In silico investigation of ADAM12 effect on TGF- receptors trafficking

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- 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- receptors and modulates their trafficking among membranes, a crucial point in TGF- signaling and development of fibrosis. The present study aims to better understand how ADAM12 impacts on TGF- receptors trafficking and TGF- 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- receptors internalization rate between the cell surface and the endosomal membrane. It also appears that ADAM12 modifies TGF- 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- signaling and hepatic fibrosis process. © 2009 Gruel et al; licensee BioMed Central Ltd.