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Modulation of hepatic acute phase gene expression by epidermal growth factor and src protein tyrosine kinases in murine and human hepatic cells
Author(s) -
Wang Yanping,
Ripperger Juergen,
Fey Georg H.,
Samols David,
Kordula Tomek,
Wetzler Meir,
Van Etten Richard A.,
Baumann Heinz
Publication year - 1999
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510300318
Subject(s) - proto oncogene tyrosine protein kinase src , tyrosine protein kinase csk , stat protein , biology , stat3 , microbiology and biotechnology , tyrosine kinase , epidermal growth factor , kinase , cancer research , janus kinase , protein tyrosine phosphatase , glycoprotein 130 , sh3 domain , signal transduction , receptor , biochemistry
As part of systemic inflammatory reactions, interleukin 6 (IL‐6) induces acute phase protein (APP) genes through the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. Epidermal growth factor (EGF), which contributes to the regenerative process after liver injury and also activates STATs, does not induce but attenuates IL‐6–stimulated expression of several APP genes in primary mouse hepatocytes. The APP‐modifying action of EGF receptor (EGFR) was characterized in HepG2 cells. Although EGF less effectively engages STAT proteins in these cells, it reduces expression of fibrinogen and haptoglobin, but stimulates production of α 1 ‐antichymotrypsin and induces transcription through the α 1 ‐antichymotrypsin and C‐reactive protein promoter. The stimulatory EGFR signal is insensitive to inhibition of JAKs and appears to involve Src kinases and STAT proteins as shown by inhibition through overexpression of C‐terminal Src kinase (Csk) and transdominant negative STAT3, respectively. A mediator role of Src is supported by the ability of c‐Src and v‐Src to activate STATs and induce transcription through APP promoters. Src kinases have been observed in association with the IL‐6 receptor; however, inhibition of Src kinases by Csk enhances IL‐6–induced transcription. The Csk effect is attributed to prevention of Src kinases from phosphorylating gp130 at the docking site for the signal‐moderating protein tyrosine phosphatase SHP‐2. The inhibitory EGFR signal on APP expression correlates with the activation of Erk1 and Erk2. The study shows a dual signaling function for EGFR and suggests that the ratio of receptor‐activated STATs and Erks influence the level of stimulated or inhibited expression of individual APPs.