Quantitative modeling and analysis of the transforming growth factor β signaling pathway

Transforming growth factor β (TGF-β) 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-β 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-β elicits such diverse responses during cancer progression are still not entirely clear. As a first step toward understanding TGF-β signaling quantitatively, we have developed a comprehensive, dynamic model of the canonical TGF-β pathway via Smad transcription factors. By describing how an extracellular signal of the TGF-β ligand is sensed by receptors and transmitted into the nucleus through intracellular Smad proteins, the model provides quantitative insight into how TGF-β-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-β-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-β's tumor-suppressive roles may appear to morph into tumor-promotion during cancer progression.