Related Experiment Video

Updated: Jun 8, 2026

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
06:54

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells

Published on: October 27, 2020

TGFβ induces proHB-EGF shedding and EGFR transactivation through ADAM activation in gastric cancer cells

Masahide Ebi1, Hiromi Kataoka, Takaya Shimura

  • 1Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

Biochemical and Biophysical Research Communications
|October 12, 2010
PubMed
Abstract

Insights

Transforming growth factor-beta (TGFβ) promotes gastric cancer cell growth by activating ADAM17, which leads to nuclear translocation of HB-EGF-CTF and EGFR transactivation. Inhibiting ADAM17 blocks this pathway, suppressing cancer cell proliferation.

Area of Science:

  • Cell Biology
  • Cancer Research
  • Molecular Signaling

Background:

  • Transforming growth factor-beta (TGFβ) typically inhibits cell growth, but its role in cancer progression is complex.
  • Loss of TGFβ responsiveness is common in cancers, yet the underlying mechanisms remain unclear.
  • Heparin-binding EGF-like growth factor (HB-EGF) signaling, particularly the nuclear translocation of its C-terminal fragment (CTF), has been linked to cell growth.

Purpose of the Study:

  • To investigate the association between TGFβ signaling and HB-EGF shedding via ADAM activation in gastric cancer.
  • To elucidate the role of ADAM-mediated proHB-EGF processing in TGFβ-induced gastric cancer cell proliferation.
  • To examine the involvement of EGFR transactivation and HB-EGF-CTF nuclear translocation in this pathway.

Main Methods:

  • Utilized CCK-8 assays to assess cell growth in gastric cancer cell lines.
  • Employed ADAM inhibitors to evaluate their effects on TGFβ-induced signaling and cell proliferation.
  • Analyzed EGFR phosphorylation, proHB-EGF shedding, HB-EGF-CTF nuclear translocation, and cell growth under ADAM17 knockdown conditions.

Main Results:

  • TGFβ induced EGFR phosphorylation, which was inhibited by ADAM inhibitors.
  • TGFβ stimulated proHB-EGF shedding, leading to HB-EGF-CTF nuclear translocation, an effect blocked by ADAM inhibitors.
  • TGFβ enhanced gastric cancer cell growth, and ADAM inhibitors suppressed this proliferation.
  • ADAM17 knockdown abrogated TGFβ-induced EGFR phosphorylation, HB-EGF-CTF nuclear translocation, and cell growth.

Conclusions:

  • TGFβ activates ADAM17, promoting proHB-EGF shedding and subsequent HB-EGF-CTF nuclear translocation.
  • This pathway, involving EGFR transactivation, is a key mechanism by which TGFβ drives gastric cancer cell proliferation.
  • Targeting ADAM17 may offer a therapeutic strategy for gastric cancers exhibiting resistance to TGFβ-induced growth inhibition.

More Related Videos

Multiomics Analysis of TMEM200A as a Pan-Cancer Biomarker07:47

Multiomics Analysis of TMEM200A as a Pan-Cancer Biomarker

Published on: September 15, 2023

Related Concept Videos

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 are of three kinds RI, RII, and RIII. The RI...
Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
GPCRs Regulate Adenylyl Cylase Activity01:09

GPCRs Regulate Adenylyl Cylase Activity

Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of cells.
Two...
Activation and Inactivation of G Proteins01:22

Activation and Inactivation of G Proteins

Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high affinity and are together...
Regulation of Angiogenesis and Blood Supply01:24

Regulation of Angiogenesis and Blood Supply

Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits.  Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl hydroxylase and factor...
Intracellular Signaling Affects Focal Adhesions01:17

Intracellular Signaling Affects Focal Adhesions

Integrins act both as extracellular input receivers and as intracellular processing activators. As their name suggests, integrins are entirely integrated into the membrane structure. Their hydrophobic membrane-spanning regions interact with the phospholipid bilayer's hydrophobic region. These membrane receptors provide extracellular attachment sites for effectors like hormones and growth factors. They activate intracellular response cascades when their effectors are bound and active.
Some...