.2K