In silico investigation of ADAM12 effect on TGF-β receptors trafficking

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-β receptors internalization rate between the cell surface and the endosomal membrane. It also appears that ADAM12 modifies TGF-β signaling shape favoring a permanent response by removing the transient component observed under physiological conditions.In this work, confronting differential models with qualitative biological observations, we obtained predictions giving new insights into the role of ADAM12 in TGF-β signaling and hepatic fibrosis process.During chronic liver injury, the sustained wound healing response leads to fibrosis and cirrhosis. Among the molecular components involved in fibrogenesis, the transforming growth factor, TGF-β is the most potent profibrotic cytokine. Indeed, several authors have shown that alteration of TGF-β dependent signaling pathway is associated with liver fibrosis [1,2]. In this system, the first cellular control point is at the membrane. TGF-β transmits its signal through a heteromeric complex of two types of transmembrane receptors, TβRI and TβRII. TGF-β binding to TβRII induces recruitment and phosphorylation of TβRI, which activates R-Smad intracellular signaling [3]. At the membrane, an important feature of TGF-β signaling is the continuous internalization of receptors and ligand-receptor complexes through two endocytosis pathways: the clathrin-coated pit endocytosis, mediating R-Smad signaling cascade, and the caveolin mediated endocytosis, leading to degradation of receptors through the proteasome pathway [4,5].We have recently demonstrated that ADAM12, a member of the disintegrin and metalloproteinase family associated with liver fibrogenesis [6,7], facilitates TGF-β signaling at the membrane [8]. ADAM12 interacts