Quantitative modeling and analysis of the transforming growth factor beta signaling pathway.
Transforming growth factor beta (TGF-beta) signaling, which regulates multiple cellular processes including proliferation, apoptosis, and differentiation, plays an important but incompletely understood role in normal and cancerous tissues. For instance, although TGF-beta functions as a tumor suppressor in the premalignant stages of tumorigenesis, paradoxically, it also seems to act as a tumor promoter in advanced cancer leading to metastasis. The mechanisms by which TGF-beta elicits such diverse responses during cancer progression are still not entirely clear. As a first step toward understanding TGF-beta signaling quantitatively, we have developed a comprehensive, dynamic model of the canonical TGF-beta pathway via Smad transcription factors. By describing how an extracellular signal of the TGF-beta ligand is sensed by receptors and transmitted into the nucleus through intracellular Smad proteins, the model provides quantitative insight into how TGF-beta-induced responses are modulated and regulated. Subsequent model analysis shows that mechanisms associated with Smad activation by ligand-activated receptor, nuclear complex formation among Smad proteins, and inactivation of ligand-activated Smad (e.g., degradation, dephosphorylation) may be critical for regulating TGF-beta-targeted functional responses. The model was also used to predict dynamic characteristics of the Smad-mediated pathway in abnormal cells, from which we generated four testable hypotheses regarding potential mechanisms by which TGF-beta's tumor-suppressive roles may appear to morph into tumor-promotion during cancer progression.
Chung
Seung-Wook
SW
Department of Chemical Engineering, University of Delaware, Newark, Delaware 19716, USA
Miles
Fayth L
FL
Sikes
Robert A
RA
Cooper
Carlton R
CR
Farach-Carson
Mary C
MC
Ogunnaike
Babatunde A
BA
D021581:Active Transport, Cell Nucleus; D000465:Algorithms; D002467:Cell Nucleus / Q000378:metabolism; D015870:Gene Expression; D016018:Least-Squares Analysis; D008024:Ligands; D008954:Models, Biological; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism; D010766:Phosphorylation; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D008024:Ligands; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta