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. 2012:2012:289243.
doi: 10.1155/2012/289243. Epub 2012 Jan 29.

The Roles of Mitogen-Activated Protein Kinase Pathways in TGF-β-Induced Epithelial-Mesenchymal Transition

Ting Gui  1 , Yujing Sun, Aiko Shimokado, Yasuteru Muragaki
Affiliations

The Roles of Mitogen-Activated Protein Kinase Pathways in TGF-β-Induced Epithelial-Mesenchymal Transition

Ting Gui et al. J Signal Transduct. 2012.

Abstract

The mitogen-activated protein kinase (MAPK) pathway allows cells to interpret external signals and respond appropriately, especially during the epithelial-mesenchymal transition (EMT). EMT is an important process during embryonic development, fibrosis, and tumor progression in which epithelial cells acquire mesenchymal, fibroblast-like properties and show reduced intercellular adhesion and increased motility. TGF-β signaling is the first pathway to be described as an inducer of EMT, and its relationship with the Smad family is already well characterized. Studies of four members of the MAPK family in different biological systems have shown that the MAPK and TGF-β signaling pathways interact with each other and have a synergistic effect on the secretion of additional growth factors and cytokines that in turn promote EMT. In this paper, we present background on the regulation and function of MAPKs and their cascades, highlight the mechanisms of MAPK crosstalk with TGF-β signaling, and discuss the roles of MAPKs in EMT.

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Figures

Figure 1
Figure 1
The network of the mitogen-activated protein kinase (MAPK) family. Extracellular stimuli transduce signals to the nucleus. The sequential phosphorylation of MAPKKK, MAPKK, and MAPK activates their nuclear targets, kinases, and transcription factors. For details, refer to the text.
Figure 2
Figure 2
The involvement of JNK and p38 MAPK pathways in the TGF-β-induced epithelial-mesenchymal transition. Upon TGF-β ligation, the receptor phosphorylates Smad2/3 and interacts with TRAF6, which recruits TAK1 and TAB1 to activate JNK and p38 MAPK. The activated JNK and p38 MAPK can act in a Smad-dependent or -independent manner to regulate EMT by controlling the downstream transcriptional factors. This figure depicts the cross-talk between JNK, p38 MAPK, and TGF-β signaling in different cellular systems and illustrates how these networks may function in a stimuli-dependent manner to determine the EMT response.
Figure 3
Figure 3
The involvement of the ERK pathway in the TGF-β-induced epithelial-mesenchymal transition. After TGF-β induces the phosphorylation of serine and/or tyrosine on TβRI and/or ShcA, ShcA is capable of recruiting Grb2 and Sos to active ERK1/2 through Ras, Raf, and MEK1/2. The activation of Ras can also be induced by HGF to control the EMT, which is regulated by Snail. This figure depicts the cross-talk between ERK, TGF-β, and other factors in different cellular systems and illustrates how these networks may function in a stimuli-dependent manner to determine the EMT response.
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