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Updated: Mar 8, 2026

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
Force interacts with macromolecular structure in activation of TGF-β
Xianchi Dong1, Bo Zhao1, Roxana E Iacob2
1Children's Hospital Boston and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Integrins like αVβ6 remodel extracellular matrix by binding and applying force to pro-TGF-β1. This binding stabilizes a specific orientation, enabling force transmission for growth factor release.
Area of Science:
- Cellular Biology
- Biochemistry
- Structural Biology
Background:
- Integrins are crucial adhesion receptors mediating cell-matrix interactions and force transmission.
- Integrin binding to transforming growth factor-β1 precursor (pro-TGF-β1) is essential for releasing active TGF-β.
- Mechanisms of integrin binding to macromolecular ligands and force transmission remain poorly understood.
Purpose of the Study:
- To elucidate the binding mechanism of integrin αVβ6 to pro-TGF-β1.
- To understand how integrin binding remodels extracellular matrix ligands.
- To define the pathway of force transmission from the actin cytoskeleton to pro-TGF-β1 via integrins.
Main Methods:
- Structural analysis of integrin αVβ6 bound to pro-TGF-β1.
- Computational simulations of force-dependent activation.
- Analysis of conformational changes in pro-TGF-β1 upon integrin binding.
Main Results:
- Integrin αVβ6 binds pro-TGF-β1 in a specific orientation critical for TGF-β release.
- Integrin binding induces conformational changes extending beyond the binding interface, remodeling the prodomain.
- Specific regions, both within and outside the interface, stabilize the integrin-pro-TGF-β1 complex and dictate force transmission pathways.
Conclusions:
- Integrin αVβ6 binding to pro-TGF-β1 involves extensive remodeling of the ligand, influencing its conformation.
- The study reveals how integrins transmit force through macromolecular ligands, utilizing specific orientations and evolutionary specializations.
- Force is transmitted through the pro-TGF-β1 prodomain and the β-subunit of the integrin, highlighting subunit-specific roles in activation.
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