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Cross-talk between TGFβ1 and EGFR signaling pathways induces TM4SF5 expression and Epithelial-Mesenchymal Transition.

Cited 37 time in Web of Science Cited 38 time in Scopus
Authors
Kang, Minkyung; Choi, Suyong; Jeong, Soo-Jin; Lee, Sin-Ae; Kwak, Tae Kyoung; Kim, Hyeonjung; Jung, Oisun; Lee, Mi-Sook; Park SY; Ko, Youra; Ryu, Jihye; Jeong, Doyoung; Lee, Hyo Jeong; Ye, Sang-Kyu; Kim, Sung-Hoon; Lee, Jung Weon; Choi, Yoon-Ju
Issue Date
2012-05
Publisher
Portland Press
Citation
BIOCHEMICAL JOURNAL Vol.443 No.3, pp. 691-700
Keywords
복합학epidermal growth factor receptor (EGFR)epithelial–
mesenchymal transition (EMT)
gene inductionsignalling
cross-talk
tetraspanintransforming growth factor β1 (TGFβ1)
Abstract
The EMT (epithelial–mesenchymal transition) is involved in
fibrosis and cancer, and is regulated by different signalling
pathways mediated through soluble factors, actin reorganization
and transcription factor actions. Because the tetraspan (also called
tetraspanin) TM4SF5 (transmembrane 4 L6 family member 5)
is highly expressed in hepatocellular carcinoma and induces
EMT, understanding how TM4SF5 expression in hepatocytes is
regulated is important. We explored the mechanisms that induce
TM4SF5 expression and whether impaired signalling pathways
for TM4SF5 expression inhibit the acquisition of mesenchymal
cell features, using human and mouse normal hepatocytes. We
found that TGFβ1 (transforming growth factor β1)-mediated
Smad activation caused TM4SF5 expression and EMT, and
activation of the EGFR [EGF (epidermal growth factor) receptor]
pathway. Inhibition of EGFR activity following TGFβ1 treatment
abolished acquisition of EMT, suggesting a link from Smads to
EGFR for TM4SF5 expression. Further, TGFβ1-mediated EGFR activation and TM4SF5 expression were abolished by EGFR
suppression or extracellular EGF depletion. Smad overexpression
mediated EGFR activation and TM4SF5 expression in the
absence of serum, and EGFR kinase inactivation or EGF
depletion abolished Smad-overexpression-induced TM4SF5 and
mesenchymal cell marker expression. Inhibition of Smad, EGFR
or TM4SF5 using Smad7 or small compounds also blocked
TM4SF5 expression and/or EMT. These results indicate that
TGFβ1- and growth factor-mediated signalling activities mediate
TM4SF5 expression leading to acquisition of mesenchymal cell
features, suggesting that TM4SF5 induction may be involved in
the development of liver pathologies.
ISSN
0264-6021
Language
English
URI
https://hdl.handle.net/10371/82068
DOI
https://doi.org/10.1042/BJ20111584
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College of Pharmacy (약학대학)Dept. of Pharmacy (약학과)Journal Papers (저널논문_약학과)
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