Modulation of hepatic acute phase gene expression by epidermal growth factor and Src protein tyrosine kinases in murine and human hepatic cells.
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 alpha(1)-antichymotrypsin and induces transcription through the alpha(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.
Wang
Y
Y
Roswell Park Cancer Institute, Department of Molecular and Cellular Biiology, Buffalo, NY 14263, USA.
Ripperger
J
J
Fey
G H
GH
Samols
D
D
Kordula
T
T
Wetzler
M
M
Van Etten
R A
RA
Baumann
H
H
D000209:Acute-Phase Proteins / Q000235:genetics*; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000032:analysis; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000032:analysis; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000032:analysis; D019061:src-Family Kinases / Q000502:physiology*
D000209:Acute-Phase Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D019061:src-Family Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse