TGF-beta-induced epithelial to mesenchymal transition

Abstract

During development and in the context of different morphogenetic events, epithelial cells undergo a process called epithelial to mesenchymal transition or transdifferentiation (EMT). In this process, the cells lose their epithelial characteristics, including their polarity and specialized cell-cell contacts, and acquire a migratory behavior, allowing them to move away from their epithelial cell community and to integrate into surrounding tissue, even at remote locations. EMT illustrates the differentiation plasticity during development and is complemented by another process, called mesenchymal to epithelial transition (MET). While being an integral process during development, EMT is also recapitulated under pathological conditions, prominently in fibrosis and in invasion and metastasis of carcinomas. Accordingly, EMT is considered as an important step in tumor progression. TGF-beta signaling has been shown to play an important role in EMT. In fact, adding TGF-beta to epithelial cells in culture is a convenient way to induce EMT in various epithelial cells. Although much less characterized, epithelial plasticity can also be regulated by TGF-beta-related bone morphogenetic proteins (BMPs), and BMPs have been shown to induce EMT or MET depending on the developmental context. In this review, we will discuss the induction of EMT in response to TGF-beta, and focus on the underlying signaling and transcription mechanisms.

Figure 1

Epithelial-mesenchymal transition (EMT) occurs when epithelial cells lose their epithelial cell characteristics, including dissolution of cell-cell junctions, i.e. tight junctions (black), adherens junctions (blue) and desmosomes (green), and loss of apical-basolateral polarity, and acquire a mesenchymal phenotype, characterized by actin reorganization and stress fiber formation (red), migration and invasion.

Figure 2

Transcriptional regulation of EMT induced by TGF-β. In response to TGF-β, Smad2 and 3 are activated, and form complexes with Smad4, which then regulate transcription of target genes through interactions with other DNA binding transcription factors. In the induction of EMT, the activated Smads mediate transcriptional regulation through three families of transcription factors, resulting in repression of epithelial marker gene expression and activation of mesenchymal gene expression.

Figure 3

Non-Smad signaling in response to TGF-β. (A) TGF-β activates p38 MAP kinase and JNK MAP kinase signaling through the activation of TAK1 by receptor-associated TRAF6, and Erk MAP kinase signaling through recruitment and phosphorylation of Shc by the TβRI receptor. (B) Activation of RhoA in response to TGF-β and induction of ubiquitin-mediated RhoA degradation at tight junctions. (C) TGF-β induces PI3-kinase signaling, leading to the activation of Akt-mTOR signalin, and consequently to increased translation.

Figure 4

Signaling crosstalk between the TGF-β-activated Smad pathway and the Wnt- and Notch-activated signaling pathways during EMT. TGF-β signaling interacts with the Wnt pathway at multiple levels, by regulating the activity of β-catenin, or through interactions of Smad complexes with β-catenin and/or TCF/LEF1. TGF-β signaling crosstalks with the Notch pathway, through interactions of Smad complexes with RBPJK/CBF1/Su to regulate EMT-related gene transcription.