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Published on: October 27, 2020
In silico investigation of ADAM12 effect on TGF-beta receptors trafficking
Jérémy Gruel1, Michel Leborgne, Nolwenn LeMeur
1EA 4427 SeRAIC/INSERM U620, Université de Rennes 1, Rennes, France. gruelj@gmail.com
Background:
The transforming growth factor beta is known to have pleiotropic effects, including differentiation, proliferation and apoptosis. However the underlying mechanisms remain poorly understood. The regulation and effect of TGF-beta signaling is complex and highly depends on specific protein context. In liver, we have recently showed that the disintegrin and metalloproteinase ADAM12 interacts with TGF-beta receptors and modulates their trafficking among membranes, a crucial point in TGF-beta signaling and development of fibrosis. The present study aims to better understand how ADAM12 impacts on TGF-beta receptors trafficking and TGF-beta signaling.
Findings:
We extracted qualitative biological observations from experimental data and defined a family of models producing a behavior compatible with the presence of ADAM12. We computationally explored the properties of this family of models which allowed us to make novel predictions. We predict that ADAM12 increases TGF-beta receptors internalization rate between the cell surface and the endosomal membrane. It also appears that ADAM12 modifies TGF-beta signaling shape favoring a permanent response by removing the transient component observed under physiological conditions.
Conclusion:
In this work, confronting differential models with qualitative biological observations, we obtained predictions giving new insights into the role of ADAM12 in TGF-beta signaling and hepatic fibrosis process.
Insights
The disintegrin and metalloproteinase ADAM12 enhances transforming growth factor beta (TGF-β) receptor internalization and signaling. This modulation favors a sustained cellular response, impacting liver fibrosis development.
Area of Science:
- Cell Biology
- Biochemistry
- Systems Biology
Background:
- Transforming growth factor beta (TGF-β) exhibits diverse cellular effects, but mechanisms are unclear.
- TGF-β signaling is context-dependent and influenced by protein interactions.
- ADAM12 interacts with TGF-β receptors, affecting their trafficking and liver fibrosis.
Purpose of the Study:
- To elucidate the impact of ADAM12 on TGF-β receptor trafficking.
- To understand how ADAM12 influences TGF-β signaling pathways.
Main Methods:
- Qualitative biological observations from experimental data.
- Computational modeling and analysis of biological systems.
- Differential modeling confronted with biological data.
Main Results:
- ADAM12 accelerates TGF-β receptor internalization between cell surface and endosomes.
- ADAM12 alters TGF-β signaling, promoting a sustained response by reducing transient signaling.
- Computational models predicted novel insights into ADAM12 function.
Conclusions:
- Differential modeling provided new perspectives on ADAM12's role in TGF-β signaling.
- ADAM12's modulation of TGF-β signaling is crucial for understanding hepatic fibrosis.
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