Signal Transduction Pathways of EMT Induced by TGF-β, SHH, and WNT and Their Crosstalks

Abstract

Epithelial-to-mesenchymal transition (EMT) is a key step in development, wound healing, and cancer development. It involves cooperation of signaling pathways, such as transformation growth factor-β (TGF-β), Sonic Hedgehog (SHH), and WNT pathways. These signaling pathways crosstalk to each other and converge to key transcription factors (e.g., SNAIL1) to initialize and maintain the process of EMT. The functional roles of multi-signaling pathway crosstalks in EMT are sophisticated and, thus, remain to be explored. In this review, we focused on three major signal transduction pathways that promote or regulate EMT in carcinoma. We discussed the network structures, and provided a brief overview of the current therapy strategies and drug development targeted to these three signal transduction pathways. Finally, we highlighted systems biology approaches that can accelerate the process of deconstructing complex networks and drug discovery.

Keywords: EMT; SHH; TGF-β; WNT; modeling; signaling transduction pathways.

Figure 1

Schematic of the overall signal reception, transduction, and response process of EMT. Intracellular and extracellular signals are relayed via four basic units and regulated by positive and negative feedback loops.

Figure 2

Crosstalk among the TGF-β (a, proteins in pink), SHH (b, proteins in orange), and WNT (c, proteins in green) signaling pathways converging to the core regulation unit. In the inserted regulation networks, point arrows represent activation, blunt ones represent inhibition, and dashed lines represent indirect links.

Figure 3

Systems biology study on the core EMT network. (a) Core regulatory network of TGF-β induced EMT revealed by experimental studies. Point arrows represent activation, and blunt ones represent inhibition; and (b) mathematically-predicted bifurcation diagram. Also shown are the corresponding dose-response (D-R) curves that are more familiar to experimentalists. Notice that the D-R curves are different for cells starting from different phenotypes and treated with increasing (blue curve) and decreasing (purple curves) exogenous TGF-β, respectively. This history-dependent hysteresis is a signature of bistable dynamics. The predicted bifurcation diagram has been experimentally confirmed in MCF10A cells. Adapted from [142,144].