Bile acids activate EGF receptor via a TGF-α-dependent mechanism in human cholangiocyte cell lines

Nathan W. Werneburg, Jung-Hwan Yoon, Hajime Higuchi, Gregory J. Gores

Research output: Contribution to journalArticle

122 Citations (Scopus)

Abstract

Bile acids transactivate the EGF receptor (EGFR) in cholangiocytes. However, the mechanisms by which bile acids transactivate the EGFR remain unknown. Our aims were to examine the effects of bile acids on EGFR activation in human cholangiocyte cell lines KMBC and H-69. Bile acids stimulated cell growth and induced EGFR phosphorylation in a ligand-dependent manner. Although cells constitutively expressed several EGFR ligands, only transforming growth factor-α (TGF-α) antisera effectively blocked bile acid-induced EGFR phosphorylation. Consistent with the concept that matrix metalloproteinase (MMP) activity is requisite for TGF-α membrane release and ligand function, bile acid transactivation of EGFR and cell growth was blocked by an MMP inhibitor. In conclusion, bile acids activate EGFR via a TGF-α-dependent mechanism, and this EGFR activation promotes cellular growth.

Original languageEnglish
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume285
Issue number1 48-1
StatePublished - 1 Jul 2003

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Transforming Growth Factors
Bile Acids and Salts
Epidermal Growth Factor Receptor
Cell Line
Growth
Phosphorylation
Ligands
Matrix Metalloproteinase Inhibitors
Matrix Metalloproteinases
Transcriptional Activation
Immune Sera
Membranes

Keywords

  • c-Src kinase
  • Ligand dependent
  • Matrix metalloproteinase
  • Transactivation

Cite this

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title = "Bile acids activate EGF receptor via a TGF-α-dependent mechanism in human cholangiocyte cell lines",
abstract = "Bile acids transactivate the EGF receptor (EGFR) in cholangiocytes. However, the mechanisms by which bile acids transactivate the EGFR remain unknown. Our aims were to examine the effects of bile acids on EGFR activation in human cholangiocyte cell lines KMBC and H-69. Bile acids stimulated cell growth and induced EGFR phosphorylation in a ligand-dependent manner. Although cells constitutively expressed several EGFR ligands, only transforming growth factor-α (TGF-α) antisera effectively blocked bile acid-induced EGFR phosphorylation. Consistent with the concept that matrix metalloproteinase (MMP) activity is requisite for TGF-α membrane release and ligand function, bile acid transactivation of EGFR and cell growth was blocked by an MMP inhibitor. In conclusion, bile acids activate EGFR via a TGF-α-dependent mechanism, and this EGFR activation promotes cellular growth.",
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Bile acids activate EGF receptor via a TGF-α-dependent mechanism in human cholangiocyte cell lines. / Werneburg, Nathan W.; Yoon, Jung-Hwan; Higuchi, Hajime; Gores, Gregory J.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 285, No. 1 48-1, 01.07.2003.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Bile acids activate EGF receptor via a TGF-α-dependent mechanism in human cholangiocyte cell lines

AU - Werneburg, Nathan W.

AU - Yoon, Jung-Hwan

AU - Higuchi, Hajime

AU - Gores, Gregory J.

PY - 2003/7/1

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N2 - Bile acids transactivate the EGF receptor (EGFR) in cholangiocytes. However, the mechanisms by which bile acids transactivate the EGFR remain unknown. Our aims were to examine the effects of bile acids on EGFR activation in human cholangiocyte cell lines KMBC and H-69. Bile acids stimulated cell growth and induced EGFR phosphorylation in a ligand-dependent manner. Although cells constitutively expressed several EGFR ligands, only transforming growth factor-α (TGF-α) antisera effectively blocked bile acid-induced EGFR phosphorylation. Consistent with the concept that matrix metalloproteinase (MMP) activity is requisite for TGF-α membrane release and ligand function, bile acid transactivation of EGFR and cell growth was blocked by an MMP inhibitor. In conclusion, bile acids activate EGFR via a TGF-α-dependent mechanism, and this EGFR activation promotes cellular growth.

AB - Bile acids transactivate the EGF receptor (EGFR) in cholangiocytes. However, the mechanisms by which bile acids transactivate the EGFR remain unknown. Our aims were to examine the effects of bile acids on EGFR activation in human cholangiocyte cell lines KMBC and H-69. Bile acids stimulated cell growth and induced EGFR phosphorylation in a ligand-dependent manner. Although cells constitutively expressed several EGFR ligands, only transforming growth factor-α (TGF-α) antisera effectively blocked bile acid-induced EGFR phosphorylation. Consistent with the concept that matrix metalloproteinase (MMP) activity is requisite for TGF-α membrane release and ligand function, bile acid transactivation of EGFR and cell growth was blocked by an MMP inhibitor. In conclusion, bile acids activate EGFR via a TGF-α-dependent mechanism, and this EGFR activation promotes cellular growth.

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KW - Matrix metalloproteinase

KW - Transactivation

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