Characterization of negative feedback network motifs in the TGF-β signaling pathway.

Abstract

The transforming growth factor-β (TGF-β) superfamily of cytokines plays a fundamental role in a wide variety of cellular processes, including growth, differentiation, apoptosis, and tissue homeostasis [corrected]. Its relevance is emphasized by the mutations of its core components that are associated with diverse human diseases, such as cancer and cardiovascular pathologies. A prominent regulator of the pathway is Smad7, which attenuates the signal and controls its duration in a cell-type-dependent manner through a negative feedback loop. Here, we characterize all the potential Smad7-mediated negative feedback network motifs and investigate their effects on the signaling dynamics upon stimulation with TGF-β and bone morphogenetic protein (BMP) ligands. The results show that the specific negative feedback implementation is a key determinant of both the response of the system to single and multiple ligands of the TGF-β superfamily and its robustness and sensitivity to parameter perturbations.