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Am J Physiol Gastrointest Liver Physiol (February 26, 2003). doi:10.1152/ajpgi.00536.2002
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Submitted on December 20, 2002
Accepted on February 21, 2003

Bile Acids Activate Epidermal Growth Factor Receptor via a Transforming Growth Factor-alpha-dependent Mechanism in Human Cholangiocyte Cell Lines

Nathan W. Werneburg1, Jung-Hwan Yoon1, Hajime Higuchi1, and Gregory J. Gores1*

1 Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic and Foundation, Rochester, MN, USA

* To whom correspondence should be addressed. E-mail: gores.gregory{at}mayo.edu.

Bile acids transactivate the epidermal growth factor 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-alpha (TGF-{alpha}) antisera effectively blocked bile acid-induced EGFR phosphorylation. Consistent with the concept that matrix metalloproteinase (MMP) activity is requisite for TGF-{alpha} 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-{alpha}-dependent mechanism, and this EGFR activation promotes cellular growth.




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