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Activation of the Raf‐1/MEK/ERK cascade by bile acids occurs via the epidermal growth factor receptor in primary rat hepatocytes
Author(s) -
Rao YiPing,
Studer Elaine J.,
Stravitz R. Todd,
Gupta Seema,
Qiao Liang,
Dent Paul,
Hylemon Phillip B.
Publication year - 2002
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2002.31104
Subject(s) - mapk/erk pathway , deoxycholic acid , phosphorylation , epidermal growth factor , chemistry , activator (genetics) , epidermal growth factor receptor , signal transduction , g protein coupled bile acid receptor , mapk cascade , receptor , microbiology and biotechnology , bile acid , cancer research , biology , biochemistry
Bile acids have been reported to activate several different cell signaling cascades in rat hepatocytes. However, the mechanism(s) of activation of these pathways have not been determined. This study aims to determine which bile acids activate the Raf‐1/MEK/ERK cascade and the mechanism of activation of this pathway. Taurodeoxycholic acid (TDCA) stimulated (+235%) the phosphorylation of p 74 Raf‐1 in a time (5 to 20 minutes) and concentration‐dependent (10 to 100 μmol/L) manner. Raf‐1 and ERK activities were both significantly increased by most bile acids tested. Deoxycholic acid (DCA) was the best activator of ERK (3.6‐fold). A dominant negative Ras (N17) construct expressed in primary hepatocytes prevented the activation of ERK by DCA. The epidermal growth factor receptor (EGFR)‐specific inhibitor (AG1478) significantly inhibited (∼81%) the activation of ERK by DCA. DCA rapidly (30 to 60 seconds) increased phosphorylation of the EGFR (∼2‐fold) and Shc (∼4‐fold). A dominant negative mutant of the EGFR (CD533) blocked the ability of DCA to activate ERK. In conclusion, these results show that DCA activates the Raf‐1/MEK/ERK signaling cascade in primary hepatocytes primarily via an EGFR/Ras‐dependent mechanism.