BMC research notes · 2009
In silico investigation of ADAM12 effect on TGF-beta receptors trafficking.
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Gruel Jérémy, Leborgne Michel, LeMeur Nolwenn, Théret Nathalie
Аннотация
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.
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.