Signaling pathway cooperation in TGF-β-induced epithelial-mesenchymal transition

Abstract

Transdifferentiation of epithelial cells into cells with mesenchymal properties and appearance, that is, epithelial-mesenchymal transition (EMT), is essential during development, and occurs in pathological contexts, such as in fibrosis and cancer progression. Although EMT can be induced by many extracellular ligands, TGF-β and TGF-β-related proteins have emerged as major inducers of this transdifferentiation process in development and cancer. Additionally, it is increasingly apparent that signaling pathways cooperate in the execution of EMT. This update summarizes the current knowledge of the coordination of TGF-β-induced Smad and non-Smad signaling pathways in EMT, and the remarkable ability of Smads to cooperate with other transcription-directed signaling pathways in the control of gene reprogramming during EMT.

Figure 1

TGF-β-activated non-Smad pathways in epithelial-mesenchymal transition. In addition to the well-established Smad signaling pathway that controls target gene transcription during EMT, TGF-β family proteins also activate non-Smad pathways. These pathways have non-transcriptional roles in EMT, including dissolution of epithelial junctions, cytoskeletal reorganization and motility, and translational control. They also target Smads and thus help define their functions, while also controling the expression and activation of transcription factors, with which Smad complexes cooperate in the control of gene expression.

Figure 2

Smad complexes can cooperate with transcription pathways in the control of gene expression in epithelial-mesenchymal transition. The Notch, Hedgehog, Wnt and Hippo signaling pathways direct transcriptional activation or repression of target genes by their respective effectors. TGF-β/BMP-activated Smad complexes control target gene transcription in cooperation with an extensive array of DNA binding transcription factors and coactivators and corepressors. This versatility enables the Smad complexes to associate and functionally cooperate with transcription effectors of Notch, Hedgehog, Wnt and Hippo signaling, and, thus, to coordinately control gene reprogramming in EMT. The genes encoding EMT transcription factors are known to be directly activated by TGF-β-activated Smad complexes and may represent examples of such coordinate control. In addition to the pathways shown and discussed, Smads can also coordinately control gene expression with IκB/NFκB, STAT transcription factors and an array of other transcription factors that are respond to signaling pathways.