Cross-talk between TGFβ1 and EGFR signalling pathways induces TM4SF5 expression and epithelial-mesenchymal transition

Minkyung Kang, Suyong Choi, Soo Jin Jeong, Sin Ae Lee, Tae Kyoung Kwak, Hyeonjung Kim, Oisun Jung, Mi Sook Lee, Youra Ko, Jihye Ryu, Yoon Ju Choi, Doyoung Jeong, Hyo Jeong Lee, Sang Kyu Ye, Sung Hoon Kim, Jung Weon Lee

Research output: Contribution to journalArticlepeer-review

43 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)691-700
Number of pages10
JournalBiochemical Journal
Issue number3
StatePublished - May 1 2012
Externally publishedYes


  • Epidermal growth factor receptor (EGFR)
  • Epithelial-mesenchymal transition (EMT)
  • Gene induction
  • Signalling cross-talk
  • Tetraspanin
  • Transforming growth factor β1 (TGFβ1)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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