Journal Article

TGF-β regulates isoform switching of FGF receptors and epithelial-mesenchymal transition

Horiguchi, Kana, Miyazawa, Keiji, Ehata, Shogo, Saitoh, Masao, Shirakihara, Takuya, Morita, Ikuo, Shibata, Tatsuhiro, Miyazono, Kohei

2011

Overview

The epithelial–mesenchymal transition (EMT) is a crucial event in wound healing, tissue repair, and cancer progression in adult tissues. Here, we demonstrate that transforming growth factor (TGF)‐β induced EMT and that long‐term exposure to TGF‐β elicited the epithelial–myofibroblastic transition (EMyoT) by inactivating the MEK‐Erk pathway. During the EMT process, TGF‐β induced isoform switching of fibroblast growth factor (FGF) receptors, causing the cells to become sensitive to FGF‐2. Addition of FGF‐2 to TGF‐β‐treated cells perturbed EMyoT by reactivating the MEK‐Erk pathway and subsequently enhanced EMT through the formation of MEK‐Erk‐dependent complexes of the transcription factor δEF1/ZEB1 with the transcriptional corepressor CtBP1. Consequently, normal epithelial cells that have undergone EMT as a result of combined TGF‐β and FGF‐2 stimulation promoted the invasion of cancer cells. Thus, TGF‐β and FGF‐2 may cooperate with each other and may regulate EMT of various kinds of cells in cancer microenvironment during cancer progression. Both TGF‐β and FGF signalling regulate the epithelial–mesenchymal transition. Here, TGF‐β is found to promote myofibroblast differentiation, while concomitant FGF pathway activation instead drives cells towards an invasive mesenchymal fate.

• Publisher: John Wiley & Sons, Ltd,Nature Publishing Group UK,Nature Publishing Group
• Subject: Actins - genetics / Actins - metabolism / Alcohol Oxidoreductases - metabolism / Alternative Splicing - drug effects / Alternative Splicing - genetics / Cell Differentiation - drug effects / Cell Differentiation - genetics / Cell Differentiation - physiology / Cells, Cultured / DNA-Binding Proteins - metabolism / EMT / Epithelial-Mesenchymal Transition - drug effects / Epithelial-Mesenchymal Transition - genetics / Epithelial-Mesenchymal Transition - physiology / FGF receptor / FGF-2 / Fibroblast Growth Factor 2 - metabolism / Fibroblast Growth Factor 2 - pharmacology / Gene Expression Regulation, Neoplastic - drug effects / Homeodomain Proteins - metabolism / Humans / Models, Biological / Myofibroblasts - drug effects / Myofibroblasts - metabolism / Myofibroblasts - physiology / Neoplasm Invasiveness / Neoplasms - genetics / Neoplasms - metabolism / Neoplasms - pathology / Protein Binding - drug effects / Protein Binding - genetics / Protein Isoforms - genetics / Protein Isoforms - metabolism / Protein Isoforms - physiology / Receptors, Fibroblast Growth Factor - genetics / Receptors, Fibroblast Growth Factor - metabolism / Signal Transduction - genetics / TGF-β / Transcription Factors - metabolism / Transforming Growth Factor beta - pharmacology / Transforming Growth Factor beta - physiology / Zinc Finger E-box-Binding Homeobox 1 / δEF1