Computational Modeling and Analysis of the TGF-β-induced ERK and SMAD Pathways

Abstract

TGF-{beta}, an important cytokine that plays a key role in many diseases regulates a wide array of cellular and physiologic processes via several TGF-{beta}-driven signaling cascades, including the SMAD and non-SMAD-driven pathways. However, the detailed mechanisms by which TGF-{beta} induces such diverse responses remain poorly understood. In particular, compared to the SMAD-dependent pathway, SMAD-independent pathways such as the ERK/MAPK pathway, which is critical in cancer progression, are less characterized. Here, we develop an integrated mechanistic model of the TGF-{beta}-triggered ERK activation pathway and its crosstalk with the SMAD pathway, an analysis of which demonstrates how SMAD dynamics can be significantly modulated and regulated by the ERK pathway. In particular, SMAD-mediated transcription can be altered and delayed due to expedited phosphorylation of the linker of SMAD by TGF-{beta}-activated ERK; and enhanced ERK activity, but attenuated SMAD activity, can be achieved simultaneously by fast turnover of TGF-{beta} receptors via lipid-rafts. Also, in silico mutations of the TGF-{beta} pathways reveal that the dynamic characteristics of both SMAD and ERK signaling may change significantly during cancer development. Specifically, normal cells may exhibit enhanced and sustained SMAD signaling with transient ERK activation, whereas cancerous cells may produce elevated and prolonged ERK signaling with enervated SMAD activation. These distinctive differences between normal and cancerous signaling behavior provide clues concerning, and potential explanations for, the seemingly contradictory roles played by TGF-{beta} during cancer progression. We demonstrate how crosstalk among various branch pathways of TGF-{beta} can influence overall cellular behavior. Based on model analysis, we hypothesize that aberrant molecular alterations drive changes in the intensity and duration of SMAD and ERK signaling during cancer progression and ultimately lead to an imbalance between the SMAD and ERK pathways in favor of tumor promotion. Thus, to treat cancer patients with a genetic signature of oncogenic Ras effectively may require at least a combination therapy to restore both the expression of TGF-{beta} receptors and the GTPase activity of Ras.