(416f) Quantitative Modeling and Analysis of the Transforming Growth Factor Beta Signaling Pathway

Transforming growth factor β (TGF-β) signaling
regulates a wide range of cellular and physiologic processes including
proliferation, cell survival, differentiation, migration, angiogenesis, and
immune surveillance. It is therefore not surprising that this ligand plays a
significant role in the development and progression of cancer. The current
consensus is that TGF-β affects tumor pathogenesis both positively and
negatively, functioning as a tumor suppressor in the premalignant stages of
tumorigenesis and apparently as a tumor promoter in later stages of cancer
leading to metastasis. Despite the prominent roles of TGF-β in both normal
and cancerous cellular processes, the detailed mechanisms of how TGF-β
induces such diverse and sometimes contradictory responses remain poorly
understood. To help understand TGF-β signaling quantitatively, we have
developed a dynamic mathematical model of the canonical TGF-β pathway via
Smad transcription factors, the major intracellular mediators of the signaling
cascades, based on reported experimental observations in literature. 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 yields
quantitative insight into how TGF-β-induced
responses can be modulated and regulated. Considering that Smad nuclear
accumulation is necessary for transcriptional regulation, our model analysis
reveals that mechanisms associated with Smad activation by ligand-activated
receptor, nuclear complex formation between Smad proteins, and inactivation of
ligand-activated Smad (e.g. degradation, dephosphorylation) may be critical for
regulating TGF-β-targeted functional responses by affecting the intensity
and duration of nuclear retention of Smad proteins. The model also predicts
possible dynamic behavior of the Smad-mediated pathway in abnormal cells, and
provides clues regarding possible mechanisms for explaining the seemingly contradictory
roles of TGF-β during cancer progression. Based on the reported
observations that TGF-β receptors are abnormally altered in a variety of
human cancers, simulations of cancerous signaling using our model indicate that
reduction in the levels of functional receptors may lead to altered TGF-β
signaling behavior where tumor suppression characteristics are lost as a result
of attenuated and transient Smad nuclear accumulation. Considering the differences
in the dynamics of transcriptionally active Smad in the nucleus between the
normal and cancerous signaling systems, the TGF-β paradox may be partially
explained by a hypothesis that signaling thresholds of anti-oncogenic responses
are different from those of pro-oncogenic responses.