In silico investigation of ADAM12 effect on TGF-beta receptors trafficking.

Jérémy Gruel 1, 2, * Michel Leborgne 3 Nolwenn Lemeur 1, 2 Nathalie Théret 1, 2
* Corresponding author
3 SYMBIOSE - Biological systems and models, bioinformatics and sequences
IRISA - Institut de Recherche en Informatique et Systèmes Aléatoires, Inria Rennes – Bretagne Atlantique
Abstract : 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.
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Jérémy Gruel, Michel Leborgne, Nolwenn Lemeur, Nathalie Théret. In silico investigation of ADAM12 effect on TGF-beta receptors trafficking.. BMC Research Notes, BioMed Central, 2009, 2 (1), pp.193. ⟨10.1186/1756-0500-2-193⟩. ⟨inserm-00663589⟩

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