title: 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.
authors.affiliation: Modeling of Biological Networks Laboratory, Department of Biomedical Engineering, University of California Davis, Davis, California, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Nicklas
authors.affiliation: Modeling of Biological Networks Laboratory, Department of Biomedical Engineering, University of California Davis, Davis, California, United States of America.
authors.forename: Leonor
authors.initials: L
authors.lastname: Saiz
mesh_terms: D000465:Algorithms; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D016000:Cluster Analysis; D003198:Computer Simulation; D025461:Feedback, Physiological; D006801:Humans; D008024:Ligands; D051379:Mice; D008954:Models, Biological; D015398:Signal Transduction; D051906:Smad7 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D008024:Ligands; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta