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.

The Molecular Connections between Lung and Pancreatic Cancer Metastases: are we not seeing the Forest for the Trees?

“…Likewise, the Hh pathway crosstalks with other pathways such as TGFβ and IGF-R. If TGFβ and IGF-R pathways are abrogated, their downstream targets are still activated by Hh [160,161]. Thus, genetic redundancy fortifies natural selection for cell survival (drug resistance) [162].…”

“…Indeed, this is what we see in acquired and intrinsic drug resistance. Despite treatment with pathway inhibitors, LC and PC phenotypes and variations thereof continue to progress and metastasize [80,160]. The 'synthetic lethality' approach aims to thwart oncogene addiction and panresistance -fortified disease progression through the exploits of functional redundancy [157,160].…”

Primary Cilia and Coordination of Receptor Tyrosine Kinase (RTK) and Transforming Growth Factor β (TGF-β) Signaling

“…These include mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)-AKT, Hippo, nuclear factor k light-chain enhancer of activated B cells (NF-kB), and mammalian target of rapamycin (mTOR) pathways (Boehlke et al 2010;Christensen et al 2012;Wann et al 2014;Hansen et al 2015;Umberger and Caspary 2015). In addition, primary cilia were proposed to play a critical role in coordinating the balanced regulation of WNT/b-catenin versus WNT/PCP ( planar cell polarity) pathways (Lienkamp et al 2012;Oh and Katsanis 2013;Veland et al 2013;Li et al 2015;Saito et al 2015), which extensively cross talk with SHH, TGF-b, RTK, MAPK, Hippo, and Notch signaling (Bernascone and Martin-Belmonte 2013;Zhang et al 2014;Borggrefe et al 2016;Zhang et al 2016).…”

“…In canonical signaling, the type I receptor is responsible for phosphorylation of R-SMADs, which comprise SMAD2/3 in TGF-b -activin -Nodal signaling and SMAD1/ 5/8 in BMP signaling. The R-SMADs then interact with SMAD4 for nuclear translocation as well as with different DNA-binding transcription factors, which are activated by other receptor pathways, such as in RTK, HH, Hippo, and WNT signaling (Guo and Wang 2009;Varelas and Wrana 2012;Zhang et al 2016). Signaling includes the expression of SMAD7, which antagonizes TGF-b signaling through multiple mechanisms in the cytoplasm and in the nucleus, including SMURF1/2-mediated ubiquitination and degradation of TGF-bRI and RSMADs (Yan and Chen 2011).…”

The progression of epithelial-mesenchymal transformation in gliomas

“…Zhang J. et al found that the EMT and mesenchymal-to-epithelial transition (MET, its reverse process), were reduplicative and alternatively occurred in chicken's epithelial cells [1]. In the recent 30 years, EMT becomes a hot research field and is generally divided into three different subtypes [2].…”