(541b) Quantitative Modeling and Analysis of TGF-β-Induced Erk/MAPK and Smad Signaling

Transforming growth factor β (TGF-β), which plays a pivotal role in regulating a wide array of cellular and physiologic processes in both normal and pathological cells, is known to function as a potent tumor suppressor during the early stage of tumorigenesis, primarily by inhibiting cell proliferation and inducing apoptosis. However, in the late phases of tumor progression, the role of TGF-β appears to become one of tumor promotion, apparently supporting growth, subverting the immune system, and also facilitating epithelial-to-mesenchymal transition (EMT), invasion and angiogenesis. While these various cellular responses are known to be induced via several TGF-β-driven signaling cascades that include both the canonical Smad and non-Smad pathways, significant research efforts have been devoted almost exclusively to the canonical Smad-meditated intracellular signaling pathway due to its primary anti-proliferative effects; the non-Smad pathways, are less well-characterized, even though they also play non-trivial roles in carcinogenesis. Of the various non-Smad pathways of interest, a growing body of evidence has demonstrated the importance of Erk/MAPK signaling during cancer progression because TGF-β-induced Erk activation is critical for EMT, a process that ultimately leads to tumor cell invasion and metastasis. To obtain a more complete quantitative understanding of the role of TGF-β signaling during cancer progression, we have developed a comprehensive mathematical model of TGF-β signaling that combines the Erk-MAPK pathways with the canonical Smad pathway using information from experimental observations reported in the literature. By describing how an extracellular TGF-β ligand signal is sensed by receptors and transmitted via these two separate intracellular pathways, the model yields quantitative insight into how TGF-β-induced responses can be modulated and regulated. The model also predicts possible dynamic behavior of the Erk-mediated pathway in cancerous cells that provide clues regarding possible explanatory mechanisms for the seemingly contradictory roles of TGF-β during cancer progression. In particular, a comparison of the differences in the dynamics of transcriptionally active Smad and Erk between normal and cancerous signaling systems suggests that an imbalance between lipid-raft and non-raft TGF-β receptor internalization can lead to TGF-β-induced EMT in cancer cells.